Method of producing 3-[5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2, 3-dihydro-1, 2-benzisoxazol-6-yl)methoxy]phenyl]propionic acid ester and intermediate product for said method

FIELD: chemistry.

SUBSTANCE: invention relates to versions of a method of producing a phenylpropionic acid derivative of general formula: or salt thereof, where R2a is a methoxy group or ethoxy group; R3b is a cyclopentyl group and R5 is a methyl group which can be substituted with one or more phenyl groups, or an oxygen-containing heterocyclic group used as an intermediate compound during synthesis of 3-{5-[4-(cyclpentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (T-5224), having anti-arthritic action and osteoclast inhibitory action. One of the versions of the method involves reaction of a benzophenol derivative of general formula: 3 , where R2a and R3b are as described above, or salts thereof with a 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-one derivative of general formula: , where R5 is as described above, and X is a halogen atom. The disclosed method can be used as a method for simple and safe synthesis of T-5224 with high output. The invention also relates to methods of producing intermediate compounds and novel intermediate compounds.

EFFECT: high efficiency of the composition.

28 cl, 23 ex

 

The technical FIELD TO WHICH the INVENTION RELATES.

The present invention relates to a process for the preparation of ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid and intermediate product for this method.

The LEVEL of TECHNOLOGY

3-{5-[4-(Cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (hereinafter referred to as T-5224) has excellent anti-arthritis effect and osteoclastogenesis action and, in addition, highly secure, excellent pharmacokinetics and useful as an Antirheumatic agents (non-Patent document 1).

T-5224 get the release of ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (hereinafter referred to as an intermediate product to obtain T-5224) (Patent document 1).

The intermediate product to obtain T-5224 receive the engagement 6-(methyl bromide)-2-(methoxymethyl)-1,2-benzisoxazol-3(2H)-it (hereinafter referred to as the intermediate 1-1) or 6-(methyl bromide)-3-(methoxyethoxy)-1,2-benzisoxazole (hereinafter referred to as the intermediate 1-2) with complex methyl ether 3-{5-[4-cyclopentyloxy is)-2-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid (hereinafter referred to as the intermediate 2) (Patent document 1).

However, as an intermediate product 1-1, and the intermediate product 1-2 have disadvantages, namely that they are both (a) oily substances and (b) have low purity and stability.

Methods of obtaining the intermediate product 1-1 and intermediate 1-2 have disadvantages, namely that they (c) require complicated procedures, such as chromatography on a column of silica gel, (d) have a low output and (e) and require a source of substances that are dangerous and have a high toxicity (chlorodimethylsilyl ether).

The method of obtaining the intermediate product 2 has drawbacks, namely that it requires (f) complicated procedures, such as distillation and column chromatography, and (g) the use of very expensive, flammable and smoragiewicz reagents (azodicarbonamide compounds such as diethylazodicarboxylate and diisopropylsalicylic), and (h) produce large quantities containing aluminium chloride waste solution, which requires complex processing.

Intermediate products to get T-5224 received by the engagement of the intermediate product 1-1 or intermediate 1-2 intermediate product 2, have disadvantages, namely, that (i) they are all oily substances and that (j) selection requires complex is rocedure, such as chromatography on a column of silica gel.

The method of obtaining the intermediate product to obtain T-5224, carried out with the use of intermediate 1-1, intermediate 1-2 product and intermediate product 2 is not satisfactory.

The intermediate product 2 can be obtained from 2-oxo-2H-romancenovel acid or its salts. Examples of the method of obtaining 2-oxo-2H-romancenovel acid or a salt thereof include, for example, (A) a method in which after the synthesized 6-methyl-2H-chromen-2-she and interaction with hexamethylenetetramine conduct hydrolysis and oxidation (Patent document 2); (B) how close the loop of ester cinnamic acid obtained in various ways from p-hydroxybenzoic acid or its ether complex (non-Patent document 2); (C) how close the loop on p-hydroxybenzoic acid or its ether complex (non-Patent document 3); (D) a method in which after carrying out the condensation on Knoevenagel 3-formyl-4-hydroxybenzoic acid and maleic acid carry out heating and decarboxylation (non-Patent document 4).

However, the method of obtaining (a) has disadvantages, namely, that he (k) requires complicated procedures, (l) requires many kinds of reagents that road.

The method of obtaining (B) has drawbacks, namely, h is o (m) the response of the circuit of the cycle is carried out at high temperatures, (n) there are many stages and (o) there are many types of reagents, and they are expensive.

The method of obtaining (C) has drawbacks, namely, that (p) he gives a low output.

The method of obtaining (D) has drawbacks, namely, that (q) starting material is expensive, and (r) the decarboxylation reaction is carried out at high temperatures.

Methods of industrial production of 2-oxo-2H-romancenovel acid or its salts were not satisfactory.

Patent document 1: description of international publication WO03/042150.

Patent document 2: description of international publication WO2004/050082.

Non-patent document 1: Arthritis Rheum, 2006 Vol. 54 (9), S232.

Non-patent document 2: Chem. Pharm. Bull., 1994, Vol. 42, p.2170-2173.

Non-patent document 3: J. Org. Chem. 1951, Vol. 16, p. 253-261.

Non-patent document 4: Annali di Chimica (Rome) 1966 Vol. 56 (6), p. 700-716.

There is a great need in the way of receiving that provides the ability to easily carry out the mass production of T-5224 using inexpensive raw materials and which is safe for humans and do not have a significant impact on the environment.

DISCLOSURE of the INVENTION

In the described circumstances, the authors of the present invention have conducted intensive studies and found that:

(1) benzophenone derivative represented by the General formula [1]:

[Formula 1]

,

where R1represents a hydrogen atom and R2is alkoxygroup, or R1and R2taken together, represent a bond; R3represents cycloalkyl group, and R4represents a hydrogen atom, or R3and R4are the same and each represents a hydrogen atom or alkyl group, provided that when R1represents a hydrogen atom and R2is alkoxygroup, R3represents cycloalkyl group, and R4represents a hydrogen atom, or its salt is an important intermediate product intermediate product 2;

(2) benzophenone derivative represented by the General formula [2]:

[Formula 6]

,

where R2ais alkoxygroup and R3brepresents cycloalkyl group, or its salt can be easily obtained by(a) the implementation of the dealkylation reaction benzophenone derivative represented by the General formula [1a]:

[Formula 2]

,

where R3aand R4arepresent an alkyl group, to obtain the benzophenone derivative represented by the formula [1b]:

[Formula 3]

,

or its salt, then the implementation of the reaction the AI alkylation received benzophenone derivative or its salt in the presence of a base to obtain a derivative of benzophenone, represented by the General formula [1c]:

[Formula 4]

,

where R3bsuch as defined above, or its salt, and then the reaction breaking the cycle obtained benzophenone derivative or its salt in the presence of a base to obtain benzophenone derivative represented by the General formula [1d]:

[Formula 5]

,

where R2aand R3bsuch as defined above, or its salt, and then the reaction of the recovery obtained benzophenone derivative or its salt;

(3) the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula [3]:

[Formula 7]

where R5represents a methyl group which is substituted by one or more optionally substituted phenyl groups, or optionally substituted oxygen-containing heterocyclic group; and X represents a halogen atom, it is useful as an intermediate product to obtain T-5224, and, in particular, the compound in which R5represents an optionally substituted triphenylmethyl or tetrahydro-2H-Piran-2-ilen group (a) is a solid substance which can be easily handled, (b) has a high purity and stability, (c) is obtained without application of the complex procedures such as chromatography on a column of silica gel, (d) is obtained with a high yield, (e) safe for humans, (g) has only a minor impact on the environment, (h) can be obtained in mass production using inexpensive starting compounds than the known intermediate 1-1 product and intermediate product 1-2;

(4) the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula [3]:

[Formula 9]

,

where R5and X are such as defined above, can be easily obtained by protection of the 2 positions 6-methyl-1,2-benzisoxazol-3-ol methyl group which is substituted by one or more optionally substituted phenyl groups, or optionally substituted oxygen-containing heterocyclic group with obtaining the derivative of 6-methyl-1,2-benzisoxazol-3(2H)-it is represented by the General formula [4]:

[Formula 8]

,

where R5such as defined above, and then halogenoalkanes;

(5) the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula [3]

[Formula 13]

,

where R5and X are such as defined above, can be easily obtained by the implementation of synergies derived complex ester (hydroxymethyl)benzoic acid, etc is stavlennika General formula [5]:

[Formula 10]

,

where R6represents an alkyl group, or its salt with hydroxylamine or its salt with derivatization (hydroxymethyl)benzamidoxime acid represented by the formula [6]:

[Formula 11]

,

or its salt, then the implementation of synergies derived (hydroxymethyl)benzamidoxime acid or its salts with thionylchloride, then the reaction of intramolecular cyclization of the obtained compound or its salt in the presence of a base to obtain the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3-ol represented by the General formula [7]:

[Formula 12]

,

where X is as defined above, or its salt, and then protection 2 provisions derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3-ol or its salts methyl group which is substituted by one or more optionally substituted phenyl groups, or optionally substituted oxygen-containing heterocyclic group;

(6) the intermediate product to obtain T-5224 obtained from compounds of General formula [2] or its salts and compounds of General formula [3], is a solid substance which is easy to apply;

(7) 2-oxo-2H-romancebuy acid represented by the General formula [10]

[Formula 16]

,

or its salt can be easily obtained by oxidation of methyl-2H-chromen-2-it is represented by the General formula [8]:

[Formula 14]

,

the manganese dioxide to obtain 2-oxo-2H-romancelanguage represented by the General formula [9]:

[Formula 15]

,

and then oxidation of the obtained compound salt halogenate acid, in particular, the oxidation of compounds of General formula [8] the manganese dioxide in the presence of sulfuric acid and water, whereby the compound of General formula [9] get high yield, and as manganese, which is a by-product, is dissolved by the solvent for this reaction, the special procedure for removal of manganese is not required, and, in addition, the compound of General formula [10] or its salt with high purity receive a simple procedure without isolating the compounds of General formula [9],

which was created by the present invention.

Using the compound of the present invention and the method for the present invention, to easily get T-5224 on an industrial scale.

The method of receiving according to the present invention differs in that (1) complex cleaning procedures, such as distillation and column chromatography, are not necessary, (2) reagents, which are dangerous and toxic (azodicarbonamide connection such as diethylazodicarboxylate and diisopropylsalicylic; simple chloromethylation ether)not used, (3) the reaction process is simple and the like. In other words, the method of receiving according to the present invention is safe for humans and has little impact on the environment and is useful as a simple way to obtain for the mass production of T-5224.

The compound of the present invention (1) is a solid substance, which is easy to apply, (2) has a high purity and stability, (3) is obtained without the necessity to use complex procedures, such as chromatography on a column of silica gel, (4) is obtained with a high yield, (5) safe for humans, has little impact on the environment and enables mass production with the use of inexpensive raw materials.

Using the compound of the present invention can easily obtain T-5224.

The BEST WAY of carrying out the INVENTION

Further, the present invention is described in more detail.

When used in this description, unless otherwise specified, the halogen atom means a chlorine atom, a bromine atom and an iodine atom; an alkyl group means an unbranched or branched C1-6alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and butil, tert-butyl and pentyl; cycloalkyl group means C3-8cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; alkoxygroup means an unbranched or branched C1-6alkyloxy, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentane; alkylsulfonates means C1-6alkylsulfonates, such as methylsulfonate, tripterocalyx, ethylsulfonyl; arylsulfonate means, for example, benzosulfimide and toluensulfonate.

Examples of leaving groups include halogen atom, alkylsulfonate and arylsulfonate.

"Methyl group which is substituted by one or more optionally substituted phenyl groups, R5represents benzyl, diphenylmethyl and triphenylmethyl group, where the phenyl group can be optionally substituted by one or more groups selected from a halogen atom, nitro group, alkyl groups, alkoxygroup and the like.

"Optionally substituted oxygen-containing heterocyclic group" R5represents a heterocyclic group which contains an oxygen atom as a heteroatom in the structure is of Tcl, such as tetrahydro-2H-Piran-2-yl and tetrahydro-2H-furan-2-yl, which may be optionally substituted by one or more groups selected from a halogen atom, alkyl group and alkoxygroup, and the like.

As for the compounds represented by the General formula [1]or salts thereof, examples of preferred compounds are the following compounds.

Compounds in which R1represents a hydrogen atom and R2represents a methoxy group or ethoxypropan, as well as compounds in which R1and R2taken together form a bond, are preferred. Compounds in which R1represents a hydrogen atom and R2represents a methoxy group, and compounds in which R1and R2taken together form a bond are more preferable.

Compounds in which R3and R4are the same and each represents a hydrogen atom, methyl group or ethyl group, and compounds in which R3represents cycloalkyl group, and R4represents a hydrogen atom, are preferred. Compounds in which R3and R4are the same and each represents a hydrogen atom or methyl group, and compounds in which R3the present is the focus of cyclopentyloxy group, and R 4represents a hydrogen atom are more preferable.

When R1represents a hydrogen atom and R2is alkoxygroup, compounds in which R3represents cycloalkyl group, and R4represents a hydrogen atom, are preferred. When R1represents a hydrogen atom and R2represents a methoxy group or ethoxypropan, compounds in which R3represents cyclopentyloxy group, and R4represents a hydrogen atom are more preferable.

As for the compounds represented by the General formula [1]or its salts, preferred salts include salts of sodium.

Examples of the preferred method of obtaining compounds of General formula [2] or salts thereof include the following methods.

In the preferred method of obtaining R3aand R4acompounds of General formula [1a] are the same and each represents an alkyl group; R3bcompounds of General formula [1c] and [1d] is cycloalkyl group; R2acompounds of General formula [1d] is alkoxygroup.

In the preferred method of obtaining R3aand R4acompounds of General formula [1a] are identical, and each of them represents me the ilen group or ethyl group; R3bcompounds of General formula [1c] and [1d] is cyclopentyloxy group; R2acompounds of General formula [1d] represents a methoxy group or ethoxypropan.

In the preferred method of obtaining R3aand R4acompounds of General formula [1a] are the same, and each represents a methyl group; R3bcompounds of General formula [1c] and [1d] is cyclopentyloxy group; R2acompounds of General formula [1d] represents a methoxy group.

As for the compounds represented by the General formula [3], the preferred compounds include the following examples.

The compound in which R5represents an optionally substituted triphenylmethyl or optionally substituted tetrahydro-2H-Piran-2-ilen group, is preferred. The compound in which R5represents an optionally substituted triphenylmethyl group is more preferable. The compound in which R5represents triphenylmethyl group which may be optionally substituted by a halogen atom or a methoxy group is more preferable. The compound in which R5represents triphenylmethyl group is even more preferred.

The compound in which X submitted is a chlorine atom or a bromine atom, is preferred.

Regarding the preferred method of obtaining compounds of General formula [3] the following examples.

In the preferred method of obtaining used as a compound in which R5represents an optionally substituted triphenylmethyl or optionally substituted tetrahydro-2H-Piran-2-ilen group. In the preferred method of obtaining used as a compound in which R5represents an optionally substituted triphenylmethyl group. In an even more preferred method of obtaining used as a compound in which R5represents triphenylmethyl group which may be optionally substituted by a halogen atom or a methoxy group. In an even more preferred method of obtaining used as a compound in which R5represents triphenylmethyl group. In the preferred method of obtaining used as a compound in which X represents a chlorine atom or a bromine atom.

Regarding the preferred method of obtaining compounds of General formula [10] or its salt to the following examples.

In the preferred method of obtaining the compound of General formula [8] are oxidized by manganese dioxide in the presence of sulfuric acid and water and having connection with the General formula [9], its salt oxidizes haloge the East acid.

Way to obtain is the preferred method, which uses manganese dioxide is activated manganese dioxide.

Way to obtain is preferably a method in which the concentration of sulfuric acid relative to sulfuric acid and water is 10-99% (wt./wt.), more preferably 35-75% (wt./wt.) and even more preferably 45-65% (wt./wt.).

Way to obtain is preferably a method in which the compound of General formula [8] is a 6-methyl-2H-chromen-2-one or 7-methyl-2H-chromen-2-it, and more preferably a method in which the compound is a 6-methyl-2-oxo-2H-chromen.

The compound of General formula [9] can be isolated and purified, but preferably it is served on a stage next reaction without isolation.

With regard to the way in which produce crystals of compounds of General formula [10] or its salt, is the preferred method of crystallization from a mixed solvent of ketones such as methyl isobutyl ketone and the like, and water, a mixed solvent of alcohols, such as methanol and the like, and water or a mixed solvent of sulfoxidov, such as dimethyl sulfoxide and the like, and water. The method of crystallization from a mixed solvent of methanol and water or a mixed solvent of dimethylsulfoxid the a and water is more preferred.

Regarding the preferred method of obtaining the intermediate product to obtain T-5224 the following examples.

In the preferred method of obtaining R2acompounds of General formula [2] represents alkoxygroup, R3brepresents cycloalkyl group, R5compounds of General formula [3] represents optionally substituted triphenylethylene or tetrahydro-2H-Piran-2-ilen group.

In the preferred method of obtaining R2acompounds of General formula [2] represents a methoxy group or ethoxypropan, R3brepresents cyclopentyloxy group, R5General formula [3] represents optionally substituted triphenylmethyl group.

In an even more preferred method of obtaining R2acompounds of General formula [2] represents a methoxy group, R3brepresents cyclopentyloxy group, R5General formula [3] represents triphenylmethyl group.

In the preferred method of obtaining X in the compounds of General formula [3] represents a chlorine atom or a bromine atom.

The following describes the method of obtaining of the present invention.

[Method of obtaining 1]

In this diagram, L is a leaving group; and R2a, R3a, R3band R4athat is s, as specified above.

(1-1)

The compound of formula [1b] or its salt obtained by conducting the reaction dealkylation of compounds of General formula [1a].

The above reaction is carried out, for example, a method described in Protective Groups In Organic Synthesis, by T.W. Greene, John Wiley & Sons, Inc. 1999, third edition, p. 249-276, or in a way appropriate to the specified method.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aliphatic hydrocarbons such as hexane and cyclohexane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; sulfoxidov, such as dimethyl sulfoxide; esters such as methyl acetate and ethyl acetate; amides such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; ketones such as acetone and 2-butanone; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol, NITRILES, such as acetonitrile. These solvents may be used individually, or two or more solvents may be used in combination. Preferred solvents include mixed solvents of the amide is in and aromatic hydrocarbons. A mixed solvent of 1-methyl-2-pyrrolidone and toluene is more preferable. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [1a].

Examples dealkylase agent used for this reaction include salts of mineral acids and organic bases. Examples of mineral acids include chloroethanol acid, Hydrobromic acid and iodomethane acid. Examples of organic bases include dimethylaminopyridine, triethylamine and pyridine. Preferred dealkylase agents include salts of mineral acids and pyridine, preferably is a salt of chloroethanol acid and pyridine. Salt is used in a molar ratio that is 2-10-fold, more preferably 4-10-fold relative to the compounds of General formula [1a].

In addition, the salt of the mineral acid and organic base may be formed within the reaction system. Mineral acid is used in a molar ratio that is 2-10-fold, more preferably 4-10-fold relative to the compounds of General formula [1a]. Organic base is used in a molar ratio that is 2-10-fold, and more preferably 4-10-fold relative to soedineniya formula [1a].

The reaction temperature is, but it is not limited to, 150-250°C, preferably 180-220°C. the reaction Time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

The compound of formula [1b], obtained by this method, or its salt can be used in the next reaction without isolation.

(1-2)

The compound of General formula [1c] or its salt obtained by conducting the alkylation reaction of compounds of formula [1b] or its salt with the compound of General formula [11] in the presence of a base.

As compounds of General formula [11] is commercially available, for example, cyclopentylamine or the like.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; amides such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; ketones such as acetone and 2-butanone, halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene. These solvents may be used individually, or two or more solvents may be used in combination, the Preferred solvents include amides, and more preferred is N,N-dimethylformamide. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [1b] or its salt.

Examples of the base used for this reaction include organic base, such as dimethylaminopyridine, triethylamine, pyridine, alkali metal hydride such as sodium hydride, and the carbonate of an alkali metal such as potassium carbonate and sodium carbonate. Preferred bases include carbonates of alkali metals such as potassium carbonate and sodium carbonate, and potassium carbonate is preferable. The base is used in molar ratio, 0.5 to 20 times, preferably 0.5 to 5-fold relative to the compounds of formula [1b] or its salt.

The compound of General formula [11] is used for this reaction in a molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of formula [1b] or its salt.

The reaction temperature is not particularly limited and ranges from 0 to 120°C, preferably from 50 to 120°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

The compound of General formula [1c]obtained by this method, or its salt can be kind of what Leno(a) and purified(a), but preferably is used in the next reaction without isolation.

(1-3)

The compound of General formula [1d] or its salt obtained by conducting the reaction to breaking the cycle of compounds of General formula [1c] or its salt in the presence of a base.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; esters such as methyl acetate and ethyl acetate; ketones, such as acetone and 2-butanone; alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; NITRILES, such as acetonitrile; amides such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene. These solvents may be used individually, or two or more solvents may be used in combination. Preferred solvents include mixed solvents of alcohols and aromatic hydrocarbons, and more preferred is a mixed solvent of methanol and toluene. The amount used of the solvent is, but im not particularly limited to the W preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [1c] or its salt.

Examples of the base used for this reaction include alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl and potassium tert-piperonyl sodium. Preferred bases include sodium methoxide and ethoxide sodium, and the sodium methoxide is preferred. The base is used in molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of General formula [1c] or its salt. The base can be dissolved in an organic solvent and used. If your base is sodium methoxide, it is preferably dissolved in methanol and used. When the ground is atoxic sodium, it is preferably dissolved in ethanol and used.

The reaction temperature is not particularly limited and ranges from 0 to 100°C, preferably from 30 to 80°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

The compound of General formula [1d], obtained by this method, or its salt is preferably isolated in the form of sodium salt, but can be used in the next reaction without isolation.

(1-4)

Connection General form is s [2] or its salt obtained by carrying out reduction reaction of compounds of General formula [1d] or its salt.

Examples of reduction reaction include catalytic hydrogenation using a catalyst in the presence of a hydrogen source.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include alcohols such as methanol, ethanol, 2-propanol and 2-methyl-2-propanol; amides such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; NITRILES, such as acetonitrile; ketones such as acetone and 2-butanone; esters such as methyl acetate and ethyl acetate; carboxylic acids such as acetic acid, and water. These solvents may be used individually, or two or more solvents may be used in combination. Preferred solvents include mixed solvent of water and one or more solvents selected from the group consisting of alcohols, ketones and ethers. A mixed solvent of 2-propanol and water is more preferable. The amount used of the solvent is,but im not particularly limited, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [1d] or its salt.

Examples of the catalyst used for this reaction include palladium catalysts such as palladium on carbon, palladium chloride, palladium acetate and palladium black; Nickel catalysts such as Raney Nickel, and platinum oxide. The amount used of the catalyst is 0.01 to 1-fold (wt./wt.), preferably from 0.01 to 0.5-fold (wt./wt.) the amount of compounds of General formula [1d] or its salt.

Examples of the hydrogen source to be used for this reaction include hydrogen, formic acid, formate, such as sodium formate and ammonium formate, and hypophosphite sodium. Hydrogen, formic acid and formate are the preferred sources of hydrogen. Formic acid and formate are preferred. Formic acid, sodium formate and ammonium formate are even more preferred.

When the source of hydrogen using formic acid or a formate, formic acid or formate is used in molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of General formula [1d] or its salt.

When the source of hydrogen use hydrogen, the hydrogen pressure is 130 ATM, preferably 1-10 ATM.

In addition, the acid is preferably added to the reaction in order to suppress the formation of by-products. Examples of the acid include organic acids such as acetic acid and formic acid, and mineral acids such as chloromethane acid and sulfuric acid. The acid is used in molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of General formula [1d] or its salt.

The reaction temperature is not particularly limited and ranges from 0 to 100°C, preferably from 30 to 80°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

[Method of obtaining 2]

In this diagram, R5and X are such as defined above.

(2-1)

The compound of General formula [4] is obtained by protection of the 2 position of the compounds of formula [12] or its salt of a methyl group which is substituted by one or more optionally substituted phenyl groups, or optionally substituted oxygen-containing heterocyclic group.

The compound of formula [12] or its salt is produced by a method described, for example, in the description of international publication WO03/042150 or in the application publication No. 2005/0143434 for a U.S. patent. In addition, the compound of formula [12] or its salt m which can be obtained by(a) the method of obtaining A described below.

When R5represents triphenylmethyl group which may be substituted, a compound of General formula [4] receive, for example, a method described in Protective Groups In Organic Synthesis, by T.W. Greene, John Wiley & Sons Inc., 1999, third edition, p. 86-113, 573-586.

More specifically, in the presence of a base a compound of the formula [12] or its salt is subjected to interaction with triphenylmethylchloride.

Examples of the base used for this reaction include organic bases such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine, and carbonates of alkali metals such as potassium carbonate and sodium carbonate. As a preferred base is an organic base, and preferred is pyridine. The base is used in molar ratio, 1 to 20 times, preferably 1 to 10-fold relative to the compounds of formula [12] or its salt.

Examples of triphenylmethylchloride used for this reaction include triphenylmethylchloride, triphenylmethane, (4-methoxyphenyl)diphenylmethane, (4,4'-acid)phenylmethane and (2-chlorophenyl)diphenylmethane. Triphenylmethylchloride and triphenylmethane are preferred, and triphenylmethylchloride is preferable. Triphenylmethylchloride used in molar relationship is, 1-10 times, preferably 1-3 times relative to the compound of formula [12] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include NITRILES such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene; esters such as methyl acetate, ethyl acetate and butyl acetate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, and the methylene chloride is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [12] or its salt.

The reaction temperature is not particularly limited and ranges from -50 to 150°C, preferably from -30 to 100°C.

The reaction time is not particularly ogranichivayas and is from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

When R5is a tetrahydro-2H-Piran-2-strong group which may be substituted, a compound of General formula [4] receive, for example, a method described in Protective Groups In Organic Synthesis, by T.W. Greene, John Wiley & Sons Inc., 1999, third edition, p. 27-58, 249-280.

More specifically, for example, the compound of formula [12] or its salt is subjected to interaction with dihydropyran in the presence of a catalyst.

Examples of the catalyst used for this reaction include acid, such as chloromethane acid, sulfuric acid and p-toluensulfonate acid; salts such as p-toluensulfonate pyridinium, triphenylphosphorane, copper chloride(I), aluminum sulfate and zeolite. Preferred catalysts include salts, and n-toluensulfonate pyridinium is preferable. The catalyst is used in a molar ratio, 0.01 to 10 times, preferably from 0.01 to 3-fold relative to the compounds of formula [12] or its salt.

Examples dihydropyran used for this reaction include 3,4-dihydro-2H-Piran, 3,4-dihydro-2-methoxy-2H-Piran and 5,6-dihydro-4-methoxy-2H-Piran. 3,4-Dihydro-2H-Piran is preferred. Dihydropyran used in molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of formula [12] or its salt.

Examples of the solvent, the COI is lisemore for this reaction and is not particularly limited, if only he did not influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; esters such as methyl acetate, ethyl acetate and butyl acetate; NITRILES such as acetonitrile; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene, and the like. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, and the methylene chloride is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [12] or its salt.

The reaction temperature is not particularly limited and ranges from -50 to 100°C, preferably from -30 to 50°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

The compound of General formula [4], obtained by this method can be used in the next reaction without isolation.

(2-2)

The compound of General formula [3] are halogenoalkanes soy is inane General formula [4].

Examples of the halogenation agent used for this reaction and is not particularly limited, if only he was a halogenation agent, which can be used for the halogenation of alkyl side chain aromatic compounds include elemental halogen, such as chlorine, bromine and iodine; imides, such as N-chlorosuccinimide, N-bromosuccinimide, N-chloritoid and N-bromophthalimide; hydantoins such as 1,3-dibromo-5,5-dimethylhydantoin and 1,3-dichloro-5,5-dimethylhydantoin, and sulfurylchloride. The preferred halogenation agents include imides and N-bromosuccinimide is preferable. Halogenation agent used is not particularly limited to, in molar ratio, times 1 or more, preferably 1-3 relative to the compounds of General formula [4].

The above reaction is preferably carried out in the presence of a radical initiator. Examples of the radical initiator is not limited, if only he was an ordinary radical initiator include dialkylamide, such as di-tert-butylperoxide, di-tert-AMYLPEROXY and di(2-methyl-2-pentyl)peroxide; diazepamonline, such as Dibenzoyl peroxide, dicumylperoxide and difluorinated; alkylhydroperoxide, such as tert-butylhydroperoxide and cumylhydroperoxide; percarbonate acid, such as derbentina acid, monoperoxyphthalic acid, VT is Ravina acid and peracetic acid; inorganic paracaseinate, such as personna acid, and organic azo compounds such as 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile), 2,2'-azobis(2-methyl butyronitrile), 2,2'-azobisisobutyronitrile, 1,1'-azobis(cyclohexanecarbonitrile), 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile), 2,2'-azobis(2-amidinopropane)dihydrochloride and dimethyl 2,2'-azobisisobutyronitril. Organic azo compounds are preferred radical initiators, and more preferred are 2,2'-azobisisobutyronitrile, 2,2'-azobis(2,4-dimethylvaleronitrile) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile). Radical initiators are used, but without limiting it, in molar ratio, a multiple of 0.01 or more, preferably 0.05 to 1 with respect to the compounds of General formula [4].

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aliphatic hydrocarbons such as hexane, cyclohexane and heptane; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; esters such as methyl acetate, ethyl acetate and butyl acetate; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene. These solvents may be used with etani. Preferred solvents include esters and halogenated hydrocarbons. Methylene chloride and chlorobenzene are more preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [4].

The reaction temperature is not particularly limited and varies from 0 to 200°C, preferably from 0 to 100°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

In this reaction may be by-products in the form of compounds in which the methyl group of the compounds of General formula [4] dihalogenoalkane and trihalomethane. In this case, for example, by the method described in Synthesis, 2001, Vol. 14, p. 2078-2080, and more specifically, the reaction of ester dialkylphosphorous acid in the presence of a base compound, in which a methyl group dihalogenoalkane or trihalomethane, can be converted into a compound of General formula [3].

Examples of the base used for this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine; hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide cesium hydroxide and barium hydroxide; carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate and barium carbonate. Preferred bases include carbonates of alkali metals or alkaline earth metals, and potassium carbonate is preferable. The base is used in molar ratio, times 0.5 or more, preferably 0.5 to 10 with respect to the compounds of General formula [4].

Examples of ester dialkylphosphorous acid used for this reaction include ester dimethylphosphinic acid, ester diethylphosphonate acid, ester diisopropylphenol acid and ester dibutylphthalate acid, and ester dimethylphosphinic acid and ester diethylphosphonate acid are preferred. Ester dialkylphosphorous acid is used in molar ratio, times 0.5 or more, preferably 0.5 to 10 with respect to the compounds of General formula [4].

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include ethers such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol, and halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons. Methylene chloride is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-20 times (about./wt.) the amount of compounds of General formula [4].

The reaction temperature is not particularly limited and varies from 0 to 200°C, preferably from 0 to 100°C.

The reaction time is not particularly limited and is from 1 to 50 hours, preferably from 1 to 24 hours.

[Method of obtaining 3]

In this diagram, R5, R6and X are such as defined above.

As an example, compounds of General formula [5] or its salt is known methyl ester of 2-hydroxy-4-(hydroxymethyl)benzoic acid. In addition, the compound of General formula [5] or its salt get, for example, by the method described in the description of international publication WO2004/113281 or the Japan patent No. 3197011.

In addition, the compound of General formula [5] or its salt is produced by way of getting B, described below.

(3-1)

The compound of the formula [6] or its salt is produced by engagement of the compounds of General formula [5] or its salt with hydroxylamine or its salt in the presence or in the absence of base.

Examples of the hydroxylamine or its salt used(Oh for this reaction, include hydroxylamine, hydrosulfate, hydroxylamine, hydroxylamine hydrochloride, and hydroxylamine oxalate. Hydroxylamine hydrochloride is preferred. The hydroxylamine or its salt can be dissolved in a solvent such as water and methanol, and used(a). The hydroxylamine or its salt is used in molar ratio, times 1 or more, preferably 1-5 relative to the compounds of General formula [5] or its salt.

The above reaction is preferably carried out in the presence of a base. Examples of the base include hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and barium hydroxide; carbonates of alkali metals such as sodium bicarbonate and potassium bicarbonate; carbonates of alkali metals or alkaline earth metals such as sodium carbonate, potassium carbonate, barium carbonate; aluminates such as sodium aluminate and potassium aluminate; alkoxides of metals such as sodium methoxide, ethoxide sodium tert-piperonyl potassium. When two or more types of bases can be used in combination. In addition, if necessary, the base can be dissolved in a solvent such as water and methanol, and used. Preferred bases include alkoxides of metals. The sodium methoxide is one is to be more preferred. When the base using sodium methoxide, it is preferably used in the form of a methanol solution. The base is used in molar ratio, times 1 or more, preferably 1-10 relative to the compounds of General formula [5] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and water. These solvents may be used in combination. Preferred solvents include alcohols, and methanol is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [5] or its salt.

The reaction temperature is not particularly limited and varies from 0 to 200°C, preferably from 0 to 100°C.

The reaction time is not particularly Ogre is nicelets and ranges from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

The compound of the formula [6] or its salt obtained(th) in this way, can be used in the next reaction without separation, but preferably emit.

(3-2)

The compound of General formula [13] or its salt is produced by engagement of the compounds of formula [6] or its salt with thionylchloride.

Examples of thionylchloride used for this reaction include thionyl chloride and thienylboronic, and thionyl chloride is preferred. Thionylchloride used in molar ratio, times 1 or more, preferably 1-10 relative to the compounds of formula [6] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene, and sulfolan. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, and the methylene chloride is preferred. The amount used of the solvent is, but what about them is not limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [6] or its salt.

The above reaction is preferably carried out in the presence of a catalyst. Examples of the catalyst include N,N-dimethylformamide. The catalyst is used in a molar ratio, times 0.001 to 1, preferably from 0.01 to 0.5 relative to the compounds of formula [6] or its salt.

The reaction temperature is not particularly limited and ranges from 0 to 100°C, preferably from 0 to 50°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

The compound of General formula [13] or its salt obtained(th) in this way, preferably used in the next reaction without isolation.

(3-3)

The compound of General formula [7] or its salt is produced by engagement of the compounds of General formula [13] or its salt with thionylchloride and then carrying out the reaction of intramolecular cyclization in the presence of a base.

Examples of thionylchloride used for this reaction include thionyl chloride and thienylboronic, and thionyl chloride is preferred. Thionylchloride used in molar ratio, times 1 or more, preferably 1-10 relative to the compounds of formula [13] or its salt.

Examples of the base used is about for this reaction, include organic bases such as triethylamine, N,N-diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Preferred bases are organic bases, and the pyridine is preferable. The base is used in molar ratio, times 1 or more, preferably 1-5 relative to the compounds of General formula [13] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene, and sulfolan. These solvents may be used in combination. Preferred solvents include halogenated hydrocarbons, and the methylene chloride is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) Koli is estu compounds of General formula [13] or its salt.

The reaction temperature is not particularly limited and ranges from 0 to 100°C, preferably from 0 to 50°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

The compound of General formula [7] or its salt obtained(th) in this way, preferably used in the next reaction without isolation.

(3-4)

The compound of General formula [3] is obtained by protection of the 2 position of the compounds of General formula [7] or its salt of a methyl group which is substituted by one or more optionally substituted phenyl groups, or optionally substituted oxygen-containing heterocyclic group. The above reaction is carried out in accordance with the method of obtaining a (2-1).

[Method 4]

(4-1)

The compound of General formula [9] is obtained by oxidation of compounds of General formula [8] the manganese dioxide in the presence of sulfuric acid and water.

With regard to compounds of General formula [8], is commercially available, for example, 6-methyl-2H-chromen-2-it.

The quantity of sulfuric acid and water used for this reaction are not particularly limited and is preferably 1-50 times (about./wt.), more preferably 3-15-fold (about./wt.) the amount of compounds of General formula [8]. The concentration of sulfuric acid otnositelnostn acid and water is preferably 10-99% (wt./wt.), more preferably 35-75% (wt./wt.) and even more preferably 45-65% (wt./wt.).

Can be added to the solvent not affecting the reaction. Examples of the solvent is not limited, if it does not affect the reaction include aliphatic halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, and aromatic halogenated hydrocarbons such as chlorobenzene and dichlorobenzene. These solvents may be used in combination. Preferred solvents include halogenated aromatic hydrocarbons, and the chlorobenzene is preferable. The amount used of the solvent is, but im not particularly limited to, preferably 0.1 to 10 times (about./wt.), more preferably 0.5 to 3-fold (about./wt.) the amount of compounds of General formula [8].

The manganese dioxide used for this reaction are not particularly limited, but preferred is activated manganese dioxide.

Activated manganese dioxide can be obtained by known methods, in which participate in the interaction, for example, manganese sulfate and potassium permanganate. Additionally, there may be used commercially available activated manganese dioxide and the one that's produce on an industrial scale for use in the batteries.

Used quantity is the proportion of manganese dioxide is 0.5 to 10-fold (wt./wt.), more preferably 1-3-fold (wt./wt.) the amount of compounds of General formula [8].

Manganese dioxide can be added at one time, but preferably it is added 2-50 an aliquot, more preferably 8-20 the aliquot.

The reaction temperature is not particularly limited and ranges from 0 to 150°C, preferably from 50 to 90°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 20 hours.

The compound of General formula [9], obtained by this method is preferably used in the next reaction without isolation.

(4-2)

The compound of General formula [10] or its salt is produced by oxidation of compounds of General formula [9] salt halogenate acid.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aliphatic halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane; aromatic halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; ethers, such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxidov, such as dimethyl sulfoxide; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; to the tones, such as acetone and 2-butanone; NITRILES, such as acetonitrile; esters such as methyl acetate and ethyl acetate; nitro compounds such as nitromethane and nitrobenzene; aromatic hydrocarbons such as benzene, toluene and xylene, and water. These solvents may be used in combination. Preferred solvents include mixed solvent of ketones, sulfoxidov and water, and a mixed solvent of 2-butanone, dimethyl sulfoxide and water is more preferable. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 3-30-fold (about./wt.) the amount of compounds of General formula [9].

Examples of salt halogenate acid used for this reaction include chlorite, bromic and yodit. Examples of salts include salts of alkali metals such as sodium and potassium, salts of alkaline earth metals such as calcium. More specifically, the chlorite is preferred that the alkali metal chlorite is more preferred, and sodium chlorite is even more preferred. These salts can be used in aqueous solution.

Salt halogenate acid is used in molar ratio, times 1 or more, preferably 1-2 relative to the compounds of General formula [9].

Usually the above reaction is carried out preferably in the presence of one or more of halogen acceptors selected from the group consisting of dimethyl sulfoxide, sulfamic acid, hydrogen peroxide and 2-methyl-2-butene, and the like. The preferred halogen acceptors include dimethylsulfoxide.

The amount of the halogen acceptor is equal to 0.4-fold (about./wt.), preferably 0.4 to 4-fold (about./wt.) or more number of compounds of General formula [9].

In addition, the above reaction is preferably carried out under acidic conditions by adding an acid or a buffer agent, and more preferably carried out at pH 4,0-7,0. Examples of the acid include organic acids such as acetic acid and formic acid, and mineral acids such as chloromethane acid and sulfuric acid. Mineral acids, such as chloromethane acid and sulfuric acid are preferred, and chloromethane acid is more preferable. Examples of the buffer agent include sodium dihydrophosphate or potassium dihydrophosphate.

In addition, when the compound of General formula [9] is used for this reaction without isolation, the reaction mixture may be added to the base and the reaction is carried out at pH 4,0-7,0. Examples of the base include organic bases such as triethyl is in N,N-diisopropylethylamine; hydroxides of alkali metals or alkaline earth metals such as sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide and barium hydroxide, and ammonia water. Preferred bases include sodium hydroxide, potassium hydroxide and ammonia water, and ammonia water is preferable.

The reaction temperature is not particularly limited and ranges from -20 to 120°C, preferably from 0 to 50°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 20 hours.

[Method of obtaining 5]

In this diagram, R3aand R4asuch as defined above.

With regard to compounds of General formula [14], are commercially available, for example, 1,3-dimethoxybenzene and 1,3-diethoxybenzene.

(5-1)

The compound of General formula [1a] is obtained by engagement of the compounds of formula [10a] or its salt with a compound of General formula [14] in the presence of acid.

Examples of the acid used for this reaction include strong organic acids, such as methanesulfonate acid, triftormetilfullerenov acid and the mixture methanesulfonic acid and pentoxide Diaspora. The mixture methanesulfonic acid and pentoxide Diaspora is preferable. Using the mixture of meta is sulfonic acid and pentoxide Diaspora the number methanesulfonic acid is 1-50 times (about./wt.), preferably 2-20-fold (about./wt.) the amount of the compounds of formula [10a] or its salt. The pentoxide Diaspora used in molar ratio, 0.5 to 10 times, preferably 0.5 to 4 times the amount of the compounds of formula [10a] or its salt.

Can be added to the solvent not affecting the reaction. The solvent is not particularly limited, if only it did not affect the reaction. And his examples include halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; aliphatic hydrocarbons such as hexane and cyclohexane; nitro compounds such as nitromethane and nitrobenzene, and carbon disulphide. Can be used with these solvents, one type or two or more types in combination. Preferred solvents include halogenated hydrocarbons, and the chlorobenzene is preferable. The amount used of the solvent is, but im not particularly limited to, preferably 0.05 to 10-fold (about./wt.) and more preferably 0.1 to 3 times (about./wt.) the amount of the compounds of formula [10a] or its salt.

The compound of General formula [14] is used in molar ratio, 1-10 times, preferably 1-2 times relative to the compound of the formula [10a] or its salt.

The reaction temperature is not particularly limited and ranges from 30 to 150°C, preferably from 50 to 00°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

The compound of General formula [1a], obtained by this method can be used in the next reaction without isolation.

(5-2)

The compound of General formula [1a] is produced by the reaction Friedel-between reactive derivatives of the compounds of formula [10a] or its salt with the compound of General formula [14].

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene; aliphatic hydrocarbons such as hexane and cyclohexane; nitro compounds such as nitromethane and nitrobenzene, and carbon disulphide. Can be used with these solvents, one type or two or more types in combination. Preferred solvents include nitro compounds, and halogenated hydrocarbons, and nitromethane and methylene chloride are preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [10a] or its salt.

As for the reaction-sposobov the derivative compounds of formula [10a] or its salt, used for this reaction, examples of it include the acid halides or acid anhydrides.

Gelegenheid acid or anhydride of the acid compounds of the formula [10a] or its salt is produced by engagement of the compounds of formula [10a] or its salt with an activator, such as thionyl chloride, oxalicacid, pentachloride phosphorus, acetic anhydride and ethyl ether harpalinae acid. The activator is used in molar ratio, 1-10 times, preferably 1-3 times relative to the compound of the formula [10a] or its salt. In addition, when carrying out the reaction, giving gelegenheid acid compounds of the formula [10a] or its salt, add as a catalyst N,N-dimethylformamide in molar ratio, 0.001 to 1-fold, preferably about 0.001 to 0.5-fold relative to the compounds of formula [10a] or its salt.

Examples of the acid used for this reaction include tin tetrachloride, aluminium chloride, trevormoran and zinc chloride. The acid is used in molar ratio, 1-10 times, preferably 1-5 times relative to the compound of the formula [10a] or its salt.

The compound of General formula [14] is used in molar ratio, 1-10 times, preferably 1-2 times relative to the compound of the formula [10a] or its salt.

The reaction temperature is not particularly limited and ranges from -78 to 100°C, predpochtite the flax from -50 to 70°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 10 minutes to 24 hours.

[Method of obtaining 6]

In this diagram, R2a, R3b, R5and X are such as defined above.

The compound of General formula [20] or its salt is produced by engagement of the compounds of General formula [2] or its salt with a compound of General formula [3].

The compound of General formula [20] or its salt obtained by implementation of the alkylation reaction between the compound of General formula [2] or its salt and the compound of General formula [3].

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; amides such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and N,N-dimethylacetamide; ketones such as acetone and 2-butanone; halogenated hydrocarbons such as methylene chloride, chloroform, 1,2-dichloroethane, chlorobenzene and dichlorobenzene. These solvents may be used individually, or two or more solvents may be used in combination. Preferred solvents include ketones and acetone is 2-butanone are more preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [2] or its salt.

Examples of the base used for this reaction include organic bases such as dimethylaminopyridine, triethylamine and pyridine; hydrides of alkali metals, such as sodium hydride; carbonates of alkali metals such as potassium carbonate and sodium carbonate. Preferred bases include carbonates of alkali metals such as potassium carbonate and sodium carbonate, and the like, and the potassium carbonate is preferable. The base is used in molar ratio, 0.5 to 20 times, preferably 0.5 to 5-fold relative to the compounds of General formula [2] or its salt.

The compound of General formula [3] is used for this reaction in a molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of General formula [2] or its salt.

The reaction temperature is not particularly limited and ranges from 0 to 120°C, preferably from 50 to 120°C.

The reaction time is not particularly limited and is generally from 10 minutes to 50 hours, preferably from 30 minutes to 24 hours.

Next described is a method of obtaining compounds of the formula [5] and formula [12] or their salts, which are used in the floor of the attachment of the present invention. These connections receive, by combining the methods that are already known, and they can, for example, be obtained in the following way to obtain.

[Method of receiving A]

The compound of the formula [15] or its salt get, for example, by methods described in the description of international publication WO03/042150 or application No. 2005/0143434 patent of the United States.

The compound of formula [12] or its salt is produced by engagement of the compounds of formula [15] or its salt with thionylchloride and then, in the presence of a base, carrying out the reaction of intramolecular cyclization.

Examples of thionylchloride used for this reaction include thionyl chloride and thienylboronic, and thionyl chloride is preferred. Thionylchloride used in molar ratio, times 1 or more, preferably 1-10 relative to the compounds of formula [15] or its salt.

Examples of the base used for this reaction include organic bases such as triethylamine, N,N-diisopropylethylamine, tributylamine, pyridine, dimethylaminopyridine, N-methylmorpholine and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate. Preferred bases are organic bases, and tributylamine is more is preferred. The base is used in molar ratio, times 1 or more, preferably 1-5 relative to the compounds of formula [15] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, tert-butyl methyl ether, cyclopentylmethyl ether, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene, and sulfolan. These solvents may be used in combination. Preferred solvents include ethers, and tert-butyl methyl ether is more preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of the compounds of formula [15] or its salt.

The reaction temperature is not particularly limited and ranges from -30 to 30°C, preferably -20 to 20°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

The compound of formula [12] or its salt obtained(th) in this way, you can use the with in the next reaction without isolation, but preferably it distinguish, for example, conventional methods such as extraction and crystallization.

[Method of obtaining B]

In this diagram, R6such as defined above.

With regard to compounds of General formula [16] or its salts, for example the known methyl ester of 2-hydroxy-4-methylbenzoic acid.

(B-1)

The compound of General formula [17] can be obtained, for example, a method described in Protective Groups In Organic Synthesis, by T.W. Greene, John Wiley & Sons, Inc. 1999, third edition, p. 149-179, 276-280. More specifically, it is obtained, for example, by engagement of the compounds of General formula [16] or its salt with benzoylchloride in the presence of a base.

Examples of the base used for this reaction include organic bases such as dimethylaminopyridine, triethylamine, pyridine and N-methylmorpholine, and carbonates of alkali metals such as potassium carbonate and sodium carbonate. Preferred bases are organic bases, and triethylamine is preferable. The base is used in molar ratio, 1 to 20 times, preferably 1-5 times relative to the compound of General formula [16] or its salt.

As benzoylchloride used for this reaction, its examples include benzoyl chloride and benzylbromide, and be taillored is preferred. Benzoylecognine used in molar ratio, 1-10 times, preferably 1-3 times relative to the compound of General formula [16] or its salt.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include NITRILES such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene; esters such as methyl acetate, ethyl acetate and butyl acetate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide. These solvents may be used in combination. Preferred solvents include aromatic hydrocarbons, and toluene is more preferable. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [16] or its salt.

The reaction temperature is not particularly limited and ranges from -50 to 150°C, preferably about is -30 to 100°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

(B-2)

The compound of General formula [18] is obtained by bromirovanii compounds of General formula [17]. The above reaction is carried out in accordance with the method of obtaining (2-2).

(B-3)

The compound of General formula [19] receive, for example, by engagement of the compounds of General formula [18] acetate.

As for the acetate used for this reaction, examples of it include potassium acetate and sodium acetate, and potassium acetate is preferred. Acetate is used in molar ratio, 1-10 times, preferably 1-3 times relative to the compound of General formula [18].

In addition, the acetate can be obtained in situ.

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include NITRILES such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene; esters such as methyl acetate, ethyl acetate and Buti is acetate; amides such as N,N-dimethylformamide and N,N-dimethylacetamide, and sulfoxidov, such as dimethylsulfoxide. These solvents may be used in combination. Preferred solvents include mixed solvents of esters and amides, and a mixed solvent of ethyl acetate and N,N-dimethylformamide is preferred. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [18].

The reaction temperature is not particularly limited and varies from 0 to 200°C, preferably from 0 to 100°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

(B-4)

The compound of General formula [5] or its salt obtained by hydrolysis of compounds of General formula [19]. More specifically, it is obtained, for example, by engagement of the compounds of General formula [19] with the metal alkoxide.

Examples of the metal alkoxide used for this reaction include sodium methoxide and ethoxide sodium, and the sodium methoxide is preferred. When the metal alkoxide is sodium methoxide, it is preferably used in the form of a methanol solution. The metal alkoxide and the use in molar ratio, 2-10-fold, preferably 2-3-fold relative to the compounds of General formula [19].

Examples of the solvent used for this reaction and is not particularly limited, but he would not influence the reaction include NITRILES such as acetonitrile; aromatic hydrocarbons such as benzene, toluene, xylene and mesitylene; ethers, such as dioxane, tetrahydrofuran, anisole, dimethyl ether of ethylene glycol and dimethyl ether of diethylene glycol; aliphatic hydrocarbons such as hexane and cyclohexane; halogenated hydrocarbons such as chloroform, methylene chloride, chlorobenzene and dichlorobenzene; alcohols such as methanol, ethanol, propanol, 2-propanol and butanol; amides, such as N,N-dimethylformamide and N,N-dimethylacetamide; sulfoxidov, such as dimethyl sulfoxide, and water. These solvents may be used in combination. Preferred solvents include mixed solvent of aromatic hydrocarbons and alcohols, and more preferred is a mixed solvent of toluene and methanol. The amount used of the solvent is, but im not particularly limited to, preferably 1-50 times (about./wt.), more preferably 1-15 times (about./wt.) the amount of compounds of General formula [19].

The reaction temperature is not particularly limited and ranges from 0 to 150°C, predpochtitel is but from 0 to 100°C.

The reaction time is not particularly limited and varies from 5 minutes to 50 hours, preferably from 5 minutes to 24 hours.

Compounds obtained by the methods of preparation, described above, can be isolated and purified by conventional methods such as extraction, crystallization, distillation and column chromatography.

In addition, when there are isomers of the compounds used in the methods of manufacturing described above (for example, optical isomers, geometrical isomers and tautomers), all of these isomers can be used, and can also be used a metal salt, hydrate, solvate and all crystalline forms.

Further, the present invention is described with examples and examples of the preparation, but the present invention is not limited to these examples.

As silica gel, unless otherwise noted, we used B.W. Silica gel BW-127ZH (Fuji Silysia Chemical Ltd.).

The ratio of the concentrations of the components suantai mixture is the volume ratio.

For each example and example getting each of the abbreviations mean the following.

Me: methyl; THP: tetrahydropyranyl; Tr: triphenylmethyl; DMSO-d6: deuterated dimethyl sulfoxide.

Example 1-1

17 l of water was added dropwise in 79 l of 62.5% sulfuric acid and, after addition of 13.0 kg 6-methyl-2H-chromen-2-she and 13 l chlorobenzo is a, 20,8 kg of manganese dioxide was divided into 8 parts and added at 70-90°C. for Another 10 l of 62.5% sulfuric acid was added dropwise at 70-90°C., and the mixture was stirred for 1 hour at 80-90°C. After cooling, the reaction mixture was added 75 l of water and 22 l of 25% ammonia water. Then added 26 l of ethyl acetate and 52 l 2-butanone, and the aqueous layer was removed. To the obtained reaction mixture was added 111 l 2-butanone and 13 l of water, the separated organic layer was added to 7.8 l of dimethyl sulfoxide and 3.9 l chloroethanol acid. Was added dropwise 26 l 25% aqueous solution of sodium chlorite at 15-40°C, and the mixture was stirred for 30 minutes at the same temperature. After stirring the reaction mixture at 74-80°C for 15 minutes, separated the organic layer. To the organic layer were added 65 l of water was added dropwise at 30-40°C 13 l 25% ammonia water and the separated aqueous layer. To the aqueous layer was added 52 l of dimethyl sulfoxide was added dropwise 8 l chloroethanol acid at 30-40°C, then 8 l chloroethanol acid was added dropwise at 65-75°C, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was cooled, and the solid was filtered to obtain 9,03 kg pale yellow-brown solid 2-oxo-2H-chromen-6-carboxylic acid.

1H-NMR (DMSO-d6) δ: 6,59 (1H, d, J=9.6 Hz), 7,49(1H, d, J=8.6 Hz), to 8.12 (1H, DD, J=8,6, 1, Hz), to 8.20 (1H, d, J=9.6 Hz), at 8.36 (1H, d, J=1.9 Hz), 13,22 (1H, users).

Example 1-2

260 ml of water was added dropwise in 1220 ml of 62.5% sulfuric acid and, after addition of 200 g of 6-methyl-2H-chromen-2-she and 200 ml of chlorobenzene, 320 g of manganese dioxide was divided into 8 parts and added at 70-90°C. 160 ml of 62.5% sulfuric acid was added dropwise at 70-90°C, and the mixture was stirred for 30 minutes at 80-90°C. After cooling, the reaction mixture was added 1160 ml of water was added dropwise 340 ml of 25% ammonia water. Then added 400 ml of ethyl acetate and 800 ml of 2-butanone and the aqueous layer was removed. To the obtained reaction mixture was added 1700 ml of 2-butanone and 200 ml of water, the separated organic layer was added 120 ml of dimethyl sulfoxide and water (800 ml). Was added dropwise 80 ml of 25% ammonia water. Was added dropwise 360 ml of 25% aqueous solution of sodium chlorite at 25-40°C, and the mixture was stirred for 1 hour at the same temperature. Then the reaction mixture was added dropwise 108 ml of 25% ammonia water at 25-35°C, and separated water layer. To the aqueous layer was added 600 ml of methanol and added dropwise 40 ml chloroethanol acid. Then add two parts of 15.7 g of sodium sulfite at 25-30°C, and the mixture was stirred for 30 minutes. After adding dropwise 200 ml chloroethanol acid at 40-50°C, the reaction mixture was cooled, and the solid was filtered and collected to obtain 144 g bled what about the yellow-brown solid 2-oxo-2H-chromen-6-carboxylic acid.

The values of 1H-NMR in DMSO-d6were the same as example 1-1.

Example 2

7 ml of water was added dropwise in 31 ml of 62.5% sulfuric acid and, after addition of 5.00 g of 7-methyl-2H-chromen-2-it and 5 ml of chlorobenzene, 8.00 g of manganese dioxide was divided into 8 parts and added at 70-90°C. for Another 4 ml of 62.5% sulfuric acid was added dropwise at 70-90°C, and the mixture was stirred for 1 hour at 80-90°C. After cooling, the reaction mixture was added 29 ml of water was added dropwise 9 ml of 25% ammonia water. Then added 10 ml of ethyl acetate and 20 ml of 2-butanone and the aqueous layer was removed. To the obtained reaction mixture was added 43 ml of 2-butanone and 5 ml of water, the separated organic layer was added 3 ml of DMSO and 2 ml chloroethanol acid. Was added dropwise 10 ml of 25% aqueous solution of sodium chlorite at 15-40°C, and the mixture was stirred for 30 minutes at the same temperature. The reaction mixture was stirred at 74-80°C, and separated the organic layer. To the organic layer were added 40 ml of water and 15 ml of 2-butanone. Was added dropwise 5 ml of 25% ammonia water at 30-40°C, and separated water layer. To the aqueous layer was added 30 ml of dimethyl sulfoxide was added dropwise at 30-40°C 3 ml chloroethanol acid. After adding dropwise 5 ml chloroethanol acid at 65-75°C and the mixture was stirred for 30 minutes at the same himself the first temperature. The reaction mixture was cooled, and the solid was filtered and collected to obtain a rate of 1.67 g of pale yellow-brown solid 2-oxo-2H-chromen-7-carboxylic acid.

1H-NMR (DMSO-d6) δ: 6,63 (1H, d, J=9,5 Hz), 7,80-of 7.90 (3H, m)to 8.14 (1H, d, J=9.5 Hz).

Example 3

6,85 kg pentoxide Diaspora was added to 46 l methanesulfonic acid and after stirring for 1 hour at 70-80°C was added 17,0 kg 2-oxo-2H-chromen-6-carboxylic acid and 1.7 l of chlorobenzene, was added dropwise 13,0 kg of 1,3-dimethoxybenzene at 70-80°C, and the mixture was stirred for 3 hours at the same temperature. After cooling, the reaction mixture was added 94 l 2-butanone and added dropwise 34 liters of water and then 55 l of 25% ammonia water. Then the reaction mixture was heated to 65-75°C, and separated the organic layer. Was added to the organic layer 26 l 2-butanone and 34 l of water was added dropwise 2.6 liters of 25% ammonia water. The reaction mixture was heated to 65-75°C, and separated the organic layer. The organic layer was heated and 77 l of solvent drove away under reduced pressure. Was added to the reaction mixture 17 l 4-methyl-2-pentanone and 60 l of methanol and then added dropwise to 120 l of water at 40-65°C. After stirring the reaction mixture for 30 minutes at 10-25°C, the solid was filtered and collected to obtain 19,0 kg pale yellow-brown, the CSO solids 6-(2,4-dimethoxybenzoyl)-2H-chromen-2-it.

1H-NMR (CDCl3) δ: at 3.69 (3H, s)to 3.89 (3H, s), 6,47 (1H, d, J=9.8 Hz), of 6.52 (1H, d, J=2.2 Hz), 6,59 (1H, DD, J=8,5 and 2.2 Hz), 7,35 (1H, d, J=8.5 Hz), was 7.45 (1H, d, J=8.5 Hz), 7,74 (1H, d, J=9.8 Hz), to $ 7.91 (1H, DD, J=8,5, 2.0 Hz), 7,95 (1H, d, J=2.0 Hz)

Example 4

478 g of 6-(2,4-dimethoxybenzoyl)-2H-chromen-2-it was added to the mixed solution, 480 ml of pyridine, 240 ml of 1-methyl-2-pyrrolidone and 480 ml of toluene. Then 454 ml chloroethanol acid was added dropwise. The reaction mixture was heated in the course of carrying out azeotropic dehydration was stirred for 2 hours at 200-210°C. After cooling the reaction mixture to 85-110°C was added 480 ml of N,N-dimethylformamide was added dropwise 2.4 liters of water at 85-95°C. After stirring the reaction mixture for 30 minutes at 10-25°C, the solid was filtered and collected. Received 421 g of pale yellow-brown solid of 6-(2,4-dihydroxybenzyl)-2H-chromen-2-it.

1H-NMR (DMSO-d6) δ: 6,38-6.42 per (2H, m), 6,60 (1H, d, J=9.5 Hz), 7,41 (1H, d, J=8,8 Hz), 7,53 (1H, d, J=8.5 Hz), 7,86-7,88 (1H, m), of 8.06 (1H, d, J=2.0 Hz), 8,18 (1H, d, J=9.5 Hz), 10,69 (1H, s), 11,82 (1H, s).

Example 5-1

9,25 kg of potassium carbonate, 21,0 kg 6-(2,4-dihydroxybenzyl)-2H-chromen-2-she and 16.6 kg of cyclopentylamine was added to 63 l of N,N-dimethylformamide, and the mixture was stirred for 2 hours at 90-100°C. After cooling, the reaction mixture was added 63 l of toluene, 21 l 2-butanone and 84 liters of water. Then obavljale of 1.26 kg of potassium carbonate and separated the organic layer. Once added to the organic layer 11 l of methanol and 21 l of toluene kept at reduced pressure 63 l of solvent. To the obtained reaction mixture was added dropwise at 55-65°C 33,0 kg of a 28% methanol solution of sodium methoxide. The mixture was stirred for 1 hour at the same temperature. The reaction mixture was cooled, and after successive addition of 16 l chloroethanol acid and 32 l of toluene was added dropwise at 60-70°C 63 l of water. Separated the organic layer and after adding 21 l of toluene kept at reduced pressure 42 l of solvent. After stirring the reaction mixture for 30 minutes at 75-85°C was added dropwise at 10-25°C 42 l of cyclohexane and 42 liters of water. After stirring for 30 minutes at the same temperature, the solid was filtered and collected to obtain 20,3 kg pale yellow-brown solid methyl ester (E)-3-{5-[4-cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}acrylic acid.

1H-NMR (DMSO-d6) δ: 1,50-1,80 (6H, m), 1,90-2,00 (2H, m), and 3.72 (3H, s), 4,85-of 4.95 (1H, m), 6.48 in-6,50 (2H, m), of 6.68 (1H, d, J=16.1 Hz), 7,05 (1H, d, J=8.5 Hz), 7,44-7,47 (1H, m), to 7.59-to 7.61 (1H, m), 7,86 (1H, d, J=16.1 Hz), a 7.92 (1H, d, J=2.2 Hz), 11,20 (1H, users), 11,94 (1H, s).

Example 5-2

8,81 g of potassium carbonate, to 20.0 g of 6-(2,4-dihydroxybenzyl)-2H-chromen-2-she and 15.8 g of cyclopentylamine was added to 60 ml of N,N-dimethylformamide, and the MCA is ü was stirred for 2.5 hours at 90-100°C. After cooling, the reaction mixture was added 60 ml of toluene and 80 ml of water. Then added to 2.40 g of potassium carbonate and separated the organic layer. Once added to the organic layer with 10 ml of methanol and 30 ml of toluene kept at a reduced pressure of 60 ml of solvent. To the obtained reaction mixture was added dropwise to 31.4 g of a 28% methanol solution of sodium methoxide at 55-65°C. After stirring for 1 hour at the same temperature is kept under reduced pressure, 10 ml of solvent. The reaction mixture was cooled and added dropwise to 100 ml of 2-butanone at 10-25°C. After stirring for 30 minutes at the same temperature, the solid was filtered and collected. Then the obtained solid was added to a mixed solution of 80 ml of 2-propanol, 5,44 g of formic acid, of 7.23 g of acetic acid and 16 ml of water. In addition, there was added a suspension of 1.50 g of 10% palladium on carbon in 10 ml of water, and the mixture was stirred for 3 hours at 40-45°C. After cooling the reaction mixture to 25-35°C was added 1.0 g of cellite, and after stirring for 5 minutes at the same temperature, was filtered, the insoluble material. The filter residue washed with a mixed solution of 20 ml of 2-propanol and 14 ml of water. The filtrate and the washing solution were mixed, and after adding 30 ml of water and 20 mg of methyl ester of 3-{5-[4-(cyclopentyloxy)-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid, and the mixture was stirred for 1 hour at 10-20°C. To the reaction mixture was added dropwise 100 ml of water at 10-25°C, and after stirring for 30 minutes at 10-20°C, the solid was filtered to obtain 15.7 g of pale yellow-brown solid methyl ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid.

Values1H-NMR in DMSO-d6were identical to the values of example 8.

Example 6

13.3 ml of cyclopentylamine and 17.1 g of potassium carbonate was added to 75 ml of N,N-dimethylformamide solution of 25.0 g of 6-(2,4-dihydroxybenzyl)-2H-chromen-2-it. The resulting mixture was stirred for 4 hours at 78-82°C. After cooling, the reaction mixture was added 125 ml of water and 50 ml of toluene, and the mixture was heated to 40-50°C, and separated the organic layer. Once added to the organic layer 125 ml of 2-propanol solid substance was heated and dissolved. After stirring the reaction mixture for 30 minutes at 40-45°C and for 1 hour at 10°C, the solid was filtered and collected with the receipt of 22.8 g of pale yellow-brown solid of 6-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2H-chromen-2-it.

1H-NMR (DMSO-d6) δ: 1.55V and 1.80 (6H, m), 1,90-of 2.05 (2H, m), 4,85-5,00 (1H, m), 6,50-6,53 (2H, m), 6,59 (1H, d, J=9.5 Hz), was 7.45 (1H, d, J=8,8 Hz), 7,54 (1H, d, J=8.5 Hz), 7,87-of 7.90 (1H, m), 8,08 (1H, d, J=2.2 Hz), 8,18 (1H, d, J=9.5 Hz), 11,67 (1H, users).

Example 7

of 33.0 g of a 28% methanol solution of sodium methoxide was added to a suspension of 30.0 g of 6-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2H-chromen-2-it in 60 ml of toluene and 60 ml of methanol. The mixture was heated under reflux for 3 hours. After cooling the reaction mixture with ice was added 90 ml of water, and the mixture is brought to pH 1,2 chloroethanol acid. Then add 90 ml of ethyl acetate and the separated organic layer. After adding 30 ml of ethyl acetate the organic layer was away under reduced pressure 140 ml of solvent. To the reaction mixture was added dropwise 90 ml of cyclohexane at 70-75°C. After stirring the mixture for 30 minutes at 65-70°C and for 1 hour at 10°C, the solid was filtered and collected to obtain 24.2 g of pale yellow-brown solid methyl ester (E)-3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}acrylic acid.

Values1H-NMR in DMSO-d6were identical to the values of example 5-1.

Example 8

20.5 kg methyl ester (E)-3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}acrylic acid, 5,47 kg of acetic acid and 5.47 kg of sodium formate was added to 62 l of 2-propanol. Was added, the suspension is 3.08 kg of 5% palladium on carbon in 21 liters of water, and the mixture was stirred for 7 hours at 40-45°C. After cooling the reaction mixture to 25-35°C EXT is ulali 2 kg of celite. After stirring for 5 minutes at the same temperature, was filtered, the insoluble material, and the filter residue washed with a mixed solution of 41 liters of 2-propanol and 20 l of water. The filtrate and the washing solution were mixed and separated the organic layer. After adding 31 liters of water to the organic layer and the mixture was stirred for 1 hour at 10-20°C. To the reaction mixture was added dropwise 82 l of water at 10-25°C, and after stirring for 1 hour at 10-20°C, the solid was filtered and collected to obtain 18,0 kg pale yellow-brown solid methyl ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid.

1H-NMR (DMSO-d6) δ: 1,50-1,80 (6H, m), 1.85 to a 2.00 (2H, m), 2,61 (2H, t, J=7,6 Hz), and 2.83 (2H, t, J=7,6 Hz)to 3.58 (3H, s), 4,85-of 4.95 (1H, m), 6,45-of 6.49 (2H, m), 6,92 (1H, d, J=8,3 Hz), 7,42-7,47 (3H, m), the 10.40 (1H, users), 12,07 (1H, s).

Example 9

to 20.0 g of 6-methyl-1,2-benzisoxazol-3-ol, to 9.93 g of pyridine and 35,0 g triphenylmethylchloride was added to 100 ml of methylene chloride, and the mixture was stirred for 1 hour at 35-45°C. was Added to the reaction mixture, 40 ml of water and 24 ml of 20% aqueous sodium hydroxide solution, and separated the organic layer. The aqueous layer was extracted with 20 ml of methylene chloride, and the organic layers were combined and drove away under reduced pressure 70 ml of solvent was added 100 ml of 2-propanol and from anjali under reduced pressure, 40 ml of solvent. Was added to the reaction mixture, 40 ml of water, and after stirring for 30 minutes at 10-25°C, the solid was filtered and collected with getting to 46.0 g of pale yellow solid 6-methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it.

1H-NMR (DMSO-d6) δ: at 2.36 (3H, s), 7,03 (1H, d, J=8.0 Hz), 7.18 in-7,33 (10H, m), 7,43-7,47 (7H, m).

Example 10

24,0 kg 6-methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-she and 18.6 kg of N-bromosuccinimide was added to 48 l of chlorobenzene. A solution of 0.30 kg 2,2'-azobis(2,4-dimethylvaleronitrile) in 4.8 l of methylene chloride was added dropwise 5 times each for 1 hour at 70-80°C. after introducing the mixture was stirred for 1 hour at the same temperature. Was added to the reaction mixture 96 l of methylene chloride, 2,40 kg celite, 24 l of 20% aqueous sodium hydroxide solution, of 0.77 kg of sodium sulfite and 48 liters of water. Was filtered, the insoluble material and the filter residue was washed 72 l of methylene chloride. The filtrate and the washing solution were combined and separated the organic layer. To the organic layer were added 24 l of methylene chloride, 12.7 kg of potassium carbonate and 6,07 kg complicated dimethyl ester phosphonic acid, and the mixture was stirred for 4 hours at 40-50°C. was Added to the reaction mixture 48 liters of water and 14 l of 20% aqueous sodium hydroxide solution, and separated the organic layer. The aqueous layer was extracted with 24 l of methylene chloride is, the organic layers were combined, added 24 l of methylene chloride and drove away under reduced pressure 210 liters of solvent. Was added to the reaction mixture 24 l of acetone and kept at a reduced pressure of 40 l of solvent. Was added dropwise 96 l of 2-propanol and 24 l of water, and the solid was filtered and collected to obtain 25,2 kg of white solid 6-(methyl bromide)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it.

1H-NMR (DMSO-d6) δ: 4,72 (2H, s), 7,22-7,49 (17H, m), 7,58 (1H, d, J=8.0 Hz)

Example 11

350 g of methyl ester of 2-hydroxy-4-(hydroxymethyl)benzoic acid and 160 g of hydroxylaminopurine was added to 700 ml of methanol. When reflux was added dropwise 1,11 kg of a 28% methanol solution of sodium methoxide, and the mixture was stirred for 3 hours. To the mixture was added to 2.1 l of water and kept under reduced pressure 850 ml of solvent. Then added 196 ml chloroethanol acid at 40-50°C. the resulting mixture was stirred for 30 minutes at the same temperature and added dropwise 116 ml chloroethanol acid. After filtering off the solid particles received 291 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide as a pale yellowish white solid.

1H-NMR (DMSO-d6) δ: 4,46 (2H, d, J=5.8 Hz), 5,26 (1H, t, J=5.8 Hz), 6,78 (1H, d, J=8,2 Hz), 6,85 (1H, s), a 7.62 (1H, d, J=8,2 Hz), 9.28 are (1H, s)of 1.39 (1H, C), 12,25 (1H, s).

Example 12

In 50 ml of methylene chloride added 10.0 g of N,2-dihydroxy-4-(hydroxymethyl)benzamide. To the resulting suspension were added to 0.21 ml of N,N-dimethylformamide. The mixture was cooled and added dropwise at 8.36 ml of thionyl chloride under ice cooling. After 2 hours of stirring at reflux drove under reduced pressure 13 ml of solvent. To the reaction mixture was added 13 ml of methylene chloride was added dropwise with 4.64 ml of pyridine at 20-30°C, and the resulting mixture was stirred for 1 hour at the same temperature. After adding 20 ml of water and 50 ml of acetone drove away under reduced pressure, 50 ml of the solvent was filtered and the solid particles with the receipt of 6.45 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol as a pale yellowish white solid.

1H-NMR (DMSO-d6) δ: 4,91 (2H, s), 7,39 (1H, DD, J=8,1, 1.1 Hz), the 7.65 (1H, s), 7,76 (1H, d, J=8.1 Hz), 12,41 (1H, s).

Example 13

(1) In 20 ml of methylene chloride added to 1.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol, and to the resulting suspension were added 27.0 mg p-toluensulfonate pyridinium and 0,596 ml of 3,4-dihydro-2H-Piran. The mixture was stirred for 24 hours at room temperature. Drove away under reduced pressure, the solvent, and the obtained residue was purified by chromatography on a column with silicagel the m (eluent: hexane:ethyl acetate = 3:1). As a result received 1.10 g of 6-(chloromethyl)-2-(tetrahydro-2H-Piran-2-yl)-1,2-benzisoxazol-3(2H)-it is in the form of a white solid. This substance was used as a seed crystal.

(2) In 75 ml of methylene chloride added to 5.00 g of 6-(chloromethyl)-1,2-benzisoxazol-3-ol, and the resulting suspension was added 0,137 g pyridine p-toluensulfonate acid and 2,98 ml of 3,4-dihydro-2H-Piran. The mixture was stirred for 8 hours at room temperature. To the reaction mixture were added 30 ml of water and the organic layer was separated. The aqueous layer was extracted with 10 ml of methylene chloride, and this, combined with the organic layer was washed saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. Drove away under reduced pressure, the solvent and the obtained residue was added 20 ml of diisopropyl ether. Added seed crystal, and after 30 minutes stirring at room temperature was filtered solids with the receipt of 6.65 g of 6-(chloromethyl)-2-(tetrahydro-2H-Piran-2-yl)-1,2-benzisoxazol-3(2H)-it is in the form of a pale yellowish-white solid.

1H-NMR (DMSO-d6) δ: 1,45-1,55 (2H, m), 1,62-to 1.77 (1H, m), 1.85 to a 2.00 (2H, m), 2.00 in to 2.15 (1H, m), 3,57-of 3.64 (1H, m), 3,89-3,93 (1H, m), 4,89 (2H, s), 5,47-of 5.50 (1H, m), 7,42 (1H, d, J=8.0 Hz), a 7.62 (1H, s), 7,83 (1H, d, J=8,0 Hz).

Example 14

In 50 ml of methylene chloride added to 5.00 g of 6-(chloromethyl-1,2-benzisoxazol-3-ol, to 7.59 g triphenylmethylchloride and 2,20 ml of pyridine and stirred for 5 hours at room temperature. To the reaction mixture was added 15 ml of water and 15 ml of methylene chloride, and the resulting mixture was stirred for 5 minutes under reflux. After cooling, the reaction mixture was added 2.50 g of silica gel. After filtering off the insoluble material, the filter residue was washed with 10 ml of methylene chloride. The filtrate and the washing solution were combined and, after adding 8 ml of methylene chloride and 15 ml of water, kept at a reduced pressure of 45 ml of solvent. To the reaction mixture was added 35 ml of acetone and drove away under reduced pressure 33 ml of solvent. After adding 20 ml of water was filtered solids to obtain 11.3 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it is in the form of a pale yellowish-white solid.

1H-NMR (DMSO-d6) δ: rate 4.79 (2H, s), 7,19-7,50 (l7H, m), 7,60 (1H, d, J=8.0 Hz).

Example 15

10,5 kg of N,2-dihydroxy-4-(hydroxymethyl)benzamide and 0.10 kg of N,N-dimethylformamide was added to 105 l of methylene chloride. To the mixture was added dropwise to 14.3 kg of thionyl chloride under reflux, and then the resulting mixture was stirred for 6 hours at the same temperature. Then drove under reduced pressure 11 l of solvent and at 20-30°C is obavljale 24 l of methylene chloride and 13.6 kg of triphenylmethylchloride. To the mixture was added dropwise to 4, 31 kg of pyridine, and the mixture was stirred for 4 hours at the same temperature. To the reaction mixture was added 21 l of water and the organic layer was separated. The aqueous layer was extracted with 11 l of methylene chloride. For extraction of the mixture with an organic layer was added 21 l of water and 2.10 kg celite. Then at 20-30°C was added dropwise 12,6 l of 20% aqueous sodium hydroxide solution. After filtering off the insoluble material, the filter residue washed with 21 l of methylene chloride. The filtrate and the washing solution were combined and drove away under reduced pressure 57 l of solvent. To the reaction mixture was added 53 l of 2-propanol and drove away under reduced pressure 53 l of solvent. To the reaction mixture was added 53 l of 2-propanol. Then drove under reduced pressure 46 l of solvent, and the residue was stirred for 30 minutes at 15-20°C. Then was filtered solids with obtaining 17.6 kg 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it is in the form of a pale yellowish-white solid.

Values1H-NMR in DMSO-d6coincided with the values of example 14.

Example 16

30.0 g of 6-(methyl bromide)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-she and 13.9 ml of diethylamine was added to 90 ml of N,N-dimethylformamide. The mixture was stirred for 50 minutes at room Tempe is the atur. Was added to the reaction mixture ethyl acetate, methylene chloride and water and the organic layer was separated. To the organic layer was added water and chloroethanol acid and the separated aqueous layer. The organic layer was extracted with water and added together with the aqueous layer 180 ml of acetone and added dropwise 13 ml of 20% aqueous sodium hydroxide solution. Was filtered solids with the receipt of 22.2 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it is in the form of a pale yellowish-white solid.

1H-NMR (DMSO-d6) δ: of 0.94 (6H, t, J=7,1 Hz), 2,42 (4H, q, J=7,1 Hz), of 3.56 (2H, s), 7.18 in-7,34 (11N, m), 7,45-7,51 (7H, s).

Example 17

to 20.0 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-she and 5.1 ml of atilglukuronida was added to 60 ml of methylene chloride. The mixture then was stirred for 3 hours at room temperature, and the reaction mixture was added dropwise 140 ml of 2-propanol for 30 minutes. The resulting mixture was stirred for 2 hours at 5-15°C and was filtered solids to obtain 16.6 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it is in the form of a pale yellowish-white solid.

1H-NMR (DMSO-d6) δ: 4,80 (2H, s), 7.18 in-7,50 (l7H, m), 7,60 (1H, d, J=8.0 Hz).

Example 18

10.0 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-she, 35 ml bromatan and 2,42 g of sodium bromide were added to 80 ml of N-methyl-2-pyrrolidone, and the mixture was stirred for 1.5 hours at 55-60°C. After cooling, the reaction mixture was added dropwise 20 ml of 2-propanol and 50 ml of water, and was filtered solids to obtain white solids. The obtained white solid, 35 ml of brometane and 2,42 g of sodium bromide were added to 80 ml of N-methyl-2-pyrrolidone, and the mixture was stirred for 1 hour at 55-60°C. After cooling, the reaction mixture was added dropwise 20 ml of 2-propanol and 50 ml of water, and was filtered solids with getting 9,04 g of 6-(methyl bromide)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-it is in the form of a white solid.

1H-NMR (DMSO-d6) δ: 4,72 (2H, s), 7,20-7,51 (l7H, m), 7,58 (1H, d, J=8.0 Hz).

Example 19

50.0 g of N,2-dihydroxy-4-methylbenzamide was added to 350 ml of tert-butyl methyl ether and added dropwise to 38.1 g of thionyl chloride at-1-0°C. the Mixture was stirred for 30 minutes at the same temperature. Then added dropwise 164 ml tributylamine at a temperature of from -5 to -3°C, and the mixture was stirred for 1.5 hours at-5-5°C. To the reaction mixture were added 200 ml of 20% aqueous sodium hydroxide solution, the organic layer was separated and added to 100 ml of water, 42 ml of 20% aqueous sodium hydroxide solution and 5.0 g of celite. After filtering off the insoluble material, the filter residue was washed with 100 ml water. The filtrate and washing the second solution were combined and the aqueous layer was separated. To the aqueous layer were added at 40-50°C in 10 ml of acetone and 50 ml of acetic acid. After stirring at the same temperature for 30 minutes and was filtered solids with getting to 40.1 g of 6-methyl-1,2-benzisoxazol-3-ol as a pale yellow solid.

1H-NMR (CDCl3) δ: of 2.51 (3H, s), 7,13 (1H, d, J=8.0 Hz), 7,21 (1H, s), the 7.65 (1H, d, J=8.0 Hz).

Example 20

12.5 kg methyl ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid, 15,6 kg 6-(methyl bromide)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-she 4,49 kg of potassium carbonate was added to 125 l of acetone. The resulting mixture was stirred for 5 hours while heating under reflux. After cooling, the reaction mixture was added 29 l of water was added dropwise 2.9 litres chloroethanol acid was filtered and the solid particles. The result of 19.7 kg methyl ester 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-triphenylmethyl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid as a pale yellowish white solid.

1H-NMR (DMSO-d6) δ: 1,55-of 1.78 (6H, m), 1,90-2,00 (2H, m), 2.63 in (2H, t, J=7,6 Hz), with 2.93 (2H, t, J=7,6 Hz), 3,49 (3H, s), 4,88-4,94 (1H, m), 5,33 (2H, s), 6,46-6,51 (2H, m), 7,13 (1H, d, J=8,3 Hz), 7,22-of 7.25 (3H, m), 7,30-7,34 (7H, m), 7,42-7,56 (10H, m), 7,63 (1H, d, J=8.0 Hz), 12,00 (1H, s).

Example obtain 1

(1 300 g of methyl ester of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-triphenylmethyl-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid was added to a mixture of 1200 ml of isobutyl ketone and 600 ml of methanol. Was added dropwise under ice cooling to 43.5 ml of sulfuric acid. The resulting mixture was stirred for 1 hour while cooling with water and then was stirred for 1 hour and 30 minutes at room temperature. After adding 1200 ml of water and 200 ml of 20% aqueous sodium hydroxide solution and the mixture was stirred at room temperature for 30 minutes and was filtered solids with getting 167 g of methyl ester of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid as a pale yellowish white solid.

(2) In 182 ml of methanol suspended 26,0 g of methyl ester of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid. After adding dropwise 78 ml of water to 10.5 g of sodium hydroxide at room temperature the resulting mixture was stirred for 30 minutes at the same temperature. The reaction mixture was added to water. After adjusting to pH of 1.5 by addition of 6 mol/l chloroethanol acid was filtered solids. The obtained solids were dissolved in a mixed solution of chloroform and methanol. After washing with water drove away under reduced pressure, the solvent is getting to 22.5 g of 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propio the OIC acid as a pale yellowish solid.

1. The method of deriving phenylpropionic acid represented by the General formula:
[Formula 15]
,
where R2arepresents a methoxy group or ethoxypropan; R3brepresents cyclopentyloxy group, and R5represents a methyl group which is substituted by one or more phenyl groups, or oxygen-containing heterocyclic group, or its salt, including:
the engagement benzophenone derivative represented by the General formula:
[Formula 9]
,
where R2aand R3bsuch as defined above, or its salt derivative 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula:
[Formula 14]
,
where X represents a halogen atom, and R5such as defined above; and
specified benzophenone derivative obtained by oxidation of methyl-2H-chromen-2-it is represented by the General formula:
[Formula 1]
,
the manganese dioxide in the presence of sulfuric acid and water to obtain 2-oxo-2H-romancelanguage represented by the General formula:
[Formula 2]
,
then oxidation of the obtained compound salt halogenate acid to obtain 2-oxo-2 is-romancenovel acid, represented by the General formula:
[Formula 3]
,
or a salt thereof, then the implementation of the interaction of the compounds in the presence of an acid with a compound represented by the General formula:
[Formula 4]
,
where R3aand R4arepresents a C1-6alkyl group, to obtain the benzophenone derivative represented by the General formula:
[Formula 5]
,
where R3aand R4asuch as defined above, then the reaction dealkylation derived benzophenone with obtaining a benzophenone derivative represented by the formula:
[Formula 6]
,
or its salt, then the implementation of the alkylation reaction obtained benzophenone derivative or its salt with a compound of General formula R3bL, where L is a leaving group, a R3bsuch as defined above, in the presence of a base to obtain benzophenone derivative represented by the General formula:
[Formula 7]
,
where R3bsuch as defined above, or its salt, and then the reaction breaking the cycle obtained benzophenone derivative or its salt in the presence of sodium methoxide or ethoxide sodium obtaining proizvodi the th benzophenone, represented by the General formula:
[Formula 8]
,
where R2aand R3bsuch as defined above, or its salt, and then the reaction of the recovery obtained benzophenone derivative or its salt; and
the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-she will receive the following way (1):
(1) a method including the implementation of protection 2 positions 6-methyl-1,2-benzisoxazol-3-ol methyl group which is substituted by one or more phenyl groups, or oxygen-containing heterocyclic group with obtaining the derivative of 6-methyl-1,2-benzisoxazol-3(2H)-it is represented by the General formula:
[Formula 10]
,
where R5such as defined above, followed by halogenoalkanes.

2. The method of receiving according to claim 1, where R2arepresents a methoxy group.

3. The method of receiving according to claim 1, where X represents a chlorine atom or a bromine atom.

4. The method of receiving according to claim 1, where R5represents triphenylmethyl or tetrahydro-2H-Piran-2-ilen group.

5. The method of receiving according to claim 1, where the manganese dioxide is an active manganese dioxide and sulfuric acid concentration relative to the sulfuric acid and water is 35-75% (wt./wt.).

6. The method of receiving according to claim 5, where the methyl-2H-chromen-2-it is a 6-m is Teal-2H-chromen-2-one or 7-methyl-2H-chromen-2-it.

7. A method of obtaining a benzophenone derivative represented by the General formula:
[Formula 20]
,
where R2arepresents a methoxy group or ethoxypropan and R3brepresents cyclopentyloxy group, or its salt, including: implementation of the dealkylation reaction benzophenone derivative represented by the General formula:
[Formula 16]
,
where R3aand R4arepresents a C1-6alkyl group, to obtain the benzophenone derivative represented by the formula:
[Formula 17]
,
or its salt, then the implementation of the alkylation reaction obtained benzophenone derivative or its salt with a compound of General formula R3bL, where L is a leaving group, a R3bsuch as defined above, in the presence of a base to obtain benzophenone derivative represented by the General formula:
[Formula 18]
,
where R3bsuch as defined above, or its salt, then the implementation of the response to breaking the cycle obtained benzophenone derivative or its salt in the presence of sodium methoxide or ethoxide sodium obtaining benzophenone derivative represented by the General formula:
[Formula 19]
,
where R2a/sup> and R3bsuch as defined above, or its salt, and then the implementation of the reduction reaction of the obtained benzophenone derivative or its salt.

8. The method of receiving according to claim 7, where R2arepresents a methoxy group.

9. A method of obtaining a benzophenone derivative represented by the General formula:
[Formula 22]
,
where R2arepresents a methoxy group or ethoxypropan and R3brepresents cyclopentyloxy group, or its salt, including the implementation of the reduction reaction of benzophenone derivative represented by the General formula:
[Formula 21]

where R2aand R3bsuch as defined above, or its salt.

10. The method of receiving according to claim 9, where R2arepresents a methoxy group.

11. The method of deriving phenylpropionic acid represented by the General formula:
[Formula 25]
,
where R2arepresents a methoxy group or ethoxypropan, R3brepresents cyclopentyloxy group, and R5represents a methyl group which is substituted by one or more phenyl groups, or oxygen-containing heterocyclic group, or its salt, including the engagement of a derivative of benzophenone, p is establing General formula:
[Formula 23]
,
where R2aand R3bsuch as defined above, or its salt derivative 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula:
[Formula 24]
,
where R5such as defined above, and X represents a halogen atom.

12. The method for claim 11, where R2arepresents a methoxy group.

13. The method for claim 11, where X represents a chlorine atom or a bromine atom.

14. The method for claim 11, where R5represents triphenylmethyl or tetrahydro-2H-Piran-2-ilen group.

15. The method of obtaining the derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the General formula:
[Formula 27]
,
where X represents a halogen atom, and R5represents a methyl group which is substituted by one or more phenyl groups, or oxygen-containing heterocyclic group, including the implementation of protection 2 positions 6-methyl-1,2-benzisoxazol-3-ol methyl group which is substituted by one or more phenyl groups, or oxygen-containing heterocyclic group with obtaining the derivative of 6-methyl-1,2-benzisoxazol-3(2H)-it is represented by the General formula:
[Formula 26]
,
where R5such as defined above, and then halogenoalkane.

16. The way of getting 15, where X represents a chlorine atom or a bromine atom.

17. The way of getting 15, where R5represents triphenylmethyl or tetrahydro-2H-Piran-2-ilen group.

18. The method of obtaining 2-oxo-2H-romancenovel acid represented by the General formula:
[Formula 34]
,
or a salt thereof, comprising the oxidation of methyl-2H-chromen-2-it is represented by the General formula:
[Formula 32]
,
the manganese dioxide in the presence of sulfuric acid and water to obtain 2-oxo-2H-romancelanguage represented by the General formula:
[Formula 33]
,
and then oxidizing the obtained compound salt halogenate acid.

19. The way of getting p, where manganese dioxide is an active manganese dioxide and sulfuric acid concentration relative to the sulfuric acid and water is 35-75% (wt./wt.).

20. The way of getting p, where methyl-2H-chromen-2-it is a 6-methyl-2H-chromen-2-one or 7-methyl-2H-chromen-2-it.

21. The derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it is represented by the formula:
[Formula 35]
,
where R5represents a methyl group which is substituted od is Oh or more phenyl groups, or oxygen-containing heterocyclic group, and X represents a halogen atom.

22. The derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it item 21, where X represents a chlorine atom or a bromine atom.

23. The derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it item 21 or 22, where R5represents triphenylmethyl or tetrahydro-2H-Piran-2-ilen group.

24. The derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it on any of PP and 22, where R5represents an optionally substituted triphenylmethyl group.

25. The derivative of 6-(halogenmethyl)-1,2-benzisoxazol-3(2H)-it item 21, where R5represents triphenylmethyl group, and X represents a chlorine atom or a bromine atom.

26. A derivative of benzophenone represented by the General formula:
[Formula 36]
,
where R1represents a hydrogen atom and R2represents a methoxy group or ethoxypropan, or R1and R2taken together form a bond, R3represents cyclopentyloxy group, and R4represents a hydrogen atom, or R3and R4are the same and each represents a hydrogen atom or a C1-6alkyl group, provided that when R1represents a hydrogen atom and R2represents methoxyl the PUF or ethoxypropan, R3represents cyclopentyloxy group, and R4represents a hydrogen atom, or its salt.

27. A derivative of benzophenone or its salt p, where R1represents a hydrogen atom and R2represents a methoxy group or ethoxypropan, or R1and R2taken together form a bond, R3represents cyclopentyloxy group, and R4represents a hydrogen atom, or R3and R4are the same and each represents a hydrogen atom, methyl group or ethyl group, provided that when R1represents a hydrogen atom and R2represents a methoxy group or ethoxypropan, R3represents cyclopentyloxy group, and R4represents a hydrogen atom.

28. A derivative of benzophenone or its salt p, where R1represents a hydrogen atom, R2represents a methoxy group or ethoxypropan, R3represents cyclopentyloxy group, and R4represents a hydrogen atom.



 

Same patents:

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a new improved method for preparing derivatives of 3,3-diarylpropylamines of the general formula (I) and sterically highly pure stable intermediate substances and their using for preparing pharmaceutical compositions. Method for preparing 3,3-diarylpropylamines of the general formula (I) wherein R means hydrogen atom, linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl; R' and R'' can be similar or different and mean linear or branched (C1-C6)-alkyl but preferably methyl or isopropyl. Method involves condensation of cinnamic acid with compound of the general formula (1) to form compound of the general formula (2a) and the following reaction of the latter with chiral tertiary amine - cinchonidine to yield the corresponding salt of compound of the general formula (2b): and then from this compound the crystalline form of compound of the formula (3): is isolated followed by its either direct reduction with equivalent excess of hydride to yield lactol of the formula (5a) or via intermediate step by formation of corresponding acid chloroanhydride to form ester with alcohols of type R-OH wherein R is given above and the following conversion to compound of the formula (4): and the latter is hydrogenated with diisobutylaluminum-hydride or tri-tert.-butoxyaluminum-hydride to yield lactol of the formula (5) . Prepared lactols of the formula (5a) or (5) after reductive amination with secondary amine form compounds of the formula (I).

EFFECT: improved preparing method.

10 cl, 1 sch, 1 tbl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel benzo[d]isoxazol-3-ylamine compounds of formula I in free form or in form of salts with physiologically compatible acids, having antagonistic effect on KCNQ2/3 ion channel. In formula I , R1, R2, R3 and R4 independently denote H, F, CI, Br, I, -NR7R8, -OR9 or C1-C10alkyl, R5 denotes -C(=S)NR21R22 or (CHR6)n-R25, where n equals 1, 2 or 3, R6 denotes H or C1-C6 alkyl, R25 denotes aryl or heteroaryl, R7 and R8 independently denote H or C1-C10 alkyl, R9 denotes H, C1-C10alkyl or -(C1-C5alkylene)aryl, R21 denotes H, R22 denotes C1-C10alkyl, C2-C10alkenyl, C3-C8cycloalkyl, -(C1-C5alkylene)-C3-C8cycloalkyl, -(C1-C3alkylene)heterocycloalkyl, aryl, heteroaryl or -(C1-C5alkylene)aryl, wherein each of the heterocycloalkyl residues has 5-6 members, contains 1 or 2 heteroatoms in the ring, independently selected from oxygen and nitrogen, each of the aryl residues is phenyl, anthracenyl or naphthyl, each of the heteroaryl residues has 5 or 6 members and contains 1 or 2 heteroatoms in the ring, independently selected from oxygen, sulphur and nitrogen.

EFFECT: said compounds can be used to prepare a medicinal agent for curing pain, migraine, anxiety, uroclepsia or epilepsy.

17 cl, 203 ex

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds, which possess qualities to estrogen modulators, of general formula (1) or its pharmaceutically acceptable salt, where R1 represents hydrogen atom or (C1-C6)alkyl, -SO2NR7R8, phenyl (C1-C3)alkyl or (C1-C3)alkyl, substituted with 5-8-member heterocyclic radical, containing nitrogen atom; R2 and R3 each independently represents hydrogen atom or hydroxyl, halogen atom or (C1-C6)alkoxy; X represents O, S, SO, SO2 or NR4; R4 represents hydrogen atom or (C1-C6)alkyl, phenyl, phenyl(C1-C3)alkyl, (C1-C3)alkyl, substituted with 5-8-member saturated heterocyclic radical, containing one nitrogen atom, or group -COR7, -CO2R7 or -SO2NR7R8, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom or phenyl(C1-C3)alkoxy; Y represents direct bond, -(CR10R11)n- or -R10C=CR11-; R7 and R8 each independently represents hydrogen atom or (C1-C6)alkyl group; R10 and R11 each independently represent hydrogen atom or cyano, or group CONR7R8; n equals 1 or 2; A represents (C3-C12)cycloalkyl or phenyl, where phenyl is not substituted or is substituted with at least one substituent, selected from group which includes hydroxyl, halogen atom, (C1-C3)alkyl, (C1-C3)alkoxy; when X represents NR4, Y and R2 together with containing them indazole cycle can also form 1H-pyrano[4,3,2-cd)indazole; on condition that: 1) when X represents O, S or NR4, R1 represents hydrogen atom or (C1-C6)alkyl, and Y stands for direct bond, then A is not optionally substituted phenyl; 2) when X represents O, R1O represents 6-OH or 6-OCH3, Y represents direct bond and A represents cyclopeptyl, then (R2, R3) or (R3, R2) are different from (H, CI) in position 4, 5; 3) when X stands for O, R1O represents 6-OH, R2 and R3 represent H, and Y represents CH=CH, then A is not phenyl or methoxyphenyl; 4) when X represents SO2, A represents phenyl and R1O represents 5-or 6-OCH3, then (R2, R3) or (R3, R2) are different from (H, OCH3) in position 6- or 5-, compound not being one of the following: 3-phenyl-5-(phenylmethoxy)-1H-indazole; n-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5]isoxazole; 3-(4-chlorphenylmethyl)-6-hydroxy-7-(n-propyl)-benz[4,5]isoxazole; 6-hydroxy-3-(2-phenylethyl)-7(n-propyl)-benz[4,5]isoxazole; 3-cyclopropyl-6-hydroxy-3-phenylmethyl-7-(n-propyl)-benz[4,5|isoxazole; 3-cyclohexylmethyl-6-hydroxy-3-phenylmethyl-7-propyl-benz[4,5]isoxazole. Invention also relates to pharmaceutical composition, application and method of prevention and treatment of disease, where modulation of estrogen receptors is required.

EFFECT: obtaining novel compounds, which possess qualities of estrogen receptors modulators.

18 cl, 7 dwg, 8 tbl, 97 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula IA and their pharmaceutically acceptable salts. Claimed compounds have inhibitory effect on DAAO. In formula IA , A denotes hydrogen; Z denotes O; R1 is selected from a hydrogen atom, hydroxy or methoxy; R2 is selected from a hydrogen atom, F, Cl, hydroxy, methoxy and methyl; or R1 is selected from a hydrogen atom, F, hydroxy and methoxy; and R2 is selected from a hydrogen atom, Cl, hydroxy, methoxy and methyl; R3 is selected from C1-C6alkyl, hydroxy, methoxy, halogen, cyano, CH2-CH2-phenyl and OCH2-phenyl; R4a is selected from C1-C6alkyl, hydroxy, methoxy and halogen. The invention also relates to use of compounds in which R3a denotes hydrogen, C1-C6alkyl, hydroxy, methoxy, halogen, cyano, CH2-CH2-phenyl, O-CH2-phenyl, NH-CO-O-CH2-phenyl, R4a denotes H, C1-C6alkyl, hydroxy, methoxy, halogen, NH-CO-O-CH2-phenyl, for making a medicinal agent.

EFFECT: wider field of use of the compounds.

14 cl, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel hexafluoroisopropanol-substituted ether derivatives of formula (I) to their pharmaceutically acceptable salts and to esters which are capable of bonding with LXR-alpha and/or LXR-beta, as well as to pharmaceutical compositions based on said compounds. In formula (I) R1 is hydrogen, lower alkyl or halogen, one of groups R2 and R3 is hydrogen, lower alkyl or halogen, and the second of groups R2 and R3 is -O-CHR4-(CH2)m-(CHR5)n-R6. Values of R4, R5, R6 m and n are given in the formula of invention.

EFFECT: novel compounds have useful biological properties.

22 cl, 4 dwg, 102 ex

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining the derivatives 3-aroilanra-(1,9-cd)isoxazole-6-one of the general formula where X - hydrogen, halogen or the lowest alkyl, which are used as intermediate products in synthesis of derivatives 7,8-phthalylclaridone used as dyes for various polymeric materials and polyester fibres. The essence of the method lies in boiling 1(triazene-N-sulfonate)-2-aroihtranquonine in spirit solution of alkali with the subsequent neutralisation by acetic acid.

EFFECT: simpler technology and safer process.

1 cl, 2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining the derivatives of 3-aroilantra(1,9-cd)isoxazol-6-one with the general formula of where X - hydrogen, halogen or the lowest alkyl, which are used as intermediate products in synthesis of derivatives 7,8-phthalylclaridone, used as dyes for the polyester fibres. The essence of the method lies in heating 1-hydroxytriazone-2-aroilantraquinone in acetic anhydride.

EFFECT: simpler technology and safer process.

1 cl, 2 tbl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing derivatives of 3-phenylsulfonylanthra-[1,9-cd]-isoxazole-6-one of the general formula: wherein X means hydrogen, halogen atom or lower alkyl; Y means hydrogen atom or hydroxy-group. Method involves heating derivative of 2-phenylsulfonylanthraquinone in organic solvent wherein 1-(triazene-N-sulfonate)-2-phenylsulfonylanthraquinone of the general formula: wherein X and Y have above given values is used as derivative of 2-phenylsulfonylanthraquinone that is boiled in alkali alcoholic solution followed by neutralization with acetic acid. Invention provides simplifying technology of the process and expanding assortment of the end products.

EFFECT: improved preparing method.

2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthesis of 1,3-dicarboxylic compounds, specifically to a method for synthesis of ethyl ethers of 2-alkyl-4-aryl-3-oxobutanoic acids of general formula:

,

where for R=3,5-Me2C6H3, R1=Me, Et, i-Pr; for R=2,6-Cl2C6H3, R1=Me; for R=2- CI-6-FC6H3, R1=Me, involving acylation of di(bromine-magnesium)salt of ethyl ether of 2-alkyl-3,3-dihydroxyacrylic acid, selected from a group comprising di(bromine-magnesium)salt of ethyl ether of 2-methyl-3,3-dihydroxyacrylic acid, di(bromine-magnesium) salt of ethyl ether of 2-ethyl-3,3-dihydroxyacrylic acid and di(bromine-magnesium) salt of ethyl ether of 2-isopropyl-3,3-dihydroxyacrylic acid, obtained in situ from isopropyl magnesium bromide and the corresponding 2-(carbethoxy)alkanoic acid, arylacetyl chloride, selected from 3,5-dimethylphenylacetyl chloride, 2,6-dichlorophenylacetyl chloride and 2-fluoro-6-chlorophenylacetyl chloride, in molar ratio of arylacetyl chloride: di(bromine-magnesium) salt of ethyl ether of 2-alkyl-3,3-dihydroxyacrylic acid equal to 1: 1.6-2.2, in a medium of anhydrous tetrahydrofuran with subsequent treatment of the reaction mass with aqueous solution of citric acid and extraction of the end product.

EFFECT: high output and purity of disclosed compounds.

7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to chemical and pharmaceutical industry and specifically to an agent which is ethyl ether (±)-11,15-dideoxy-16-methyl-16-hydroxyprostaglandin E1 of formula (I), which exhibits uterotonic activity. This compound relates to the family of 11-deoxyprostaglandines and has a chemical structure similar to misoprostol.

EFFECT: agent, which is more chemically stable and is twice less toxic, surpasses misoprostol on uterotonic activity which, along with synthetic availability and absence of side effects, makes it exceptionally promising in practical use for replacing misoprostol in gynaecological binary preparations.

2 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts which are able to inhibit the replication of HIV-virus, to pharmaceutical composition thereof and to the method of inhibition of HIV-virus replication. formula (A) where R1 is hydrogen; R2 is OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is (CH2)bCOOR9 where b takes up the integer values from 1 to 5; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.

EFFECT: claimed compounds inhibit the replication of HIV-virus.

4 cl, 6 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to the new benzotropolone derivatives of general structural formula (A) as well to their pharmaceutically acceptable salts possessing anti hiv-activity, to the pharmaceutical composition thereof and to the method of HIV-integrase inhibition. formula (A) where R1 is selected from the group consisting of the hydrogen and halogen; R2 is selected from the group consisting of the hydrogen and OC1-6alkyl; each of R3, R4, R5 independently is hydrogen; G is selected from the group consisting of the structures I, II; R6 is hydrogen; R7 is COOR9; R8 is selected from C1-6alkyls substituted with one or more halogen atoms; W is O; R9 is selected from hydrogen or C1-6alkyl. The structures I, II are represented in the formula of invention.

EFFECT: claimed compounds possess anti HIV-activity.

5 cl, 6 dwg, 13 ex

FIELD: chemistry.

SUBSTANCE: novel compounds of formulas , , , , , , (designation of all groups are given in invention formula) are used for treatment of different metabolic diseases, such as insulin resistance syndrome, diabetes, hyperlipidemia, fatty liver, cachexia, obesity, atherosclerosis and arteriosclerosis.

EFFECT: using compounds as biologically active agent and creating pharmaceutical compositions based on said compounds.

124 cl, 52 ex, 17 tbl, 2 dwg

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to photoinitiating agents of phenylglyoxylic acid order used in polymerizing compositions to be subjected for hardening. Invention describes a photoinitiating agent of the formula (I): wherein Y means (C3-C12)-alkylene, butenylene, butinylene or (C4-C12)-alkylene that are broken by groups -O- or -NR2- and not following in sequence; R1 means a reactive group of the following order: -OH, -SH, -HR3R4, -(CO)-OH, -(CO)-NH2, -SO3H, -C(R5)=CR6R7, oxiranyl, -O-(CO)-NH-R8-NCO and -O-(CO)-R-(CO)-X; R2 means hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R3 and R4 mean hydrogen atom, (C1-C4)-alkyl, (C2-C4)-hydroxyalkyl; R, R and R mean hydrogen atom or methyl; R8 means linear or branched (C4-C12)-alkylene or phenylene; R9 means linear or branched (C1-C16)-alkylene, -CH=CH-, -CH=CH-CH2-, C6-cycloalkylene, phenylene or naphthylene; X, X1 and X2 mean -OH, Cl, -OCH3 or -OC2H5. Also, invention describes a method for synthesis of a photoinitiating agent, polymerizing composition and substrate covered by its. Proposed photoinitiating agent possesses the effective introducing capacity and absence of migration in thermal treatments.

EFFECT: improved and valuable properties of agent.

13 cl, 1 tbl, 16 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel intermediate compounds and inmproved method for synthesis of compound of the formula (C): . Proposed method is based on using inexpensive parent substances and provides synthesis of intermediate compounds with the high yield and high purity degree being without carrying out procedures for chromatographic purification and can be realized in large-scale industry manufacture. Invention relates to improved methods for synthesis of compound of the formula (I): , compound of the formula (II): , compound of the formula (III): , compound of the formula (VIII): , compound of the formula (IX): , and to a reagent consisting of boron tribromide and 2,6-dimethylpyridine. Method is used for a sparing and selective splitting a methyl group in aromatic methyl ethers.

EFFECT: improved method of synthesis.

12 cl, 8 ex

FIELD: organic chemistry, perfumery.

SUBSTANCE: invention relates to an aromatizing composition containing at least compound of the formula (I): as an active component wherein values w, m, P, X, G, Q and n are given in claim 1 of the invention description, and one or more aromatizing component. Also, invention relates to a method for improving, enhancing or modifying odor, to a method for aromatizing surface, method for enhancing or prolonging the diffusion effect of component on surface and to novel compounds of the formula (I) with exception of compounds enumerated in claim 10 of the invention description and to invention relating to aromatizing article using compounds of the formula (I).

EFFECT: valuable cosmetic properties of compounds.

13 cl, 14 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to synthesis of 1,3-dicarbonyl compounds and to a new method for preparing 4-substituted alkyl-3-oxobutanoates of the formula: wherein: R is C6H5CH2, 2-F-6-ClC6H3CH2, 2,6-Cl2C6H3CH2, 1-C10H7CH2, Ph2CH; Alk is Me; R is 1-AdCH2; Alk is i-Pr that are used precursors of antiviral agents of pyrimidine order. Method involves acylation of 2,2-dimethyl-1,3-dioxane-4,6-dione with acyl chlorides in dichloromethane in the presence of triethylamine followed by alcoholysis of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione wherein acylation is carried out with acyl chlorides in the presence of trimethylsilyl chloride in the mole ratio 2,2-dimethyl-1,3-dioxane-4,6-dione : acyl chloride : trimethylsilyl chloride : triethylamine = (1-2):1:1.1:3.5, respectively, with formation of an intermediate product 5-[1-(trimethylsilyloxy)ethylidene]-2,2-dimethyl-1,3-dioxane-4,6-dione that is subjected for hydrolysis with formation of 5-(1-hydroxyethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione and its following alcoholysis and formation of the end product. Method provides enhancing yield and purity of claimed compounds.

EFFECT: improved method for preparing.

2 cl, 8 ex

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