Amine compound and its application in medicinal purposes

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

 

The technical field

The present invention relates to amine compounds and their use as pharmaceuticals.

Prior art

In recent years, inhibitors of calcineurin, such as cyclosporine and FK506, are used to suppress rejection in patients undergoing transplantation of organs. However, the specific inhibitor of calcineurin, such as cyclosporine, sometimes causes adverse side effects, such as toxic effects on the kidneys, toxic effects on the liver, neurotoxicity and the like. So continues the development of safer and highly effective pharmaceutical agents for suppressing rejection in patients undergoing transplantation.

In patent references 1-3 are disclosed compounds 2-aminopropan-1,3-diol, which can be used as suppressants (acute or chronic) rejection in transplantation of an organ or bone marrow, as well as therapeutic drugs about the various autoimmune diseases, such as psoriasis, Behcet's disease and the like, and rheumatic diseases.

One of these compounds, 2-amino-2[2-(4-octylphenyl)ethyl]propane-1,3-diol hydrochloride (hereinafter sometimes referred to as FTY720) is currently undergoing clinical development for the operation of suppressant rejection in kidney transplantation. FTY720 is rapidly becoming phospho-FTY720 (hereinafter sometimes referred to as FTY720-P, for example, 2-amino-2-(phosphorylmethyl-4-(4-octylphenyl)butanol) sphingosine-kinase in vivo. FTY720-P acts as an agonist 4 types of S1P receptors (other than S1P2) 5 types of receptors for sphingosine-1-phosphate (hereinafter sometimes referred to as S1P) (hereinafter sometimes referred to as, respectively, S1P1-5) (non-patent reference 1).

Recently it has been suggested that the receptors S1P1 and S1P is essential for the migration of Mature lymphocytes from thymus and secondary lymphoid tissues. FTY720-P acts as an agonist for S1P1 suppressive regulation of S1P1 on lymphocytes. As a result, inhibited migration of Mature lymphocytes from thymus and secondary lymphoid tissues and circulating Mature lymphocytes in the blood sequestered in the secondary lymphoid tissues, whereby apparent immunosuppressive action (non-patent reference 2).

On the other hand, there is a fear that the usual connection 2-aminopropan-1,3-diol as side effects will cause transient bradycardia, and to resolve this problem was reported several new compounds obtained by modifying the chemical structures of compounds 2-aminopropan-1,3-diol. Among them, as compounds having the substituents on the benzene ring PTY720, in the patent reference 4 discloses a derivative aminopropanol in image quality is as of the S1P receptor modulator with a phosphorus group, and both patent references 5 and 6 disclose derivative aminopropanol as mediators of S1P receptors. However, this document does not disclose troglodytella group, for example triptorelin group as a substituent on the benzene ring. In the end, at the present time level of security as a pharmaceutical product has not reached a satisfactory level.

Patent reference 1: WO94/08943

Patent reference 2: WO96/06068

Patent reference 3: WO98/45429

Patent reference 4: WO02/076995

Patent reference 5: WO2004/096752

Patent reference 6: WO2004/110979

Non-patent reference 1: Science, 2002, vol. 296, pages 346 - 349

Non-patent reference 2: Nature, 2004, vol. 427, pages 355 - 360

Description of the invention

The problems to be solved by invention

The aim of the invention is the provision of a new amine compounds, providing superior immunosuppressive action, an overwhelming rejection of the action and the like, which exhibits reduced side effects such as bradycardia and the like.

Means of resolving problems

Applicants have conducted further research in connection with the above situation and found that the amine compound having the following specific structural formula, can achieve the purpose that led to the creation of the present invention.

The meet is but the essence of the present invention is as follows.

1. The compound represented by the following formula (I)

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, R3and R4may be the same or different, and each represents a hydrogen atom or alkyl having 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

2. The compound according to claim 1, where each of R3and R4each represents a hydrogen atom, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

3. The compound according to claim 1 or 2, having the following formula (Ia) or (Ib)

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents the t of an alkyl, having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms), halogen, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

4. The compound according to any one of claims 1 to 3, where X represents an oxygen atom, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

5. The compound according to any one of PP-1-4, where Y is CH2CH2or its pharmaceutically acceptable acid additive salt, hydrate or MES.

6. The compound according to any one of claims 1 to 5, where R1represents methyl, substituted atom (atoms), halogen, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

7. The compound according to any one of claims 1 to 6, where R1represents trifluoromethyl or its pharmaceutically acceptable acid additive salt, hydrate or MES.

8. The compound according to any one of claims 1 to 7, where R2represents methyl, optionally substituted with hydroxyl group (or groups), or its pharmaceutically acceptable acid additive salt, hydrate or MES.

9. The compound according to any one of claims 1 to 8, where R2represents hydroxymethyl or its pharmaceutically acceptable acid additive salt, hydrate or MES.

10. The compound according to any one of claims 1 to 9, where R represents the t of a hydrogen atom, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

11. The compound according to any one of claims 1 to 4, where the compound of formula (I) represents any connection the following subparagraphs a) to e) or its pharmaceutically acceptable acid additive salt, hydrate or MES.

a) 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol or its pharmaceutically acceptable acid additive salt, hydrate or MES;

b) (E)-2-amino-2-[2-(4-heptyloxy-3-triptoreline)vinyl]propane-1,3-diol or its pharmaceutically acceptable acid additive salt, hydrate or MES;

C) 2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol or its pharmaceutically acceptable acid additive salt, hydrate or MES;

d) (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol or its pharmaceutically acceptable acid additive salt, hydrate or MES;

e) 2-amino-2-[2-(3-cyano-4-heptyloxybiphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable acid additive salt, hydrate or MES.

12. The compound according to any one of claims 1 to 4, where the compound of formula (I) represents any connection the following subparagraphs f-j or its pharmaceutically acceptable acid additive salt, hydrate or MES.

f) 2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol or its pharmaceutically acceptable acid additive salt, g is the dratha or MES;

g) (E)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)-3-butene-1-ol or pharmaceutically acceptable acid additive salt, hydrate or MES;

h) complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] ester of phosphoric acid or its pharmaceutically acceptable acid additive salt, hydrate or MES;

i) complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (R)-phosphoric acid or its pharmaceutically acceptable acid additive salt, hydrate or MES;

j) 2-amino-4-(3-cyano-4-heptyloxybiphenyl)-2-(phosphorylmethyl)butanol or its pharmaceutically acceptable acid additive salt, hydrate or MES.

13. 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol or its hydrochloride.

14. Pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to 14, which is used for treatment or prevention of autoimmune diseases; prevention or suppression of resistance or acute rejection or chronic rejection of organ transplant or tissue; treatment or prevention of a disease graft-versus-host (GvH) due to bone marrow transplantation; or treatment or prevention of allergic diseases.

16. The pharmaceutical composition according to 14, where the autoimmune disease is a rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis or diabetes mellitus type I.

17. The pharmaceutical composition according to 14, where the allergic disease is a atopic dermatitis, allergic rhinitis or asthma.

The effect of the invention

In accordance with the present invention provides a new connection, providing stronger than the prior art, the effect of reducing the number of lymphocytes in the peripheral blood and reduce side effects such as bradycardia and the like.

The best way of carrying out the invention

Below explains in detail the present invention.

The compound of the present invention is a compound represented by the following formula (I)

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents alkyl having 1-4 carbon atoms, and n is necessarily substituted by a hydroxyl group (or groups) or atom (atoms) halogen, R3and R4may be the same or different, and each represents a hydrogen atom or alkyl having 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid additive salt, hydrate or MES.

In the present invention, the halogen atom is a fluorine atom, chlorine atom, bromine atom or iodine atom, and preferred example is a fluorine atom.

Alkyl having 1-4 carbon atoms means a linear or branched alkyl having 1-4 carbon atoms. Its examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, isobutyl, secondary butyl, tertiary butyl (hereinafter "tertiary" sometimes identified as tert - or tert-) and the like. Preferred examples include methyl, ethyl, n-propyl and isopropyl, and more preferred examples include methyl and ethyl.

Preferred examples of R in the above formula (I) include a hydrogen atom.

Preferred examples of X include an oxygen atom, and preferred examples of Y include CH2CH2.

Preferably, n = 6 or 7, and preferably, n = 6.

Preferred examples of R1include vermeil, deformity, trifluoromethyl, 2,2,2-triptorelin and cyano, and more preferred examples include trifluoromethyl and cyan is, and even more preferable example is trifluoromethyl.

Preferred examples of R2include methyl, ethyl, hydroxymethyl, hydroxyethyl, vermeil, chloromethyl, foradil, defloratin, triptorelin and trichlorethyl, more preferable examples include methyl, ethyl, hydroxymethyl, 2-hydroxyethyl and 2-foretel, more preferred examples include methyl and hydroxymethyl, and most preferred is hydroxymethyl.

Preferred examples of R3and R4include a hydrogen atom, methyl and ethyl, which may be the same or different, more preferable examples include a hydrogen atom and methyl, and most preferred is a hydrogen atom.

Examples of pharmaceutically acceptable acid additive salts of the compounds of the present invention include a salt of an inorganic acid, salt with organic acid, salt, alkali metal salt, alkaline earth metal and the like. The compound of the present invention comprises the above compound of formula (I) and its pharmaceutically acceptable acid additive salt, as well as its geometrical isomers, optically active form, hydrate and MES.

Specific examples of the compounds of the present invention include the following.

2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-dio and its hydrochloride

(E)-2-amino-2-[2-(4-heptyloxy-3-triptoreline)vinyl]propane-1,3-diol and its hydrochloride

(R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol and its hydrochloride.

Of the compounds of the present invention, the preferred compound is 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol and its hydrochloride.

For example, use the following method of synthesis of compounds of the present invention.

1) Of the compounds of the present invention is synthesized compound (I-1)represented by the formula (Ia)where R represents a hydrogen atom, X represents an oxygen atom and R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen-free, according to the following scheme (II).

Scheme (II)

where Ra, Rb, Rcand Rdrepresent a protective group, Xaand Xbrepresent a leaving group, R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen.

Rain the formula represents a hydrogen atom or a variety of carboxyl protective group. For example, alkyl (in particular methyl, ethyl and the like), the same Deputy for Rband like them. Rbthe formula is not specifically limited, while it protects the phenolic hydroxyl group. For example, alkyl (in particular methyl, heptyl and the like), aralkyl (benzyl and the like) and the like. When heptyl used as Rbthe connection according to the invention (I-1) can be obtained without removal of Rb. Rcthe formula is not limited, while it protects the hydroxyl group. For example, acyl (preferably, acyl having 2-4 carbon atoms, in particular, acetyl and the like), trialkylsilyl (in particular, trimethylsilyl and the like), benzyl and Deputy forming a connection acetal (in particular, methoxymethyl, tetrahydropyranyl and the like). When R2has a hydroxyl group, the protective group Re(Rein particular, similar to Rcand Rccan also be linked to the formation of a cyclic acetal. Protective group shown in the formula, Rdnot limited to, yet it protects the amino group. For example, acyl (preferably, acyl having about 2-4 carbon atoms, in particular, acetyl and the like), urethane group (in particular, tert-butyloxycarbonyl, benzyloxycarbonyl and the like) and the like. Leaving group for Xandnot limited to, until she dissociated during the reaction Thames is of alkoxide ion (R b-O-). For example, a halogen atom (particularly, fluorine atom and the like), toluensulfonate and the like. Leaving group for Xbnot limited to, until she dissociated during condensation of the intermediate compound (II-4) and triphenylphosphine, and does not show the subsequent Wittig reaction. For example, a halogen atom (in particular, iodine atom, bromine atom, chlorine atom and the like), methansulfonate, toluensulfonate and the like.

In the first stage, the intermediate compound (II-2) obtained by condensation of a derivative of benzoic acid (II-1)having a leaving group Xain position 4, with alcohol Rb-OH for the introduction of oxygen functional group having a protective group, Rbin position 4. This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like, or an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide and the like, or an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 100°C for about 10 min to 10 h After the reaction, the target product can be obtained extraction is, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (II-3)having a hydroxyl group, obtained by restoring the carboxyl group of the intermediate compound (II-2). The reagent to be used for restore is not limited to, until it is accepted. Its examples include alkali metals such as sodium and the like, alkaline earth metals, metal hydrides, such as hydride diisobutylaluminum and others like him, metallovedenie complex compounds, such as hydride socialmedia, sodium borohydride and the like, boron compounds such as DIBORANE and the like; possible catalytic hydrogenation using homogeneous catalyst or a heterogeneous type, and the like. As the reaction conditions chosen temperature and time appropriate for the subject using the reducing reagent. Its specific examples include restoration using DIBORANE, hydride socialmedia or lithium borohydride in an ether solvent such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling temperature than the s from 10 min to 12 h, recovery using sodium borohydride or calcium borohydride in an alcohol solvent such as ethanol and the like or a mixed solvent of an alcohol solvent and an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice to boiling point during the period from 30 min to 24 h, and the like. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the hydroxyl group of the intermediate compound (II-3) is converted to a leaving group Xb. The reagent is not limited to, until he is a reagent capable of converting an alcohol hydroxyl group in the Xb. Examples of the reagent used, when Xbrepresents a halogen atom include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride, and their combination, and the connection that contribute to the reaction, such as triphenylphosphine, base and the like, inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, tribromide phosphorus, pentabromide phosphorus, trichloride is asfora, pentachloride phosphorus, iodine, bromine, chlorine, halogenated thionyl and the like. The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like at temperatures from -30°C to 130°C for a period of from 10 min to 6 hours When using inorganic acid, the reaction can be performed in aqueous solution or in a two-layer system of an organic solvent, such as toluene, and the like, and water. Examples of the reagent used, when Xbrepresents sulfonyloxy include a combination of sulphonylchloride, such as methanesulfonate, toluensulfonate and the like, organic bases such as triethylamine, pyridine and the like. The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like at temperatures from -30°C to 50°C for a period from about 5 minutes to 3 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by distillation, chromatog what afia on a column of silica gel, the recrystallization and the like methods.

In the fourth stage phosphonium salt (II-5) is produced by interaction of the intermediate compound (II-4)having a leaving group Xbwith triphenylphosphine. The reaction is performed, for example, in an inactive solvent such as simple diethyl ether, benzene, toluene and the like, at temperatures from room temperature up to the boiling temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by evaporating the solvent, cooling and addition of poorly soluble solvent, such as by having a simple diisopropyl ether, hexane and the like, and then produce a collection of precipitated solids by filtration.

At the fifth stage phenolic intermediate compound (II-7) is produced by condensation of phosphonium salts of (II-5) with aldehyde (II-6), separately synthesized using the Wittig reaction, the recovery obtained olefinic compounds and the removal of the protective group Rb. The conditions of the Wittig reaction are the conditions generally used for the Wittig reaction. For example, the reaction is performed using a base such as tert-piperonyl potassium and the like, ether solvents such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling point over a period from about 30 minutes to 12 cosla reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods. The reagent to be used in the subsequent restoration of the double bond, is not limited to, until it is used for General recovery of the olefin. Its examples include catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol, and the like, ether solvents such as dioxane, and the like, or a hydrocarbon solvent such as toluene, and the like, 1-20 atmospheres pressure of hydrogen, at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid, and the like, or a base, such as triethylamine, and the like, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing the tion, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Conditions subsequent removal of the protective group Rbnot limited to, until they are used to remove Rb. For example, when Rbrepresents methyl, then you can use the method of using a Lewis acid such as tribromide boron and similar connection, in the solvent methylene chloride. When Rbrepresents acyl, such as acetyl and the like, you can use the method of using inorganic bases such as sodium hydroxide and the like, a mixed solvent of an alcohol solvent and water. When Rbrepresents a protective group such as the simple ester, such as methoxymethyl, tetrahydropyranyl, tert-butyl, and the like, you can use the method of using acids, such as chloride-hydrogen acid, triperoxonane acid, and the like. When Rbrepresents a protective group which can be removed by catalytic hydrogenation (for example, benzyl, substituted benzyl, benzyloxyethyl and the like), then unprotect Rbcan be performed simultaneously with the above-mentioned restoration of the double bond. When Rbpresent is employed, a heptyl, there is no need to remove the Rband the alkylation of phenol in the next stage it is also possible not to include.

At the sixth stage, the compound of the present invention (I-1) is obtained by alkylation of the phenolic hydroxyl group of the intermediate compound (II-7) and remove Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Examples of the reagent to be used for alkylation of a phenolic hydroxyl group, which is an intermediate compound (II-7)include a combination of an alkylating agent, such as reptilase and the like, and inorganic bases such as potassium carbonate, sodium hydride and the like. The reaction is carried out, for example, in a polar solvent such as N,N-dimethylformamide and the like, or in an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about from 30 minutes to 12 o'clock For the alkylation of phenolic hydroxyl group, which is an intermediate compound (II-7), you can use the reaction Mitsunobu condensation of p alcohol and using phosphine compound, such as triphenylphosphine and the like, and a derivative of azodicarboxylic sour is s, such as diisopropylethylamine, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, and the like, at a temperature of from cooling with ice up to 50°C for a period from about 10 minutes to 6 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Subsequent removal of the protection is not specifically limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butoxycarbonyl, they may be deprived of protection by using acid. Examples of the acid include inorganic acids, such as chloride-hydrogen acid and the like, triperoxonane acid and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 o'clock is the ass of the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

2) Of the compounds of the present invention, the compound (I-1), i.e. a compound where in formula (Ia), R represents a hydrogen atom, X represents an oxygen atom and R1represents alkyl having 1-4 carbon atoms, substituted atom (halogen atoms, also synthesized using intermediate compound (III-1), which is synthesized according to the following scheme (III) of the intermediate compound (II-2, where Rarepresents H) in scheme (II) or known compounds represented by formula (III-2).

Scheme (III)

where Rbrepresents a protective group, Rf-OH is an alcohol used for the reaction of solvolysis, and R1represents alkyl having 1-4 carbon atoms, substituted atom (atoms) halogen.

Rbrepresents, as defined in the schema formula (II). Examples Rfinclude methyl, ethyl, benzyl and the like. For the synthesis of compounds (II-2) in the above diagram you can use the General terms of engagement for the reaction Arndt-Eistert. In addition, to restore derived complex ester m is tenderly to use the reagent and conditions used for the second stage of the scheme (II). For the synthesis of compound (III-2) in the above diagram you can use the General terms of engagement for the Wittig reaction. For further processing by the acid used is an inorganic acid, such as chloride-hydrogen acid and the like, in water or a mixed solvent of an organic solvent, such as tetrahydrofuran and the like, and water. For recovery, you can recover using a complex compound of the metal with hydrogen, such as a hydride layalina, sodium borohydride and the like, catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, or a homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I), and the like) and the like, or they can consistently perform continuously. The obtained alcohol intermediate compound (III-1) in the diagram can be transformed into a compound of the present invention in a known manner (see for example, Journal of Medicinal Chemistry vol.43 (2000) 2946-2961).

3) Compound (I-2), i.e. a compound where in formula (Ia), R represents a hydrogen atom, X represents an oxygen atom, and R1represents trifluoromethyl or cyano, is synthesized according to the following scheme (IV).

Schema (IV)

where Rc, Rdrepresents a protective group, Xaand Xcrepresent a leaving group, R1represents trifluoromethyl or cyano, and R2is as defined above.

Rc, Rdand Xain the formula are as defined above. Leaving group for Xcnot specifically limited, while it is activated catalyst and dissociated during the reaction Sonogashira. Their examples include a halogen atom (preferably, an iodine atom, a bromine atom and the like), tripterocalyx and the like.

In the first stage, the intermediate compound (IV-2) is produced by condensation of the compound (IV-1)having a leaving group Xandwith p alcohol. This stage can be performed in a polar solvent such as N,N-dimethylformamide and dimethyl sulfoxide, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. Examples of the base include inorganic bases such as sodium hydride, potassium hydroxide and the like, and organic bases, such as 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 100°C for about 10 min to 10 h After the reaction, the target product can be obtained of the extras is the response, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (IV-4)having a triple bond, obtained by condensation of intermediate compounds (IV-2) with an intermediate compound (IV-3), which is synthesized from the intermediate compound (II-6), in a known manner (for example, Tetrahedron vol.57 (2001) 6531-6538, Chemical & Pharmaceutical Bulletin, vol.53 (2005) 100-102), under the reaction conditions Sonogashira. Examples of the catalyst include a compound of palladium, such as tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), dichlorobis(acetonitrile)palladium(II) and the like. To facilitate the reaction, it is possible to add an organic base, such as triethylamine, and the like, an inorganic base, such as ammonia and the like, a compound of copper, such as copper iodide, copper bromide and the like, phosphine compound, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylsilyl, and the like, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, dioxane and the like, a polar solvent, such as acetonitrile, dimethylformamide, and the like, or a hydrocarbon solvent such as benzene, and the mu such that at a temperature of from cooling with ice to the boiling temperature for about 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the intermediate compound (IV-5) is obtained by restoring the triple bond of the intermediate compound (IV-4). Subject to use of the reagent is not limited to, until it is used for General recovery unsaturated carbon linkages. For example, you can use catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel, palladium-carbon-Ethylenediamine and the like, or a homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, when the hydrogen pressure from 1 to 20 atmospheres at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture can be is to add acid, such as acetic acid and the like, or a base such as triethylamine and the like, depending on the speed of response, stability and the like. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage the protection of the intermediate compound (IV-5) is removed to obtain the compound of the present invention (I-2). Remove Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s)is not limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butyloxycarbonyl, protection of the cyclic acetal is removed by catalytic amount of acid, and then used a stronger acidic conditions, whereby it is possible to remove Rd. The conditions used to remove the protecting acetal, represent, e.g. the, alcohol solvent such as methanol, and the like, or a mixed solution of an alcohol solvent and other organic solvent, a catalytic amount of chloride-hydrogen acid or toluensulfonate acid, at a temperature of from cooling with ice up to 80°C for about from 30 minutes to 12 o'clock on the other hand, the deletion criteria Rdthat are performed after removal of the protecting acetal represent, for example, not less than the equivalent amount of an inorganic acid, such as chloride-hydrogen acid, and the like, triperoxonane acid and the like, in an alcohol solvent such as ethanol, and the like, ether solvents such as tetrahydrofuran, and the like, water or a mixed solvent, at a temperature of from cooling with ice up to 80°C for about 10 min to 12 h After the reaction, the target product can be obtained by extraction, washing, drying, removing solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

4) Compound (I-3)represented by the formula (Ia)where R represents a hydrogen atom, X represents a sulfur atom, and R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms is) halogen, synthesized according to the following scheme (V).

Scheme (V)

where Ra, Rcand Rdrepresent a protective group, Xband Xdrepresent a leaving group, R1represents alkyl having 1-4 carbon atoms, substituted atom (atoms) halogen, and R2is as defined above.

Ra, Rc, Rdand Xbin the formula are as defined above. Leaving group for Xdnot limited to, until she dissociated during the substitution reaction ion reptillia (C7H15S-). For example, you can specify a halogen atom (particularly, fluorine atom and the like), toluensulfonate and the like.

In the first stage, a derivative of benzoic acid (V-1)having a group Xdin position 4, is condensed with reptillian for introducing Reptilia in position 4, whereby to receive the intermediate compound (V-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide and dimethylsulfoxide, ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as potassium carbonate, sodium hydroxide and the like, or an organic base such as triethylamine, 1,8-diazabicylo what about[5.4.0]undec-7-ene and the like. Reaction conditions are, for example, a temperature of about -30°to about 80°C for about 10 min to 10 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the carboxyl group of the intermediate compound (V-2) is restored to obtain the intermediate compound (V-3)having a hydroxyl group. The reagent to be used for restore is not specifically limited, as he generally used. Its examples include alkali metals such as sodium and the like, alkaline earth metals, metal hydrides, such as hydride diisobutylaluminum and the like, metallovedenie complex compounds, such as hydride socialmedia, sodium borohydride and the like, boron compounds such as DIBORANE and the like; possible catalytic hydrogenation using homogeneous catalyst or a heterogeneous system, and the like. As the reaction conditions chosen temperature and time appropriate for the subject using the reducing reagent. Its specific examples include restore the pressure using DIBORANE, hydride socialmedia or lithium borohydride in an ether solvent such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling temperature for 10 min to 12 h recovery using sodium borohydride or calcium borohydride and the like in an alcohol solvent such as ethanol and the like, or a mixed solvent of an alcohol solvent and an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice to boiling point during the period from 30 min to 24 h, and the like. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the hydroxyl group of the intermediate compound (V-3) is converted to a leaving group Xb. The reagent is not limited to, until he is a reagent capable of converting an alcohol hydroxyl group in the Xb. Examples of the reagent used, when Xbrepresents a halogen atom include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride, and their combination, and the connection conducive reacts and, such as triphenylphosphine, base and the like, inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, iodine-hydrogen acid tribromide phosphorus, pentabromide phosphorus, trichloride phosphorus, pentachloride phosphorus, iodine, bromine, chlorine, halogenated thionyl and the like. The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like at temperatures from -30°C to 130°C for a period of from 10 min to 6 hours When using inorganic acid, the reaction can be performed in aqueous solution or in a two-layer system of an organic solvent, such as toluene, and the like, and water. Examples of the reagent used, when Xbrepresents sulfonyloxy include a combination of sulphonylchloride (for example, methanesulfonamido, toluensulfonate and the like) and organic bases (e.g. triethylamine, pyridine and the like). The reaction conditions are, for example, an organic solvent, such as halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like, at temperatures from -30°C to 50°C during the s period from about 5 minutes to 3 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage phosphonium salt (V-5) is produced by interaction of the intermediate compound (V-4)having a leaving group Xbwith triphenylphosphine. The reaction is performed, for example, in an inactive solvent such as simple diethyl ether, benzene, toluene and the like, at temperatures from room temperature up to the boiling temperature for about from 30 minutes to 6 hours After the reaction, the target product can be obtained by evaporating the solvent, cooling and addition of poorly soluble solvent, such as by having a simple diisopropyl ether, hexane and the like, and then produce a collection of precipitated solids by filtration.

At the fifth stage of intermediate compound (V-6) is produced by condensation of phosphonium salts of (VI-5) with aldehyde (II-6), separately synthesized using the Wittig reaction, and recovering the obtained olefinic compounds. The conditions of the Wittig reaction are the conditions generally used for the Wittig reaction. For example, the reaction is performed using the basics of the tion, such as tert-piperonyl potassium and the like, ether solvents such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling point over a period from about 30 minutes to 12 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. The reagent to be used in the subsequent restoration of the double bond, is not limited to, until it is used for General recovery of the olefin. Its examples include catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol, and the like, ether solvents such as dioxane, and the like, or a hydrocarbon solvent such as toluene, and the like, 1-20 atmospheres pressure of hydrogen, at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as the UKS SNA acid, and like her, or base, such as triethylamine, and the like, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

At the sixth stage, the compound of the present invention (I-3) obtained by removing the intermediate compound (V-6)with Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Removing the protection of the intermediate compound (V-6) is not specifically limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butoxycarbonyl, they can be simultaneously removed using acid. Examples of the acid include inorganic acids, such as chloride-hydrogen acid and the like, triperoxonane acid and the like. The reaction of the imp is both, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or a mixed solvent representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

5) Compound (I-4)represented by formula (Ia)where R represents a hydrogen atom, X represents a sulfur atom, and R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, is synthesized according to the following scheme (VI).

Scheme (VI)

where Rc, Rdrepresent a protective group, Xerepresents activating the hydroxyl group, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R2is as defined above.

Rcand Rdin the formula are as defined above. As the activating hydroxyl groups for Xeyou can specify sulfonylurea groups who, such as trifloromethyl, toluensulfonyl and the like.

In the first stage, the intermediate compound (VI-1) is obtained by introducing an activating group in the phenolic hydroxyl group of the intermediate compound (II-7) in scheme (II). This stage can be performed in a halogen solvent such as methylene chloride and chloroform, or ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a reagent for this reaction are activated derivatives of sulfonic acid such as the anhydride triftormetilfullerenov acid, 1-(trifloromethyl)imidazole, toluensulfonate. This reaction can also be performed by using a sulfonic acid and a condensing agent in combination. As a basis it is possible to use an organic base, such as triethylamine, pyridine, lutidine and the like. Reaction conditions are, for example, temperatures from -50°C to 50°C for about from 5 minutes to 3 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (VI-1) is condensed hept what ltila to obtain the intermediate compound (VI-2). This stage can be performed in an ethereal solvent such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, in the presence of palladium catalyst. Examples of the palladium catalyst include palladium (II)acetate, Tris(dibenzylideneacetone)dipalladium(0) and the like. In addition, as a compound that promotes this reaction, you can add a phosphine compound or base. Examples of the phosphine compound include triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like. On the other hand, as a base, you can specify an inorganic base such as cesium carbonate and the like, and an organic base, such as N,N-diisopropylethylamine and the like. Reaction conditions are, for example, a temperature from room temperature up to the boiling temperature for about 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the compound (I-4) of the present invention is obtained by removal of the intermediate compound (VI-2)with Rcand Rdand the protective group Re edefined above), which protects a hydroxyl group, when R2represents a hydroxyl group. Removing protection from intermediate compound (VI-2) is not specifically limited in time and all the protective groups can be removed at once or sequentially. For example, when Rcrepresents a protective group which can be removed by acid, such as methoxymethyl and the like, and Rdrepresents a tert-butyloxycarbonyl, they can be removed simultaneously by the acid. Examples of the acid include inorganic acids, such as chloride-hydrogen acid, and triperoxonane acid or the like.

The reaction conditions are, for example, an alcohol solvent, such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or a mixture of solvents at a temperature of from cooling with ice up to 80°C for from about 10 minutes to 12 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

6) Of the compounds of the present invention, the compound (I-5)represented by formula (Ia), where the R represents P(=O)(OH) 2synthesized according to the following scheme (VII).

Scheme (VII)

where X represents an oxygen atom or a sulfur atom, Rdand Rgrepresent a protective group, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R2is as defined above.

Rdthe formula is as defined above. The protective group for Rgnot specifically limited, while it protects the group of phosphoric acid. For example, you can specify alkyl (predpochtitelno having 1-6 carbon atoms, in particular, tert-butyl and the like), benzyl, phenyl and the like.

In the first stage form with a protected amino group, (VII-2) synthesized by protecting the amino group of compound (VII-1), where R represents a hydrogen atom, compounds of the present invention. This stage you can perform the overall response of the protection of the amino group. In particular, when acyl, allyloxycarbonyl, benzyloxycarbonyl and the like is used as a protective group (Rd), this stage can be performed in alcohol, such as methanol and the like, or in a two-layer system or a mixture of water and an organic solvent, such as ethyl acetate, chloroform and the like. Examples to be used reagent include an acid chloride,such as acetylchloride, benzyloxycarbonyl and the like, or an acid anhydride such as acetic anhydride, di-tert-BUTYLCARBAMATE and the like. Organic base such as triethylamine and the like, or an inorganic base such as sodium bicarbonate and the like, can be added as an activator of this reaction. For example, reaction conditions: temperature from cooling with ice up to 50°C for 30 min - 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage phosphorylated form (VII-3) synthesized by the interaction of form with a protected amino group, (VII-2) phosphorylation reagent (e.g., chloride of phosphorus, phosphoramidites and oxidant complex tetrabenzyl ether pyrophosphoric acid and the like). When using complex tetrabenzyl ether pyrophosphoric acid as reagent phosphorylation this stage can be performed in anhydrous conditions, preferably in an organic solvent, such as toluene, dichloromethane, solvent, representing a mixture thereof, and the like, using an additive (for example, oxide of CE is Abra, iodide, Tetra-n-hexylamine and the like). For example, reaction conditions: temperature from cooling with ice up to 50°C. for 5-24 hours After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. For this reaction, the interaction of the General phosphorylation reagent (chloride of phosphorus and grounds, phosphoramidite and oxidant and the like) can be provided in accordance with the known method.

In the third stage, the compound of the present invention (I-5) is derived from phosphorylated forms (VII-3). This stage can perform a total removal of the protection. In particular, this stage can be accomplished by hydrogenolysis acids, such as chloride-hydrogen acid, triperoxonane acid and the like or a Lewis acid such as trimethylsilylmethyl and the like. When this reaction is used hydrogenolysis, this stage is performed by, for example, in an alcohol solvent such as methanol and the like, using a catalyst such as palladium-carbon and the like, in an atmosphere of hydrogen. For example, reaction conditions: temperature from room temperature to 60°C teenieporn 1-24 hours The target product can be obtained by filtration, concentration of the reaction mixture, and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Reaction conditions, when the acid used for this reaction, for example, the following: an alcohol solvent, such as ethanol and the like, or a solvent, representing its mixture with water at a temperature of from room temperature to 100°C for about from 30 minutes to 12 o'clock

7) Of the compounds of the present invention, the compound (I-1a)represented by the formula (I), where R represents a hydrogen atom, X represents an oxygen atom, Y represents CH2CH2, R1is cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (VIII).

Scheme (VIII)

where n = 5-8, Rarepresents a hydrogen atom or a protective group, Rb, Rcand Rdrepresent a protective group, Xaand Xbrepresent a leaving group, R1represents cyano or alkyl having 1-4 carbon atoms and substituted atom (atoms) halogen, and R2is the AK defined above.

Rathe formula is not limited to, while he protects a hydrogen atom or a carboxyl group. For example, you can specify alkyl (in particular methyl, ethyl and the like), aralkyl (benzyl and the like), the same Deputy for Rband like them. Rbthe formula is not limited, while it protects the phenolic hydroxyl group. For example, you can specify alkyl (in particular methyl, ethyl and the like), aralkyl (benzyl and the like). When -(CH2)nCH3(n is as defined above), which is a partial structure of the compounds according to the invention (I-Ia), is used as Rbthe connection according to the invention (I-Ia) can be obtained without removal of Rb. Rcthe formula is not limited, while it protects the hydroxyl group. For example, you can specify acyl (preferably, acyl having 2-4 carbon atoms, in particular, acetyl and the like), trialkylsilyl (in particular, trimethylsilyl and the like), benzyl and Deputy forming acetylene connection (in particular, methoxymethyl, tetrahydropyranyl and similar). When R2has a hydroxyl group, the protective group Re(Rein particular, similar to Rc), and Rccould also be relevant for the formation of a cyclic acetal. Protective group, shown Rdin the formula, not on rangiwaea, while it protects the amino group. For example, you can specify acyl (preferably, acyl having 2-4 carbon atoms, in particular, acetyl and the like), carbamate (in particular, tert-butyloxycarbonyl, benzyloxycarbonyl and the like) and the like. Leaving group for Xanot specifically limited, as she dissociated during the substitution reaction alkoxide ion (Rb-O-). For example, you can specify a halogen atom (particularly, fluorine atom and the like), toluensulfonate and the like. Leaving group for Xbnot specifically limited, as she dissociated during condensation of intermediate compound (VIII-4) and triphenylphosphine, and did not inhibit the subsequent Wittig reaction. For example, you can specify a halogen atom (in particular, iodine atom, bromine atom, chlorine atom and the like), methansulfonate, toluensulfonate and the like.

In the first stage, the intermediate compound (VIII-2) is obtained by condensation of a derivative of benzoic acid (II-1)having a leaving group Xain position 4, with alcohol (VIII-1) for the introduction of oxygen functional group having a protective group, Rbin position 4. This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like, or an ether solvent such as tetrahydrofuran and the like, when outstay Foundation. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide and the like, or an organic base such as 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 100°C for about 10 min to 10 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (VIII-3)having a hydroxyl group, obtained by restoring the carboxyl group of the intermediate compound (VIII-2). The reagent to be used for restore is not limited to, until it is accepted. Its examples include alkali metals such as sodium and the like, alkaline earth metals, metal hydrides, such as hydride diisobutylaluminum and others like him, metallovedenie complex compounds, such as hydride socialmedia, sodium borohydride and the like, boron compounds such as DIBORANE and the like; possible catalytic hydrogenation using homogeneous catalyst or a heterogeneous type and the mu like that. As the reaction conditions chosen temperature and time appropriate for the subject using the reducing reagent. Its specific examples include restoration using DIBORANE, hydride socialmedia or lithium borohydride in an ether solvent such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling temperature for 10 min to 12 h recovery using sodium borohydride or calcium borohydride in an alcohol solvent such as ethanol and the like, or in a solvent which is a mixture of an alcoholic solvent and ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice to boiling point over a period of from 30 minutes to 24 hours, and things like that. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the hydroxyl group of the intermediate compound (VIII-3) is converted to a leaving group Xb. The reagent is not limited to, until he is a reagent capable of converting an alcohol hydroxyl gr the foam in the X b. Examples of the reagent used, when Xbrepresents a halogen atom include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride, and their combination, and the connection that contribute to the reaction, such as triphenylphosphine, base and the like, inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, iodine-hydrogen acid, tribromide phosphorus, pentabromide phosphorus, trichloride phosphorus, pentachloride phosphorus, iodine, bromine, chlorine, halogenated thionyl and the like. The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like at temperatures from -30°C to 130°C for a period of from 10 min to 6 hours When using inorganic acid, the reaction can be performed in aqueous solution or in a two-layer system of an organic solvent, such as toluene, and the like, and water. Examples of the reagent used, when Xbrepresents sulfonyloxy include a combination of sulphonylchloride (for example, methanesulfonamido, toluensulfonate and the like) and organic bases (e.g. triethylamine, pyridine and the like). Reaction conditions are as follows: the reaction of the imp is both, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like at temperatures from -30°C to 50°C for a period from about 5 minutes to 3 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage phosphonium salt of (VIII-5) is produced by interaction of the intermediate compound (VIII-4)having a leaving group Xbwith triphenylphosphine. The reaction is performed, for example, in an inactive solvent such as simple diethyl ether, benzene, toluene and the like, at temperatures from room temperature up to the boiling temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by evaporating the solvent, cooling and addition of poorly soluble solvent, such as by having a simple diisopropyl ether, hexane and the like, and then produce a collection of precipitated solids by filtration.

At the fifth stage phenolic intermediate compound (VIII-6) is produced by condensation of salt phospho who Oia (VIII-5) with aldehyde (II-6), separately synthesized using the Wittig reaction, the recovery obtained olefinic compounds and the removal of the protective group Rb. The conditions of the Wittig reaction are the conditions generally used for the Wittig reaction. For example, the reaction is performed using a base such as tert-piperonyl potassium and the like, ether solvents such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling point over a period from about 30 minutes to 12 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. The reagent to be used in the subsequent restoration of the double bond, is not limited to, until it is used for General recovery of the olefin. Its examples include catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, or a homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol, and the like, ether is the solvent, such as dioxane, and the like, or a hydrocarbon solvent such as toluene, and the like, 1-20 atmospheres pressure of hydrogen, at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid, and the like, or a base, such as triethylamine, and the like, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Conditions subsequent removal of the protective group Rbnot limited to, until they are used to remove Rb. For example, when Rbrepresents methyl, then you can use the application of the Lewis acid, such as tribromide boron and similar connection, in the solvent methylene chloride. When Rbrepresents acyl, such as acetyl and the like, you can use the method of using inorganic bases such as sodium hydroxide and the like, a mixed solvent of an alcohol solvent and water. When Rbthe submitted is a protective group such as the simple ester, such as methoxymethyl, tetrahydropyranyl, tert-butyl, and the like, it is possible to use the method of using acids, such as chloride-hydrogen acid, triperoxonane acid, and the like. When Rbrepresents a protective group which can be removed by catalytic hydrogenation (for example, benzyl, substituted benzyl, benzyloxyethyl and the like), then delete Rbcan be performed simultaneously with the above-mentioned restoration of the double bond. When the Rbused -(CH2)nCH3(n is as defined above), which is a partial structure of the compounds according to the invention (I-1a), there is no need to remove the Rband the alkylation of phenol in the next stage it is also possible not to include.

At the sixth stage, the compound of the present invention (I-1A) is obtained by alkylation of the phenolic hydroxyl group of the intermediate compound (VIII-6) and remove Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Examples of the reagent to be used for alkylation of a phenolic hydroxyl group, which is an intermediate compound (VIII-6)include a combination of the alkyl is an enabling agent, such as reptilase and the like, and inorganic bases such as potassium carbonate, sodium hydride and the like. The reaction is carried out, for example, in a polar solvent such as N,N-dimethylformamide, and the like, or in an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about from 30 minutes to 12 o'clock For the alkylation of phenolic hydroxyl group, which has an intermediate compound (VIII-6), you can use the reaction Mitsunobu condensation of p alcohol and using phosphine compound such as triphenylphosphine and the like, and azodicarboxylic acid derivative such as diisopropylethylamine, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, and the like, at a temperature of from cooling with ice up to 50°C for a period from about 10 minutes to 6 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Subsequent removal of the protection is not specifically limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed immediately and the stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butoxycarbonyl, they can be simultaneously removed using acid. Examples of the acid include inorganic acids, such as chloride-hydrogen acid and the like, triperoxonane acid and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

8) Of the compounds of the present invention, the compound (I-1a)represented by the formula (I), where R represents a hydrogen atom, X represents an oxygen atom, Y represents CH2CH2, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R3and R4represent hydrogen atoms, it is also possible to synthesize with what ispolzovaniem intermediate compound (VIII-2, Rarepresents H) in scheme (VIII), or intermediate (IX-1), synthesized from the compound represented by formula (IX-2), according to the following scheme (IX).

Scheme (IX)

where R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, Rbrepresents a protective group, and Rf-OH is an alcohol used for the reaction of solvolysis.

Rbin the formula represents the same as in scheme (VIII). As Rfyou can specify methyl, ethyl, benzyl and the like. In the above scheme for the synthesis of compound (VIII-2) are General reaction conditions Arndt-Eistert. To restore obtained through her group of ester, you can specify the reagent and conditions used in the second stage scheme (VIII). In the above scheme for the synthesis of compound (IX-2) used conditions the General reaction of the Wittig. For further processing by acid inorganic acid, such as chloride-hydrogen acid and the like, is used in water or a mixed solvent of an organic solvent, such as tetrahydrofuran and the like, and water. Subsequent recovery can be performed using the complex compound of the metal with hydrogen, such as a hydride layalina, borohydride NAT the Oia and the like, catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, or a homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I), and the like) and the like, or they can consistently perform continuously. The obtained alcohol intermediate compound (IX-1) in this scheme can be converted into the compound of the present invention in a known manner (see for example, Journal of Medicinal Chemistry vol.43 (2000) 2946-2961).

9) Of the compounds of the present invention, compound (I-1c)represented by the formula (I), where R represents a hydrogen atom, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2is an ω-foralkyl, and R3and R4represent a hydrogen atom, can also be synthesized according to the following scheme.

Scheme X

where m is an integer equal to 1 to 4, X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen.

In the first stage oxazolinone form (X-1) is synthesized protective compound (I-1b) of the formula (I), where R represents an atom is odorata, and R2is an ω-hydroxyalkyl. This stage can be performed by the interaction of a polar solvent such as acetonitrile, N,N-dimethylformamide, and the like, a halogen solvent such as methylene chloride and the like, or in a hydrocarbon solvent such as toluene and the like, with the use of ester octoxynol acid as reagent. To facilitate the reaction, you can add a base, such as N,N-diisopropylethylamine and the like, or acid, such as p-toluensulfonate acid and the like. Reaction conditions are, for example, a temperature from room temperature up to the boiling temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage fluoride form (X-2) is synthesized by fluorination of hydroxyl group of compound (X-1). Examples of the fluorinating agent include TRIFLUORIDE (dimethylamino)sulfur (DAST), 2,2-debtor-1,3-dimethylimidazolidine (DFI) and the like. This stage can be accomplished by interaction in a halogen solvent such as methylene chloride and the like, or in uglevodorov the nom solvent, such as hexane and the like. The reaction conditions are, for example, -78°C to room temperature for from about 30 minutes to 12 hours. After the interaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar methods General way and, if necessary, purification chromatography on a column of silica gel, recrystallization and the like methods. This stage can also be performed by a method including the transformation of the hydroxyl group of compound (X-1) to the corresponding sulfate form, and then its interaction with fluoride ion. For example, when using p-toluensulfonate and tetrabutylammonium fluoride (TBAF), the reaction is performed in an ethereal solvent such as tetrahydrofuran and the like, at temperatures from room temperature up to 80°C for about 1 h to 24 h In this reaction, you can add a dehydrating agent such as molecular sieves and the like. After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

At the third stage removes the protection of the compound (X-2) to obtain the compound is of the present invention (I-1c). This stage can be performed by a General removal of protection. In particular, it can be performed by using an acid such as chloride-hydrogen acid, triperoxonane acid and the like. Reaction conditions are, for example, an alcohol solvent, such as ethanol, and the like, or a mixed solvent of him and water at a temperature of from room temperature to 100°C for from about 30 minutes to 12 o'clock the Target product can be obtained by filtration, concentration and the like methods from the reaction mixture General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

10) the Compound (I-2A)represented by the formula (I), where R represents a hydrogen atom, X represents an oxygen atom, Y represents CH2CH2, R1represents trifluoromethyl or cyano, and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (XI).

Scheme (XI)

where R1represents trifluoromethyl or cyano, Rcand Rdrepresent a protective group, Xaand Xcrepresent a leaving group, and R2and n is as defined above. Rc, Rdand Xain the formula are as defined above. the walking group for X cnot specifically limited, while it is activated catalyst and dissociated during the Sonogashira reaction. For example, you can specify a halogen atom (preferably, an iodine atom, a bromine atom and the like), tripterocalyx and the like.

In the first stage, the intermediate compound (XI-3) is obtained by condensation of compound (XI-1)having a leaving group Xandwith alcohol (XI-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide, and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis it is possible to use inorganic bases, such as sodium hydride, potassium hydroxide and the like, or an organic base such as 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 100°C for about 10 min to 10 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (XI-4)having a triple bond, obtained by condensation of intermediate what about the compounds (XI-3) with an intermediate compound (IV-3), the Sonogashira reaction. Examples of the catalyst include a compound of palladium, such as tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), dichlorobis(acetonitrile)palladium(II) and the like. To facilitate the reaction, it is possible to add an organic base, such as triethylamine, and the like, an inorganic base, such as ammonia and the like, a compound of copper, such as copper iodide, copper bromide and the like, phosphine compound, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylsilyl, and the like, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, dioxane and the like, a polar solvent, such as acetonitrile, dimethylformamide, and the like, or a hydrocarbon solvent such as benzene, and the like, at a temperature of from cooling with ice to the boiling temperature for about 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the intermediate compound (XI-5) is obtained by restoring the triple bond of the intermediate (XI-4). Be using the reagent n is limited, while it is used for General recovery unsaturated carbon linkages. For example, you can specify catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel, palladium-carbon-Ethylenediamine and the like, homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium (I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, when the hydrogen pressure from 1 to 20 atmospheres at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid and the like, or a base such as triethylamine and the like, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage the protection of the intermediate (XI-5) adelayda for obtaining compounds of the present invention (I-2A). Remove Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s)is not limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butyloxycarbonyl group, the protection of the cyclic acetal is removed by catalytic amount of acid, and then used a stronger acidic conditions, whereby it is possible to remove Rd. The conditions used to remove the protecting acetal represent, for example, an alcohol solvent such as methanol, and the like, or a mixed solution of an alcohol solvent and other organic solvent, a catalytic amount of hydrochloric acid or toluensulfonate acid, at a temperature of from cooling with ice up to 80°C for about from 30 minutes to 12 o'clock on the other hand, the deletion criteria Rdthat is performed after removal of the protecting acetal represent, for example, not less than the equivalent amount of an inorganic acid, such as chloride-hydrogen acid, and the like, trithorax the Naya acid and the like, in an alcohol solvent such as ethanol, and the like, ether solvents such as tetrahydrofuran, and the like, water or a mixed solvent, at a temperature of from cooling with ice up to 80°C for about 10 min to 12 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

11) the Compound represented by formula (I), where R represents a hydrogen atom, X represents a sulfur atom, Y represents CH2CH2, R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (XII).

Scheme (XII)

where R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, Rarepresents a hydrogen atom or a protective group, Rcand Rdrepresent a protective group, Xband Xdrepresent a leaving group, and R2and n is as defined above. Ra, Rc, RdXband Xdin the formula presented is Aut a, as defined above. Leaving group for Xdnot specifically limited, as she dissociated during the substitution reaction ion of alkylthio (CH3(CH2)nS-. For example, you can specify a halogen atom (particularly, fluorine atom and the like), toluensulfonate and the like.

In the first stage, the intermediate compound (XII-2) is obtained by condensation of a derivative of benzoic acid (V-1)having a leaving group Xandin position 4 with a thiol (XII-1) for introducing alkylthio in position 4. This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide, and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as potassium carbonate, sodium hydroxide and the like, or an organic base such as triethylamine, 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like. The reaction is performed, for example, at a temperature of from -30 to 80°C for about 10 min to 10 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

N the second stage of intermediate compound (XII-3), having a hydroxyl group, obtained by restoring the carboxyl group of the intermediate (XII-2). The reagent to be used for restore is not specifically limited, as it is used by the conventional method. Its examples include alkali metals such as sodium and the like, or alkaline earth metals, metal hydrides, such as hydride diisobutylaluminum and others like him, metallovedenie complex compounds, such as hydride socialmedia, sodium borohydride and the like, boron compounds such as DIBORANE and the like; possible catalytic hydrogenation using homogeneous catalyst or a heterogeneous type, and the like. As the reaction conditions chosen temperature and time appropriate for the subject using the reducing reagent. Its specific examples include restoration using DIBORANE, hydride socialmedia or lithium borohydride in an ether solvent such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling temperature for 10 min to 12 h recovery using sodium borohydride or calcium borohydride in an alcohol solvent such as ethanol and the like, or a mixed solvent of an alcohol solvent and an ether solvent such as Tetra is hydrofuran and others like him, at a temperature of from cooling with ice to boiling point during the period from 30 min to 24 h, and the like. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the hydroxyl group of the intermediate (XII-3) is converted to a leaving group Xb. The reagent is not limited to, until he is a reagent capable of converting an alcohol hydroxyl group in the Xb. Examples of the reagent used, when Xbrepresents a halogen atom include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride, and their combination, and the connection that contribute to the reaction, such as triphenylphosphine, base and the like, inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, iodine-hydrogen acid, tribromide phosphorus, pentabromide phosphorus, trichloride phosphorus, pentachloride phosphorus, iodine, bromine, chlorine, halogenated thionyl and the like. The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), evern the second solvent (for example, tetrahydrofuran and the like), and the like at temperatures from -30°C to 130°C for a period of from 10 min to 6 hours When using inorganic acid, the reaction can be performed in aqueous solution or in a two-layer system of an organic solvent, such as toluene, and the like, and water. Examples of the reagent used, when Xbrepresents sulfonyloxy include a combination of sulphonylchloride (for example, methanesulfonamido, toluensulfonate and the like) and organic bases (e.g. triethylamine, pyridine and the like). Reaction conditions, for example, the following: use an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like, at temperatures from -30°C to 50°C for a period from about 5 minutes to 3 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage phosphonium salt (XII-5) is produced by interaction of the intermediate (XII-4)having a leaving group Xbwith three what edelfosine. The reaction is performed, for example, in an inactive solvent such as simple diethyl ether, benzene, toluene and the like, at temperatures from room temperature up to the boiling temperature for about from 30 minutes to 6 hours After the reaction, the target product can be obtained by evaporating the solvent, cooling and addition of poorly soluble solvent, such as by having a simple diisopropyl ether, hexane and the like, and then produce a collection of precipitated solids by filtration.

At the fifth stage phenolic intermediate compound (XII-6) is produced by condensation of phosphonium salts of (XII-5) with aldehyde (II-6), separately synthesized using the Wittig reaction, and recovering the obtained olefinic compounds. The conditions of the Wittig reaction are the conditions generally used for the Wittig reaction. For example, the reaction is performed using a base such as tert-piperonyl potassium and the like, ether solvents such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling point over a period from about 30 minutes to 12 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica the LEM, the recrystallization and the like methods. The reagent to be used in the subsequent restoration of the double bond, is not limited to, until it is used for General recovery of the olefin. Its examples include catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel and the like, homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium(I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol, and the like, ether solvents such as dioxane, and the like, or a hydrocarbon solvent such as toluene, and the like, 1-20 atmospheres pressure of hydrogen, at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid, and the like, or a base, such as triethylamine, and the like, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like IU is the od.

At the sixth stage, the compound of the present invention (I-3A) is obtained by removing the intermediate (XII-6), with Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Unprotect the intermediate (XII-6) is not specifically limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butyloxycarbonyl, they can be simultaneously removed by using acid. Examples of the acid include inorganic acids, such as chloride-hydrogen acid and the like, triperoxonane acid and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, when necessary, is Timoti, purification by chromatography on a column of silica gel, recrystallization and the like methods.

12) the Compound (I-4A)represented by the formula (I), where R represents a hydrogen atom, X represents a sulfur atom, and R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (XIII).

Scheme (XIII)

where R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, Rcand Rdrepresent a protective group, Xerepresents activating the hydroxyl group, Y is CH2-CH2or CH=CH, and R2and n are as defined above.

Rcand Rdin the formula are as defined above. As the activating hydroxyl groups for Xeyou can specify sulfonyl, such as trifloromethyl, toluensulfonyl and the like.

In the first stage, the intermediate compound (XIII-1) is obtained by introducing an activating group in the phenolic hydroxyl group of the intermediate compound (VIII-6) in scheme (VIII). This stage can be performed in a halogen solvent such as methylene chloride and chloroform, in ether dissolve the e, such as tetrahydrofuran and the like, in the presence of a base. As a reagent for this reaction are activated derivatives of sulfonic acid such as the anhydride triftormetilfullerenov acid, 1-(trifloromethyl)imidazole, toluensulfonate. This reaction can also be performed by using a sulfonic acid and a condensing agent in combination. As a basis it is possible to use an organic base, such as triethylamine, pyridine, lutidine and the like. The reaction conditions are, for example, from -50°C to 50°C for from about 5 minutes to 3 hours. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (XIII-2) is produced by condensation of intermediate compound (XIII-1) and thiol (XII-1). This stage can be performed in an ethereal solvent such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, in the presence of palladium catalyst. Examples of the palladium catalyst include palladium (II)acetate, Tris(dibenzylideneacetone)on the palladium(0) and the like. In addition, as a compound that promotes this reaction, you can add a phosphine compound or base. Examples of the phosphine compound include triphenylphosphine, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and the like. On the other hand, as a base, you can specify an inorganic base such as cesium carbonate and the like, and an organic base, such as N,N-diisopropylethylamine and the like. Reaction conditions are, for example, a temperature from room temperature up to the boiling temperature for about 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the compound of the present invention (I-4a) is obtained by removal of the intermediate compound (XIII-2), with Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Unprotect intermediate compound (XIII-2) is not specifically limited, as long as it is used for General removal of the protective groups, and all protective gr is PPI can be removed at once or in stages. For example, when Rcrepresents a protective group which can be removed by acid, such as methoxymethyl and the like, and Rdrepresents a tert-butoxycarbonyl, they can be removed simultaneously by the acid. Examples of the acid include inorganic acid, such as chloride-hydrogen acid and the like, triperoxonane acid and the like. Reaction conditions are, for example, the following: an alcohol solvent, such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or a solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

13) Of the compounds of the present invention, the compound (I-5A)represented by the formula (I), where R represents a hydrogen atom, Y represents CH2CH2, R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents hydroxymethyl, and R3and R4p is establet a hydrogen atoms, can also be synthesized according to the following scheme (XIV).

Scheme (XIV)

where R1represents alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, X represents an oxygen atom or a sulfur atom, Xfrepresent a leaving group, Rgrepresents a protective group, or -(CH2)nCH3, R2represents hydroxymethyl, and n is as defined above.

Leaving group for Xfnot specifically limited, as she dissociated during the substitution reaction of the alkoxide anion or thiol. For example, you can specify a halogen atom (particularly, fluorine atom and the like), tripterocalyx and the like. When Rgin the formula represents a protective group, Rgnot limited to, yet it protects the phenolic group or Tilney group. Examples Rgwhen X represents an oxygen atom include alkyl (methyl and the like), aralkyl (benzyl and the like), the protective group forming an acetal (methoxymethyl, ethoxyethyl and the like) and the like. When X represents a sulfur atom, alkyl (methyl and the like), aralkyl (4-methoxybenzyl and similar), you can specify the protective group, forming thioacetal (methoxymethyl, phenylthiomethyl, atsetamidometil and under the data) and the like.

In the first stage, the intermediate compound (XIV-3) is obtained by condensation of acetophenone (XIV-1)having a leaving group Xfin position 4, and alcohol or thiol (XIV-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide, and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide and the like, or an organic base such as 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 100°C for about 10 min to 10 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage phenacylbromides form (XIV-4) are bromirovanii acetyl groups of the intermediate compound (XIV-3). This stage can be performed in a solvent such as a halogen solvent such as chloroform and the like, ether solvents such as dioxane and the like, an alcohol solvent, such as ETANA and others like him, or acetic acid and the like. As reagent synthesized, you can specify bromine, pyridinethione, phenyltrimethylammonium and the like. Reaction conditions are, for example, the following: at a temperature of from cooling with ice to about 60°C for about from 30 minutes to 10 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the intermediate compound (XIV-5) is produced by condensation of intermediate compound (XIV-4) and diethylenetriaminepenta. This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of base. As a basis it is possible to use inorganic bases, such as sodium hydride, potassium hydroxide, tert-piperonyl potassium and the like. Reaction conditions, for example, the following: temperature from cooling with ice to about 50°C for about 10 minutes to 5 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and that the such methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage of the intermediate compound (XIV-6) is obtained by restoring the carboxyl group of the intermediate compound (XIV-5) in methylene. As the reducing agent, you can use a combination of trialkylsilanes and triperoxonane acid, a combination of trialkylsilanes and titanium tetrachloride and the like in a halogen solvent such as 1,2-dichloroethane and the like, or without solvent. Reaction conditions, for example, the following: temperature from cooling with ice to boiling point over a period of about 1 to 48 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

The obtained intermediate compound can be converted to the compound of the present invention (I-5a) in a known manner (for example, Journal of Medicinal Chemistry vol. 43 (2000) 2946-2961).

14) Of the compounds of the present invention, the compound (I-6A), represented by formula (I)where one of R3and R4or both of R3and R4is (are) an alkyl having 1-4 atoms ug is erode, synthesized according to the following scheme (XV).

Scheme (XV)

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, one or both of R3and R4represent alkyl having 1-4 carbon atoms, Y represents CH2CH2or CH=CH, and n is as defined above.

At this stage, the compound of the present invention (1-6A) is synthesized by alkylation of the amino group of compound (XV-1)having a primary amino group, of the compounds of the present invention. For this synthesis, you can use the reaction of reductive amination or alkylation reaction amine using alkylhalides and grounds. When using reductive amination of the target product is produced by the interaction of the aldehyde with the same number of carbon atoms as R3or R4with compound (XV-1) in an alcohol solvent such as ethanol and the like, or a halogen solvent such as dichloroethane and the like, the application of a reducing agent, such as sodium borohydride, cyanoborohydride sodium, triacetoxyborohydride sodium and the like. Recovery can also be performed using hydrogen and a catalyst, such as Raney Nickel, platinum oxide and the like. For this reaction can also be run sequentially generating Schiff bases and reaction recovery. Acid, such as acetic acid and the like, can be added as an activator of the reaction for the reaction of reductive amination. Reaction conditions, for example, the following: temperature from cooling with ice to about 50°C for a period from about 30 minutes to 10 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When R3and R4represent methyl, then you can also perform the methylation reaction Eschweiler-Clarke using a reducing agent such as formic acid and formaldehyde, or formaldehyde and cyanoborohydride sodium, and the like.

15) Of the compounds of the present invention, the compound (I-7a), represented by formula (I), where R represents a hydrogen atom, Y not only is et a CH=CH, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (XVI).

Scheme (XVI)

where X represents an oxygen atom or a sulfur atom, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, Rcand Rdrepresent a protective group, Rgrepresents a protective group, or -(CH2)nCH3Xaand Xbrepresent leaving groups, Xgrepresent a leaving group containing phosphorus, and n is as defined above.

Rcthe formula is not limited, while it protects the hydroxyl group. For example, acyl (preferably having 2-4 carbon atoms, in particular, acetyl and the like), trialkylsilyl (in particular, trimethylsilyl and the like), benzyl and Deputy forming acetylene connection (in particular, methoxymethyl, tetrahydropyranyl and the like). When R2has a hydroxyl group, the protective group Re(Rein particular, the analogy is of ican R cand Rcmay also be related to formation of the cyclic acetal. Protective group, shown Rdin the formula, is not limited, while it protects the amino group. For example, acyl (preferably, acyl having 2-4 carbon atoms, in particular, acetyl and the like), carbamate (in particular, tert-butyloxycarbonyl, benzyloxycarbonyl and the like), and the like. When Rgin the formula represents a protective group, Rgnot specifically limited, while it protects the phenolic group or Tilney group. Examples Rgwhen X represents an oxygen atom include alkyl (methyl and the like), aralkyl (4-methoxybenzyl and similar), the protective group forming an acetal (methoxymethyl, ethoxyethyl and the like) and the like. When X represents a sulfur atom, alkyl (methyl and the like), aralkyl (4-methoxybenzyl and similar), you can specify the protective group, forming thioacetal (methoxymethyl, phenylthiomethyl, atsetamidometil and the like) and the like. Leaving group for Xanot limited to, until she dissociated during the substitution reaction alkoxide ion (Rg-O-or tialata (Rg-S-). For example, you can specify a halogen atom (particularly, fluorine atom and the like), toluensulfonate and the like. Leaving group for Xbthe e limited, while she dissociated during the reaction between the intermediate compound (XVI-5) and a compound of phosphorus and did not inhibit subsequent reaction with aldehyde (II-6). For example, you can specify a halogen atom (in particular, iodine atom, bromine atom, chlorine atom and the like), methansulfonate, toluensulfonate and the like. Examples of leaving groups containing phosphorus for Xginclude P(C6H5)3and P(O)(ORh)2(Rhrepresents alkyl having 1-4 carbon atoms).

In the first stage, the intermediate compound (XVI-3) is obtained by condensation of benzoic acid (XVI-1)having a leaving group Xain position 4, with the alcohol or thiol (XVI-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like, or an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide, potassium carbonate and the like, or an organic base such as alkoxide (for example, tert-piperonyl potassium and the like), 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 80°C for approximately 30 min to 24 h After the reaction, the target product can be obtained uh what stryrofoam, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage, the intermediate compound (XVI-4)having a hydroxyl group, obtained by restoring the carboxyl group of the intermediate compound (XVI-3). The reagent to be used for restore is not limited to, until it is accepted. Its examples include alkali metals such as sodium and the like, alkaline earth metals, metal hydrides, such as hydride diisobutylaluminum and others like him, metallovedenie complex compounds, such as hydride socialmedia, hydride bis(2-methoxyethoxy)aluminum and the like, boron compounds such as DIBORANE and the like; possible catalytic hydrogenation using homogeneous catalyst or a heterogeneous type, and the like. As the reaction conditions chosen temperature and time appropriate for the subject using the reducing reagent. Its specific examples include restoration using DIBORANE, hydride socialmedia in ethereal solvent such as tetrahydrofuran and the like, at temperatures from -30°C up to the boiling temperature for 10 min is about 12 hours, recovery using hydride, sodium bis(2-methoxyethoxy)aluminum in an inactive solvent such toluene and the like, at a temperature of from cooling with ice up to 50°C for periods from 30 min to 24 h, and the like. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the hydroxyl group of the intermediate compound (XVI-4) is transformed into a leaving group Xb. The reagent is not limited to, until he is a reagent capable of converting an alcohol hydroxyl group in the Xb. Examples of the reagent used, when Xbrepresents a halogen atom include N-chlorosuccinimide, N-bromosuccinimide, carbon tetrachloride, and their combination, and the connection that contribute to the reaction, such as triphenylphosphine, base and the like, inorganic acids such as chloride-hydrogen acid, Hydrobromic acid, iodine-hydrogen acid, tribromide phosphorus, pentabromide phosphorus, trichloride phosphorus, pentachloride phosphorus, iodine, bromine, chlorine, halogenated thionyl, α-halogenation and the like. The reaction of the issue is neetsa, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like, at temperatures from

-30°C to 130°C for a period of from 10 min to 6 hours When using inorganic acid, the reaction can be performed in aqueous solution or in a two-layer system of an organic solvent, such as toluene, and the like, and water. Examples of the reagent used, when Xbrepresents sulfonyloxy include a combination of sulphonylchloride, such as methanesulfonate, toluensulfonate and the like, and organic bases (e.g. triethylamine, pyridine and the like). The reaction is performed, for example, in an organic solvent such as a halogen solvent (e.g. methylene chloride and the like), ether solvent (e.g. tetrahydrofuran and the like), and the like, at temperatures from -30°C to 50°C for a period from about 5 minutes to 3 hours After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

On the fourth stud and the intermediate compound (XVI-6), having a leaving group Xgcontaining phosphorus, produced by interaction of the intermediate compound (XVI-5)having a leaving group Xbwith a compound of phosphorus. When Xgrepresents P(C6H5)3intermediate compound (XVI-6) can be obtained by the interaction of the intermediate compound (XVI-5) with triphenylphosphine. The reaction is performed, for example, in an inactive solvent such as simple diethyl ether, benzene, toluene and the like, at temperatures from room temperature up to the boiling temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by evaporating the solvent, cooling and addition of poorly soluble solvent, such as a simple diisopropyl ether, hexane and the like, and then produce a collection of precipitated solids by filtration. When Xgrepresents P(O)(ORh)2, (Rhis as defined above), the intermediate compound (XVI-6) can be obtained by Arbuzov reaction by reacting the intermediate compound (XVI-5) with triethylphosphite. The reaction, for example, carried out without solvent or in an inactive solvent such as xylene, and the like, at temperatures from 100°C to 170°C for a period from about 30 minutes to 12 hours After the reaction, the target product can be obtained by evaporation of the Il is the distillation of the excess triethyl phosphate.

At the fifth stage phenolic intermediate compound (XVI-6)containing phosphorus and separately synthesized aldehyde (II-6), condensed to obtain olefinic form (XVI-7). When Xgrepresents P(C6H5)3criteria are used, in General, used for the Wittig reaction. For example, the reaction is performed in an ethereal solvent such as tetrahydrofuran and the like, using a base such as sodium hydride, tert-piperonyl potassium and the like, at temperatures from -30°C up to the boiling point over a period of about 30 min to 12 h of Z shape can preferably be obtained by reaction in an aprotic solvent in salt-free conditions, or E-form can also preferable to obtain improved method Schlosser. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When Xgrepresents P(O)(ORh)2, (Rhis as defined above), then use the General reaction conditions Horner-Wadsworth-Emmons. For example, the reaction is performed in a hydrocarbon solvent such as benzene and the like, or in an ether solvent such as tetrahydrofuran and the like, using a base such as sodium hydride, tert-piperonyl potassium, hexamethyldisilazane lithium and the like, at temperatures from -20°C to the boiling point over a period from about 30 minutes to 12 hours Olefin can preferably be obtained in the form E form. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

At the sixth stage, the compound of the present invention (I-7a) is obtained by removing the intermediate (XVI-7)with Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s). Conditions are not limited to, until they are used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcrepresents a protective group which forms an acetal, and Rdrepresents a tert-butyloxycarbonyl, they can simultaneously be removed by using acid. Examples of the acid include inorganic acids, such as chloride-hydrogen keys, the PTA and the like, triperoxonane acid and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, in water or solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for a period from about 10 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When Rgrepresents a protective group, before removing the protective groups Rcand Rd, you can delete Rgand the alkylation of phenol or thiol obtained through this. Conditions to be used for the removal of Rgnot limited to, until they are used for General removal of the protective groups. For example, when Rgis a 4-methoxybenzyl, it uses the oxidation reaction of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like, when Rgrepresents allyl, you can use the reaction using palladium compounds as catalysts. Examples of the reagent to be used for the application for the alkylation of phenolic hydroxyl group or Tilney group, which has received the connection include a combination of an alkylating agent, such as alkylated and the like, and inorganic bases such as potassium carbonate, sodium hydride and the like. For example, reaction conditions are the following: a polar solvent such as N,N-dimethylformamide and the like, ether solvents such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about 10 minutes before 12 o'clock in Addition, for the alkylation of phenolic hydroxyl groups can also use the Mitsunobu reaction.

16) the Compound (I-8a), represented by formula (I), where R represents a hydrogen atom, and R1is deformity, can also be synthesized according to the following scheme (XVII).

Scheme (XVII)

where X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, Rcand Rdrepresent a protective group, Rgrepresents a protective group, or -(CH2)nCH3Xaand Xbrepresent a leaving group, and n is as defined above.

Rc, Rd, Rgthe ,Xaand Xcare as defined above.

In the first stage, the intermediate compound (XVII-3) is obtained by condensation of the source material (XVII-1)having a leaving group Xandwith alcohol or thiol (XVII-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide, and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide, potassium carbonate and the like, or an organic base such as an alkoxide, such as tert-piperonyl potassium and the like, 1,8-diazabicyclo[5,4,0]undec-7-ene, and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 80°C for approximately 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way, and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. In addition, the compound (XVII-1), where the leaving group Xarepresents a phenolic hydroxyl group, or thiol, can also be used as source material. In this case, the first stage before the hat is the alkylation of a phenolic hydroxyl group, or thiol. Examples of the reagent to be used for alkylation include a combination of an alkylating agent, such as alkylated and the like, and inorganic bases such as potassium carbonate, sodium hydride and the like. Reaction conditions, for example, the following: a polar solvent such as N,N-dimethylformamide and the like, or an ethereal solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about 10 minutes before 12 o'clock For the alkylation of phenolic hydroxyl group, in addition, you can use the reaction Mizunami.

In the second stage, the intermediate compound (XVII-4), with diplomatic get the fluoridation of the formyl groups of the intermediate compound (XVII-3). This stage can be performed in a halogen solvent such as metalenclosed, and the like, using a fluorinating agent such as TRIFLUORIDE (dimethylamino)sulfur (DAST), differed xenon and the like. For this reaction fluoridation oxidant such as N-jodatime and others like him, can interact in the presence of ion farinata, such as a fluoride of tetrabutylammonium, instead of using one fluorinating agent. The reaction is performed, for example, at a temperature of from cooling with ice to about 50°C for about 1 to 24 hours After the reaction, the target product can is about to get extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the intermediate compound (XVII-5)having a triple bond, obtained by condensation of intermediate compound (XVII-4) with an intermediate compound (IV-3) the Sonogashira reaction. Examples of the catalyst include a compound of palladium, such as tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), dichlorobis(acetonitrile)palladium(II) and the like. To facilitate the reaction, it is possible to add an organic base, such as triethylamine, and the like, an inorganic base, such as ammonia and the like, a compound of copper, such as copper iodide, copper bromide and the like, phosphine compound, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylsilyl, and the like, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, dioxane and the like, a polar solvent, such as acetonitrile, dimethylformamide, and the like, or a hydrocarbon solvent such as benzene, and the like, at a temperature of from cooling with ice to the boiling temperature for about 30 min to 24 h After the reaction, the target product can be obtained uh what stryrofoam, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage of the intermediate compound (XVII-6) is obtained by restoring the triple bond of the intermediate compound (XVII-5). Be used reagent, when Y represents CH2CH2not limited to, until it is used for General recovery unsaturated carbon linkages. For example, you can specify catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel, palladium-carbon-Ethylenediamine and the like, homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium(I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, when the hydrogen pressure from 1 to 20 atmospheres at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid and the like, or a base such as triethylamine and the like, in which depending on the speed of reaction, stability and similar factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. On the other hand, as a reaction that is used when Y is CH=CH, you can specify catalytic hydrogenation in the presence of a catalyst with a regulated activity, such as Lindlar catalyst, Nickel-graphite-ethylendiamine complex, various complex diene compound and a phosphine compound and rhodium, and the like. In addition, it is also possible reduction using metal hydride, such as hydride diisobutylaluminum, and the like. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

At the fifth stage, the compound of the present invention (I-8a) is obtained by removing the protection of the intermediate compound (XVII-6). Remove Rcand Rdand the protective group Re(Rerepresents, as of the designated above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s)is not limited, as long as it is used for General removal of the protective groups, and all of the protective group can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butyloxycarbonyl, protection of the cyclic acetal is removed by catalytic amount of acid, and then used a stronger acidic conditions, whereby it is possible to remove Rd. The conditions used to remove the protecting acetal represent, for example, an alcohol solvent, such as ethanol, and the like, or a mixed solution of an alcohol solvent and other organic solvent, a catalytic amount of chloride-hydrogen acid or toluensulfonate acid, at a temperature of from cooling with ice up to 80°C for a period from about 30 minutes to 12 o'clock on the other hand, the deletion criteria Rdthat will subsequently be performed after removal of the protecting acetal represent, for example, not less than the equivalent amount of an inorganic acid, such as chloride-hydrogen acid, and the like, triperoxonane acid and the like, in an alcohol solvent such as ethanol, and the like, EF is Pnom solvent, such as tetrahydrofuran, and the like, water, or solvent, representing their mixture, at a temperature of from cooling with ice up to 80°C for about 10 min to 12 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When Rgrepresents a protective group, the alkylation of phenol or thiol, resulting from the removal of Rgyou can perform before you remove the protective groups Rcand Rd. Conditions to be used for the removal of Rgnot limited to, until they are used for General removal of the protective groups. When, for example, Rgis a 4-methoxybenzyl, it is possible to perform the oxidation reaction of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and the like, and when Rgrepresents allyl, it is possible to perform the reaction using palladium compounds as catalysts. Examples of the reagent to be used for alkylation of a phenolic hydroxyl group or Tilney group, the compounds include a combination of an alkylating agent, such as alkylated and the like, and inorganic bases, so the th as potassium carbonate, gidirim sodium and the like. The reaction conditions are as follows: the reaction is conducted in a polar solvent such as N,N-dimethylformamide and the like, or an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about 10 minutes before 12 o'clock For the alkylation of phenolic hydroxyl groups can also use the reaction Mizunami.

17) the Compound (I-9a), represented by formula (I), where R represents a hydrogen atom, and R1is vermeil, can also be synthesized according to the following scheme (XVIII).

Scheme (XVIII)

where X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, Rc, Rdand Rirepresent a protective group, Xaand Xcrepresent a leaving group, and n is as defined above.

Specific examples Rc, RdXaand Xcin the formula are those specified above. The protective group for R1not specifically limited, while it protects the hydroxyl group in the formula. For example, you can specify trialkylsilyl (in particular, tert-butyldimethylsilyl and similar).

In the first stage, the intermediate compound (XVIII-3) is obtained by condensation of the source material (XVIII-1)having a leaving group Xawith alcohol or thiol (XVIII-2). This stage can be performed in a polar solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like, or in an ether solvent such as tetrahydrofuran and the like, in the presence of a base. As a basis you can use inorganic base such as sodium hydride, potassium hydroxide, potassium carbonate and the like, or an organic base such as alkoxide (for example, tert-piperonyl potassium and the like), 1,8-diazabicyclo[5.4.0]undec-7-ene and the like. The reaction is performed, for example, at a temperature of from cooling with ice to about 80°C for approximately 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. In addition, compound (XVIII-1), where the leaving group Xarepresents a phenolic hydroxyl group, or thiol, can also be used as source material. In this case, the first stage represents alkali the Finance phenolic hydroxyl group, or thiol. Examples of the reagent to be used for alkylation include a combination of an alkylating agent, such as alkylated and the like, and inorganic bases such as potassium carbonate, sodium hydride and the like. Reaction conditions, for example, the following: a polar solvent such as N,N-dimethylformamide, and the like, or an ethereal solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice up to 80°C for about 10 minutes before 12 o'clock For the alkylation of phenolic hydroxyl group, in addition, you can use the reaction Mizunami.

In the second stage formyl group of the intermediate compound (XVIII-3) is recovered to obtain hydroxymethyl and it is introduced protective group Ri. The reagent to be used for recovery of the formyl group is not limited as long as it is accepted. Its examples include a metal hydride, such as hydride diisobutylaluminum and others like him, metallovedenie complex compounds, such as hydride socialmedia, sodium borohydride, and the like, it is possible catalytic hydrogenation using a catalyst in a homogeneous system or a heterogeneous system, and the like. Choose the reaction conditions, temperature and time suitable for the reducing agent, which galgenberg used. In particular, you can specify the recovery hydride socialmedia or lithium borohydride, which is performed in an ether solvent such as tetrahydrofuran and the like, at temperatures from -30°C to room temperature for 10 min to 3 h, the recovery of the sodium borohydride or calcium borohydride, which is performed in an alcohol solvent such as ethanol and the like, or a mixed solvent of an alcohol solvent and an ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice to room temperature over a period of from 10 min to 3 h, and so like that. After the reaction, the target product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods. For the introduction of a protective group, Rithere is a common reaction to the introduction of protective groups. When trialkylsilyl group is used for Rithe agent sililirovanie, such as tert-butyldimethylchlorosilane and the like, is used as a reagent, and a base, such as imidazole, triethylamine and the like can be added as a stimulant reaction. After the reaction CE the eve of the product can be obtained by quenching the reaction, extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the intermediate compound (XVIII-5)having a triple bond, obtained by condensation of intermediate compound (XVIII-4) with an intermediate compound (IV-3), which is synthesized by the Sonogashira reaction. Examples of the catalyst include a compound of palladium, such as tetrakis(triphenylphosphine)palladium(0), Tris(dibenzylideneacetone)dipalladium(0), dichlorobis(acetonitrile)palladium(II) and the like. To facilitate the reaction, it is possible to add an organic base, such as triethylamine, and the like, an inorganic base, such as ammonia and the like, a compound of copper, such as copper iodide, copper bromide and the like, phosphine compound, such as 2-dicyclohexylphosphino-2',4',6'-triisopropylsilyl, and the like, and the like. The reaction is performed, for example, in the ether solvent such as tetrahydrofuran, dioxane and the like, a polar solvent, such as acetonitrile, dimethylformamide, and the like, or a hydrocarbon solvent such as benzene, and the like, at a temperature of from cooling with ice to the boiling temperature for about from 30 minutes to 24 hours is the ass of the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the fourth stage of the intermediate compound (XVIII-6) is obtained by restoring the triple bond of the intermediate compound (XVII-5). When Y represents CH2CH2subject to use of the reagent is not limited to, until it is used for General recovery unsaturated carbon linkages. For example, you can specify catalytic hydrogenation using a heterogeneous catalyst such as palladium-carbon, Raney Nickel, palladium-carbon-Ethylenediamine and the like, or a homogeneous catalyst, such as rhodium complex (chlorotris(triphenylphosphine)rhodium(I) and the like) and the like. The reaction is performed, for example, in an alcohol solvent such as ethanol and the like, ether solvents such as dioxane and the like, or a hydrocarbon solvent such as toluene and the like, when the hydrogen pressure from 1 to 20 atmospheres at a temperature of from cooling with ice to boiling point for 30 minutes to 1 week. To the reaction mixture, you can add the acid, such as acetic acid and the like, or a base such as triethylamine and his podobn is e, depending on the speed of response, stability and the like factors. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. On the other hand, as a reaction that is used when Y is CH=CH, you can specify catalytic hydrogenation in the presence of a catalyst having a regulated activity, such as Lindlar catalyst, Nickel-graphite-ethylendiamine complex, various diene complexes and phosphine and rhodium, and the like. In addition, it is also possible reduction using metal hydride, such as hydride diisobutylaluminum, and the like. After the reaction, the target product can be obtained by filtration, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

At the fifth stage fluoride form (XVIII-7) is synthesized by removing Ricompound (XVIII-6) and by fluorination of hydroxyl group of the obtained compound. The protective group Riyou can delete shared the removal of protection. Examples of the reagent to be used when Rirepresents trialkylsilyl include fluoride, such as tetrabutylammonium fluoride and the like. Reaction conditions, for example, the following: in the ether solvent such as tetrahydrofuran and the like at a temperature of from cooling with ice to boiling point over a period from about 30 minutes to 24 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by distillation, chromatography on a column of silica gel, recrystallization and the like methods. As a reagent to be used for subsequent fluorination, you can specify TRIFLUORIDE (diethylamino)sulfur (DAST), 2,2-debtor-1,3-dimethylimidazolidine (DFI) and the like. At this stage, the reaction can be performed in a halogen solvent such as methylene chloride and the like, or in a hydrocarbon solvent such as hexane and the like. The reaction is performed, for example, at temperatures from -78°C to room temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, cleaning chrome is cografya on a column of silica gel, the recrystallization and the like methods. This stage can also be performed by a method including the transformation of the hydroxyl group to the corresponding sulfate form, and its interaction with fluoride ion. For example, when using p-toluensulfonate and tetrabutylammonium fluoride (TBAF), the reaction is performed in an ethereal solvent such as tetrahydrofuran and the like, at temperatures from room temperature up to 80°C for a period of from about 1 h to 24 h In this reaction, you can add a dehydrating agent such as molecular sieves and the like. After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When Rirepresents trialkylsilyl, you can do fluoridation without removing Ri.

At the sixth stage, the compound of the present invention (I-9a) is obtained by removing the protection of the intermediate compound (XVIII-7). Remove Rcand Rdand the protective group Re(Reis as defined above), which protects the hydroxyl group (s), when R2has this hydroxyl group (s)not specifically limited, as long as it is used is for the total removal of the protective groups, and all the protective groups can be removed at once or in stages. For example, when Rcand Rerelated for the formation of a cyclic acetal, and Rdrepresents a tert-butoxycarbonyl, protection of the cyclic acetal is removed by catalytic amount of acid, and then used a stronger acidic conditions, whereby it is possible to remove Rd. The conditions used to remove the protecting acetal represent, for example, an alcohol solvent such as methanol, and the like, or a mixed solution of an alcohol solution and another organic solvent using a catalytic amount of chloride-hydrogen acid or toluensulfonate acid at a temperature of from ice cooling to 80°C for a period from about 30 minutes to 12 o'clock on the other hand, the deletion criteria Rdto follow the removal of the protecting acetal represent, for example, not less than the equivalent amount of an inorganic acid, such as chloride-hydrogen acid and the like, triperoxonane acid and the like, in an alcohol solvent such as ethanol and the like, ether solvents such as tetrahydrofuran and the like, water or restoritive representing their mixture, at a temperature of from cooling with ice to room temperature over a period of about the 10 min to 5 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. In addition, the solvent having a low solubility, such as simple Diisopropylamine ether and the like, can be added to the reaction solution, and the precipitated target product can be collected by filtering.

18) Of the compounds of the present invention, the compound (I-10A)represented by the formula (I), where R is a P(=O)(OH)2and R3and R4represent hydrogen atoms, is synthesized according to the following scheme (XIX).

Scheme (XIX)

where X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R1represents cyano or alkyl having 1-4 carbon atoms, and substituted atom (atoms) halogen, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, Rdand Rjrepresent a protective group, and n is as defined above.

Rdthe formula is as defined above. When R2compound(XIX-2) contains a hydroxyl group, the hydroxyl group can be protected by a protective group, Re(Reis as defined above). When R2represents a protected hydroxymethyl or hydroxyethyl, his protective group Reassociated with or nitrogen atom that is attached to Rdfor the education of the next cyclic compound (XIX-2', XIX-2”)

where p = 1 or 2 , and other symbols are as defined for scheme (XIX), whereby a protected amino group and hydroxyl group.

The protective group for R3the formula is not limited, while it protects the group of phosphoric acid. For example, you can specify alkyl (preferably having about 1-6 carbon atoms, in particular, tert-butyl and the like), benzyl, phenyl and the like.

In the first stage form with a protected amino group, (XIX-2) is synthesized by protection of the amino group, (XIX-1), where R represents a hydrogen atom, compounds of the present invention. This stage you can perform the overall response of the protection of the amino group. In particular, when acyl, allyloxycarbonyl, benzyloxycarbonyl and the like are used as a protective group (Rd), this stage can be performed in alcohol, such as methanol and the like, or in a two-layer system or a mixture of water and an organic solvent, is such as ethyl acetate, chloroform and the like. Examples to be used regenta include acid chloride, such as acetylchloride, benzyloxycarbonyl and the like, an acid anhydride, such as acetic anhydride, di-tert-BUTYLCARBAMATE and the like. Organic base such as triethylamine and the like, an inorganic base such as sodium bicarbonate and the like, can be added as a promoter for the reaction. The reaction conditions, for example, are: temperature from cooling with ice up to 50°C for approximately 30 min to 24 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. When the amino group and hydroxyl group contained in R2protected at the same time as the oxazoline of the formula (XIX-2'), this stage can be accomplished by interaction of a polar solvent such as acetonitrile, N,N-dimethylformamide, and the like, a halogen solvent such as methylene chloride and the like, or in a hydrocarbon solvent such as toluene and the like, with the use of ester octoxynol acid as reagent. In addition, to facilitate the reaction m is tenderly add base such as N,N-diisopropylethylamine and the like, or acid, such as p-toluensulfonate acid and the like. Reaction conditions are, for example, a temperature from room temperature up to the boiling temperature for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and similar procedures General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the second stage phosphorylated form (XIX-3) is synthesized by the interaction of form with a protected amino group, (XIX-2) phosphorylation reagent (e.g., chloride of phosphorus, phosphoramidites and oxidant complex tetrabenzyl ether pyrophosphoric acid and the like). When using complex tetrabenzyl ether pyrophosphoric acid as reagent phosphorylation this stage can be performed in anhydrous conditions, preferably in an organic solvent, such as toluene, dichloromethane, solvent, representing a mixture thereof, and the like, using an additive (for example, silver oxide, iodide, Tetra-n-ammonium and the like). For example, reaction conditions: temperature from cooling with ice up to 50°C. for 5-24 hours After the reaction, the target product is the returns filtering, extraction, washing, drying, removal of solvent and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. For this reaction, the interaction of the General phosphorylation reagent (chloride of phosphorus and grounds, phosphoramidite and oxidant and the like) can be provided in accordance with the known method. For example, when using phosphoramidite and xilitol, the reaction is performed in a halogen solvent such as dichloromethane and the like, ether solvents such as tetrahydrofuran and the like, a polar solvent, such as acetonitrile and the like, or in a solvent represents from the mixture, using phosphoramidite such as di-tert-butyl of diisopropylphosphoramidite and the like at a temperature of from cooling with ice up to 50°C for about 10 minutes before 5 o'clock 1H-tetrazole and the like can be added as a promoter for this reaction. For the oxidation of phosphorus is performed sequentially after phosphorylation, it is possible to use an organic peroxide, such as m-chloroperbenzoic acid, tert-butylperoxide, and the like, or an inorganic peroxide such as hydrogen peroxide and the like. The reaction is performed at a temperature from a cooling gap is placed ice up to 50°C for approximately 3 min to 1 h After the reaction, the target product can be obtained by extraction, washing, drying, removal of solvent and such a procedure accepted way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods.

In the third stage, the compound of the present invention (I-10A) is obtained from the phosphorylated form (XIX-3). This stage can perform a total removal of the protection. In particular, this stage can be accomplished by hydrogenolysis using acid such as chloride-hydrogen acid, triperoxonane acid and the like, a Lewis acid such as trimethylsilylmethyl and the like. When this reaction is used hydrogenolysis, this stage is performed by, for example, in an alcohol solvent such as methanol and the like, using a catalyst such as palladium-carbon and the like, in an atmosphere of hydrogen. For example, reaction conditions: temperature from room temperature to 60°C. for about 1-24 hours Target product can be obtained by filtration, concentration of the reaction mixture, and the like methods General way and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Reaction conditions, when the acid used for this reaction, for example, a trace is the following: an alcohol solvent, such as ethanol and the like, or a solvent, representing its mixture with water at a temperature of from room temperature to 100°C for about from 30 minutes to 12 hours After the reaction, the target product can be obtained by adding the reaction mixture to water and collecting the precipitated target product by filtration or by extraction, washing, drying, removal of solvent and the like methods and, if necessary, purification by chromatography on a column of silica gel, recrystallization and the like methods. Of the compounds of the present invention, the compound of formula (I), where R is a P(=O)(OH)2and one of R3and R4represents alkyl having 1-4 carbon atoms, is also synthesized in a manner analogous to the above scheme (XIX). The compound of formula (I), where R is a P(=O)(OH)2and R3and R4represent alkyl having 1-4 carbon atoms, is synthesized in a manner analogous to the above scheme (XIX), without the use of amino-protective group, Rdused in the schema (XIX).

The compound of the present invention can optionally converted into an acid additive salt by treatment with an acid in a suitable solvent (water, alcohol, simple ester and the like). In addition, the compound obtained according to the present invention Nonoperating in the hydrate or MES processing water, water-containing solvent or other solvent (for example, alcohol etc).

The compound of the present invention can be used for treatment or prevention of autoimmune diseases (e.g. rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis, diabetes type I, and so on); the prevention or suppression of resistance or acute rejection or chronic rejection of organ transplant or tissue (e.g., including transplantation and heterogeneous transplantation of heart, kidney, liver, lung, bone marrow, cornea, pancreas, small intestine, limb, muscle, nerve, bone marrow adipose tissue, 12 duodenal ulcer, skin, islet cells of the pancreas and the like) in mammals such as human, dog, cat, cow, horse, pig, monkey, mouse and the like; disease graft-versus-host (GvH) due transplantatio bone marrow; and treatment or prevention of allergic diseases (for example, atopic dermatitis, allergic rhinitis, asthma and so on).

In the present invention "prevention" means the act of introducing the compounds of the present invention or pharmaceutical compositions containing this compound, the individual, that n the development of the disease or symptom. In addition, "treatment" means the act of introducing the compounds of the present invention or pharmaceutical compositions containing this compound, the individual who has already developed the disease or disorder, or symptom. Accordingly, the act of introducing the individual who has already developed the disease or disorder, or symptoms, to prevent worsening of the symptom and the like, preventing attacks or prevent recurrence, is one variant of implementation of the "treatment".

When the compound of the present invention is used as pharmaceutical agents, the compound of the present invention is mixed with pharmaceutically acceptable carrier (excipient linking agent, baking powder, corrective agent, flavoring, emulsifier, diluent, solubilizer and the like), and the resulting pharmaceutical composition or preparation (oral, injectable solution, and the like) can be administered orally or parenterally. The pharmaceutical composition can be obtained in accordance with the generally accepted method.

In the present description "parenteral" includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, drip method or local introduction (trancdermalnoe, intraocular introduction, pulmonary-bronchial introduction, intranasal introduction, introduction transrectal and the like) and the like.

The content of compounds of the present invention, which can be combined with the carrier may vary depending on subject to treatment of the individual and the dosage form. However, the specific dose for a particular patient depends on various factors, including age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion and the severity of being treated for a specific disease.

The dose of a compound of the present invention is based on age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion and the severity of the disease in affected patients, as well as other factors. The compound of the present invention does not affect the heart rate and can safely be applied. The daily dose varies depending on the condition and body weight of patients, type of connection, route of administration and like factors. For example, for injecting it subcutaneously, intravenously, intramuscularly, transdermal, Trincomalee, transpulmonary or bronchial, transnasal or re the quarterly dose of about 0.01 to 50 mg/patient/day, for oral administration, it is introduced in a dose of about 0.01 to 150 mg/patient/day.

EXAMPLES

The present invention is explained in more detail below by reference to examples, which should not be construed as limiting.

Reference example 1

Complex tert-butyl ether (2,2-dimethyl-5-formyl-1,3-dioxane-5-yl)carbamino acid

(1-1) Synthesis of compound tert-butyl ether (2,2-dimethyl-5-hydroxymethyl-1,3-dioxane-5-yl)carbamino acid (compound 1-1 Reference example)

Tris(hydroxymethyl)aminomethane hydrochloride (2 g) dissolved in N,N-dimethylformamide (50 ml), add 2,2-dimethoxypropane (7.8 ml) and the monohydrate p-toluensulfonate acid (229 mg) and the mixture is stirred at room temperature for 15 hours in a mixed solution add triethylamine (9.5 ml), methanol (20 ml) and di-tert-butyl dicarbonate (4,17 g) and the mixture is stirred at room temperature for 12 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (3.11 g) as a colourless solid.

1H-NMR (CDCl3) δ (ppm): the 1.44 (3H, s)of 1.46 (12H, s), of 3.73 (2H, d, J=6.4 Hz), 3,80 (2H, d, J=11,6 Hz), a-3.84 (2H, d, J=11,6 Hz), 4,20 (1H, users), 5,32 (1H, users).

(1-2) When ntes complex tert-butyl ether (2,2-dimethyl-5-formyl-1,3-dioxane-5-yl)carbamino acid (compound 1-2 Reference example)

Connection (2,96 g) compounds 1-1 Reference example was dissolved in dimethyl sulfoxide (50 ml), add triethylamine (11 ml) and the complex of sulfur trioxide-pyridine (5.4 g), and the mixture is stirred at room temperature for 2 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue is washed simple diethyl ether to obtain the target product (2.4 g) as colorless powder.

1H-NMR (CDCl3) δ (ppm): 1,46 (15H, s), of 3.96 (2H, d, J=11.7 Hz), 4,07 (2H, d, J=11.7 Hz), 5,54 (1H, users), for 9.64 (1H, s).

Reference example 2

Chloride (4-benzyloxy-3-trifloromethyl)triphenylphosphane

(1-1) Synthesis of complex benzyl ester (4-fluoro-3-triftorperasin acid (compound 2-1 Reference example)

4-fluoro-3-triftorperasin acid (100 g) is dissolved in N,N-dimethylformamide (400 ml), add potassium carbonate (199 g) and benzylbromide (84,0 g) in conditions of ice cooling and the mixture is stirred for 20 min in conditions of ice cooling and at room temperature for 2 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under eigenem pressure to obtain the target product (144 g) as a pale yellow oil.

1H-NMR (CDCl3) δ (ppm): 5,38 (2H, s), 7,27 (1H, t, J=9,3 Hz), 7,35-7,46 (5H, m), of 8.27 (1H, m), 8,35 (1H, DD, J=6,8, 1.8 Hz).

(2-2) Synthesis of complex benzyl ester 4-benzyloxy-3-triftorperasin acid (compound 2-2 Reference example)

Benzyl alcohol (52,0 g) dissolved in N,N-dimethylformamide (300 ml), add sodium hydride (60%, 20.2 g) under ice cooling and the mixture is stirred for 50 minutes under ice cooling. Add a solution of compound 2-1 Reference example (144 g) in N,N-dimethylformamide (400 ml) and the mixture is stirred for 2 hours under ice cooling. To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (198 g of a mixture of mineral oil contained in the sodium hydride) in the form of a pale yellow solid.

1H-NMR (CDCl3) δ (ppm): of 5.26 (2H, s), to 5.35 (2H, s), 7,06 (1H, d, J=8,8 Hz), 7,31 was 7.45 (10H, m), 8,18 (1H, DD, J=8,8, 2.0 Hz), 8,32 (1H, d, J=2.0 Hz).

(2-3) Synthesis of 4-benzyloxy-3-triftormetilfosfinov alcohol (compound 2-3 Reference example)

Connection 2-2 (198 g)obtained in Reference example was dissolved in tetrahydrofuran (1000 ml), added lithium borohydride (15.7 g) and the mixture is heated in a vessel under reflux for 3 hours After a single of the OHL the statement added lithium borohydride (4.0 g) and the mixture is additionally heated in the vessel under reflux for 3 hours The reaction mixture is cooled with ice, add water (500 ml) to extinguish the reaction. The reaction mixture is added to water, and the mixture is neutralized with concentrated chloride-hydrogen acid. The mixture is extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. Admixtures (mineral oil and benzyl alcohol) are removed from the resulting mixture by heating under reduced pressure at 135°C using a vacuum pump. The resulting residue is crystallized from hexane to obtain the target product (99,2 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): of 1.62 (1H, t, J=5.7 Hz), of 4.66 (2H, d, J=5.7 Hz), 5,20 (2H, s), 7,02 (1H, d, J=8.5 Hz), 7,30-7,33 (1H, m), 7,38 (2H, t, J=7.4 Hz), 7,44 (2H, d, J=7,4 Hz), 7,46 (1H, DD, J=8,5, 2.0 Hz), to 7.61 (1H, d, J=2.0 Hz).

(2-4) Synthesis of 4-benzyloxy-3-triftormetilfullerenov (compound 2-4 Reference example)

Compound 2-3 (99,2 g) obtained in the Reference example, dissolved in methyl chloride (900 ml), add triphenylphosphine (102 g) and N-chlorosuccinimide (49,3 g) under ice cooling and the mixture is stirred under ice cooling for 40 min and then at room temperature for 1 h, the Reaction mixture was washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. Add a simple ether (500 m is), deposited first oxide triphenylphosphine removed and the residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=99:1-4:1) to obtain the target product (99,5 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): 4,56 (2H, s), 5,20 (2H, s), 7,01 (1H, d, J=8.6 Hz), 7,31-7,34 (1H, m), 7,39 (2H, t, J=7.4 Hz), the 7.43 (2H, d, J=7,4 Hz), of 7.48 (1H, DD, J=8,6, 2.0 Hz), a 7.62 (1H, d, J=2.0 Hz).

(2-5) Chloride (4-benzyloxy-3-trifloromethyl)triphenylphosphine (compound 2-5 Reference example)

Connection 2-4 (99,0 g)obtained in Reference example 2-4, dissolved in toluene (450 ml), add triphenylphosphine (90,7 g) and the mixture is heated in a vessel under reflux for 8 hours After cooling, the crystals in the reaction mixture is collected by filtration and washed with simple ether to obtain the target compound (132 g) in the form of a white powder. Uterine fluid concentrate, add toluene (200 ml) and the above operation is performed to obtain the target compound (31.0 g). Further, the mother liquor is treated in the same way to obtain the target compound (12.3 g). Total output is 176,

MS (ESI) m/z:527 [M+]

1H-NMR (DMSO-d6) δ (ppm): 5,17 (2H, d, J=15.1 Hz), 5,23 (2H, s), 7,02? 7.04 baby mortality (1H, m), 7,26-7,30 (2H, m), 7,31-7,37 (1H, m), 7,38-7,42 (4H, m), 7,65-of 7.70 (6H, m), 7,72 for 7.78 (6H, m), of 7.90-7,94 (3H, m).

Reference example 3

5-bromo-2-heptyloxybenzoic

(3-1) Synthesis of 5-bromo-2-GateLock is benzonitrile

(compound 3-1 Reference example)

1-heptanol (1.55 g) was dissolved in N,N-interforaminal (24 ml) and add sodium hydride (0,321 g) at room temperature. The mixture is stirred for 1 h, add 5-bromo-2-perbenzoate (2,43 g) and the mixture is additionally stirred for 50 minutes, the Reaction mixture was poured into water, extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. For consumption of starting material, 5-bromo-2-perbenzoate, the reaction is performed again under the same conditions and the residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1-5:1) to obtain the target product (3,10 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.4 Hz), 1,24-of 1.35 (6H, m)to 1.48 (2H, Quint., J=7,2 Hz), of 1.84 (2H, Quint., J=6.4 Hz), Android 4.04 (2H, t, J=6.4 Hz), at 6.84 (1H, d, J=8,8 Hz), to 7.59 (1H, DD, J=8,8, 2.4 Hz), the 7.65 (1H, d, J=2,4 Hz).

Example 1

Hydrochloride of 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol

(1-1) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-hydroxy-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 1-1)

Compound 2-5 (70,3 g) of Reference example was dissolved in tetrahydrofuran (500 ml), add tert-piperonyl potassium (13,0 g) and the mixture is stirred for 1 hour To the mixture is nomu the solution is added dropwise a solution of the compound (15.0 g) of Reference example 1 in tetrahydrofuran (100 ml) under ice cooling and the mixture is stirred for 2 hours under ice cooling. To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue is distilled chromatographia on a column of silica gel (hexane:ethyl acetate=3:1) to obtain a pale yellow oil (31.0 g). The ratio of geometric isomers the obtained compound is (E:Z=1:6).

The pale yellow oil is dissolved in ethyl acetate (200 ml), add 10% palladium-carbon (3.00 g) and the mixture is stirred at room temperature for 7 h in a hydrogen atmosphere. The internal environment of the reaction container is replaced with nitrogen and the solution is filtered, and the filtrate concentrated. The residue is washed simple diisopropyl ether to obtain the target product (22,3 g) as colorless powder.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,91-to 1.98 (2H, m), 2,50-of 2.56 (2H, m), of 3.69 (2H, d, J=11,6 Hz)to 3.89 (2H, d, J=11,6 Hz), 5,02 (1H, users), 5,52 (1H, users), 6,86 (1H, d, J=8,2 Hz), 7,22 (1H, DD, J=8,2) and 1.7 Hz), 7,29 (1H, d, J=1.7 Hz).

(1-2) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-heptyloxy-3-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 1-2)

Compound 1-1 (510 mg) was dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (506 mg) and n-heptylamine (0,235 ml) and the mixture was stirred at 80°C for 2 h For the reaction is Oh mixture is added water and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (640 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), of 1.30 to 1.37 (6H, m), 1,42 of 1.50 (2H, m)of 1.42 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,76-to 1.82 (2H, m), 1.91 a-to 1.98 (2H, m), 2,50-to 2.57 (2H, m), of 3.69 (2H, d, J=11,6 Hz)to 3.89 (2H, d, J=11,6 Hz), of 4.00 (2H, t, J=6.4 Hz), to 4.98 (1H, users), to 6.88 (1H, d, J=8.5 Hz), 7,26-7,29 (1H, m), 7,35 (1H, d, J=1.5 Hz).

(1-3) Synthesis of hydrochloride of 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol (compound 1-3)

Compound 1-2 (640 mg) was dissolved in ethanol (15 ml), add concentrated chloride-hydrogen acid (3 ml) and the mixture was stirred at 80°C for 2 h, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (492 mg) as a white powder.

MS (ESI) m/z:378 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), 1,24-of 1.39 (6H, m), 1,39 of 1.46 (2H, m), 1,68-of 1.78 (4H, m), 2,55-2,62 (2H, m), 3,51 (4H, d, J=5,1 Hz)4,06 (2H, t, J=6.2 Hz), 5,38 (2H, t, J=5,1 Hz), 7,18 (1H, d, J=8,4 Hz), 7,42 was 7.45 (2H, m), 7,76 (3H, users).

Example 2

2-amino-4-(4-heptyloxy-3-triptoreline-2-(phosphorylmethyl)butanol

(2-1) Synthesis of complex benzyl ester [1,1-bis(hydroxymethyl)-3-(4-heptyloxy-3-triptoreline)propyl]carbamino acid (compound 2-1)

Two-layer mixture of compounds 1-3 (90 mg), ethyl acetate (5 ml), saturated aqueous sodium hydrogen carbonate solution (5 ml) and benzyloxycarbonyl (0,129 ml) was stirred at room temperature for 5 hours, the ethyl acetate Layer is separated and the aqueous layer was extracted with ethyl acetate. The separated layer of ethyl acetate and the ethyl acetate layer obtained by extraction, combine, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:3) to obtain the target product (230 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,26-of 1.39 (6H, m), 1.41 to a rate of 1.51 (2H, m), a 1.75 of-1.83 (2H, m), 1,84 is 1.91 (2H, m), 2,45-2,60 (2H, m), 3,03 (2H, users), 3,66-3,71 (2H, m), 3,88-3,93 (2H, m)to 3.99 (2H, t, J=6.3 Hz), 5,09 (2H, s), 5,31 (1H, users), 6,87 (1H, d, J=8.5 Hz), 7,22-7,26 (2H, m), 7,31-to 7.35 (5H, m).

(2-1) Synthesis of complex benzyl ester [1-(dibenzyl)phosphorylmethyl-1-hydroxymethyl-3-(4-heptyloxy-3-triptoreline)propyl]carbamino acid (compound 2-2)

Compound 2-1 (230 mg), complex tetrabenzyl ether pyrophosphoric acid (485 mg), silver oxide (208 mg) and iodide, Tetra-n-hexylamine (433 mg) are added to a mixed solvent of toluene (4 ml), dichloromethane (4 ml) and perftorgeksan (4 ml) and the mixture is stirred at room temperature for 15 hours, the Insoluble material hoteltravel the t and the solvent is evaporated under reduced pressure. The residue is purified preparative HPLC to obtain the desired product (210 mg) as a colourless oil.

MS (ESI) m/z: 772 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.4 Hz), 1,29-of 1.44 (6H, m), 1,45-of 1.53 (2H, m), 1,74-of 1.84 (3H, m), 1.85 to 2,02 (1H, m), 2.49 USD at 2.59 (2H, m)and 3.59 (1H, d, J=11.2 Hz), of 3.69 (1H, d, J=11.2 Hz), was 4.02 (2H, t, J=6.2 Hz), 4,15-4,20 (1H, m), 4.26 deaths-or 4.31 (1H, m), 4,99-5,03 (6H, m), 6,98 (1H, d, J=8.5 Hz), 7,22-7,34 (17H, m).

(2-3) Synthesis of 2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 2-3)

Connection 2-2 (210 mg) was dissolved in methanol (10 ml), add 10% palladium-carbon (100 mg) and the reaction environment of the container is replaced by hydrogen. The mixture is stirred at room temperature for 4 h, the medium of the reaction container is replaced with nitrogen and the reaction mixture is filtered. The filtrate is concentrated to obtain the target product (33,0 mg) as a white powder.

MS (ESI) m/z: 458 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.4 Hz), 1,29-of 1.44 (6H, m), 1,45-of 1.53 (2H, m), 1,74-to 1.82 (2H, m), 1,90 of 1.99 (2H, m), 2,60-of 2.75 (2H, m), 3,70 (2H, users), 3,93-3,99 (2H, m), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8,3 Hz), 7,42-7,46 (2H, m).

Example 3

(S)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol

(3-1) Synthesis of N-[1,1-bis(hydroxymethyl)-3-(4-heptyloxy-3-triptoreline)propyl]ndimethylacetamide (compound 3-1)

To a mixture of compound 1-1 (3.00 g), chloroform (300 ml) and saturated aqueous bicarbonate (300 ml) add CC is just anhydride (1,03 ml) 8 times in 10-minute intervals with stirring. The mixture is stirred for 1.5 h from the end of the addition of acetic anhydride. The organic layer is separated, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (2,96 g) as a white solid.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1.30 and to 1.38 (6H, m)of 1.46 (2H, Quint., J=7,3 Hz), of 1.80 (2H, Quint., J=6.9 Hz), 1,91 is 1.96 (2H, m), 2,02 (3H, s), 2,59-2,63 (2H, m)and 3.59 (2H, users), 3,63 (2H, d, J=11.8 Hz), 3,85 (2H, d, J=10.4 Hz), of 4.00 (2H, t, J=6.5 Hz), of 5.92 (1H, users), of 6.90 (1H, d, J=8.6 Hz), 7,29 (1H, DD, J=2,1, 8.6 Hz), was 7.36 (1H, d, J=2.1 Hz).

(3-2) Synthesis of [2-acetamido-4-(4-heptyloxy-3-triptoreline)-2-hydroxymethyl]butyl acetate (compound 3-2)

To a solution of compound 3-1 (2,96 g) in dichloromethane (70 ml) is added pyridine (0,742 ml) and acetic anhydride (0,734 ml) under ice cooling and the mixture is stirred for 7 h under ice cooling. Add pyridine (0,371 ml) and acetic anhydride (0,367 ml) and the mixture stirred for 1 h under ice cooling and then at room temperature for 14 hours, the Reaction mixture was diluted with dichloromethane (200 ml), washed sequentially with 0,1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue purified, chromatographi the th on a column of silica gel to obtain the target product (1.55 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,28-to 1.38 (6H, m)of 1.46 (2H, Quint., J=7,3 Hz)to 1.79 (2H, Quint., J=7,0 Hz), 1,84-of 1.92 (1H, m), a 2.01 (3H, s)to 2.13 (3H, s), 2,13-2,22 (1H, m), 2,53 (1H, dt, J=5,1, 13.1 Hz), 2,66 (1H, dt, J=4,9, 13,2 Hz), 3.72 points of 3.75 (2H, m)4,00 (2H, t, J=6.4 Hz), 4,16 (1H, d, J=11.5 Hz), to 4.38 (1H, d, J=11.5 Hz), and 4.40 (1H, t, J=6.8 Hz), of 5.82 (1H, users), of 6.90 (1H, d, J=8.6 Hz), 7,28 (1H, DD, J=1,7, 8.6 Hz), 7,35 (1H, d, J=1.7 Hz).

(3-3) Synthesis of 2-acetamido-2-di(tert-butyl)phosphorylmethyl-4-(4-heptyloxy-3-triptoreline)butyl acetate (compound 3-3)

To a solution of compound 3-2 (1.55 g) and 1H-tetrazole (0,282 g) in dichloromethane (50 ml) and acetonitrile (50 ml) is added di-tert-butyldiethanolamine (1,27 ml) under ice cooling and the mixture is stirred for 1.5 hours under ice cooling. Add 1H-tetrazol (0,282 g) and di-tert-butyldiethanolamine (1,27 ml) and the mixture is additionally stirred for 2 hours To the reaction mixture add m-chloroperbenzoic acid (25%water-containing 0,994 g) under ice cooling, and the mixture is stirred for Additional 20 minutes add m-chloroperbenzoic acid (25%water-containing 0,994 g) and the mixture is stirred for 10 minutes, the Reaction mixture was diluted with dichloromethane (100 ml), washed sequentially with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the residue purified XP is matography on a column of silica gel to obtain the target product (1,71 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1.30 and to 1.38 (6H, m), 1,42 of 1.50 (2H,m)of 1.50 (9H, s)and 1.51 (9H, s)to 1.79 (2H, Quint., J=7,0 Hz)to 1.98 (3H, s), 2,02-2,10 (1H, m)2,07 (3H, s), 2,32-to 2.40 (1H, m), 2,50-to 2.65 (2H, m)4,00 (2H, t, J=6.3 Hz), 4.09 to (2H, d, J=8,4 Hz), 4,37 (1H, d, J=11,1 Hz), 4,47 (1H, t, J=11,1 Hz), to 6.67 (1H, users), to 6.88 (1H, d, J=8.6 Hz), 7,28 (1H, DD, J=1.5 and 8.6 Hz), 7,35 (1H, d, J=1.5 Hz).

(3-4) Synthesis of (S)-2-ndimethylacetamide-2-di(tert-butyl)phosphorylmethyl-4-(4-heptyloxy-3-triptoreline)butyl acetate (compound 3-4-1) and (R)-2-ndimethylacetamide-2-di(tert-butyl)phosphorylmethyl-4-(4-heptyloxy-3-triptoreline)butyl acetate (compound 3-4-2)

Compound 3-3 (1.47 g) is separated by HPLC using a CHIRALPAK (registered trademark) AD-H (hexane/ethanol/Diisopropylamine) to obtain both enantiomers in the form of a colorless oil. The first peak with a short retention time was an S shape (0.55 g, the connection 3-4-1) and the second peak with a long retention time was an R shape (0.5 g, the connection 3-4-2).

(3-5) Synthesis of (S)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 3-5)

Connection 3-4-1 (0.55 g) was dissolved in ethanol (15 ml) and chloride-hydrogen acid (3 ml) and the mixture was stirred at 50°C for 3 hours, the Reaction mixture was poured into water (150 ml) and the mixture assert within 7 hours the Precipitated solid is collected by filtration, washed with water and dried to obtain the target product is (0.33 g) as a white powder.

MS (ESI) m/z: 458 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,29-of 1.41 (6H, m), 1,45-of 1.53 (2H, m), 1,74-of 1.81 (2H, m), 1,89 of 1.99 (2H, m), 2,60-of 2.75 (2H, m), 3,70 (2H, users), 3,94-was 4.02 (2H, m), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=and 8.4 Hz), 7,42-7,46 (2H, m).

Example 4

(4-1) Synthesis of (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 4-1)

Connection 3-4-2 (0.65 g) was dissolved in ethanol (15 ml) and chloride-hydrogen acid (3 ml) and the mixture was stirred at 50°C. for 2.5 hours, the Reaction mixture was poured into water (150 ml) and the mixture assert within 4 hours the Precipitated solid is collected by filtration, washed with water and dried to obtain the target product (0.35 g) as a white powder.

MS (ESI) m/z: 458 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,29-of 1.41 (6H, m), 1,45-of 1.53 (2H, m), 1,74-of 1.81 (2H, m), 1,90 for 2.01 (2H, m), 2,61-to 2.74 (2H, m), of 3.69 (1H, d, J=12.0 Hz), 3,70 (1H, d, J=12.0 Hz), 3,93-was 4.02 (2H, m), Android 4.04 (2H,, t, J=6.2 Hz), 7,07 (1H, d, J=8,4 Hz), 7,42-7,46 (2H, m).

Example 5

Hydrochloride of 2-amino-2-[2-(3-cyano-4-heptyloxybiphenyl)ethyl]propane-1,3-diol

(5-1) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(3-cyano-4-heptyloxybiphenyl)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 5-1)

Compound 3-1 (386 mg) of reference example (complex tert-butyl methyl ether of 2,2-dimethyl-5-ethinyl-1,3-dioxane-5-yl)carbamino acid (482 mg)synthesized by a known method (for example, Tetrahedron vol.57 (2001) 6531-6538), 2-dizik hexylphenyl-2',4',6'-triisopropylphenyl (54 mg), dichloride, bis(acetonitrile)palladium(II) (10 mg), cesium carbonate (919 mg) is stirred in a mixed solvent of acetonitrile (15 ml) and tetrahydrofuran (2 ml) at 70°C for 4 h To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under Polygonum pressure. The residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1) to obtain the complex tert-butyl ether [2,2-dimethyl-5-(3-cyano-4-heptyloxybiphenyl)ethinyl-1,3-dioxane-5-yl]carbamino acid as a brown oil (493 mg). The intermediate compound is dissolved in ethyl acetate (5 ml), added Lindlar catalyst (80 mg) and the mixture is stirred overnight in a hydrogen atmosphere. The reaction mixture is filtered and concentrated and the residue is dissolved in ethanol (4 ml), add 10% palladium-carbon (poisoning Ethylenediamine, 40 mg) and the mixture is stirred at room temperature for 2.5 h in an atmosphere of hydrogen. The solution is filtered and the filtrate concentrated to obtain the target product (182 mg).

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=7.2 Hz), of 1.26 to 1.31 (6H, m), of 1.35 to 1.37 (2H, m), USD 1.43 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,78 is 1.86 (2H, m), 1,91 is 1.96 (2H, m), 2.49 USD of $ 2.53 (2H, m), 3,68 (2H, d, J=11,6 Hz), a 3.87 (2H, d, J=11,6 Hz), was 4.02 (2H, t, J=6.4 Hz), 4,99 (1H, users), 6,85 (1H, d, J=8,4 Hz), 7,32 (1H, DD, J=8,4, and 1.6 Hz), 7,33 (1H, m).

(5-2) the Synthesis of the guide is ochloride 2-amino-2-[2-(3-cyano-4-heptyloxybiphenyl)ethyl]propane-1,3-diol (compound 5-2)

Compound 5-1 (255 mg) was dissolved in ethanol (2 ml), add n-toluensulfonate acid (19 mg) and the mixture is stirred at room temperature for 4 hours To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=4:1) to obtain oil. To this oil is added dioxane containing hydrochloride (4 mol/l), and the mixture is stirred at room temperature for 3 hours the Precipitate is collected by filtration and dried to obtain the target product (45 mg) as a white powder.

MS (ESI) m/z: 335 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), of 1.26 to 1.37 (6H, m), 1,38-of 1.44 (2H, m), 1,69-to 1.77 (4H, m), 2,55 at 2.59 (2H, m), 3,50 (4H, d, J=4.4 Hz), 4.09 to (2H, t, J=6.4 Hz), 5,38 (2H, t, J=4.4 Hz), 7,18 (1H, d, J=8,8 Hz), 7,49 (1H, DD, J=8,8, 2.0 Hz), 7,55 (1H, d, J=2.0 Hz), 7,82 (3H, users).

Example 6

2-amino-4-(3-cyano-4-heptyloxybiphenyl)-2-(phosphorylmethyl)butanol

(6-1) Synthesis of compound tert-butyl ester [3-(3-cyano-4-heptyloxybiphenyl)-1-(dibenzyl)phosphorylmethyl-1-hydroxymethylpropane]carbamino acid (compound 6-1)

Compound 5-1 (340 mg) was dissolved in ethanol (3 ml), add n-monohydrate toluensulfonate acid (0.025 g) and see what camping is stirred at room temperature for 6 hours To the reaction mixture, water is added and the mixture is neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated to obtain the acetonide deprived of the protection of the compound (300 mg) as a colorless oil. It's a colorless oil (205 mg) taken and dissolved in a mixed solvent of dichloromethane (2 ml), toluene (2 ml) and perftorgeksan (2 ml), added silver oxide (219 mg)and complex tetrabenzyl ether pyrophosphoric acid (508 mg) and the mixture is stirred at room temperature. After 5 min add iodide, Tetra-n-hexylamine (454 mg) and the mixture is additionally stirred for 5 hours, the Insoluble material is filtered off and the solvent is evaporated. The residue is purified by chromatography on a column of silica gel and preparative HPLC to obtain the target product (81,0 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.4 Hz), 1,31-of 1.36 (6H, m), USD 1.43 (9H, s), 1,64-1,71 (2H, m), 1,79 is 1.86 (2H, m), 1,99 e 2.06 (2H, m), 2,39-2,49 (2H, m), 3,50-3,55 (2H, m), was 4.02 (2H, t, J=6.4 Hz), 4,10 (1H, d, J=7,2 Hz), 4,13 (1H, d, J=7,2 Hz), 5,00 (1H, s), 5,03-5,09 (4H, m), PC 6.82 (1H, d, J=8,4 Hz), 7,26-7,27 (2H, m), 7,32-7,34 (10H, m).

(6-2) the Synthesis of 2-amino-4-(3-cyano-4-heptyloxybiphenyl)-2-(phosphorylmethyl)butanol (compound 6-2)

Compound 6-1 (81,0 mg) dissolved in acetonitrile (2 ml), add sodium iodide (140 mg) and x is altematively (0,12 ml) and the mixture is stirred at room temperature for 4.5 hours Add water and ethyl acetate and the mixture is treated with ultrasound. The obtained solid is collected by filtration. The solid is washed with water and ethyl acetate and dried to obtain the target product (35,0 mg) as pale yellow powder.

MS (ESI) m/z: 415 [M+H]

1H-NMR (CD3OD) δ (ppm): 0,86 (3H, t, J=6.8 Hz), 1.32 to 1.39 in (6H, m), 1,47-of 1.53 (2H, m), 1,79 of-1.83 (2H, m), 1,89-of 1.95 (2H, m), 2,63-to 2.67 (2H, m), 3,68 (2H, d, J=2.0 Hz), of 3.96 (2H, t, J=6.4 Hz), 4,10 (2H, t, J=6.4 Hz), was 7.08 (1H, d, J=9,2 Hz), 7,49-7,51 (2H, m).

Example 7

Hydrochloride of 2-amino-2-[2-(3-cyano-4-octyloxyphenyl)ethyl]propane-1,3-diol

(7-1) Synthesis of 5-bromo-2-octyloxybenzoate (compound 7-1)

Octanol (0,834 mg) dissolved in N,N-dimethylformamide (10 ml) and add sodium hydride (60%, 0,256 g). After stirring for 30 min, add 5-bromo-2-perbenzoate (0,640 g) and the mixture is additionally stirred at 40-50°C for 1 h, the Reaction mixture was poured into water and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure and the residue purified by chromatography on a column of silica gel to obtain the target product (1,042 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), of 1.24 to 1.37 (8H, m), 1,44-is 1.51 (2H, m), 1,80-to 1.87 (2H, m), Android 4.04 (2H, t, J=6.4 Hz), 6,83 (1H, d, J=8,8 Hz), to 7.59 (1H, DD, J=8,8, 2.4 Hz), to 7.64 (1H, d, J=2,4 Hz).

(7-2) the Synthesis of SL is mportant tert-butyl ester {2,2-dimethyl-5-[2-(3-cyano-4-octyloxyphenyl)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 7-2)

Compound 7-1 (0,636 g), complex tert-butyl ester of {2,2-dimethyl-5-ethinyl-1,3-dioxane-5-yl}carbamino acid (0,571 g), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (0,045 g), dichloride, bis(acetonitrile)palladium(II) (0.008 g) and cesium carbonate (0,668 g) is stirred in acetonitrile (10 ml) at 70-80°C for 2 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue cleans chromatography on a column of silica gel to obtain complex tert-butyl ether [2,2-dimethyl-5-(3-cyano-4-octyloxyphenyl)-1,3-dioxane-5-yl]carbamino acid as a brown oil. The oil is dissolved in ethyl acetate (6 ml), add 10% palladium-carbon (containing about 50% water, 0,080 g) and the mixture is stirred at room temperature for 3.5 h in a hydrogen atmosphere. The solution is filtered and the filtrate concentrated to obtain the target product (0,610 g) as pale yellow powder.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), of 1.27 to 1.34 (8H, m), 1.41 to USD 1.43 (2H, m)of 1.42 (3H, s)of 1.43 (3H, s)of 1.46 (9H, s), 1,78-of 1.85 (2H, m), 1,92 is 1.96 (2H, m), 2.49 USD of $ 2.53 (2H, m)to 3.67 (2H, d, J=11,6 Hz), 3,86 (2H, d, J=11,6 Hz), was 4.02 (2H, t, J=6.4 Hz), equal to 4.97 (1H, s), at 6.84 (1H, d, J=8,8 Hz), 7,33 (1H, DD, J=8,8, 2.0 Hz), 7,34 (1H, d, J=2.0 Hz).

(7-3) the Synthesis of the hydrochloride of 2-amino-2-[2-(3-cyano-4-octyloxyphenyl)ethyl]propane-1,3-diol (is soedineniya 7-3)

Compound 7-2 (0,610 g) dissolved in a mixed solvent of ethanol (5 ml) and tetrahydrofuran (2 ml), add monohydrate p-toluensulfonate acid (0,043 g) and the mixture is stirred at room temperature for 3.5 h and then at 50-60°C for 2.5 hours To the reaction mixture is added saturated aqueous sodium bicarbonate and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue cleans chromatography on a column of silica gel to obtain deprived of the protection of the acetal compound of example (6-2) in the form of oil. To the obtained Mac add dioxane containing hydrochloride (4 mol/l, 2 ml), and the mixture is stirred at room temperature for 8 hours the Precipitate is collected by filtration and dried to obtain the target product (145 mg) as a white powder.

MS (ESI) m/z: 349 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), of 1.26 and 1.35 (8H, m), 1,40-of 1.46 (2H, m), 1,69 to 1.76 (4H, m), 2,54-of 2.58 (2H, m), 3,49 (4H, d, J=4.4 Hz), 4.09 to (2H, t, J=6.4 Hz), of 5.39 (2H, users), 7,18 (1H, d, J=8,8 Hz), 7,49 (1H, d, J=8,8 Hz), 7,54 (1H, s), 7,63 (3H, users).

Example 8

2-amino-4-(3-cyano-4-octyloxyphenyl)-2-(phosphorylmethyl)butanol

(8-1) the Synthesis of compound tert-butyl ester [3-(3-cyano-4-octyloxyphenyl)-1-(dibenzyl)phosphorylmethyl-1 - hydroxymethylpropane]carbamino acid (compound 8-1)

Compound 7-2 (208 mg) was dissolved in ethanol (2 ml), add monohydrate p-toluensulfonate acid (73,0 mg) and the mixture was stirred at room temperature for 6.5 hours To the reaction mixture, water is added and the mixture is neutralized with saturated aqueous sodium bicarbonate, extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated and the resulting residue is dissolved in a mixed solvent of dichloromethane (2 ml), toluene (2 ml) and perftorgeksan (2 ml), added silver oxide (197 mg) and complex tetrabenzyl ether pyrophosphoric acid (459 mg) and the mixture is stirred at room temperature. After 5 min add iodide, Tetra-n-hexylamine (410 mg) and the mixture is additionally stirred for 17 hours, the Insoluble material is filtered off and the solvent is evaporated and purified by chromatography on a column of silica gel and preparative HPLC to obtain the target product (106 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), of 1.27 to 1.34 (6H, m), USD 1.43 (9H, s), 1,46-is 1.51 (2H, m), 1,78 is 1.86 (2H, m), 1,79 is 1.86 (2H, m), 2.00 in to 2.06 (2H, m), 2,39 is 2.51 (2H, m), 3,47 of 3.56 (2H, m), 3,90-to 3.92 (1H, m), 3,97-4,06 (4H, m), 4,79 (1H, s), 5,03 is 5.07 (4H, m), at 6.84 (1H, d, J=8.0 Hz), 7,26 (1H, d, J=8.0 Hz), 7,34-to 7.35 (11H, m).

(8-2) the Synthesis of 2-amino-4-(3-cyano-4-octyloxyphenyl)-2-(phosphorylmethyl)butanol (compound 8-2)

Compound 8-1 (104 mg) was dissolved in whom aconitine (2 ml), add sodium iodide (110 mg) and chlorotrimethylsilane (80.0 mg) and the mixture is stirred at room temperature for 3 hours Add water and ethyl acetate and the mixture is treated with ultrasound. The obtained solid is collected by filtration. The solid is washed with water and ethyl acetate, then washed with methanol and dried to obtain the target product (26,0 mg) as a white powder.

MS (ESI) m/z: 429 [M+H]

1H-NMR (CD3OD) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), is 1.31 and 1.35 (8H, m), 1,50-of 1.52 (2H, m), 1,79 of-1.83 (2H, m), 1,89-of 1.92 (2H, m), 2,63-to 2.67 (2H, m), 3,63-to 3.67 (2H, m), 3.95 to of 3.97 (2H, m), 4.09 to (2H, t, J=6.4 Hz), 7,07 (1H, d, J=9,2 Hz), 7,49-to 7.50 (2H, m).

Example 9

Hydrochloride of 2-amino-2-[2-(4-octyloxy-3-triptoreline)ethyl]propane-1,3-diol

(21-1) Synthesis of 4'-methoxy-3'-triftoratsetofenona (compound 9-1)

To a solution of 4'-fluoro-3 triftoratsetofenona (25,0 g) in N,N-dimethylformamide (70 ml) is added sodium methoxide (7,21 g) in terms of cooling with ice and the mixture is stirred for 2 h under ice cooling and then at room temperature for 1 h, the Reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (24.3 g) as a brown solid.

1H-NMR (CDCl3) δ (ppm): at 2.59 (3H, s), 3,99 (H, C)7,06 (1H, d, J=8.7 Hz), 8,14 (1H, DD, J=2,1, to 8.7 Hz), 8,19 (1H, d, J=2.1 Hz).

(9-2) Synthesis of 4'-methoxy-3'-triftormetilfullerenov (compound 9-2)

To a solution of compound 9-1 (24.3 g) in acetic acid (120 ml) add tribromide pyridinium (90%, to 39.6 g) and the mixture was stirred at 50°C for 1 h, the Reaction mixture was added to ice water, extracted with ethyl acetate and the organic layer washed successively with water, 1M aqueous sodium hydroxide solution, saturated ammonium chloride and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to obtain the target product (34,2 g) as a brown solid.

1H-NMR (CDCl3) δ (ppm): 4,01 (3H, s), 4,39 (2H, s), to 7.09 (1H, d, J=8.7 Hz), 8,18 (1H, DD, J=2,2, 8.7 Hz), 8,23 (1H, d, J=1.9 Hz).

(9-3) the Synthesis of complex diethyl ether 2-ndimethylacetamide-2-[2-(4-methoxy-3-triptoreline)-2-oxoethyl]malonic acid (compound 9-3)

To a solution of diethyl-2-acetamidomalonate (20,1 g) in N,N-dimethylformamide (100 ml) is added sodium hydride (60%, 4,07 g) in two portions under conditions of cooling with ice and the mixture is stirred for 30 minutes To the solution is added a solution of compound 9-2 (33,0 g) in N,N-dimethylformamide (50 ml) and the mixture is stirred for 2 hours under ice cooling. The reaction mixture was added to ice water, extracted with ethyl acetate and the organic with the Oh was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain the target product (31.8 g) as a brown oil.

1H-NMR (CDCl3) δ (ppm): a 1.25 (6H, t, J=7,1 Hz)of 1.97 (3H, s), 3,98 (3H, s), 4,22 (2H, s), 4,27 (4H, DQC., J=2,4, 7,1 Hz), 7,05 (1H, d, J=8.7 Hz), to 7.09 (1H, users), 8,13 (1H, DD, J=2,2, 8.7 Hz), to 8.20 (1H, d, J=2.0 Hz).

(9-4) the Synthesis of complex diethyl ether 2-ndimethylacetamide-2-[2-(4-methoxy-3-triptoreline)ethyl]malonic acid (compound 9-4)

To a solution of compound 9-3 (31.5 g) in triperoxonane acid (230 ml) add triethylsilane (116 ml) and the mixture was stirred at 70°C for 13 h, the Reaction mixture was concentrated under reduced pressure, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with an aqueous solution of sodium hydroxide and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain a mixture specified in the connection header and source material in the form of a yellow oil. To a solution of the oil in triperoxonane acid (230 ml) add triethylsilane (116 ml) and the mixture was stirred at 70°C for 12 h, the Reaction mixture was concentrated under reduced pressure, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with an aqueous solution of sodium hydroxide and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. To the obtained residue, add a simple diethyl ether. And the precipitated solid is collected by filtration and dried to obtain the target product (to $ 7.91 g) as a white powder. The mother liquid is concentrated under reduced pressure and the residue purified by chromatography on silica gel to obtain the target product (4,29 g). The total yield is 12.2,

1H-NMR (CDCl3) δ (ppm): a 1.25 (6H, t, J=7.2 Hz), 2,02 (3H, s), 2,44-2,48 (2H, m), 2,62 of 2.68 (2H, m), a 3.87 (3H, s), 4,15-4,27 (4H, m), 6,78 (1H, users), of 6.90 (1H, d, J=8,4 Hz), 7,27 (1H, DD, J=2.0 a, and 8.4 Hz), 7,32 (1H, d, J=2,0 Hz).

(9-5) Synthesis of N-[1,1-bis(hydroxymethyl)-3-(4-methoxy-3-triptoreline)propyl]ndimethylacetamide (connection 9-5)

To a solution of compound 9-4 (12.2 g) in ethanol (200 ml) and water (40 ml) was added calcium chloride (6,46 g) and the mixture is dissolved. To the mixture is added sodium borohydride (4,40 g) in two portions under ice cooling and the mixture is stirred for 3 h under ice cooling and then at room temperature for 20 hours To the reaction mixture add 1M chloride-hydrogen acid (300 ml) under ice cooling and the mixture is concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate magnesium. The solvent is evaporated under reduced pressure to obtain the target product(9.88 g) as a white foam.

1H-NMR (CDCl3) δ (ppm): 1,92 is 1.96 (2H, m), 2,02 (3H, s), 2,60-of 2.64 (2H, m), of 3.57 (2H, users), to 3.64 (2H, userd, J=11,6 Hz), 3,85 (2H, userd, J=11,6 Hz), a 3.87 (3H, s)5,94 (1H, users), 6,92 (1H, d, J=8.5 Hz), 7,32 (1H, DD, J=1,9, 8,5 Hz), 7,37 (1H, d, J=1.9 Hz).

(9-6) Synthesis of compound tert-butyl ether [1,1-bis(hydroxymethyl)-3-(4-hydroxy-3-triptoreline)propyl]carbamino acid (compound 9-6)

To a solution of compound 9-5 (9,70 g) in methylene chloride (90 ml) was added dropwise at -70°C 1M solution (116 ml) tribromide boron in methylene chloride. The mixture is warmed to 0°C for 1 h under stirring and further stirred for 2 hours under ice cooling. To the reaction mixture gradually add methanol (200 ml) under ice cooling and the mixture is concentrated under reduced pressure. To a solution of the obtained residue in ethanol (50 ml) is added concentrated chloride-hydrogen acid (50 ml) and the mixture was stirred at 70°C for 1 h, the Reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue and N,N-diisopropylethylamine (of 12.6 ml) in methanol (80 ml) is added di-tert-BUTYLCARBAMATE (6,94 g) under ice cooling and the mixture is stirred for 2 h under ice cooling and then at room temperature for 4 hours Add a saturated aqueous solution of sodium bicarbonate (500 ml) and the mixture is concentrated under reduced pressure and extracted with ethyl acetate. About the organic layer is washed successively with a saturated aqueous solution of sodium bicarbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain the target product (2.15 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): of 1.46 (9H, s), 1,84-1,89 (2H, m), 2.57 m-2,61 (2H, m), 3,26 (2H, users), 3,66 (2H, DD, J=5,9, and 11.4 Hz), a 3.87 (2H, DD, J=5,2, and 11.4 Hz), 5,04 (1H, users), to 5.58 (1H, users), 6,87 (1H, d, J=8,4 Hz), 7.23 percent (1H, DD, J=1,8, and 8.4 Hz), 7,30 (1H, d, J=1,8 Hz).

(9-7) Synthesis of compound tert-butyl ether [1,1-bis(hydroxymethyl)-3-(4-octyloxy-3-triptoreline)propyl]carbamino acid (compound 9-7)

Connection 9-6 (360 mg) was dissolved in N,N-dimethylformamide (10 ml) (90 ml), add potassium carbonate (263 mg) and 1-bromooctane (0,198 ml) and the mixture was stirred at 80°C for 6 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (490 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), 1,23-of 1.40 (8H, m), 1.41 to a 1.50 (2H, m)of 1.47 (9H, s), a 1.75-to 1.82 (2H, m), 1,83-1,90 (2H, m), 2.57 m-2,62 (2H, m), or 3.28 (2H, users), 3,63-to 3.67 (2H, m), 3,85-are 3.90 (2H, m)4,00 (2H, t, J=6.4 Hz), 5,02 (1H, users), 6,89 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=8,5, 1.9 Hz), was 7.36 (1H, d, J=1.9 Hz).

(9-8) Synthesis of hydrochloride of 2-amino-2-[2-(4-octyloxy-3-triptoreline)ethyl]propane-1,3-diol (compound 9-8)

Connection 9-7 (490 mg) is dissolved is in methylene chloride (5 ml), add dioxane containing hydrochloride (4 mol/l, 5 ml)and the mixture was stirred at room temperature for 12 hours, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (350 mg) as a white powder.

MS (ESI) m/z: 392 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.90 (3H, t, J=6.8 Hz), 1,24-of 1.41 (8H, m), 1,47-of 1.53 (2H, m), 1,75-of 1.81 (2H, m), 1,91-of 1.97 (2H, m), 2,63-2,70 (2H, m), of 3.69 (4H, s), of 4.05 (2H, t, J=6.2 Hz), 7,03 (1H, d, J=8,4 Hz), 7,41 (1H, d, J=8,4 Hz), 7,44 (1H, users).

Example 10

2-Amino-4-(4-octyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol

(10-1) Synthesis of 4-di(tert-butyl)phosphorylmethyl-2-methyl-4-[2-(4-octyloxy-3-triptoreline)ethyl]-2-oxazoline (compound 10-1)

To a solution of compound 9-8 (270 mg) in N,N-dimethylformamide (7 ml) is added N,N-diisopropylethylamine (0,340 ml) and triethylorthoformate (0,121 ml) and the mixture was stirred at 120°C. for 5.5 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 280 mg of a brown oil. To a solution of the brown oil (280 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) is added 1N-tetrazol (88 mg) and di-tert-butyldiethanolamine (0,377 ml) and the mixture is stirred at room temperature for 2 hours the Reaction is actor cooled with ice, add m-chloroperbenzoic acid (a product containing 25% water, 335 mg) and the mixture is stirred at room temperature for 30 minutes To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate=1:3-one acetate) to obtain the target product (190 mg) as a brown oil.

1H-NMR (CDCl3) δ (ppm): of 0.90 (3H, t, J=6.9 Hz), 1,28-of 1.40 (8H, m), 1,47-of 1.52 (2H, m)to 1.48 (9H, s), for 1.49 (9H, s), 1,70-1,90 (4H, m), a 2.01 (3H, s), of 2.51-a 2.71 (2H, m), 3,89-to 3.92 (2H, m), Android 4.04 (2H, t, J=6.2 Hz), 4,17 (1H, d, J=9.0 Hz), 4,32 (1H, d, J=9.0 Hz), 7,05 (1H, d, J=8,4 Hz), of 7.36-7,41 (2H, m).

(10-2) Synthesis of 2-amino-4-(4-octyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 10-2)

The solution 10-1 (190 mg) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 3 hours, the Solvent is concentrated under reduced pressure, to the residue is added methanol (5 ml), simple diethyl ether (5 ml) and propylene oxide (5 ml). The precipitated powder is collected by filtration, washed with ethyl acetate and simple diethyl ether to obtain the target product (137 mg) as a white solid.

MS (ESI) m/z: 472 [M+H]

1 H-NMR (CD3OD) δ (ppm): of 0.90 (3H, t, J=6.4 Hz), 1,25-1,40 (8H, m), 1,45-of 1.53 (2H, m), 1,76 of-1.83 (2H, m), 1.93 and is 2.00 (2H, m), 2,63-to 2.74 (2H, m), 3,70 (2H, users), 3,96-4,00 (2H, m), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8,3 Hz), 7,42-7,46 (2H, m).

Example 11

Hydrochloride of 2-amino-2-[2-(4-hexyloxy-3-triptoreline)ethyl]propane-1,3-diol

(11-1) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-hexyloxy-3-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 11-1)

Compound 1-1 (500 mg) is dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (494 mg) and 1-bromhexin (0,201 ml) and the mixture was stirred at 80°C for 2 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (620 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): of 0.90 (3H, t, J=6.9 Hz), 1.30 and of 1.36 (4H, m), 1.41 to a 1.50 (2H, m), USD 1.43 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,76-of 1.81 (2H, m), 1,91 of 1.99 (2H, m), of 2.51-of 2.56 (2H, m), of 3.69 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), of 4.00 (2H, t, J=6.4 Hz), to 4.98 (1H, users), to 6.88 (1H, d, J=8.5 Hz), 7,26-7,28 (1H, m), 7,35 (1H, d, J=1.6 Hz).

(11-2) the Synthesis of the hydrochloride of 2-amino-2-[2-(4-hexyloxy-3-triptoreline)ethyl]propane-1,3-diol (compound 11-2)

Compound 11-1 (620 mg) was dissolved in ethanol (15 ml), add concentrated chloride-hydrogen acid (2.5 ml) and the mixture is displaced is more at 80°C for 3 hours The reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (465 mg) as a white powder.

MS (ESI) m/z: 364 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.9 Hz), 1.32 to of 1.40 (4H, m), 1,47-of 1.53 (2H, m), 1,73-of 1.81 (2H, m), 1,90 is 1.96 (2H, m), 2,62 of 2.68 (2H, m), 3,68 (4H, d, J=5,1 Hz), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8,4 Hz), 7,41 (1H, DD, J=8,4, 1.9 Hz), was 7.45 (1H, d, J=1.9 Hz).

Example 12

2-amino-4-(4-hexyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol

(12-1) Synthesis of 4-di(tert-butyl)phosphorylmethyl-4-[2-(4-hexyloxy-3-triptoreline)ethyl]-2-methyl-2-oxazoline (compound 12-1)

To a solution of compound 11-2 (380 mg) in N,N-dimethylformamide (10 ml), add N,N-diisopropylethylamine (0,512 ml) and triethylorthoformate (0,180 ml) and the mixture was stirred at 120°C for 12 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 380 mg of a brown oil. To a solution of the brown oil (380 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) is added 1N-tetrazol (133 mg) and di-tert-butyldiethanolamine (0,569 mg) and the mixture is stirred at room temperature for 2 hours the Reaction solution is cooled with ice, add m-chloroperbenzoic acid (a product containing 25% water, 504 mg) and the mixture is stirred at room temperature for 1 h To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:4-one acetate) to obtain the target product (220 mg) as a yellow oil.

1H-NMR (CDCl3) δ (ppm): 0,93 (3H, t, J=6.9 Hz), 1,30-1,40 (4H, m), 1,47-of 1.52 (2H, m)to 1.48 (9H, s), for 1.49 (9H, s), 1,74-of 1.88 (4H, m), a 2.01 (3H, s), of 2.51-2,70 (2H, m), a 3.87-to 3.92 (2H, m), Android 4.04 (2H, t, J=6.2 Hz), 4,18 (1H, d, J=8,9 Hz), 4,32 (1H, d, J=8,9 Hz), 7,05 (1H, d, J=8,4 Hz), 7,37-7,41 (2H, m).

(12-2) Synthesis of 2-amino-4-(4-hexyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 12-2)

Connection 12-1 (220 mg) is dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 3 hours, the Solvent is concentrated under reduced pressure and to the residue is added methanol (5 ml), simple diethyl ether (5 ml) and propylene oxide (5 ml). The precipitated powder is collected by filtration and washed with ethyl acetate and simple diethyl ether to obtain the target product (118 mg) as a white solid.

MS (ESI) m/z: 444 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.9 Hz), 1,31-of 1.40 (4H, m), 1,45-and 1.54 (2H, m), 1,74-to 1.82 (2H, m), 1,92-to 1.98 (2H, m), 2,60-of 2.75 (2H, m), 3,70 (2H, users), 3,93-3,99 (2H, m), 4,0 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8,2 Hz), 7,42-7,46 (2H, m).

Example 13

Hydrochloride of 2-amino-2-(4-heptyloxy-3-triptoreline)-2-methylbutanol

(13-1) Synthesis of compound tert-butyl ether (2-hydroxy-1-hydroxymethyl-1-methyl)ethylcarbamate acid (compound 13-1)

Hydrochloride of 2-amino-2-methyl-1,3-propane diol (14.0 g) was dissolved in methanol (200 ml), add N,N-diisopropylethylamine (46,3 ml) and di-tert-BUTYLCARBAMATE (43,7 g) in terms of cooling with ice and the mixture is stirred for 40 minutes under ice cooling and then at room temperature for 27 hours To the reaction mixture are added 1M aqueous sodium hydroxide solution (100 ml) under conditions of cooling with ice and the mixture is stirred for 40 minutes, the Methanol is evaporated under reduced pressure. Water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (25,3 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): 1,17 (3H, s)of 1.44 (9H, s), of 3.45 (2H, users), 3,62 (2H, DD, J=7,1, 11.3 Hz), of 3.78 (2H, DD, J=5,4, 11.3 Hz), 4,96 (1H, users).

(13-2) the Synthesis of compound tert-butyl methyl ether (1-hydroxymethyl-2-methoxyethoxy-1-methyl)ethylcarbamate acid (compound 13-2)

To a solution of compound 13-1 (25,3 g) in methylene chloride (300 ml) was added when the cooling gap is drop ice N,N-diisopropylethylamine (26,8 ml) and methoxymethane (to 11.6 ml) and the mixture stirred for 20 min under conditions of cooling with ice and then at room temperature for 22 hours To the reaction mixture, water is added and the mixture extracted with methylene chloride. The organic layer is washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting solution was purified by chromatography on silica gel to obtain the target product (14.2 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): 1.26 in (3H, s)of 1.44 (9H, s)to 3.38 (3H, s), 3,57 (1H, d, J=9.7 Hz), 3,61 (1H, DD, J=7,8, and 11.5 Hz), 3,66 (1H, d, J=9.7 Hz), 3,71 (1H, DD, J=5.0 and 11.5 Hz), 3,91 (1H, users), with 4.64 (2H, s), 5,10 (1H, users).

(13-3) Synthesis of compound tert-butyl methyl ether (1-formyl-2-methoxyethoxy-1-methyl)ethylcarbamate acid (compound 13-3)

To a mixed solution of the compound 13-2 (14.2 g) and sodium bromide (5,86 g) in toluene (100 ml) ethyl acetate (100 ml) and water (20 ml) was added 2,2,6,6-tetramethylpiperidine-1-oxyl, free radical (178 mg) in cooling with ice. Then 10% aqueous sodium hypochlorite solution (46,7 g) and a solution of sodium hydrogen carbonate (13.8 g) in water (150 ml) is added dropwise for 1.5 hours Then the solution is stirred for 1.5 hours under ice cooling. The organic layer was separated, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (13.1 g) as pale brown oil.

1H-NMR (CDCl3) δ (ppm): 1,39 3H, C)a 1.45 (9H, s)to 3.34 (3H, in), 3.75 (2H, s), 4,60 (2H, s), of 5.39 (1H, users), of 9.51 (1H, s).

(13-4) the Synthesis of compound tert-butyl ester [3-(4-hydroxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-methyl]propellerbuying acid (compound 13-4)

The compound of Reference example 2-5 (21.8 g) is suspended in tetrahydrofuran (200 ml), add tert-piperonyl potassium (4.35 g) under ice cooling and the mixture is stirred for 1 h a Solution of compound 13-3 (4,80 g) in tetrahydrofuran (40 ml) is added to the mixed solution and the mixture is stirred under ice cooling for 1.5 h and at room temperature for 1 h, the Reaction mixture was poured into water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain complex tert-butyl ester [3-(4-benzyloxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-methyl]allylcarbamate acid (8,45 g) as a colourless oil. The ratio of geometric isomers of the compounds obtained is E:Z=3:7. Palladium carbon (containing about 50% water, 845 mg) are added to a solution of this oil in 1,4-dioxane (150 ml) and the mixture is stirred at room temperature for 24 h in an atmosphere of hydrogen. The reaction mixture is altroot through celite and concentrated to obtain the target product (6,92 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): of 1.34 (3H, s)of 1.45 (9H, s), 1,88-of 1.95 (1H, m), 2.00 in of 2.08 (1H, m), 2,52-2,60 (2H, m)to 3.38 (3H, s), 3,47 (1H, d, J=9.5 Hz), the 3.65 (1H, d, J=9.5 Hz)and 4.65 (2H, s), 4,78 (1H, users), 5,98 (1H, users), 6,85 (1H, d, J=8,4 Hz), 7,18 (1H, DD, J=1,5, and 8.4 Hz), 7,29 (1H, d, J=1.5 Hz).

(13-5) Synthesis of compound tert-butyl ester [3-(4-heptyloxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-methyl]propellerbuying acid (compound 13-5)

To a solution of compound 13-4 (1.5 g) in N,N-dimethylformamide (15 ml) is added potassium carbonate (1,53 g) and n-heptylamine (0.63 ml) and the mixture was stirred at 50°C for 6 hours, the Reaction mixture was added to water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (1,69 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,29-1,49 (6H, m)of 1.34 (3H, s), 1,42 of 1.50 (2H, m)of 1.45 (9H, s)to 1.79 (2H, Quint., J=6.9 Hz), 1,84-of 1.95 (1H, m), 2.00 in of 2.08 (1H, m), 2,54-2,61 (2H, m)to 3.38 (3H, s), 3,49 (1H, d, J=9.5 Hz), to 3.64 (1H, d, J=9.5 Hz), of 4.00 (2H, t, J=6.5 Hz), with 4.64 (2H, s), 4.72 in (1H, users), to 6.88 (1H, d, J=8,5 Hz), 7,27 (1H, DD, J=1,9, 8.5 Hz), 7,35 (1H, d, J=1.9 Hz).

(13-6) Synthesis of hydrochloride of 2-amino-4-(heptyloxy-3-triptoreline)-2-methylbutanol (connection 13-6)

To a solution of compound 13-5 (1,69 g) in ethanol (15 ml) is added concentrated chloride-hydrogen acid (3 ml) and the mixture was stirred at 50°C within 3 hours To the reaction mixture are added 1M aqueous sodium hydroxide solution (50 ml) and brine (50 ml) and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate (50 ml), add a 1M solution of ester hydrochloride (5 ml) and the solvent is evaporated. To the residue add a simple ether, and the precipitated solid is filtered and dried under reduced pressure to obtain the target product (607 mg) as a white powder.

MS (ESI) m/z: 362 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.4 Hz), 1,20 (3H, s), of 1.26 and 1.35 (6H, m), 1,37 was 1.43 (2H, m), 1,67 of-1.83 (4H, m), 2,61 (2H, t, J=8.7 Hz), 3,39 (1H, DD, J=4,6, 11.2 Hz), of 3.46 (1H, DD, J=4,6, 11.2 Hz), of 4.05 (2H, t, J=6,1 Hz), 5,52 (1H, t, J=4.9 Hz), 7,18 (1H, d, J=8.5 Hz), 7,43 was 7.45 (2H, m), 7,89 (3H, users).

Example 14

Complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] ether phosphoric acid

(14-1) the Synthesis of compound tert-butyl ester [3-(4-heptyloxy-3-triptoreline)-1-hydroxymethyl-1-methylpropyl]carbamino acid (compound 14-1)

To a solution of compound 13-6 (841 mg) in methanol (25 ml) is added N,N-diisopropylethylamine (1,10 ml) and di-tert-BUTYLCARBAMATE (692 mg) and the mixture is stirred at room temperature for 24 h, the Reaction mixture was concentrated under reduced pressure is. Add saturated sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the target product (880 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,22 (3H, s), 1,28-of 1.39 (6H, m), 1,44-1,49 (11H, m)to 1.79 (2H, Quint., J=6.9 Hz), 1,83-1,90 (1H, m), 1,99-2,07 (1H, m), 2,50-of 2.58 (1H, m), 2,61 of 2.68 (1H, m), 3,63-and 3.72 (2H, m)4,00 (2H, t, J=6.5 Hz), 4,06 (1H, users), 4,63 (1H, users), 6,89 (1H, d, J=8.5 Hz), 7,28 (1H, DD, J=1,7, 8,5 Hz), was 7.36 (1H, d, J=1.7 Hz).

(14-2) Synthesis of compound tert-butyl ester [1-di(tert-butyl)phosphorylmethyl-3-(4-heptyloxy-3-triptoreline)-1-methylpropyl]carbamino acid (compound 14-2)

To a solution of compound 14-1 (870 mg) in methylene chloride (15 ml) add a solution of 1H-tetrazole (158 mg) and acetonitrile (15 ml). To the mixture is added di-tert-butyldiethanolamine (0,713 ml) at 0°C and the mixture stirred for 1.5 h under conditions of cooling with ice. Add a solution of 1H-tetrazole (158 mg) in acetonitrile (15 ml) and di-tert-butyldiethanolamine (0,713 ml) and the mixture is further stirred for 2 hours under ice cooling. Add m-chloroperbenzoic acid (a product containing 25% of water, 600 mg) and the mixture stirred for 40 min at chilled and ice. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the target product (1.26 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), of 1.28 and 1.35 (6H, m)of 1.35 (3H, s)of 1.43 (9H, s), for 1.49 (18H, s)and 1.51-of 1.53 (2H, m)to 1.79 (2H, Quint., J=6.9 Hz), 1,86-of 1.94 (1H, m), 2,03-2,11 (1H, m), 2,52-2,62 (2H, m), 3,86 (1H, DD, J=5,6, 10,2 Hz), of 4.00 (2H, t, J=6.4 Hz), Android 4.04 (1H, DD, J=5,5, 10,2 Hz), is 4.85 (1H, users), to 6.88 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=a 1.8, 8.5 Hz), 7,35 (1H, d, J=1,8 Hz).

(14-3) the Synthesis of complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol] ether phosphoric acid (compound 14-3)

Connection 14-2 (1.24 g) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid 1 ml) and the mixture was stirred at 50°C for 1 h, the Reaction mixture was added to water (30 ml) and the precipitated powder is collected by filtration and washed with water and simple diethyl ether to obtain the target product (648 mg) as a white solid.

MS (ESI) m/z: 442 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,29-of 1.41 (6H, m)to 1.38 (3H, s), 1,46-of 1.53 (2H, m), 1,75-of 1.81 (2H, m), 1,83-,90 (1H, m), 1,97-2,05 (1H, m), 2,60 of 2.68 (1H, m), 2,70 was 2.76 (1H, m), 3,85 (1H, DD, J=5,4, and 11.4 Hz), of 3.94 (1H, DD, J=5,9, and 11.4 Hz), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8,2 Hz), 7,42-7,44 (2H, m).

Example 15

Hydrochloride (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol

(15-1) Synthesis of 2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol (compound 15-1)

Saturated aqueous sodium hydrogen carbonate solution (100 ml) is added to the compound 13-6 (1,30 g) and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (1,16 g) as a white waxy solid.

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6,7 Hz), a 1.08 (3H, s)of 1.23 and 1.35 (6H, m), 1,38-to 1.45 (2H, m), 1,58-of 1.74 (4H, m), 2,55-to 2.65 (2H, m), or 3.28 (1H, d, J=10,9 Hz), 3,32 (1H, d, J=10,9 Hz), of 4.05 (2H, t, J=6.2 Hz), 5,09 (1H, users), 5,52 (2H, users), 7,16 (1H, d, J=9.0 Hz), 7,41-7,44 (2H, m).

(15-2) Synthesis of (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol (connection 15-2-1) and (S)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol (connection 15-2-2)

Compound 15-1 (2,63 g) separating the superficial liquid chromatography (SFC) using a CHIRALPAK (registered trademark) AD-H (carbon dioxide/ethanol/diethylamine) to obtain both enantiomers in the form of a white waxy solids. The first peak with short durations; is it holding was an R shape (0,91 g, connection 15-2-1) and the second peak with a long retention time was an S shape (0.95 g, the connection 15-2-2).

(15-3) Synthesis of hydrochloride of (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol (connection 15-3)

Connection 15-2-1 (745 mg) is suspended in ethyl acetate (5 ml) and add a solution of 4M hydrochloride in ethyl acetate (2 ml). Next, add hexane (10 ml) and the mixture assert within 1 h the Precipitated solid is collected by filtration to obtain the target product (753 mg) as a white powder.

MS (ESI) m/z: 362 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6,7 Hz), 1,19 (3H, s), 1,25-1,35 (6H, m), 1,37-to 1.45 (2H, m), 1,67 of-1.83 (4H, m)2,60 (2H, t, J=8.7 Hz), 3,41-to 3.49 (2H, m)4,06 (2H, t, J=6.2 Hz), of 5.53 (1H, t, J=5,1 Hz), 7,18 (1H, d, J=8,4 Hz), 7,43 was 7.45 (2H, m), 7,78 (3H, users).

Example 16

Complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (R)-phosphoric acid

(16-1) Synthesis of compound tert-butyl ether (R)-[3-(4-heptyloxy-3-triptoreline)-1-hydroxymethyl-1-methylpropyl]carbamino acid (compound 16-1)

To a solution of compound 15-2-1 (120 mg) in methanol (10 ml) is added N,N-diisopropylethylamine (0,117 ml) and di-tert-BUTYLCARBAMATE (109 mg) and the mixture is stirred at room temperature for 24 hours To the reaction mixture is added saturated sodium bicarbonate and methanol is evaporated under reduced pressure. The obtained OST is OK diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the target product (159 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,22 (3H, s), 1,28-to 1.38 (6H, m), 1,42-1,50 (11H, m)to 1.79 (2H, Quint., J=6.9 Hz), 1,83-1,90 (1H, m), 1,99-2,07 (1H, m), 2,50-of 2.58 (1H, m), 2,61 of 2.68 (1H, m), 3,63-and 3.72 (2H, m)4,00 (2H, t, J=6.4 Hz), a 4.03 (1H, users), to 4.62 (1H, users), 6,89 (1H, d, J=8.5 Hz), 7,28 (1H, DD, J=1,6, 8,5 Hz), was 7.36 (1H, d, J=1.6 Hz).

(16-2) Complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (R)-phosphoric acid (compound 16-2)

To a solution of compound 16-1 (159 mg) in methylene chloride (5 ml) add a solution of acetonitrile (5 ml) in 1H-tetrazole (27.9 mg). To the mixture at 0°C. add di-tert-butyldiethanolamine (0,126 ml) and the mixture stirred for 1 h under ice cooling. Add 1H-tetrazol (27.9 mg) and di-tert-butyldiethanolamine (0,126 ml) and the mixture is further stirred for 1 h under ice cooling. Add 1H-tetrazol (55,8 mg) and di-tert-butyldiethanolamine (0,252 ml) and the mixture is further stirred for 1 h under ice cooling. Add m-chloroperbenzoic acid (a product containing 25% of water, 106 mg) and the mixture is stirred for 20 minutes under ice cooling. Add m-chlorine is perventing acid (product, containing 25% of water, 106 mg) and the mixture is stirred for 30 minutes under ice cooling. To the reaction mixture an aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain a colorless oil (271 mg), mainly containing complex tert-butyl ether (R)-[1-di(tert-butyl)phosphorylmethyl-3-(4-heptyloxy-3-triptoreline)-1-methylpropyl]carbamino acid. The oil is dissolved in ethanol (10 ml), add concentrated chloride-hydrogen acid (3 ml) and the mixture was stirred at 50°C for 3 hours To the reaction mixture are added water (50 ml) and the precipitated powder is collected by filtration and washed with water and simple diethyl ether to obtain the target product (81,9 mg) as a white powder.

MS (ESI) m/z: 442 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,29-of 1.41 (6H, m)to 1.37 (3H, s), 1,45-of 1.53 (2H, m), 1,75-of 1.81 (2H, m), 1,82-1,90 (1H, m), 1,96-2,04 (1H, m), 2,60-to 2.67 (1H, m), 2,69-2,77 (1H, m), 3,85 (1H, DD, J=5,3, 11,4 Hz), of 3.94 (1H, DD, J=5,9, and 11.4 Hz), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8.1 Hz), 7,42-7,44 (2H, m).

Example 17

Hydrochloride (S)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylb is canola

(17-1) Synthesis of hydrochloride of (S)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol (compound 17-1)

Connection 15-2-2 (785 mg) is suspended in ethyl acetate (5 ml) and add a solution of 4M hydrochloride in ethyl acetate (2 ml). Next, add hexane (10 ml) and assert within 1 h the Precipitated solid is collected by filtration to obtain the target product (833 mg) as a white powder.

MS (ESI) m/z: 362 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6,7 Hz)of 1.20 (3H, s), 1,25-1,35 (6H, m), 1,37-to 1.45 (2H, m), 1,67 of-1.83 (4H, m)2,60 (2H, t, J=8.7 Hz), 3,41-to 3.49 (2H, m)4,06 (2H, t, J=6.2 Hz), of 5.53 (1H, t, J=5.0 Hz), 7,18 (1H, d, J=8.5 Hz), 7,44-7,46 (2H, m), to 7.84 (3H, users).

Example 18

Complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (S)-phosphoric acid

(18-1) the Synthesis of compound tert-butyl ether (S)-[3-(4-heptyloxy-3-triptoreline)-1-hydroxymethyl-1-methylpropyl]carbamino acid (compound 18-1)

To a solution of compound 15-2-2 (120 mg) in methanol (10 ml) is added N,N-diisopropylethylamine (0,117 ml) and di-tert-BUTYLCARBAMATE (109 mg) and the mixture is stirred at room temperature for 24 hours To the reaction mixture is added saturated sodium bicarbonate and methanol is evaporated under reduced pressure. The obtained residue was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over betw denim magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the target product (139 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,22 (3H, s), 1,28-to 1.38 (6H, m), 1,42-1,50 (11H, m)to 1.79 (2H, Quint., J=6.9 Hz), 1,83-1,90 (1H, m), 1,99-2,07 (1H, m), of 2.51-of 2.58 (1H, m), 2,61-2,69 (1H, m), 3,63-and 3.72 (2H, m)4,00 (2H, t, J=6.3 Hz), was 4.02 (1H, users), 4,63 (1H, users), 6,89 (1H, d, J=8,4 Hz), 7,28 (1H, DD, J=1,7, 8,4 Hz), was 7.36 (1H, d, J=1.7 Hz).

(18-2) Complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (R)-phosphoric acid

To a solution of compound 18-1 (139 mg) in methylene chloride (5 ml) add a solution of 1H-tetrazole (27.9 mg) in acetonitrile (5 ml). To the mixture is added di-tert-butyldiethanolamine (0,126 ml) at 0°C and the mixture stirred for 1 h under ice cooling. Add 1H-tetrazol (27.9 mg) and di-tert-butyldiethanolamine (0,126 ml) and the mixture is additionally stirred for 40 minutes under ice cooling. Add 1H-tetrazol (55,8 mg) and di-tert-butyldiethanolamine (0,252 ml) and the mixture is additionally stirred for 50 minutes under ice cooling. Add m-chloroperbenzoic acid (a product containing 25% of water, 106 mg) and the mixture is stirred for 20 minutes under ice cooling. Add m-chloroperbenzoic acid (a product containing 25% of water, 106 mg) and the mixture is stirred at those who tell 50 minutes under ice cooling. To the reaction mixture an aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain a colorless oil (260 mg), mainly containing complex tert-butyl ether (S)-[1-di(tert-butyl)phosphorylmethyl-3-(4-heptyloxy-3-triptoreline)-1-methylpropyl]Karabanovo acid. The oil is dissolved in ethanol (10 ml), add concentrated hydrochloric acid (3 CL) and the mixture was stirred at 50°C for 3 hours To the reaction mixture are added water (50 ml) and the precipitated powder is collected by filtration and washed with water and simple diethyl ether to obtain the target product (63,0 mg) as a white powder.

MS (ESI) m/z: 442 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,29-of 1.41 (6H, m)to 1.37 (3H, s), 1,45-of 1.53 (2H, m), 1,75-of 1.81 (2H, m), 1,82-1,90 (1H, m), 1,96-2,04 (1H, m), 2,60 was 2.76 (2H, m), 3,85 (1H, DD, J=5,3, and 11.4 Hz), of 3.94 (1H, DD, J=5,9, and 11.4 Hz), Android 4.04 (2H, t, J=6.2 Hz), 7,07 (1H, d, J=8.1 Hz), 7,42-7,44 (2H, m).

Example 19

Hydrochloride of 2-amino-2-ethyl-4-(4-heptyloxy-3-triptoreline)butanol

(19-1) Synthesis of compound tert-butyl ether [1,1-bis(hydroxymethyl)propyl]carbamino the Oh of the acid (compound 19-1)

To a solution of 2-amino-2-ethyl-1,3-propane diol (22,0 g) in methanol (500 ml) and N,N-diisopropylethylamine (64,3 ml) is added di-tert-BUTYLCARBAMATE (60,5 g) in terms of cooling with ice and the mixture is stirred for 40 minutes under ice cooling and then at room temperature for 16 hours To the reaction mixture are added 1M aqueous sodium hydroxide solution (184 ml) in cooling with ice and the mixture is stirred for 40 minutes, the Methanol is removed under reduced pressure. Water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (41,0 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): of 0.90 (3H, t, J=7.5 Hz), a 1.45 (9H, s)to 1.59 (2H, square, J=7.5 Hz), of 3.45 (2H, users), of 3.60 (2H, DD, J=6,9, and 11.6 Hz), a-3.84 (2H, DD, J=4,8, and 11.6 Hz), 4,89 (1H, users).

(19-2) the Synthesis of compound tert-butyl ester [1-hydroxymethyl-1-(methoxyethoxy)methyl]propellerbuying acid (compound 19-2)

To a solution of compound 19-1 (41,0 g) in methylene chloride (400 ml) is added N,N-diisopropylethylamine (40,7 ml) and methoxymethane (17.6 ml) under ice cooling and the mixture is stirred for 40 min under conditions of cooling with ice and then at room temperature for 4 hours To the reaction mixture, water is added and the mixture extracted with Meiling what oredom. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silica gel to obtain the target product (21,3 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=7.5 Hz), the 1.44 (9H, s), 1,55-of 1.62 (1H, m), 1,75-of 1.84 (1H, m)to 3.38 (3H, s), 3,49 (1H, d, J=9.8 Hz), 3,68 (2H, d, J=6.6 Hz), 3,74 (1H, d, J=9.8 Hz), Android 4.04 (1H, users), 4,63 (2H, s), of 5.05 (1H, users).

(19-3) Synthesis of compound tert-butyl ester [1-formyl-1-(methoxyethoxy)methyl]propellerbuying acid (compound 19-3)

To a mixed solution of the compound 19-2 (21,3 g) and sodium bromide (8,32 g) in toluene (170 ml) ethyl acetate (100 ml) and water (30 ml) was added 2,2,6,6-tetramethylpiperidine-1-oxyl, free radical (253 mg) in cooling with ice. Then, 10% aqueous sodium hypochlorite solution (to 66.3 g) and sodium hydrogen carbonate solution (19.6 g) in water (200 ml) is added dropwise for 1.5 hours Then the mixture is stirred for 1.5 hours under ice cooling, add 10% aqueous solution of sodium hypochlorite (22.1 g) and sodium hydrogen carbonate solution (6,53 g) in water (67 ml) for 30 min and the mixture is further stirred for 30 minutes the Organic layer is divided into parts and diluted with ethyl acetate (200 ml). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated the od reduced pressure to obtain the target product (22,0 g) as pale brown oil.

1H-NMR (CDCl3) δ (ppm): 0,81 (3H, t, J=7.5 Hz), a 1.45 (9H, s), 1,74 of-1.83 (1H, m), 2,04-2,11 (1H, m), of 3.32 (3H, s), 3,81 (1H, d, J=10.0 Hz), a 4.03 (1H, d, J=10.0 Hz), 4,59 (2H, s), lower than the 5.37 (1H, users), 9,39 (1H, s).

(19-4) Synthesis of compound tert-butyl ester [1-ethyl-3-(4-hydroxy-3-triptoreline)-1-(methoxyethoxy)methyl]propellerbuying acid (compound 19-4)

The compound of Reference example 2-5 (26,3 g) is suspended in tetrahydrofuran (120 ml), add tert-piperonyl potassium (5,24 g) under ice cooling and the mixture is stirred for 50 minutes a Solution of compound 19-3 (6,10 g) in tetrahydrofuran (80 ml) is added to the mixed solution and the mixture is stirred for 2 h under ice cooling and at room temperature for 4 h the Reaction mixture was added to brine and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain complex tert-butyl ester [1-ethyl-3-(4-benzyloxy-3-triptoreline)-1-(methoxyethoxy)methyl]allylcarbamate acid (10.3 g) as a colourless oil. The ratio of geometric isomers of the compounds obtained is E:Z=1:2,8. 10% Palladium-carbon (containing about 50% water, 2 g) are added to a solution of this oil in 1,4-dioxane (200 ml) and the mixture re eshivot at room temperature for 9 h in a hydrogen atmosphere. The reaction mixture was filtered through celite and concentrated to obtain the target product (8,67 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=7.5 Hz), a 1.45 (9H, s), 1,65-of 1.74 (1H, m), 1,76 is 1.86 (1H, m), 1.93 and-of 1.97 (2H, m), 2,52-of 2.56 (2H, m), 3,39 (3H, s), 3,57 (1H, d, J=9.7 Hz), 3,63 (1H, d, J=9.7 Hz), with 4.64 (3H, m), 5,85 (1H, users), 6,85 (1H, d, J=8,3 Hz), 7,20 (1H, userd, J=8,3 Hz), 7,29 (1H, d, J=1.4 Hz).

(19-5) Synthesis of compound tert-butyl ester [1-ethyl-3-(4-heptyloxy-3-triptoreline)-1-(methoxyethoxy)methyl]propellerbuying acid (compound 19-5)

To a solution of compound 19-4 (1.5 g) in N,N-dimethylformamide (15 ml) is added potassium carbonate (1.48 g) and n-heptylamine (0,61 ml) and the mixture was stirred at 50°C for 6 hours, the Reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (1,83 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,4 Hz)to 0.89 (3H, t, J=7,6 Hz), 1,28-to 1.38 (6H, m), 1,42-1,49 (11H, m), 1,68-of 1.88 (4H, m), 1,92-of 1.97 (2H, m), 2,52-to 2.57 (2H, m)to 3.38 (3H, s), 3,57 (1H, d, J=9.7 Hz), 3,63 (1H, d, J=9.7 Hz), of 4.00 (2H, t, J=6.4 Hz), 4,60 (1H, users), with 4.64 (2H, s), to 6.88 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=1,6, 8.5 Hz), 7,35 (1H, d, J=1.6 Hz).

(19-6) Synthesis of hydrochloride of 2-amino-2-ethyl-4-(heptyloxy-3-triptoreline)butanol (compound 19-6)

To a solution of compound 19-5 (1,83 g) in ethanol (15 is l) add concentrated chloride-hydrogen acid (3 ml) and the mixture was stirred at 50°C for 4 h To the reaction mixture are added 1M aqueous sodium hydroxide solution (100 ml) and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is dissolved in ethyl acetate (30 ml), add a 1M solution of ester hydrochloride (10 ml) and the solvent is evaporated. To the residue add a simple diethyl ether and hexane, and the precipitated solid is collected by filtration and dried to obtain the target product (1.22 g) as a white powder.

MS (ESI) m/z: 376 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.4 Hz), of 0.90 (3H, t, J=7.4 Hz), 1,25-1,35 (6H, m), 1,37-to 1.45 (2H, m), 1,57-of 1.65 (2H, m), 1,67-to 1.77 (4H, m), 2,56-2,61 (2H, m), 3,43-3,51 (2H, m)4,06 (2H, t, J=6.2 Hz), 5,49 (1H, t, J=5.0 Hz), 7,18 (1H, d, J=9,2 Hz), 7,45-7,46 (2H, m), of 7.90 (3H, users).

Example 20

Complex mono[2-amino-2-ethyl-4-(4-heptyloxy-3-triptoreline)butyl] ether phosphoric acid

(20-1) Synthesis of compound tert-butyl ester [1-ethyl-3-(4-heptyloxy-3-triptoreline)-1-hydroxymethylpropane]carbamino acid (compound 20-1)

To a solution of compound 19-6 (1.04 g) in methanol (25 ml) is added N,N-diisopropylethylamine (1,32 ml) and di-tert-BUTYLCARBAMATE (825 mg) and the mixture is stirred at room temperature for 13 hours, the Reaction mixture was concentrated under reduced pressure, add saturated hydrocarbonate sodium and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel to obtain the target product (1.21 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,8 Hz)of 0.93 (3H, t, J=7.5 Hz), 1,28-of 1.39 (6H, m), 1,42-1,49 (11H, m)of 1.64 (2H, q, J=7.5 Hz), to 1.79 (2H, Quint., J=7,0 Hz), 1,82-of 1.94 (2H, m), 2,46-of 2.54 (1H, m), 2,56-of 2.64 (1H, m), and 3.72 (2H, d, J=6.3 Hz), of 4.00 (2H, t, J=6.5 Hz), 4.09 to (1H, users), of 4.57 (1H, users), 6,89 (1H, d, J=8.5 Hz), 7,28 (1H, DD, J=1,7, 8.5 Hz), 7,35 (1H, d, J=1.7 Hz).

(20-2) Synthesis of compound tert-butyl ester [1-di(tert-butyl)phosphorylmethyl-1-ethyl-3-(4-heptyloxy-3-triptoreline)propyl] carbamino acid (compound 20-2)

To a solution of compound 20-1 (1.20 g) in methylene chloride (15 ml) add a solution of 1H-tetrazole (212 mg) in acetonitrile (15 ml). To this mixture is added di-tert-butyldiethanolamine (0,956 ml) at 0°C and the mixture stirred for 1 h under the conditions cooling with ice. Add a solution of 1H-tetrazole (106 mg) in acetonitrile (15 ml) and di-tert-butyldiethanolamine (0,478 ml) and the mixture is further stirred for 1 h under ice cooling. Add m-chloroperbenzoic acid (a product containing 25% water, 8040 mg) and the mixture is stirred for 50 minutes under ice cooling. To the reaction mixture is added saturated aqueous rest the R of sodium bicarbonate and the mixture extracted with chloroform. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel to obtain the target product (1.56 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), of 0.90 (3H, t, J=7,3 Hz), 1,28-to 1.38 (6H, m), USD 1.43 (9H, s), 1,47-is 1.51 (2H, m), for 1.49 (18H, s), 1.70 to to 1.82 (4H, m), 1,86 is 2.01 (2H, m), 2,53 at 2.59 (2H, m), 3.95 to 4,06 (4H, m), 4,67 (1H, users), to 6.88 (1H, d, J=8.5 Hz), 7,28 (1H, DD, J=1,7, 8.5 Hz), 7,35 (1H, users).

(20-3) the Synthesis of complex mono[2-amino-2-ethyl-4-(4-heptyloxy-3-triptoreline)butyl] ester of phosphoric acid(compound 20-3)

Connection 20-2 (1.55 g) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 1 h To the reaction mixture are added water (50 ml), and the precipitated powder is collected by filtration and washed with water and simple diethyl ether to obtain the target product (907 mg) as a white powder.

MS (ESI) m/z: 456 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6,7 Hz)of 1.03 (3H, t, J=7.5 Hz), 1,30-1,40 (6H, m), for 1.49 (2H, Quint., J=7.5 Hz), 1,73 is 2.01 (6H, m), 2.57 m-to 2.74 (2H, m), 3,88-of 3.96 (2H, m), of 4.05 (2H, t, J=6.2 Hz), was 7.08 (1H, d, J=8,9 Hz), 7,42-7,44 (2H, m).

Example 21

Hydrochloride diethyl-2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]butane-1,4-diol/p>

(21-1) the Synthesis of complex diethyl ether 2-[(tert-butyloxycarbonyl)amino]-2-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]malonic acid (compound 21-1)

Diethyl - (tert-butyloxycarbonyl)aminomalonate (52,3 g) dissolved in tetrahydrofuran (400 ml)is added tert-piperonyl sodium (19.2 g), to the reaction mixture add a solution of 2-(2-bromoethoxy)tetrahydro-2H-Piran (40,4 g) in tetrahydrofuran (100 ml) at 70°C and the mixture is stirred under heating for 10 hours After cooling, the reaction mixture was poured into saturated brine. The mixture is extracted with ethyl acetate and the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel to obtain the target product (50.0 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): of 1.30 (6H, t, J=7,1 Hz)of 1.45 (9H, s), 1,45-1,55 (4H, m), 1,58-of 1.78 (2H, m), 2,60-of 2.64 (2H, m), 3,35-to 3.41 (1H, m), 3.46 in-3,50 (1H, m), of 3.77-a-3.84 (2H, m), 4,12-to 4.28 (4H, m), 4,49-4,51 (1H, m), between 6.08 (1H, users).

(21-2) Synthesis of compound tert-butyl ether 1,1-bis(hydroxymethyl)-3-(tetrahydro-2H-Piran-2-yloxy)propellerbuying acid (compound 21-2)

Connection 21-1 (50.0 g) was dissolved in a mixture of ethanol (530 ml), tetrahydrofuran (130 ml) and water (260 ml). To this solution was added calcium chloride (27.5 g) at 0°C , then added in several portions Borg is dried sodium (18,8 g) and the mixture is stirred at the same temperature for 2 h and then at room temperature for 18 hours The reaction mixture was concentrated under reduced pressure, added to saturated aqueous solution of ammonium chloride (3 l) and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silica gel to obtain the target product (to 21.6 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, s), 1,53-of 1.62 (4H, m), 1,71 of-1.83 (2H, m), 1,95 (1H, DDD, J=15,3, 8,0, 2,8 Hz), 2,02 (1H, DDD, J=15,3, 7,4, 2,8 Hz), 3.46 in-3,59 (4H, m), 3,69-to 3.73 (2H, m), 3,82-3,88 (1H, m), 3,91-of 3.96 (1H, m), 4,13 (2H, users), 4,60-to 4.62 (1H, m), 5,79 (1H, users).

(21-3) Synthesis of compound tert-butyl ester 1-hydroxymethyl-1-(methoxyethoxy)methyl-3-(tetrahydro-2H-Piran-2-yloxy)propellerbuying acid (compound 21-3)

To a solution of compound 21-2 (21,6 g) in methylene chloride (250 ml) is added N,N-diisopropylethylamine (14.7 ml) and methoxymethane (6,37 ml) in cooling with ice and the mixture is stirred for 1.5 h under conditions of cooling with ice and then at room temperature for 17 hours To the reaction mixture, water is added and the mixture extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silicagel is to obtain the target product (being 9.61 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 1.42 (9H, s)and 1.51-of 1.63 (4H, m), 1,68-of 1.93 (3H, m), 2,03-2,10 (1H, m), 3,37 (3H, s), 3,51-of 3.60 (3H, m), 3,69-4,00 (5H, m), 4.26 deaths, of 4.35 (1H, 2×users), br4.61-of 4.66 (3H, m), 5,61, of 5.75 (1H, 2×users).

(21-4) Synthesis of compound tert-butyl ester 1-formyl-1-(methoxyethoxy)methyl-3-(tetrahydro-2H-Piran-2-yloxy)propellerbuying acid (compound 21-4))

To a mixed solution of the compound 21-3 (9,59 g) and sodium bromide (2,72 g) in toluene (50 ml), ethyl acetate (50 ml) and water (9 ml) was added 2,2,6,6-tetramethylpiperidine-1-oxyl, free radical (82,5 mg) in cooling with ice, followed by 10% aqueous sodium hypochlorite solution (21,7 g) and sodium hydrogen carbonate solution (3,19 g) in water (75 ml) is added dropwise within 2 hours the mixture is stirred for 2 h under ice cooling, a 10% aqueous a solution of sodium hypochlorite (10,9 g) and sodium hydrogen carbonate solution (3,19 g) in water (35 ml) is added dropwise over 20 min and the mixture is further stirred for 20 minutes the Organic layer is separated and diluted with ethyl acetate (200 ml), washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (8,54 g) as a brown oil.

1H-NMR (CDCl3) δ (ppm): the 1.44 (9H, s), 1,45-of 1.78 (6H, m), 2,10-to 2.18 (1H, m), 2,35 is 2.46 (1H, m), 3,31, of 3.32 (3H, 2×s), 3,33-to 3.41 (1H, m), 3,47-3,51 (1H, m), 3,67-3,74 (1H, m), of 3.77-a-3.84 (2H, m), 4,05 is 4.13 (1H, m,), 4,43-4,45, 4,56-4,58 (1H, 2×m), 4,58, 4,58 (2H, 2 is (C), 5,72, 5,74 (1H, 2×users), 9,40, 9,44 (1H, 2×s).

(21-5) Synthesis of compound tert-butyl ester 3-(4-benzyloxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]propellerbuying acid (compound 21-5)

The compound of Reference example 2-5 (10,9 g) is suspended in tetrahydrofuran (80 ml), added tert-piperonyl potassium (2.17 g) under ice cooling and the mixture is stirred for 30 minutes a Solution of compound 21-4 (3.50 g) in tetrahydrofuran (25 ml) is added to the mixed solution and the mixture is stirred for 20 minutes under ice cooling and then at room temperature for 5 hours, the Reaction mixture is added to the brine and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel to obtain complex tert-butyl ester 3-(4-benzyloxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]allylcarbamate acid (4,95 g) as a pale yellow oil. The ratio of geometric isomers of the compounds obtained is E:Z=1:3. To a solution of this oil in toluene (200 ml) add chlorotris(triphenylphosphine)rhodium(I) (5.0 g) and the mixture was stirred at 60°C for 19 hours Add chlorotris(Triveni the phosphine)rhodium(I) (2.5 g) and the mixture was stirred at 60°C for 10 h in an atmosphere of hydrogen. The reaction mixture was filtered through celite and concentrated. The resulting residue is purified by chromatography on a column of silica gel to obtain the target product (4,95 g) as a yellow oil.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, s)and 1.51-of 1.64 (4H, m), rate of 1.67 and 1.75 (1H, m), 1,79-of 1.88 (1H, m), 1,92-of 2.28 (4H, m), 2,54-2,62 (2H, m), 3,36, 3,37 (3H, 2×s), 3.46 in-3,59 (2H, m), 3,71-of 3.78 (2H, m), 3,82-a 4.03 (2H, m), 4,60 with 4.64 (3H, m), of 5.15 (2H, s), 5,41, of 5.55 (1H, 2×users), 6,93 (1H, d, J=8.5 Hz), 7,26-to 7.32 (2H, m), of 7.36-7,44 (5H, m).

(21-6) Synthesis of compound tert-butyl ester 3-(4-hydroxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]propellerbuying acid (compound 21-6)

To a solution of compound 21-5 (4.94 g) in 1,4-dioxane (150 ml) is added 10% palladium-carbon (containing about 50% water, 2 g) and the mixture is stirred for 22 h in an atmosphere of hydrogen. The reaction mixture was filtered through celite and concentrated to obtain the target product (4,07 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (9H, s), 1,52-of 1.64 (4H, m), 1,68 is 1.75 (1H, m), 1,79-of 1.88 (1H, m), 1,92-of 2.27 (4H, m), 2,55-2,61 (2H, m), 3,36, 3,37 (3H, 2×s), 3.46 in-of 3.60 (2H, m), 3,71-a 4.03 (4H, m), br4.61-4,63 (3H, m), the 5.45, 5,59 (1H, 2×users), 5,54 (1H, users), 6,85 (1H, d, J=8,4 Hz), 7,21-of 7.23 (1H, m), 7,30 (1H, users).

(21-7) Synthesis of compound tert-butyl ester 3-(4-heptyloxy-3-triptoreline)-1-(methoxyethoxy)methyl-1-[2-(tetrahydro-2H-Piran-2-yloxy)ethyl]propellerbuying acid (compound 21-7)

Connection 21-6 (1.2 g) is dissolved in N,N-dimethylformamide (10 ml) (20 ml), add potassium carbonate (986 mg) and n-heptylamine (0,458 ml) and the mixture was stirred at 80°C for 2.5 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (1,49 g) as a pale yellow oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,25-1,40 (7H, m), 1,40-1,49 (2H, m), USD 1.43 (9H, s), 1,50 by 1.68 (3H, m), 1,69-1,90 (4H, m), 1.91 a is 2.00 (2H, m), 2.00 in of 2.20 (2H, m), 2,56-2,61 (2H, m), 3,36, 3,37 (3H, 2×s), 3,45-of 3.60 (2H, m), 3,71-of 3.96 (4H, m)4,00 (2H, t, J=6.4 Hz), br4.61-4,63 (3H, m), 5.40, is to 5.57 (1H, 2×users), to 6.88 (1H, d, J=8.5 Hz), 7,28 (1H, users), was 7.36 (1H, users).

(21-8) Synthesis of hydrochloride of 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]butane-1,4-diol (compound 21-8)

Connection 21-7 (1,49 g) dissolved in ethanol (20 ml), add concentrated chloride-hydrogen acid (3 ml) and the mixture was stirred at 80°C for 1.5 h, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (915 mg) as a white powder.

MS (ESI) m/z: 392 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), of 1.25 to 1.34 (6H, m), 1,35-1,45 (2H, m), 1,68-of 1.78 (2H, m), 1,79 of-1.83 (4H, m), 2,59-to 2.65 (2H, m), 3,51 (2H, d, J=4.4 Hz), of 3.60 (2H, t, J=6.4 Hz), of 4.05 (2H, t, J=6.2 Hz), the 5.45 (1H, t, J=4,8 Hz), 7,18 (1H, d, J=9,2 Hz), 7,43-7,46 (2H, m), of 7.75 (3H, users).

Example 22

Hydrochloride of 2-amino-4-fluoro-2-[2-(4-what heptyloxy-3-triptoreline)ethyl]butanol

(22-1) Synthesis of 4-(2-foradil)-4-[2-(4-heptyloxy-3-triptoreline)ethyl]-2-methyl-2-oxazoline (compound 22-1)

To a solution of compound 21-8 (830 mg) in N,N-dimethylformamide (20 ml) is added N,N-diisopropylethylamine (1,04 ml) and triethylorthoformate (0,368 ml) and the mixture was stirred at 120°C for 5 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 840 mg of brown oil. To a solution of the brown oil in tetrahydrofuran (30 ml) was added molecular sieves 4Å (8,4 g), p-colorselected (690 mg) and 1M solution of tetrabutylammonium fluoride/tetrahydrofuran (of 5.82 ml) and the mixture is heated at the boiling vessel under reflux for 1 day. The reaction mixture is filtered and to the filtrate add 1M aqueous solution of chloride-hydrogen acid. The mixture is extracted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:2-1:3) to obtain the target product (400 mg) as a brown oil.

1H-NMR (DMSO-d6) δ (ppm): 0,86-of 0.94 (3H, m), 1,25-,40 (6H, m), 1.41 to a rate of 1.51 (2H, m), 1,76-of 1.95 (4H, m), 1,97-of 2.08 (2H, m), a 2.01 (3H, s), 2,50-of 2.66 (2H, m)4,00 (2H, t, J=6.2 Hz), 4,06 (1H, d, J=8,8 Hz), 4,14 (1H, d, J=8,8 Hz), a 4.53 (1H, DD, J=48, and 3.8 Hz)and 4.65 (1H, DD, J=48, and 3.8 Hz), 6.89 in (1H, d, J=8,4 Hz), 7,26 (1H, users), was 7.36 (1H, users).

(22-2) Synthesis of hydrochloride of 2-amino-4-fluoro-2-[2-(4-heptyloxy-3-triptoreline)ethyl]butanol (compound 22-2)

The solution 22-1 (400 mg) is dissolved in ethanol (10 ml), add concentrated chloride-hydrogen acid (2 ml)and the mixture stirred at 70°C. for 4.5 hours, the Reaction mixture was concentrated and the residue is washed simple diisopropyl ether to obtain the target product (360 mg) as a white powder.

MS (ESI) m/z: 394 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6,7 Hz), 1,24-to 1.38 (6H, m), 1,39 of 1.46 (2H, m), 1,68-of 1.78 (2H, m), 1,79 is 1.86 (2H, m), 2,04 (1H, t, J=6.0 Hz), 2,10 (1H, t, J=6.0 Hz), 2,59-of 2.66 (2H, m), 3,53 (2H, d, J=5.0 Hz), 4,06 (2H, t, J=6.2 Hz), br4.61 (1H, dt, J=47, 6,0 Hz), to 4.73 (1H, dt, J=47, 6,0 Hz)to 5.56 (1H, t, J=5.0 Hz), 7,18 (1H, d, J=8,4 Hz), 7,42 was 7.45 (2H, m), of 8.09 (3H, users).

Example 23

Complex mono[2-amino-2-(2-foradil)-4-(4-heptyloxy-3-triptoreline)butyl] ether phosphoric acid

(23-1) the Synthesis of compound tert-butyl ester [1-di(tert-butyl)phosphorylmethyl-1-(2-foradil)-3-(4-heptyloxy-3-triptoreline)propyl]carbamino acid (compound 23-1)

To a solution of compound 22-2 (290 mg) in methanol (15 ml), add triethylamine (0,284 ml) and di-tert-BUTYLCARBAMATE (220 mg) and the mixture was stirred at anatoy temperature for 18 hours Next, add di-tert-BUTYLCARBAMATE (220 mg) and the mixture is stirred at room temperature for 5 hours, the Reaction mixture was concentrated under reduced pressure, to the residue water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 400 mg of pale yellow oil. To a solution of a pale yellow oil (400 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) is added 1N-tetrazol (94 mg) and di-tert-butyldiethanolamine (0,401 ml) and the mixture is stirred at room temperature for 2 hours the Reaction solution is cooled with ice, add a solution of the Dean, containing tert-butylhydroperoxide (5-6M, 0,402 ml), and the mixture is stirred at room temperature for 30 minutes To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:1-1:2) to obtain the target product (530 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,29-of 1.40 (6H, m), 1.41 to a 1.50 (2H, m), USD 1.43 (9H, s), for 1.49 (18H, s), 1,75-of 1.81 (2H, m), 1,90 for 2.01 (2H, m), 2,10-of 2.25 (2H, m), 2,61 (2H, t, J=8,6 the TS) a 4.03 (2H, t, J=6.2 Hz), 4.04 the-4,18 (2H, m), 4,55 (1H, dt, J=47, 5.8 Hz), of 4.66 (1H, dt, J=47, 5.8 Hz), 7,37 (1H, d, J=8,4 Hz), 7,34-7,37 (2H, m).

(23-2) the Synthesis of complex mono[2-amino-2-(2-foradil)-4-(4-heptyloxy-3-triptoreline)butyl] ester of phosphoric acid (compound 23-2)

Connection 23-1 (530 mg) was dissolved in methylene chloride (5 ml) is added dioxane containing hydrochloride (4 mol/l, 2 ml), and the mixture is stirred at room temperature for 3.5 hours, the Solvent is concentrated under reduced pressure and to the residue is added methanol (3 ml), easy-diethyl ether (7 ml) and propylene oxide (7 ml). The precipitated powder is collected by filtration and washed with ethyl acetate and simple diethyl ether to obtain the target product (182 mg) as a white solid.

MS (ESI) m/z: 474 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.4 Hz), 1,29-of 1.44 (6H, m), 1,45-of 1.52 (2H, m), 1,73-to 1.82 (2H, m), 1,92 is 2.10 (2H, m), 2,12-of 2.20 (1H, m), 2.21 are of 2.26 (1H, m), 2,60-and 2.79 (2H, m), 3,99 (2H, d, J=5.6 Hz), of 4.05 (2H, t, J=6.2 Hz), and 4.68 (1H, t, J=5.4 Hz), 4,79-to 4.81 (1H, m), 7,07 (1H, d, J=8,3 Hz), 7,41-7,44 (2H, m).

Example 24

Hydrochloride of 2-amino-2-[2-(4-Reptilia-3-triptoreline)ethyl]propane-1,3-diol

(24-1) Synthesis of compound tert-butyl ether [1,1-bis(hydroxymethyl)-3-(4-Reptilia-3-triptoreline)propyl]carbamino acid (compound 24-1)

To a solution of compound 1-1 (1,00 g) in methylene chloride (30 ml) was added under ice cooling, the triethylamine (0,503 ml), anhydrous t is iformatsionnogo acid (0,607 ml), the mixture is stirred for 1 h under the conditions cooling with ice. To the reaction mixture, water is added and the mixture extracted with methylene chloride, washed with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:2-1:4) to obtain the connection with the remote protection of acetonide-protected triflate (500 mg) of phenolic hydroxyl group in the form of a colorless oil. To a solution of the colorless oil in dioxane (10 ml) add Diisopropylamine (0,377 ml), heptanol (0,204 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (31 mg) and the adduct of Tris(dibenzylideneacetone)palladium(0)-chloroform (27 mg) and the mixture was stirred at 120°C for 4 h To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:2-1:3) to obtain the target product (390 mg) as a pale yellow oil.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), 1,23-to 1.38 (6H, m), 1,39 of 1.50 (2H, m)of 1.46 (9H, s), 1,60 by 1.68 (2H, m), 1,86 is 1.91 (2H, m), 2,61-of 2.66 (2H, m), of 2.92 (2H, t, J=7.4 Hz), 3,20 (2H, users), 3,63-3,68 (2H, m), 3,85-are 3.90 (2H, m), of 5.05 (1H, users), 7,25-7,30 (1H, m), 7,39 (1H, d, J=8.0 G is), was 7.45 (1H, users).

(24-2) Synthesis of hydrochloride of 2-amino-2-[2-(4-Reptilia-3-triptoreline)ethyl]propane-1,3-diol (compound 24-2)

Connection 24-1 (390 mg) was dissolved in methylene chloride (5 ml), add dioxane containing hydrochloride (4 mol/l, 5 ml)and the mixture was stirred at room temperature for 4 h, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain white powder. White powder purified preparative HPLC, to the obtained residue, add a simple ether containing hydrochloride (1 mol/l, 15 ml) to obtain the hydrochloride. The precipitate is collected by filtration and dried to obtain the target product (200 mg) as a white powder.

MS (ESI) m/z: 394 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,84 (3H, t, J=6.8 Hz), between 1.19 to 1.31 (6H, m), 1.32 to to 1.42 (2H, m)and 1.51 is 1.60 (2H, m), 1,75-1,80 (2H, m), 2,63 of 2.68 (2H, m), to 3.02 (2H, t, J=7.2 Hz), 3,52 (4H, d, J=4.0 Hz), are 5.36 (2H, users), 7,47 (1H, d, J=8,4 Hz), 7,56-to 7.59 (2H, m), 7,74 (3H, users).

Example 25

Hydrochloride of 2-amino-2-[2-(4-octylthio-3-triptoreline)ethyl]propane-1,3-diol

The synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-octylthio-3-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 25-1)

To a solution of compound 1-1 (1,00 g) in methylene chloride (30 ml) is added pyridine (0,926 ml)add a solution of anhydrous triftormetilfullerenov acid (to 0.480 ml) in methylene chloride (5 ml) dropwise PR is ice cooling and the mixture is stirred for 2.5 h under conditions of cooling with ice. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=3:1-2:1) to obtain compound (970 mg), where the phenolic hydroxyl group protected triflate, in the form of a white solid. To a solution of the white solid in dioxane (20 ml) add Diisopropylamine (0,631 ml), octanethiol (0,375 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (53 mg) and the adduct of Tris(dibenzylideneacetone)palladium(0)-chloroform (46 mg) and the mixture was stirred at 120°C for 2 days. Next, to the reaction solution add Diisopropylamine (0,631 ml), octanethiol (0,375 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (53 mg) and the adduct of Tris(dibenzylideneacetone)palladium(0)-chloroform (46 mg) and the mixture was stirred at 120°C for 1 day. To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=5:1-2:1) to obtain the target product (910 mg) as a pale yellow TV is Gogo substances.

1H-NMR (CDCl3) δ (ppm): to 0.88 (3H, t, J=6.8 Hz), 1,24-of 1.36 (8H, m), 1,42 of 1.50 (2H, m), USD 1.43 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,60-1,70 (2H, m), 1,96 is 2.00 (2H, m), 2,55-2,60 (2H, m), only 2.91 (2H, t, J=7.4 Hz), of 3.69 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), to 4.98 (1H, users), 7,25-7,29 (1H, m), 7,38 (1H, d, J=8,2 Hz), 7,44 (1H, d, J=1.0 Hz).

(25-2) Synthesis of hydrochloride of 2-amino-2-[2-(4-octylthio-3-triptoreline)ethyl]propane-1,3-diol (compound 25-2)

Connection 25-1 (910 mg) was dissolved in ethanol (20 ml), add concentrated chloride-hydrogen acid (2 ml) and the mixture was stirred at 80°C for 2 h, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (630 mg) as a white powder.

MS (ESI) m/z: 408 [M+H]

1H-NMR (DMSO-d6) δ (ppm): of 0.85 (3H, t, J=6.8 Hz), 1,19-of 1.32 (8H, m), 1,33 was 1.43 (2H, m)and 1.51 is 1.60 (2H, m), 1,76-of 1.81 (2H, m), 2,64-2,69 (2H, m), to 3.02 (2H, t, J=7.2 Hz), 3,52 (4H, d, J=4,8 Hz), 5,38 (2H, t, J=5.0 Hz), 7,47 (1H, d, J=8,3 Hz), 7,56-to 7.59 (2H, m), 7,83 (3H, users).

Example 26

2-amino-4-(4-octylthio-3-triptoreline)-2-(phosphorylmethyl)butanol

(26-1) Synthesis of compound tert-butyl ester [1-hydroxymethyl-3-(4-octylthio-3-triptoreline)-1-(methoxyethoxy)methyl]propellerbuying acid (compound 26-1)

Connection 25-2 (560 mg) was dissolved in methanol (10 ml), add triethylamine (mean HDI of 0.531 ml) and di-tert-BUTYLCARBAMATE (412 mg) and the mixture is stirred at room temperature for 12 h Later, the reaction mixture is added di-tert-BUTYLCARBAMATE (300 mg) and the mixture is stirred at room temperature for 12 hours Water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain a pale yellow oil. To a solution of the oil in methylene chloride (20 ml) is added N,N-diisopropylethylamine (0,285 ml) and methoxymethyl (0,121 ml) under ice cooling and the mixture is stirred for 10 minutes under ice cooling and then at room temperature for 14 hours To the reaction mixture, water is added and the mixture extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain the desired product (290 mg) and compound tert-butyl ether [1,1-bis(hydroxymethyl)-3-(4-octylthio-3-triptoreline)]propellerbuying acid (280 mg), each as a colourless oil. To the extracted above complex solution of tert-butyl methyl ether [1,1-bis(hydroxymethyl)-3-(4-octylthio-3-triptoreline)]propellerbuying acid in methylene chloride (15 ml) is added N,N-diisopropylethylamine (0,129 ml) and methoxymethanol (0,063 ml) under ice cooling and the mixture is stirred for 5 minutes under ice cooling and then at room temperature for 14 hours To the reaction mixture is added water and the mixture extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain the desired product (210 mg) as a colorless oil. The total weight of the target product, including target product, obtained first reaction is 500 mg

1H-NMR (CDCl3) δ (ppm): of 0.87 (3H, t, J=6.8 Hz), 1,25-to 1.38 (8H, m), 1,39-1,49 (2H, m)of 1.45 (9H, s), 1,59 is 1.70 (2H, m), 1.85 to of 1.93 (1H, m), 2,04-2,12 (1H, m), 2,54-of 2.64 (1H, m), 2,66 was 2.76 (1H, m), only 2.91 (2H, t, 7.4 Hz), 3,39 (3H, s), 3,51 (1H, d, J=9.6 Hz), 3,70-with 3.79 (3H, m), of 3.94 (1H, users)and 4.65 (2H, s)to 5.17 (1H, users), 7,27-7,30 (1H, m), 7,39 (1H, d, J=8.1 Hz), was 7.45 (1H, d, J=1.3 Hz).

(26-2) Synthesis of compound tert-butyl ester [1-diethylphosphonoacetate-3-(4-octylthio-3-triptoreline)-1-(methoxyethoxy)methylpropyl]carbamino acid (compound 26-2)

To a solution of compound 26-1 (500 mg) in methylene chloride (3 ml) is added pyridine (2 ml), tetrabromide carbon (334 mg) and trimethylphosphite (0,161 ml) and the mixture is stirred at room temperature for 4.5 hours Then to the reaction mixture add trimethylphosphite (0,080 ml) and the mixture is stirred at room temperature for 2.5 hours To the reaction mixture, water is added and the mixture extracted with chloroform. The organic layer is washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent of viparita the t under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:3-1:4) to obtain the target product (490 mg) as a brown oil.

1H-NMR (CD3OD) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,26-to 1.38 (8H, m), 1,39-is 1.51 (2H, m)of 1.45 (9H, s), 1,55 by 1.68 (2H, m), 1,88-of 1.97 (1H, m), 2.05 is-of 2.16 (1H, m), 2,68 (2H, t, J=8.5 Hz), 2,96 (2H, t, J=7,3 Hz), 3,60 (1H, d, J=9.7 Hz), of 3.69 (1H, d, J=9.7 Hz), of 3.77 (3H, s), of 3.80 (3H, s), 4,14-4,18 (1H, m), 4,30-4,34 (1H, m), with 4.64 (2H, s), 7,37-7,39 (1H, m), 7,49-7,52 (2H, m).

(26-3) Synthesis of 2-amino-4-(4-octylthio-3-triptoreline)-2-(phosphorylmethyl)butanol (compound 26-3)

Connection 26-2 (490 mg) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 2 hours, the Solvent is concentrated under reduced pressure. To a solution of the residue in methylene chloride (7 ml) add trimethylsilylmethyl (0,527 ml) under ice cooling and the mixture is stirred under ice cooling for 1 h, the Solvent is concentrated under reduced pressure to half and add acetonitrile (15 ml). The precipitated powder is collected by filtration, washed with acetonitrile and simple diethyl ether to obtain the target product (245 mg) as a pale yellow solid.

MS (ESI) m/z: 488 [M+H]

1H-NMR (CD3OD) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,24-to 1.38 (8H, m), 1,39 of 1.50 (2H, m), 1.56 to its 1.68 (2H, m), 1,95 for 2.01 (2H, m), 2,68 is 2.80 (2H, m), of 2.97 (2H, t, J=7,3 Hz), 3,71 (2H, users), 3,98-Android 4.04 (2H, m), 7,46 (1H, d,J=8.0 Hz), 7,53 (1H, d, J=8,2 Hz), EUR 7.57 (1H, users).

Example 27

Hydrochloride of 2-amino-2-[2-(4-hexylthio-3-triptoreline)ethyl]propane-1,3-diol

(27-1) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-hexylthio-3-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid (compound 27-1)

To a solution of compound 1-1 (1.0 g) in methylene chloride (30 ml), add pyridine (0,926 ml) under cooling with ice. Added dropwise a solution of anhydrous triftormetilfullerenov acid (to 0.480 ml) in methylene chloride (5 ml) and the mixture was stirred at for 2.5 h under ice cooling. To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with methylene chloride, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=3:1-2:1) to obtain compound (980 mg), where the phenolic hydroxyl group protected triflate, in the form of a white solid. To a solution of the white solid in dioxane (20 ml) add Diisopropylamine (0,638 ml), hexanethiol (0,301 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (53 mg) and the adduct of Tris(dibenzylideneacetone)palladium(0)-chloroform (46 mg) and the mixture was stirred at 120°C for 2 days. Next, to the reaction solution add recipients who are Diisopropylamine (0,631 ml), actantial (0,375 ml), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (53 mg) and the adduct of Tris(dibenzylideneacetone)palladium(0)-chloroform (46 mg) and the mixture was stirred at 120°C for 1 day. To the reaction mixture, water is added and the mixture extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=5:1-3:1) to obtain the complex tert-butyl ester {2,2-dimethyl-5-[2-(4-hexylthio-3-triptoreline)ethyl]-1,3-dioxane-5-yl}carbamino acid as a pale yellow solid. The pale yellow solid obtained above, dissolved in ethanol (15 ml), add concentrated chloride-hydrogen acid (1.5 ml) and the mixture was stirred at 80°C for 2 h, the reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain white solids. White solid purified preparative HPLC, to the obtained residue, add a simple ether containing hydrochloride (1 mol/l, 15 ml) to obtain the hydrochloride. The precipitate is collected by filtration and dried to obtain the target product (132 mg) as a white powder.

MS (ESI) m/z: 380 [M+H]

1H-NMR (DMSO-d6) δ (ppm): of 0.85 (3H, t, J=6.6 Hz), of 1.20 to 1.31 (4H, m), 1,32 was 1.43 (2H, m)and 1.51 is 1.60 (2H, m), 1,75-1,8 (2H, m), 2,63-2,69 (2H, m), 3,03 (2H, t, J=7.2 Hz), 3,52 (4H, d, J=5.0 Hz), 5,41 (2H, t, J=5,1 Hz), 7,47 (1H, d, J=8.7 Hz), EUR 7.57-to 7.59 (2H, m), to 7.84 (3H, users).

Example 28

(E)-2-amino-2-[2-(4-heptyloxy-3-triptoreline)vinyl]propane-1,3-diol

(28-1) Synthesis of 4-heptyloxy-3-triftorperasin acid (compound 28-1)

To a suspension of tert-butoxide potassium (20.7 g) in N,N-dimethylformamide (120 ml) is added n-heptanol (15.6 ml) and the mixture is stirred at room temperature for 30 minutes To the reaction mixture is added dropwise a solution of 4-fluoro-3-triftorperasin acid (16.7 g) in N,N-dimethylformamide (60 ml) at 0°C and the mixture was stirred at 70°C for 1 h, the Reaction mixture is cooled with ice, add water (320 ml) and 6M add-chloride-hydrogen acid (40 ml) at room temperature. The mixture is stirred at room temperature for 30 min and the precipitated crystals are collected by filtration. The crystals are dissolved in ethanol (60 ml) at 70°C., added dropwise water (96 ml) at the same temperature and the mixture is stirred for 30 minutes the Mixture allow to cool to room temperature and stirred for 30 minutes under ice cooling. The precipitated crystals are collected by filtration to obtain the target product (24,1 g) as pale brown crystals.

1H-NMR (CDCl3) δ (ppm): of 0.90 (3H, t, J=6.6 Hz), 1,28-1,49 (8H, m), 1,80-1,90 (2H, m), of 4.13 (2H, t, J=6.3 Hz),? 7.04 baby mortality (1H, d, J=8.7 G is), 8,24 (1H, DD, J=2.1 Hz, 9.0 Hz), with 8.33 (1H, d, J=1,8 Hz).

(28-2) Synthesis of 4-heptyloxy-3-triftormetilfosfinov alcohol (compound 28-2)

To a solution of compound 28-1 (30.0 g) in N,N-dimethylformamide (240 ml) is added dropwise a solution of bis(2-methoxyethoxy)aluminum hydride/solution canola (65 wt.%) (20,0 g) in toluene (80 ml) at 0°C under nitrogen atmosphere and a solution of bis(2-methoxyethoxy)aluminum hydride/rostvertolavia (65 wt.%) a (80.0 g) in toluene (80 ml). The mixture is stirred at room temperature for 2 h and cooled with ice. 5N Aqueous sodium hydroxide solution (200 ml) is added dropwise and the resulting mixture was stirred at room temperature for 30 minutes. The organic layer is separated and extracted, washed with 5N aqueous solution of sodium hydroxide (100 ml) and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (28, 3 g) as white crystals.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.6 Hz), 1,26-of 1.56 (8H, m), of 1.65 (1H, t, J=5.7 Hz), 1,77-of 1.85 (2H, m), Android 4.04 (2H, t, J=6.3 Hz)and 4.65 (2H, d, J=5.7 Hz), 6,97 (1H, d, J=8,4 Hz), 7,47 (1H, DD, J=1.5 Hz, 8,4 Hz), EUR 7.57 (1H, d, J=1,8 Hz).

(28-3) Synthesis of 4-heptyloxy-3-triftormetilfullerenov (connection 28-3)

To a solution of compound 28-2 (26,8 g) in methylene chloride (107 ml) add a few drops of N,N-dimethylformamide and added dropwise thionyl chloride (8,09 ml) at 0°C. the Mixture is stirred at t the th same temperature for 2 h and the reaction mixture are added water (50 ml). The organic layer is separated and extracted, washed with water (50 ml) and saturated aqueous hidrocarbonetos sodium (70 ml) and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (28,3 g) as white crystals.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.5 Hz), 1.26 in-and 1.54 (8H, m), 1.77 in-to 1.86 (2H, m), Android 4.04 (2H, t, J=6.4 Hz), 4,56 (2H, s), of 6.96 (1H, d, J=8.6 Hz), 7,49 (1H, DD, J=2.0 Hz, 8.5 Hz), 7,58 (1H, d, J=1.9 Hz).

(28-4) Synthesis of diethyl-(4-heptyloxy-3-trifloromethyl)phosphonate (compound 28-4)

A solution of compound 28-3 cases (27.3 g) in triethylphosphite (29.3 g) is heated in a vessel under reflux for 4 h in nitrogen atmosphere. Triethylphosphite is evaporated under reduced pressure to obtain the target product (36,1 g) as a pale yellow oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.6 Hz), 1,23-1,54 (14H, m), 1.77 in-to 1.86 (2H, m), 3,10 (2H, d, J=21,3 Hz), 3,98-4,08 (4H, m), 6,93 (1H, d, J=8,4 Hz), 7,42 (1H, DD, J=2,4 Hz and 8.4 Hz), was 7.45 (1H, d, J=2.1 Hz).

(28-5) Synthesis of compound tert-butyl ether (E)-{2,2-dimethyl-5-[2-(4-heptyloxy-3-triptoreline)vinyl]-1,3-dioxane-5-yl}carbamino acid (compound 28-5)

To a solution of tert-butoxide potassium (24,9 g) in tetrahydrofuran (177 ml) dropwise under conditions of cooling with ice add a solution of Reference example 1-2 (28.8 g) and the connection 28-4 (35.1 g) in tetrahydrofuran (203 ml) and the mixture was stirred at 0°C for 5 h To the reaction mixture add heptane (203 ml) and then water (203 ml). The organic layer is separated and extracted, washed with water and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue is suspended in hexane (50 ml) and collected by filtration to obtain the target product (32,6 g) as white crystals.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.6 Hz), 1.30 and 1.57 in (8H, m)of 1.44 (9H, s)of 1.47 (3H, s), for 1.49 (3H, s), 1,76-of 1.84 (2H, m), 3,90 (2H, d, J=11.4 in Hz)of 3.94 (2H, d, J=13,8 Hz), a 4.03 (2H, t, J=6.3 Hz), to 5.21 (1H, users), 6,10 (1H, d, J=16.5 Hz), 6.48 in (1H, d, J=16.5 Hz), 6,91 (1H, d, J=8,4 Hz), 7,43-7,46 (1H, m), 7,55 (1H, d, J=1,8 Hz).

(28-6) Synthesis of hydrochloride of (E)-2-amino-2-[2-(4-heptyloxy-3-triptoreline)vinyl]propane-1,3-diol (compound 28-6)

Connection 28-5 (500 mg) is dissolved in ethanol (15 ml), add concentrated chloride-hydrogen acid (1.5 ml) and the mixture was stirred at 80°C for 1.5 h, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (330 mg) as a white powder.

MS (ESI) m/z: 359

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), 1,25-of 1.39 (6H, m), 1,40-of 1.46 (2H, m), 1,69-to 1.77 (2H, m), 3,59-to 3.67 (4H, m), 4,11 (2H, t, J=6.2 Hz), of 5.48 (2H, t, J=5.3 Hz), 6,24 (1H, d, J=16,8 Hz), of 6.71 (1H, d, J=16,8 Hz), 7,27 (1H, d, J=9.3 Hz), 7,25-7,28 (2H, m), 8,12 (3H, users).

Example 29

(E)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)-3-butene-1-ol

(29-1) Synthesis of (E)-{4-di(tert-butyl)phosphorylmethyl-2-methyl-4-[2-(4-GE is tilox-3-triptoreline)ethynyl]-2-oxazoline} (compound 29-1)

To a solution of compound 28-6 (280 mg) in N,N-dimethylformamide (10 ml), add N,N-diisopropylethylamine (0,366 ml) and triethylorthoformate (0,129 ml) and the mixture was stirred at 120°C for 5 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 270 mg of a brown oil. To a solution of the brown oil (270 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) is added 1N-tetrazol (95 mg) and di-tert-butyldiethanolamine (0,407 ml) and the mixture is stirred at room temperature for 2 hours the Reaction solution is cooled with ice, add a solution of the Dean, containing t-butylhydroperoxide (5-6M, 0,408 ml), and the mixture is stirred at room temperature for 30 minutes To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution, and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (gascan:ethyl acetate=1:3-one acetate) to obtain the target product (200 mg) as a yellow oil.

1H-NMR (CD3OD) δ (ppm): of 0.90 (3H, t, J=6.9 Hz), 1,29-of 1.45 (6H, m), 1,47-of 1.53 (2H, m), for 1.49 (9H, s)of 1.50 (9H, s), a 1.75 of-1.83 (2H, m), is 2.05 (3H, s), 3,94-3,98 1H, m)4,00-of 4.05 (1H, m), 4,08 (2H, t, J=6.2 Hz), 4,23 (1H, d, J=8.7 Hz), 4,50 (1H, d, J=8.7 Hz), 6,30 (1H, d, J=16.2 Hz), only 6.64 (1H, d, J=16.2 Hz), 7,11 (1H, d, J=8,4 Hz), to 7.59 to 7.62 (2H, m).

(29-2) (E)-[2-amino-(4-heptyloxy-3-triptoreline)-2-phosphorylmethyl)-3-butene-1-ol} (compound 29-2)

Connection 29-1 (200 mg) is dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 3 hours, the Solvent is concentrated under reduced pressure and to the residue is added methanol (3 ml), simple diethyl ether (3 ml) and propylene oxide (5 ml). The precipitated powder is collected by filtration and washed with ethyl acetate and simple diethyl ether to obtain the target product (45 mg) as a white solid.

MS (ESI) m/z: 456 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.9 Hz), of 1.27 to 1.47 (6H, m), 1,45-and 1.54 (2H, m), 1,76 of-1.83 (2H, m in), 3.75 (1H, d, J=11,6 Hz), 3,83 (1H, d, J=11,6 Hz), 3,98-Android 4.04 (1H, m), 4,07-to 4.15 (1H, m), 4.09 to (2H, t, J=6.3 Hz), to 6.22 (1H, d, J=16,7 Hz), 6,76 (1H, d, J=16,7 Hz), 7,14 (1H, d, J=9.3 Hz), 7,65-to 7.67 (2H, m).

Example 30

Hydrochloride of 2-amino-2-[2-(3-deformity-4-heptyloxybiphenyl)ethyl]propane-1,3-diol

(30-1) Synthesis of 2-benzyloxy-5-bromobenzaldehyde (compound 30-1)

To a suspension of 5-bromosalicylaldehyde (25,0 g) and potassium carbonate (51,4 g) in N,N-dimethylformamide (250 ml) add benzylbromide (15,4 ml) in cooling with ice and the mixture is stirred for 40 minutes under ice cooling and then at room the Oh temperature for 15 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract is washed successively 0,1M aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue is suspended in hexane (200 ml) and collected by filtration to obtain the target product (32,7 g) as pale yellow powder.

1H-NMR (CDCl3) δ (ppm): 5,19 (2H, s), to 6.95 (1H, d, J=8,8 Hz), 7,34-the 7.43 (5H, m), to 7.61 (1H, DD, J=2,8, 8,8 Hz), 7,95 (1H, d, J=2,8 Hz), 10,46 (1H, s).

(30-2) Synthesis of 1-benzyloxy-4-bromo-2-deformational (connection 30-2)

To a solution of compound 30-1 (2.70 g) in methylene chloride (5 ml) add a solution TRIFLUORIDE (diethylamino)sulfur (DAST, 1.66 g) in methylene chloride (5 ml) and the mixture is stirred at room temperature for 21 hours To the reaction mixture, water is added and the mixture extracted with methylene chloride. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on silica gel to obtain the target product (2.16 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): 5,11 (2H, s)6,86 (1H, d, J=9.1 Hz), to 6.95 (1H, t, J=55,3 Hz), 7,33-7,42 (5H, m), 7,49 (1H, DD, J=1,6, or 9.8 Hz), 7,69 (1H, d, J=1.9 Hz).

(30-3) Synthesis of compound tert-butyl ester {5-[(4-benzyloxy-3-d is formationl)ethinyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamino acid (compound 30-3)

Connection 30-2 (9,48 g), complex tert-butyl ether (2,2-dimethyl-5-ethinyl-1,3-dioxane-5-yl)carbamino acid (7,34 g)synthesized by a known method (for example, Tetrahedron vol.57 (2001) 6531-6538), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (868 mg), dichloride, bis(acetonitrile)palladium(II) (157 mg) and cesium carbonate (25.6 g) in acetonitrile (200 ml) was stirred at 80°C within 8 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue cleans chromatography on a column of silica gel to obtain the target product (11.1 g) as a pale brown oil.

1H-NMR (CDCl3) δ (ppm): 1,45 (3H, s)to 1.48 (9H, s)of 1.50 (3H, s), a 4.03 (2H, d, J=11.2 Hz), 4,10 (2H, d, J=11.2 Hz), 5,13 (2H, s), 5,20 (1H, users), 6,91 (1H, d, J=8.6 Hz), 6,94 (1H, t, J=55,4 Hz), 7,33-7,40 (5H, m), 7,46 (1H, d, J=8.6 Hz), the 7.65 (1H, s).

(30-4) Synthesis of compound tert-butyl ester {5-[2-(3-deformity-4-hydroxyphenyl)ethyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamino acid (compound 30-4)

Connection 30-3 (11.1 g) was dissolved in 1,4-dioxane (250 ml) is added 10% palladium-carbon (3.5 g) and the mixture is stirred at room temperature for 3.5 h in a hydrogen atmosphere. The internal atmosphere of the reaction container is replaced with nitrogen, the solution is filtered and the filtrate concentrated. The remainder of the su is ponderous in the mixed solution is simple diisopropyl ether and hexane and collected by filtration to obtain the target product (8,17 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): USD 1.43 (3H, s)of 1.44 (3H, s)to 1.48 (9H, s), 1,92 is 1.96 (2H, m), 2,50-of 2.54 (2H, m), of 3.69 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), to 5.03 (1H, users), to 5.57 (1H, users), 6,77 (1H, d, J=8,4 Hz), at 6.84 (1H, t, J=55,5 Hz), 7,12 (1H, d, J=8,4 Hz), 7.23 percent (1H, s).

(30-5) Synthesis of hydrochloride of 2-amino-2-[2-(3-deformational-4-heptyloxybiphenyl)ethyl]propane-1,3-diol (compound 30-5)

Connection 30-4 (500 mg) is dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (516 mg) and n-heptylamine (0,240 ml) and the mixture is stirred at room temperature for 15 hours, the reaction mixture was added water, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 620 mg of a colorless oil. The colorless oil was dissolved in ethanol (15 ml), add concentrated chloride-hydrogen acid (1.5 ml) and the mixture was stirred at 80°C for 1 h, the Reaction mixture was concentrated. And the residue is washed simple diethyl ether to obtain white powder. White powder purified preparative HPLC, to the obtained residue, add a simple ether containing hydrogen chloride (1 mol/l, 15 ml) to obtain the hydrochloride. The precipitate is collected by filtration and dried to obtain the target product (160 mg) as a white powder.

MS (ESI) m/z: 360 [M+H]

1H-NMR (DMSO-d6) δ (ppm):of 0.87 (3H, t, J=6.8 Hz), 1,25-of 1.37 (6H, m), 1,38-to 1.45 (2H, m), 1,68-to 1.79 (4H, m), 2,56-2,62 (2H, m), 3,52 (4H, d, J=4.0 Hz), was 4.02 (2H, t, J=6.4 Hz), of 5.40 (2H, t, J=4.5 Hz), 7,05 (1H, t, J=55,4 Hz), 7,07 (1H, d, J=8.6 Hz), 7,32 (1H, d, J=8.6 Hz), was 7.36 (1H, s), 7,80 (3H, users).

Example 31

2-Amino-4-(3-deformity-4-heptyloxybiphenyl)-2-(phosphorylmethyl)butanol

(31-1) Synthesis of 4-di(tert-butyl)phosphorylmethyl-2-methyl-4-[2-(3-deformity-4-heptyloxybiphenyl)ethyl]-2-oxazoline (connection 31-1)

To a solution of compound 30-5 (115 mg) in N,N-dimethylformamide (5 ml) is added N,N-diisopropylethylamine (0,156 ml) and triethylorthoformate (by 0.055 ml) and the mixture was stirred at 120°C for 12,5 hours To the reaction mixture is added N,N-diisopropylethylamine (0,156 ml) and again triethylorthoformate (by 0.055 ml) and the mixture was stirred at 120°C. for 3.5 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 140 mg of brown oil. To a solution of the brown oil (140 mg) in methylene chloride (3 ml) and acetonitrile (1 ml) is added 1N-tetrazol (41 mg) and di-tert-diethylphosphoramidite (0,174 ml) and the mixture is stirred at room temperature for 2 hours the Reaction solution is cooled with ice, add a solution of the Dean, containing tert-butyl hydroperoxide (5-6M, 0,174 ml)and the mixture was stirred at room temp is the temperature for 20 minutes To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate=1:4-one acetate) to obtain the target product (110 mg) as a brown oil.

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6,7 Hz), 1.30 and of 1.42 (6H, m), USD 1.43-of 1.53 (2H, m)to 1.48 (18H, 2×s), 1,70-1,90 (4H, m), a 2.01 (3H, s), of 2.51-2,69 (2H, m), a 3.87-to 3.92 (2H, m), was 4.02 (2H, t, J=6.4 Hz), 4,17 (1H, d, J=9.0 Hz), 4,32 (1H, d, J=9.0 Hz), 6,91 (1H, t, J=55,8 Hz), 6,97 (1H, d, J=8.5 Hz), 7,29 (1H, d, J=8.5 Hz), was 7.36 (1H, s).

(31-2) Synthesis of 2-amino-4-(3-deformity-4-heptyloxybiphenyl)-2-(phosphorylmethyl)butanol (compound 31-2)

Connection 31-1 (110 mg) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C for 4 h, the Solvent is concentrated under reduced pressure, to the residue is added methanol (1 ml), easy-diethyl ether (1 ml) and propylene oxide (2 ml). The precipitated powder is collected by filtration and washed with ethyl acetate and simple diethyl ether to obtain the target product (60 mg) as a pale yellow solid.

MS (ESI) m/z: 440 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.8 Hz), 1,26 was 1.43 (6H, m), 1,44-of 1.52 (2H, m), 1,74-to 1.82 (2H, m), 1,92 is 2.00 (2H, m), 2,59-a 2.71 (2H, m), 3,70 (2, users), 3,91-Android 4.04 (4H, m), 6,92 (1H, t, J=55,8 Hz), 6,98 (1H, d, J=8.5 Hz), 7,33 (1H, d, J=8,3 Hz), 7,40 (1H, users).

Example 32

Hydrochloride of 2-amino-2-[2-(3-deformity-4-octyloxyphenyl)ethyl]propane-1,3-diol

(32-1) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(3-deformity-4-octyloxyphenyl)ethyl]-1,3-dioxane-5-yl} carbamino acid (compound 32-1)

Connection 30-4 (600 mg) is dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (412 mg) and 1-bromooctane (0,311 ml) and the mixture is stirred at room temperature for 2 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure and the resulting residue purified by chromatography on a column of silica gel (hexane:ethyl acetate=50:1 -3:1) to obtain the target product (230 mg) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,25-1,49 (8H, m), of 1.40-1.50 (2H, m)of 1.42 (3H, s)of 1.44 (3H, s)of 1.47 (9H, s), 1,75-of 1.81 (2H, m), 1.91 a-to 1.98 (2H, m), 2,50-to 2.57 (2H, m), 3,68 (2H, d, J=11.8 Hz), with 3.89 (2H, d, J=11.7 Hz), of 3.97 (2H, t, J=6.4 Hz), to 4.98 (1H, users), PC 6.82 (1H, d, J=8,4 Hz), 6,93 (1H, t, J=55,8 Hz), 7,21 (1H, d, J=8.0 Hz), 7,35 (1H, users).

(32-2) Synthesis of hydrochloride of 2-amino-2-[2-(3-deformity-4-octyloxyphenyl)ethyl]propane-1,3-diol (compound 32-2)

Connection 32-1 (230 mg) was dissolved in ethanol (10 ml), add koncentrirane the percent chloride-hydrogen acid (1 ml) and the mixture was stirred at 80°C for 2 hours The reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain the target product (105 mg) as a white powder.

MS (ESI) m/z: 374 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), 1,24-to 1.38 (8H, m), 1,39-of 1.44 (2H, m), 1,68 and 1.80 (4H, m), 2,55-2,62 (2H, m), 3,52 (4H, d, J=4.6 Hz), to 4.01 (2H, t, J=6.4 Hz), of 5.39 (2H, brt, J=4,8 Hz), 7,05 (1H, t, J=55,4 Hz), 7,07 (1H, d, J=8.5 Hz), 7,32 (1H, d, J=8.5 Hz), was 7.36 (1H, s), 7,79 (3H, users).

Example 33

2-amino-4-(3-deformity-4-octyloxyphenyl)-2-(phosphorylmethyl)butanol

(33-1) Synthesis of 4-di(tert-butyl)phosphorylmethyl-2-methyl-4-[2-(3-deformity-4-octyloxyphenyl)ethyl]-2-oxazoline (connection 33-1)

To a solution of compound 32-2 (226 mg) in N,N-dimethylformamide (10 ml) is added N,N-diisopropylethylamine (0,296 ml) and triethylorthoformate (0,139 ml) and the mixture was stirred at 120°C for 2.5 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 220 mg of a brown oil. To a solution of the brown oil (220 mg) in methylene chloride (5 ml) and acetonitrile (2 ml) is added 1N-tetrazol (77 mg) and di-tert-butyldiethanolamine (0,329 ml) and the mixture is stirred at room temperature for 2 hours the Reaction solution is cooled with ice, add a solution of the Dean, containing Gidropark the ID of tert-butyl (5-6M, 0,330 ml), and the mixture is stirred at room temperature for 20 minutes To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on a column of silica gel (hexane:ethyl acetate=1:4-one acetate) to obtain the target product (280 mg) as a yellow oil.

1H-NMR (CD3OD) δ (ppm): of 0.90 (3H, t, J=7.0 Hz), 1,28-of 1.41 (8H, m), 1,45-of 1.52 (2H, m)to 1.48 (18H, 2× s), a 1.75-1,90 (4H, m), a 2.01 (3H, s), of 2.51-2,70 (2H, m), a 3.87-to 3.92 (2H, m), was 4.02 (2H, t, J=6.3 Hz), 4,17 (1H, d, J=9.0 Hz), 4,32 (1H, d, J=9.0 Hz), 6,92 (1H, t, J=55.7 Hz), 6,97 (1H, d, J=8,4 Hz), 7,29 (1H, d, J=8,9 Hz), was 7.36 (1H, users).

(33-2) Synthesis of 2-amino-4-(3-deformity-4-octyloxyphenyl)-2-(phosphorylmethyl)butanol (compound 33-2)

Connection 33-1 (280 mg) was dissolved in ethanol (5 ml), add concentrated chloride-hydrogen acid (1 ml) and the mixture was stirred at 50°C. for 3.5 hours, the Solvent is concentrated under reduced pressure, to the residue is added methanol (2 ml), simple diethyl ether (2 ml) and propylene oxide (5 ml). The precipitated powder is collected by filtration and washed with methanol and simple diethyl ether to obtain the target product (175 mg) as a pale yellow solid.

MS (ESI) m/z: 454 [M+H]

1H-NMR (CD3OD) is (ppm): of 0.90 (3H, t, J=6.9 Hz), 1.26 in-1.42 are (8H, m), 1,44-of 1.52 (2H, m), a 1.75-to 1.82 (2H, m), 1,92 of 1.99 (2H, m), 2,62-of 2.72 (2H, m), 3,67-3,74 (2H, m), 3,94-Android 4.04 (4H, m), 6,92 (1H, t, J=55,8 Hz), 6,98 (1H, d, J=8.5 Hz), 7,33 (1H, d, J=8.5 Hz), 7,40 (1H, users).

Example 34

Hydrochloride of 2-amino-2-[2-(3-vermeil-4-heptyloxybiphenyl)ethyl]propane-1,3-diol

(34-1) Synthesis of 5-bromo-2-heptyloxybenzoic (connection 34-1)

To a suspension of 5-bromosalicylaldehyde (5,00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) add captivated (4,10 ml) and the mixture is stirred at room temperature for 1.5 h and then at 50 ° C for 5 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate. The organic layer is washed successively 1M aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (to 7.61 g) as a yellow oil.

1H-NMR (CDCl3) δ (ppm): of 0.90 (3H, t, J=6.8 Hz), 1,28-of 1.40 (6H, m), 1,44-is 1.51 (2H, m), of 1.85 (2H, Quint., J=7,0 Hz)4,06 (2H, t, J=6.5 Hz), to 6.88 (1H, d, J=8,9 Hz), 7,60 (1H, DD, J=2,8, and 8.9 Hz), 7,92 (1H, d, J=2,8 Hz), 10,42 (1H, s).

(34-2) Synthesis of 5-bromo-2-heptyloxybenzoic alcohol (compound 34-2)

To a solution of compound 34-1 (of 7.60 g) in ethanol (80 ml) is added sodium borohydride (0,48 g) under ice cooling and the mixture is stirred for 1.5 hours under ice cooling. To the reaction mixture add 1M chloride-hydrogen KIS the GTC (50 ml), and the ethanol is evaporated under reduced pressure. The obtained residue was diluted with water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (7,66 g) as a pale yellow oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,28-of 1.39 (6H, m), of 1.41 to 1.48 (2H, m), of 1.80 (2H, Quint., J=7,0 Hz), and 2.26 (1H, t, J=6.3 Hz), 3,98 (2H, t, J=6.5 Hz)and 4.65 (2H, d, J=5,9 Hz), 6,74 (1H, d, J=8.6 Hz), 7,34 (1H, DD, J=2,4, 8.6 Hz), 7,41 (1H, d, J=2,4 Hz).

(34-3) Synthesis of (5-bromo-2-heptyloxybenzoic)hydroxy-tert-butyldimethylsilyl (connection 34-3)

To a solution of compound 34-2 (7,66 g) and imidazole (4,32 g) in N,N-dimethylformamide (30 ml) is added tert-butyldimethylchlorosilane (4.59 g) and the mixture is stirred for 14 hours To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed successively saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (10.6 g) as a yellow oil.

1H-NMR (CDCl3) δ (ppm): 0,12 (6H, s)to 0.89 (3H, t, J=6,8 Hz)to 0.96 (9H, s), 1,28-to 1.38 (6H, m), of 1.40 to 1.47 (2H, m), is 1.77 (2H, Quint., J=7,0 Hz)to 3.92 (2H, t, J=6.5 Hz), 4,71 (2H, s), to 6.67 (1H, d, J=8.7 Hz), 7,27 (1H, DD, J=2,4, and 8.7 Hz), 55 (1H, d, J=2,4 Hz).

(34-4) Synthesis of compound tert-butyl ester {5-[3-(tert-butyldimethylsilyloxy)-4-heptyloxybiphenyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamino acid (compound 34-4)

Connection 34-3 (10.5 g), complex tert-butyl ether (2,2-dimethyl-5-ethinyl-1,3-dioxane-5-yl}carbamino acid (6,46 g)synthesized by a known method (for example, Tetrahedron vol.57 (2001) 6531-6538), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (725 mg), dichloride, bis(acetonitrile)palladium(II) (131 mg) and cesium carbonate (21,4 g) in acetonitrile (150 ml) was stirred at 80°C within 12 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue cleans chromatography on a column of silica gel to obtain the target product (11.7 g) as a brown oil.

1H-NMR (CDCl3) δ (ppm): 0,11 (6H, s)to 0.89 (3H, t, J=6.8 Hz), of 0.95 (9H, s), 1,28-to 1.38 (6H, m), of 1.40 to 1.47 (2H, m)of 1.45 (3H, s)to 1.48 (9H, s)of 1.50 (3H, s), is 1.77 (2H, Quint., J=6.9 Hz), of 3.95 (2H, t, J=6.4 Hz), a 4.03 (2H, d, J=11.5 Hz), 4.09 to (2H, d, J=11.5 Hz), 4,69 (2H, s), 5,19 (1H, users), of 6.71 (1H, d, J=8.5 Hz), 7,27 (1H, DD, J=1,9, 8.5 Hz), 7,49 (1H, s).

(34-5) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-heptyloxy-3-hydroxymethylene)ethyl]-1,3-dioxane-5-yl} carbamino acid (compound 34-5)

Connection 34-4 (11,7 g) is dissolved in 1,4-deok is ane (150 ml), add palladium-carbon (12.0 g) and the mixture is stirred at room temperature for 16 h in a hydrogen atmosphere. The internal atmosphere of the reaction container is replaced with nitrogen, the solution is filtered and the filtrate concentrated. To a solution of the obtained residue in tetrahydrofuran (100 ml) is added 1M solution of tetrabutylammonium fluoride-tetrahydrofuran (20 ml) under ice cooling and the mixture is stirred for 1.5 hours under ice cooling. Add a 1M solution of tetrabutylammonium fluoride-tetrahydrofuran (10 ml) and the mixture is further stirred for 4 h under ice cooling. To the reaction mixture, water is added, the mixture extracted with ethyl acetate, washed successively with water and saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain the target product (of 5.99 g) as pale brown oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6.8 Hz), 1,28-of 1.39 (6H, m), of 1.42 to 1.47 (2H, m)of 1.42 (3H, s)of 1.43 (3H, s)of 1.47 (9H, s)to 1.79 (2H, Quint., J=7,0 Hz), 1,92 is 1.96 (2H, m), is 2.40 (1H, t, J=6.5 Hz), 2,48 of $ 2.53 (2H, m)to 3.67 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), 3,98 (2H, t, J=6.5 Hz)and 4.65 (2H, d, J=6.8 Hz), equal to 4.97 (1H, users), 6,77 (1H, d, J=8,0 Hz),? 7.04 baby mortality-7,07 (2H, m).

(34-6) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(3-vermeil-4-heptyloxybiphenyl)ethyl]-1,3-dioxane-5-yl} carbamino acid (compound 34-)

The mixture of compounds 34-5 (3,74 g), p-toluensulfonate (4,08 g), molecular sieves 4A (3,74 g) and 1M solution of tetrabutylammonium fluoride-tetrahydrofuran (46,8 ml) is stirred for 12 h at the boiling vessel with reflux condenser. To the reaction mixture add celite and the mixture filtered. To the filtrate add ethyl acetate (200 ml) and water (200 ml) and the mixture is filtered by alicom. The organic layer of the filtrate was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain the target product (0,92 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,26-to 1.38 (6H, m), of 1.40 to 1.47 (2H, m)of 1.42 (3H, s)of 1.43 (3H, s)of 1.47 (9H, s), is 1.77 (2H, Quint., J=6.9 Hz), 1.93 and-of 1.97 (2H, m), 2,50-of 2.54 (2H, m), 3,68 (2H, d, J=11.7 Hz), 3,88 (2H, d, J=11.7 Hz), of 3.95 (2H, t, J=6.4 Hz), to 4.98 (1H, users), 5,42 (2H, d, J=47,9 Hz), 6,78 (1H, d, J=8.5 Hz), 7,11 (1H, d, J=8,5 Hz), 7,17 (1H, m).

(34-7) Synthesis of hydrochloride of 2-amino-2-[2-(3-vermeil-4-heptyloxybiphenyl)ethyl]propane-1,3-diol (compound 34-7)

Connection 34-6 (0,94 g) dissolved in methanol (30 ml), add n-toluensulfonate acid (15 mg) and the mixture is stirred at room temperature for 3 hours To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (100 ml), the mixture is extracted with ethyl acetate and the extract is raybaut saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure. To the obtained residue is added under ice cooling, the ethyl acetate (1 ml) and a 4M solution of hydrochloride-ethyl acetate (1 ml) and the mixture is stirred for 30 minutes under ice cooling. The precipitated solid is collected by filtration and washed with simple diisopropyl ether to obtain the target product (44,4 mg) as a white powder.

MS (ESI) m/z: 342 [M+H]

1H-NMR (DMSO-d6) δ (ppm): of 0.87 (3H, t, J=6,7 Hz), 1,26-of 1.36 (6H, m), 1,37-of 1.44 (2H, m), 1,71 (2H, Quint., J=6.9 Hz), 1,74-to 1.79 (2H, m), 2,53-to 2.57 (2H, m), 3,52 (4H, d, J=5,2 Hz), of 3.97 (2H, t, J=6.3 Hz), 5,38 (2H, d, J=48,0 Hz), of 5.40 (2H, t, J=5,1 Hz), 6,97 (1H, d, J=8,3 Hz), 7,17-7,20 (2H, m), a 7.85 (3H, users).

Example 35

Hydrochloride of 2-amino-2-[2-(3-vermeil-4-heptyloxybiphenyl)ethyl]propane-1,3-diol

(35-1) Synthesis of 5-bromo-2-octyloxybenzoate (connection 35-1)

To a suspension of 5-bromosalicylaldehyde (5,00 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (50 ml) add activated (4.52 ml) and the mixture is stirred at room temperature for 1.5 h and then at 50°C. for 3.5 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine 3 times and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to obtain the target product (7,72 g) as a white solid.

1H-NMR (CDCl3 ) δ (ppm): to 0.89 (3H, t, J=6.3 Hz), 1,25-to 1.38 (8H, m), 1,44-is 1.51 (2H, m)of 1.84 (2H, Quint., J=6,8 Hz)4,06 (2H, t, J=6.4 Hz), to 6.88 (1H, d, J=8,9 Hz), to 7.61 (1H, d, J=8,9 Hz), 7,92 (1H, s), 10,42 (1H, s).

(35-2) Synthesis of 5-bromo-2-octyloxybenzoate alcohol (compound 35-2)

To a solution of compound 35-1 (7,72 g) in ethanol (80 ml) is added sodium borohydride (0,47 g) under ice cooling and the mixture is stirred for 30 minutes under ice cooling. To the reaction mixture are added water (100 ml), 1M hydrochloric acid (30 ml) and the ethanol is evaporated under reduced pressure. The obtained residue was diluted with 0.1m chloride-hydrogen acid, and the mixture is extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent is evaporated under reduced pressure to obtain the target product (of 7.95 g) as pale brown oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,25-to 1.38 (8H, m), of 1.41 to 1.48 (2H, m), of 1.80 (2H, Quint., J=7,0 Hz in), 2.25 (1H, t, J=6.3 Hz), 3,98 (2H, t, J=6.4 Hz)and 4.65 (2H, d, J=6.0 Hz), 6,74 (1H, d, J=8.6 Hz), 7,34 (1H, DD, J=2,4, 8.6 Hz), 7,41 (1H, d, J=2,4 Hz).

(35-3) Synthesis of (5-bromo-2-octyloxyphenyl)hydroxy-tert-butyldimethylsilyl (connection 35-3)

To a solution of compound 35-2 (of 7.95 g) and imidazole (4,19 g) in N,N-dimethylformamide (35 ml) is added tert-butyldimethylchlorosilane (4,45 g) in terms of cooling with ice and the mixture is stirred for 20 min under conditions of cooling with ice and then at room the temperature for 18 hours To the reaction mixture is added saturated aqueous solution of sodium bicarbonate and the mixture extracted with ethyl acetate. The organic layer is washed successively saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (11.1 g) as a pale brown oil.

1H-NMR (CDCl3) δ (ppm): 0,12 (6H, s)to 0.89 (3H, t, J=6.9 Hz), is 0.96 (9H, s), 1,24-to 1.38 (8H, m), of 1.40 to 1.47 (2H, m)of 1.76 (2H, Quint., J=7,0 Hz)to 3.92 (2H, t, J=6.5 Hz), 4,71 (2H, s), to 6.67 (1H, d, J=8.7 Hz), 7,27 (1H, DD, J=2.5 and 8.7 Hz), 7,55 (1H, d, J=2.5 Hz).

(35-4) Synthesis of compound tert-butyl ester {5-[3-(tert-butyldimethylsilyloxy)-4-octyloxyphenyl]-2,2-dimethyl-1,3-dioxane-5-yl}carbamino acid (compound 35-4)

Connection 35-3 (11.1 g), complex tert-butyl ether (2,2-dimethyl-5-ethinyl-1,3-dioxane-5-yl}carbamino acid (6,28 g)synthesized by a known method (for example, Tetrahedron vol.57 (2001) 6531-6538), 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (706 mg), dichloride, bis(acetonitrile)palladium(II) (128 mg) and cesium carbonate (20,8 g) in acetonitrile (150 ml) was stirred at 80°C during the 10 o'clock To the reaction mixture add the brine, the mixture is extracted with ethyl acetate and the extract washed with saturated brine and dried over anhydrous sodium sulfate. The solvent is evaporated under reduced pressure is receiving. The residue cleans chromatography on a column of silica gel to obtain the target product (12.4 g) as a brown oil.

1H-NMR (CDCl3) δ (ppm): 0,11 (6H, s)to 0.89 (3H, t, J=6.8 Hz), of 0.95 (9H, s), of 1.24 to 1.37 (8H, m), of 1.40 to 1.47 (2H, m)of 1.45 (3H, s)to 1.48 (9H, s)of 1.50 (3H, s), is 1.77 (2H, Quint., J=6.9 Hz), of 3.95 (2H, t, J=6.5 Hz), a 4.03 (2H, d, J=11,6 Hz), 4.09 to (2H, d, J=11,6 Hz), 4,69 (2H, s), 5,19 (1H, users), of 6.71 (1H, d, J=8,4 Hz), 7,27 (1H, DD, J=1,9, and 8.4 Hz), 7,49 (1H, s).

(35-5) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(4-octyloxy-3-hydroxymethylene)ethyl]-1,3-dioxane-5-yl} carbamino acid (compound 35-5)

Compound 35-4 (12.4 g) was dissolved in 1,4-dioxane (100 ml), add 10% palladium-carbon (3.0 g) and the mixture is stirred at room temperature for 5.5 h in hydrogen atmosphere. The internal atmosphere of the reaction container is replaced with nitrogen, the solution is filtered and the filtrate concentrated. To a solution of the obtained residue in tetrahydrofuran (100 ml) is added 1M solution of tetrabutylammonium fluoride-tetrahydrofuran (30 ml) and the mixture is stirred for 3 hours under ice cooling. The reaction mixture was diluted with ethyl acetate (200 ml)and the extract washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain the target product (being 9.61 g) as pale brown oil.

H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,24-to 1.38 (8H, m), 1.41 to about 1.47 (2H, m)of 1.42 (3H, s)of 1.43 (3H, s)of 1.47 (9H, s)to 1.79 (2H, Quint., J=7,0 Hz), 1,92 is 1.96 (2H, m), 2,41 (1Ht, J=6.6 Hz), 2,48 of $ 2.53 (2H, m)to 3.67 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), 3,98 (2H, t, J=6.5 Hz)and 4.65 (2H, d, J=6.8 Hz), to 4.98 (1H, users), 6,77 (1H, d, J=8.0 Hz),? 7.04 baby mortality-7,07 (2H, m).

(35-6) Synthesis of compound tert-butyl ester {2,2-dimethyl-5-[2-(3-vermeil-4-octyloxyphenyl)ethyl]-1,3-dioxane-5-yl} carbamino acid (compound 35-6)

A mixture of compound 35-5 (being 9.61 g), p-toluensulfonate (10.2 g), molecular sieves 4A (being 9.61 g) and 1M solution of tetrabutylammonium fluoride-tetrahydrofuran (117 ml) was stirred for 13 h at the boiling vessel with reflux condenser. The reaction mixture was added to a mixture of water and ethyl acetate and the mixture is stirred for 5 hours the Organic layer is washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The residue is purified by chromatography on a column of silica gel to obtain the target product (1,91 g) as a colourless oil.

1H-NMR (CDCl3) δ (ppm): to 0.89 (3H, t, J=6,7 Hz), 1,24-to 1.38 (8H, m), of 1.40 to 1.47 (2H, m)of 1.42 (3H, s)of 1.43 (3H, s)of 1.47 (9H, s), is 1.77 (2H, Quint., J=7,0 Hz), 1.93 and-of 1.97 (2H, m), 2,50 is 2.55 (2H, m), 3,68 (2H, d, J=11.7 Hz), with 3.89 (2H, d, J=11.7 Hz), of 3.95 (2H, t, J=6.5 Hz), to 4.98 (1H, users), 5,42 (2H, d, J=47,9 Hz), 6,78 (1H, d, J=8,4 Hz), 7,11 (1H, d, J=8.4 and Hz), 7,17 (1H, s).

(35-7) Synthesis of hydrochloride of 2-amino-2-[2-(3-vermeil-4-heptyloxybiphenyl)ethyl]propane-1,-diol (compound 35-7)

Connection 35-6 (1,91 g) dissolved in methanol (60 ml), add monohydrate p-toluensulfonate acid (20 mg) and the mixture is stirred at room temperature for 9 hours To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (200 ml) and saturated brine (100 ml) and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure. To the obtained residue is added ethyl acetate (3 ml) and a 4M solution of hydrochloride-ethyl acetate (3 ml) under ice cooling and the mixture is stirred for 40 minutes under ice cooling. The precipitated solid is collected by filtration and washed with ethyl acetate to obtain the target product (158 mg) as a white powder.

MS (ESI) m/z: 356 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6.8 Hz), of 1.23 and 1.35 (8H, m), 1,37-of 1.44 (2H, m), 1,67-of 1.78 (4H, m), 2,52-of 2.56 (2H, m), 3,51 (4H, d, J=4.6 Hz), of 3.97 (2H, t, J=6.4 Hz), 5,38 (2H, d, J=48,0 Hz), 5,38 (2H, users), 6,97 (1H, d, J=8,3 Hz), 7,17-7,20 (2H, m), of 7.75 (3H, users).

Example 36

Hydrochloride of 2-dimethylamino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol

(36-1) Synthesis of hydrochloride of 2-dimethylamino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol (compound 36-1)

To a solution of compound 1-3 (1.24 g), 37% formaldehyde (20 ml) and 30% aqueous acetic acid (3 m is) in acetonitrile (30 ml) add cyanoborohydride sodium (0,817 g) in terms of cooling with ice and the mixture is stirred for 1 h To the reaction mixture is added saturated aqueous sodium hydrogen carbonate solution (50 ml) and acetonitrile is evaporated under reduced pressure. To the resulting concentration of added saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate and the extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. To the residue is added ethyl acetate (10 ml) and a 4M solution of hydrochloride-ethyl acetate (5 ml) and the solvent is evaporated under reduced pressure. To the residue add a simple diisopropyl ether and the resulting solid collected by filtration to obtain the target product (0,808 g) as a white solid.

MS (ESI) m/z: 406 [M+H]

1H-NMR (DMSO-d6) δ (ppm): 0,86 (3H, t, J=6,7 Hz), 1,24-of 1.35 (6H, m), 1,38-to 1.45 (2H, m), 1,71 (2H, Quint., J=6.8 Hz), 1,87 is 1.91 (2H, m), 2,60-to 2.67 (2H, m), 2,80 (6H, d, J=4,8 Hz), 3,70 (2H, DD, J=4,9, 12.9 Hz), 3,76 (2H, DD, J=4,8, to 12.8 Hz), 4,06 (2H, t, J=6.2 Hz), 5,71 (2H, t, J=4.6 Hz), 7,18 (1H, d, J=8,2 Hz), 7,49-7,51 (2H, m).

Example 1 synthesis of compounds comparison of the hydrochloride of 2-amino-2-[2-(4-heptyloxy-3-were)ethyl]propane-1,3-diol

(1-1) Synthesis of 4'-methoxy-3'-methylacetophenone (connection comparison 1-1)

To a solution of 4'-hydroxy-3'-methylacetophenone (25,0 g) in N,N-dimethylformamide (120 ml) is added potassium carbonate (69,1 g) and methyliodide (11,4 ml) in cooling with ice and the mixture peremeshivayu for 2 h under ice cooling and then at room temperature for 2 hours To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain the target product (27.5 g) as a yellow oil.

1H-NMR (CDCl3) δ (ppm): of 2.25 (3H, s)to 2.55 (3H, s)to 3.89 (3H, s), 6,85 (1H, d, J=8.6 Hz), to 7.77 (1H, d, J=1.7 Hz), 7,82 (1H, DD, J=2,2, 8.6 Hz).

(1-2) Synthesis of 4'-methoxy-3'-methylbenzylamine (connection comparison 1-2)

To a solution of compound 1-1 (27,2 g) in acetic acid (170 ml) add tribromide pyridinium (90%, 59.0 g) and the mixture was stirred at 50°C for 1 h To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water, 1M aqueous solution of peroxide sodium, saturated ammonium chloride and saturated brine. The organic layer is dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to obtain the target product (40,3 g) as a brown solid.

1H-NMR (CDCl3) δ (ppm): and 2.26 (3H, s), 3,91 (3H, s), and 4.40 (2H, s), 6.87 in (1H, d, J=8.6 Hz), 7,80 (1H, d, J=1.5 Hz), 7,86 (1H, DD, J=2,2, 8.6 Hz).

(1-3) Synthesis of complex diethyl ether 2-ndimethylacetamide-2-[2-(4-methoxy-3-were)-2-oxoethyl]malonic acid (compound comparisons 1-3)

To a solution of diethyl-2-acetamidomalonate with 29.1 g) in N,N-dimethylformamide(140 ml) is added sodium hydride (60%, 5,63 g) four portions in the conditions of cooling with ice and the mixture is stirred for 1 h To this solution add a solution of compound comparison 1-2 (39,1 g) in N,N-dimethylformamide (50 ml) and the mixture is stirred for 3 hours under ice cooling. The reaction mixture was added to ice water and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The resulting residue is purified by chromatography on silica gel to obtain the target product (45,0 g) as a brown oil.

1H-NMR (CDCl3) δ (ppm): 1,24 (6H, t, J=7.0 Hz), a 1.96 (3H, s), of 2.23 (3H, s)to 3.89 (3H, s), 4,20 (2H, s), 4.26 deaths (4H, DQC., J=1,4, 7,0 Hz), at 6.84 (1H, d, J=8.6 Hz), 7,10 (1H, users), to 7.77 (1H, d, J=1,8 Hz), 7,83 (1H, DD, J=2,2, 8.6 Hz).

(1-4) Synthesis of complex diethyl ether 2-ndimethylacetamide-2-[2-(4-methoxy-3-were)ethyl]malonic acid (compound comparisons 1-4)

To a solution of compound comparisons 1-3 (45,0 g) in triperoxonane acid (260 ml) add triethylsilane (133 ml) and the mixture was stirred at 70°C for 24 h, the Reaction mixture was concentrated under reduced pressure, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water, 1M aqueous sodium hydroxide solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated the od reduced pressure. To the obtained residue, add a simple diethyl ether and the precipitated solid is collected by filtration and dried to obtain the target product (31,3 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): a 1.25 (6H, t, J=7.0 Hz), from 2.00 (3H, s)to 2.18 (3H, s), 2,37-to 2.41 (2H, m), 2,62-to 2.67 (2H, m), with 3.79 (3H, s), 4,15-4,27 (4H, m), 6,70-of 6.73 (1H, m), of 6.75 (1H, users), 6,90-6,93 (2H, m).

(1-5) Synthesis of N-[1,1-bis(hydroxymethyl)-3-(4-methoxy-3-were)propyl]ndimethylacetamide (connection comparisons 1-5)

To a solution of compound 1-4 (31,3 g) in ethanol (300 ml) and water (60 ml) was added calcium chloride (19,0 g), the solid is dissolved. To this mixture is added sodium borohydride (13,0 g) five portions under ice cooling and the mixture is stirred for 3 h under ice cooling and then at room temperature for 19 hours To the reaction mixture while cooling with ice add 1M chloride-hydrogen acid (300 ml) and the mixture is concentrated under reduced pressure. Add 0.5m chloride-hydrogen acid (700 ml) and the mixture extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate and the solvent is evaporated under reduced pressure to obtain the target product as a solid substance. Target product (22,8 g) obtained as colorless oil by operating this white solid that is similar to the operation shown above.

1H-NMR (CDCl3) δ (ppm): 1,91-of 1.95 (2H, m), of 1.95 (3H, s), are 2.19 (3H, s), 2,55 at 2.59 (2H, m), 3,62 (2H, d, J=11,6 Hz), 3,80 (3H, s), a 3.87 (2H, d, J=11,6 Hz), of 5.84 (1H, users), 6,74 (1H, d, J=8,8 Hz), 6,97-6,98 (2H, m).

(1-6) the Synthesis of compound tert-butyl ether [1,1-bis(hydroxymethyl)-3-(4-hydroxy-3-were)propyl]carbamino acid (compound comparisons 1-6)

To a solution of compound comparisons 1-5 (of 22.5 g) in methylene chloride (200 ml) added dropwise 1M solution of tribromide boron in methylene chloride (320 ml) at -70°C. the Mixture is stirred for 1 h before raising the temperature to 0°C and further stirred for 1.5 hours under ice cooling. To the reaction mixture gradually add methanol (300 ml) under ice cooling and the mixture is concentrated under reduced pressure. To a solution of the obtained residue in ethanol (100 ml) is added concentrated chloride-hydrogen acid (100 ml) and the mixture was stirred at 80°C for 4 h, the Reaction mixture was concentrated under reduced pressure. To a solution of the obtained residue and N,N-diisopropylethylamine (34.8 ml) in methanol (150 ml) is added di-tert-BUTYLCARBAMATE (19,2 g) under ice cooling and the mixture is stirred for 1 h under ice cooling and then at room temperature for 4 h, the Reaction mixture was concentrated under reduced pressure, add saturated aqueous solution of sodium bicarbonate (500 ml)and the mixture extracted with ethyl acetate. The PR is anceschi layer washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure. The obtained residue was washed with simple diethyl ether to obtain the target product (15.1 g) as a white powder.

1H-NMR (CDCl3) δ (ppm): to 1.45 (9H, s), 1,82 is 1.86 (2H, m), of 2.21 (3H, s), 2,50-of 2.54 (2H, m), 3,39 (2H, users), to 3.64 (2H, DD, J=6,8, and 11.5 Hz), 3,88 (2H, DD, J=5,5, and 11.5 Hz), a 4.83 (1H, users), 4,99 (1H, users), of 6.68 (1H, d, J=8.1 Hz), 6,88 (1H, DD, J=1,9, 8,1 Hz)6,94 (1H, d, J=1.9 Hz).

(1-7) Synthesis of hydrochloride of 2-amino-2-[2-(4-heptyloxy-3-were)ethyl]propane-1,3-diol (compound comparison 1-7)

Connection comparison 1-6 (500 mg) is dissolved in N,N-dimethylformamide (10 ml), add potassium carbonate (425 mg) and n-heptylamine (0,2960 ml) and the mixture was stirred at 80°C for 6 hours To the reaction mixture, water is added, the mixture extracted with ethyl acetate and the extract washed with water and saturated brine and dried over anhydrous magnesium sulfate. The solvent is evaporated under reduced pressure to obtain 640 mg of colorless oil. Colorless oil (640 mg) was dissolved in methylene chloride (5 ml), add dioxane containing hydrogen chloride (4 mol/l, 5 ml) and the mixture is stirred at room temperature for 15 hours, the Reaction mixture was concentrated and the residue is washed simple diethyl ether to obtain white powder. White powder purified preparative HPLC, to the obtained residue, add a simple ether containing hydrogen chloride (1 is ol/l, 15 ml) to obtain the hydrochloride. The precipitate is collected by filtration and dried to obtain the target product (320 mg) as a white powder.

MS (ESI) m/z: 324 [M+H]

1H-NMR (CD3OD) δ (ppm): of 0.91 (3H, t, J=6.6 Hz), 1.30 and of 1.42 (6H, m), USD 1.43-of 1.52 (2H, m), 1,74-of 1.81 (2H, m), 1,88-of 1.94 (2H, m)of 2.16 (3H, s), 2,53-of 2.58 (2H, m), 3,64-3,71 (4H, m), of 3.94 (2H, t, J=6.4 Hz), 6,77 (1H, d, J=8.0 Hz), of 6.96-6,98 (2H, m).

Structure of synthetic compounds shown below.

Experimental example 1: estimation of reducing the number of lymphocytes in the peripheral blood effect in mice

The compound of the present invention dissolved or suspended in 20% cyclodextrin (they are manufactured by NIHON SHOKUHIN KAKO CO., LTD) and were injected intraperitoneally to male mice BALB/cAnNCrj at the age of 7-10 weeks (CHARLES RIVER LABORATORIES JAPAN INC.) at a dose of 0.001-10 mg/kg of body weight. After 24 hours from the moment of introduction of the compounds of the present invention, peripheral blood (approximately 0.3 ml) was taken from the posterior Vena cava mouse tuberculin syringe (made TERUMO CORPORATION), treated with heparin sodium (manufactured NovoNordisk) under ether anesthesia. Blood (0.1 ml)demolishable automatic apparatus for hemolytic processing (TQ-Prep, made BECKMAN-COULTER), and the number of lymphocytes was calculated flow cytometer (CYTOMICS FC 500, made BECKMAN-COULTER), by the method of differential transmission using scattering on the front and the side of the laser beam as indicators and using forever Flow-CountTM(made BECKMAN-COULTER), the standard number of particles which is known as internal standard. The dose required to reduce by 50% the number of lymphocytes of a group of media, taken as 100%, was calculated and used as the value of the ED50(mg/kg body weight). Reducing the number of lymphocytes in the peripheral blood effect connection comparison 1-7 caused dose component of 0.64 mg/kg of body weight when the value ED50reducing the number of lymphocytes in the peripheral blood the effect of compound 1-3, compound 13-6, connection 15-3 and connections 28-6 caused their doses respectively of 0.04, 0.02 and 0.02 and 0.03 mg/kg in value ED50.

Experimental example 2: Effect on heart rate in rats, as determined by telemetry

Male rats Sprague-Dawley (IGS) was narcoticyou by intraperitoneal injection of Nembutal (manufactured DAINIPPON PHARMACEUTICAL CO., LTD.), a pressure sensor connected to the telemetry transmitter (TL11M2-C50-PTX, made Data Sciences International)was introduced in RosNOU artery, and the transmitter was performed subcutaneously in the abdomen. Data of blood pressure and heart rate were recorded analytical software (Dataquest Art., Data Science) through the receiver (RPC-1, manufactured by Data Sciences International). After a period of 10 days to 2 weeks from time of surgery confirmed the restoration of the circadian rhythm of heart rate and rats conducted the experiment. The compound of the present invention suspended in 0.5% hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd.) and is administered orally. Heart rate was measured from 24 h before the introduction of up to 72 h after injection. Connection 1-3 had no effect on heart rate in rats up to doses of 30 mg/kg of body weight.

Experimental example 3: Effect on heart rate in rats under conditions of anesthesia

Male rats Sprague-Dawley (IGS) was narcoticyou by intraperitoneal injection of Nembutal (manufactured DAINIPPON PHARMACEUTICAL CO., LTD.) and recorded in the supine position. The electrodes were mounted on the four limbs, the electrocardiogram was recorded in standard lead II from limb, using the electrocardiogram amplifier (AC-601G, manufactured by NIHON KOHDEN CORPORATION). Heart rate was calculated using block instant counter often is s heart rate (AT-601G, manufactured by NIHON KOHDEN CORPORATION) and electrocardiographic wave as a starter. The test compound was dissolved in 20% cyclodextrin (they are manufactured by NIHON SHOKUHIN KAKO CO., LTD) and intravenously injected for 30 seconds at a dose of 0.001 to 10 mg/kg of body weight. Heart rate was measured before injection and 1, 2, 3, 4, 5, 10 and 15 min after injection.

According to the results of the above experimental example 1, because the connection of the present invention has a stronger reducing effect on the number of lymphocytes in the peripheral blood, we can expect that it will show more pronounced immunosuppressive action, action, the overwhelming rejection, and action, the vast allergies, and considered effective for the treatment or prevention of autoimmune diseases; prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplantation; treatment or prevention of a disease graft-versus-host (GvH) due to bone marrow transplantation; or treatment or prevention of allergic diseases. In addition, the results of the above experimental example 2, the compound of the present invention is a compound exhibiting reduced side effects such as bradycardia and the like.

This stated the ka is based on patent application No. 2005-361363, filed in Japan, the contents of which are fully incorporated herein in view of the references.

1. The compound represented by the following formula (I):

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, Y represents CH2CH2or CH=CH, R1represents trifluoromethyl, deformity or cyano, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (or groups) or atom (atoms) halogen, R3and R4may be the same or different, and each represents a hydrogen atom or alkyl having 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid additive salt.

2. The compound according to claim 1, where each of R3and R4represents a hydrogen atom, or its pharmaceutically acceptable acid additive salt.

3. The compound according to claim 1, having the following formula (Ia) or (Ib):

where R represents a hydrogen atom or P(=O)(OH)2X represents an oxygen atom or a sulfur atom, R1represents trifluoromethyl, deformity or cyano, R2represents alkyl having 1-4 carbon atoms, and optionally substituted hydroxyl group (GRU is the groups) or atom (atoms) halogen, or its pharmaceutically acceptable acid additive salt.

4. The compound according to claim 1, where X represents an oxygen atom, or its pharmaceutically acceptable acid additive salt.

5. The compound according to claim 1, where Y represents CH2CH2or its pharmaceutically acceptable acid additive salt.

6. The compound according to claim 1, where R1represents trifluoromethyl or deformity, or its pharmaceutically acceptable acid additive salt.

7. The compound according to claim 1, where R1represents trifluoromethyl, or its pharmaceutically acceptable acid additive salt.

8. The compound according to claim 1, where R2represents methyl, optionally substituted with hydroxyl group (or groups), or its pharmaceutically acceptable, acid additive salt.

9. The compound according to claim 1, where R2represents hydroxymethyl, or its pharmaceutically acceptable acid additive salt.

10. The compound according to claim 1, where R represents a hydrogen atom, or its pharmaceutically acceptable acid additive salt.

11. The compound according to claim 1, where the compound of formula (I) represents any connection the following subparagraphs a) to e), or its pharmaceutically acceptable acid additive salt:
a) 2-amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol or its pharmaceutically who ramlila acid additive salt,
b) (E)-2-amino-2-[2-(4-heptyloxy-3-triptoreline)vinyl]propane-1,3-diol or its pharmaceutically acceptable acid additive salt,
c) 2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol or its pharmaceutically acceptable acid additive salt,
d) (R)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanol or its pharmaceutically acceptable acid additive salt,
e) 2-amino-2-[2-(3-cyano-4-heptyloxybiphenyl)ethyl]propane-1,3-diol or its pharmaceutically acceptable acid additive salt.

12. The compound according to claim 1, where the compound of formula (I) represents any connection the following subparagraphs f-j or its pharmaceutically acceptable acid additive salt:
f) 2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)butanol or its pharmaceutically acceptable acid additive salt,
g) (E)-2-amino-4-(4-heptyloxy-3-triptoreline)-2-(phosphorylmethyl)-3-butene-1-ol or pharmaceutically acceptable acid additive salt,
h) complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl]ester of phosphoric acid or its pharmaceutically acceptable acid additive salt,
i) complex mono[2-amino-4-(4-heptyloxy-3-triptoreline)-2-methylbutanoyl] the ester (R)-phosphoric acid or its pharmaceutically acceptable acid additive salt,
j) 2-amino-4-(3-cyano-4-heptyl xifei)-2-(phosphorylmethyl)butanol or its pharmaceutically acceptable acid additive salt.

13. 2-Amino-2-[2-(4-heptyloxy-3-triptoreline)ethyl]propane-1,3-diol or its hydrochloride.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, used for the treatment or prevention of autoimmune diseases; prevention or suppression of resistance or acute rejection or chronic rejection of organ transplant or tissue; treatment or prevention of a disease graft-versus-host (GvH) due to bone marrow transplantation; or treatment, or prevention of allergic diseases.

15. The pharmaceutical composition according to 14, where the autoimmune disease is a rheumatoid arthritis, multiple sclerosis, encephalomyelitis, systemic lupus erythematosus, lupus nephritis, nephrotic syndrome, psoriasis or diabetes mellitus type I.

16. The pharmaceutical composition according to 14, where the allergic disease is a atopic dermatitis, allergic rhinitis or asthma.



 

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FIELD: chemistry.

SUBSTANCE: invention relates to aminophosphate derivatives of general formula (1a), pharmaceutically acceptable salts or hydrates thereof, which can be used in medicine as S1P (sphingosine-1-phosphate) receptor modulators,

where R3 is a straight alkyl group containing 1-3 carbon atoms; X is an oxygen or sulphur atom and n equals 2 or 3.

EFFECT: obtaining novel biologically active compounds with high S1P receptor modulating action.

9 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing di-(2-ethylhexyl) phosphoric acid, which is used in extraction processes, ion exchangers, and neodymium salt thereof, which is used during catalysis. Disclosed is a method of producing di-(2-ethylhexyl) phosphoric acid and a solution of its neodymium salt in an aliphatic or acyclic solvent by reacting phosphorus trichloride with 2-ethylhexanol, followed by chlorination of the formed di-(2-ethylhexyl)phosphate and hydrolysis of di-(2-ethylhexyl) chlorophospate, wherein in order to obtain di-(2-ethylhexyl) phosphoric acid and its high-purity neodymium salt, hydrolysis is carried out through successive treatment of chlorophophate with jet steam at temperature 95-100°C and then with 20% aqueous solution of sodium hydroxide at temperature 105 -115°C, followed by treatment with hydrochloric acid in an organic solvent to obtain di-(2-ethylhexyl) phosphoric acid or with aqueous solution of neodymium chloride to obtain a solution of neodymium tris-[di-(2-ethylhexyl)] phosphate.

EFFECT: novel method of producing a high-purity compound and its neodymium salt.

9 cl, 7 ex

FIELD: chemistry.

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EFFECT: obtaining novel effective wetting substances and dispersants.

2 cl, 19 ex, 7 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to monolysine salts of azole derivatives of general formula (I), a method of producing said salts and use in treating fungal infections.

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33 cl, 16 dwg, 12 ex, 8 tbl

FIELD: chemistry.

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EFFECT: obtainment of novel hydrotropes and efficient detergent compositions based on them.

12 cl, 7 ex, 12 tbl

FIELD: medicine.

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15 cl, 3 tbl, 1 ex

FIELD: chemistry.

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15 cl, 23 dwg, 48 tbl, 16 ex

FIELD: chemistry.

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14 cl, 5 tbl, 4 dwg, 39 ex

FIELD: agriculture.

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15 cl, 8 tbl, 1 dwg

FIELD: chemistry.

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47 cl, 3 dwg, 5 tbl, 13 ex

FIELD: medicine.

SUBSTANCE: invention relates to a method of producing 2-amino-2-[2-[4-(3-benzyloxy-phenylthio)-2-chlorophenyl]ethyl]-1,3-propanediol hydrochloride or its hydrate, involving the following steps: reacting 4-(3-benzyloxyphenylthio)-2-chlorobenzaldehyde and diethylphosphonoacetate ethyl in a solvent in the presence of a base, obtaining ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate; reducing the formed ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate with subsequent mesylation, iodizing, and nitration, obtaining 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio]benzol; hydroxymethylation of the formed 1-benzyloxy-3-[3-chloro-4-(3-nitropropyl-phenylthio] benzol with formaldehyde, obtaining 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol; as well as reduction of the formed 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol, obtaining the end product. The invention also relates to intermediate products: ethyl 3-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]acrylate, 1-benzyloxy-3-[3-chloro-4-(3-nitropropylphenylthio]benzol, 2-[2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl]-2-nitro-1,3-propanediol or to their hydrates.

EFFECT: industrial production of said compound with good output and high purity.

4 cl, 4 ex

FIELD: chemistry, medicine.

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EFFECT: improvement of the method.

19 cl, 68 ex

FIELD: organic chemistry, biochemistry, medicine, virology.

SUBSTANCE: invention relates to a compound of the general formula: (R1)-(R2)-N-CH-(CH=CH2)-CH2R3 wherein R1 represents alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, benzoyloxycarbonyl; R2 represents hydrogen atom (H), or R1 and R2 in common with nitrogen atom to which they are joined form phthalimido, succinimido or N-diformyl group; R3 represents thioalkyl or thioaryl. Also, invention relates to a method for synthesis of compounds represented by the formula (8): that involves the following steps: (a) treatment of hydroxybutene of the formula (6): with methanesulfonyl chloride in the presence of an amine base in a polar aprotonic solvent to obtain butene mesylate of the formula (7a): wherein R' represents alkyl or aryl, and (b) treatment of butene mesylate (7a) with thiophene oxide wherein thiphene is formed in situ using thiophenol and non-nucleophilic base in polar aprotonic solvent to obtain thiophenylbutene (8). Also, invention relates to a method for stereoselective conversion of compound of the formula (8) to compound of the formula (9): or the formula (10): wherein this method involves treatment of compound of the formula (8) with osmium-containing oxidizing combination of reagents: K2OsO2(OH)4/K3Fe(CN)6, K2CO3, NaHCO3 and CH3SO2NH2 in the presence of DHQD2PHAL as a chiral accessory reagent to obtain compound represented by he formula (9) or the formula (10). Invention provides synthesis of butene and butane compounds that are useful as intermediate compound in synthesis of nelfinavir mesylate relating to a protease inhibitor.

EFFECT: improved methods of synthesis.

8 cl, 8 ex

The invention relates to 1-phenyl-3-dimethylamino-propane compounds, method of their production and to the use of these compounds as pharmaceutical active substances

The invention relates to a new-aminophenylamino having aromatic substituents on the carbon atom that is joined to the amino group, the method of their derivation from NITRILES and methylergometrine and their use for the preparation of aromatic-diketones

FIELD: chemistry; pharmaceutics.

SUBSTANCE: present invention relates to novel cyclohexane derivatives of formula (I) or their pharmaceutically acceptable salts having inhibitory effect on Na+-glucose cotranspoter (SGLT2), as well as to pharmaceutical compositions based on the said compounds and their use in preventing or treating diabetes, diabetic complications caused by hyperglycaemia or obesity. , where A is -O-; n is an equal to 0 or 1; R6 and R7 each independently represents a hydrogen atom or a C1-C6alkyl group, m is an integer selected from 1-3; Q is selected from Q1 - Q5, given in formula 2.

EFFECT: obtaining novel cyclohexane derivatives or their pharmaceutically acceptable salts and preparation of a pharmaceutical composition based on the said compounds.

15 cl, 19 dwg, 11 tbl, 86 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel amidoacetonitrile derivatives of the formula I which can be applied in vermin control. In the formula I , X is Cl, Br or CF3; Y is simple link, O, S, S(O) or S(O)2; and W is O.

EFFECT: obtaining compounds of the formula I, composition, and method of vermin control.

20 cl, 6 tbl, 37 ex

FIELD: medicine.

SUBSTANCE: invention refers to preparation of new intermediate products of -3-substituted-3-(3-phenoxyphenyl)-2-propenenitriles of general formula 1 which can be used in production of biologically active substances, including insecticides, or in production of pharmacologically active compounds. The method for preparing -3-substituted-3-(3-phenoxyphenyl)-2-propenenitriles of general formula 1 where R=H, CH3, consists in reaction of carbonyl compound chosen from 3-phenoxybenzaldehyde or 3-phenoxyphenylmethylketone and acetonitrile with potassium hydroxide added and an end product to be recovered. Preferentially, process is implemented at mole ratio of carbonyl compound, acetonitrile and potassium hydroxide equal to 1:(20-22):1 respectively, in initial acetonitrile medium at boiling temperature 80-82°C. As a rule, the end product is recovered by extraction with diethyl ether. Vacuum distillation is used to distil the extractant and purify the end product.

EFFECT: high-yield and high-purity products.

2 cl, 2 ex

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