Method of nebivolol racemate obtainment

FIELD: chemistry.

SUBSTANCE: invention refers to novel method of obtaining [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyrane-2-methanol] racemate of the formula (I) (nebivolol) and its pharmaceutically acceptable salts , involving stages indicated in the claim, and to intermediate compounds and methods of obtainment thereof.

EFFECT: improved method.

106 cl, 12 tbl, 20 ex

 

The LEVEL of TECHNOLOGY

1. The technical FIELD

The present invention relates to a new method of obtaining racemic nebivolol, its enantiomeric forms and to new compounds obtained by this method

2. DESCRIPTION of the PRIOR art,

Nebivolol (see figure 1A, which shows d-Nebivolol, chemical name [2R*[R*[R*(S*)]]]-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or alternatively [2R*[R*[R*(S*)]]]-α,α'-[iminobis(methylene)]bis[6-ferroman-2-methanol]and figure 1B, which shows racemic nebivolol, which is a mixture of l - and d-nebivolol) is known as adrenergic beta-antagonist, antihypertensive agent, an inhibitor of platelet aggregation and a vasodilator agent.

Nebivolol is administered in pill form (for example, the dose of nebivolol hydrochloride of 5.45 mg equivalent to 5 mg of nebivolol), which contain nebivolol in the form of a racemic mixture of enantiomers: SRRR-nebivolol (programalso d-Nebivolol) and RSSS-nebivolol (levogyrate l-Nebivolol).

Nebivolol contains four asymmetric center and therefore theoretically possible existence of 16 stereoisomers. However, due to the peculiarities of the structure and configuration of stereoisomers (e.g., axial symmetry) can be formed only 10 stereoisomers (6 diastereomers: 4 dl-forms and 2 meso-is army) (table 1).

Nesterushkin getting these stereoisomers in General is described in U.S. patent No. 4654362 Van Lommen et al. (Janssen Pharmaceutica N. V.) (and its counterpart EP 0145067). Stereoselective synthesis of [2R,αS,2'S,α S]-isomer of α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] is described in U.S. patent No. 6545040 (Janssen Pharmaceutica N. V.) (and its analogue EP 0334429).

Separation technique diastereomers of a mixture of(±)-[2R*[1S*,5S*(S*)]]+[2R*[1S*[5R*(S*)]]]-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] by fractional crystallization of the appropriate cleaners containing hydrochloride salts described in U.S. patent No. 5759580 (Janssen Pharmaceutica N. V.) (and its analogue EP 0744946). Hydrochloride nebivolol can only be obtained with a very low yield of 6.6%.

Publication of PCT patent application WO 2004/041805 (Egis Gyogyszergyar RT.) describes a new method for producing racemic [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and clean [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]] enantiomers.

Alternative and enantioselective synthesis of d-nebivolol described in clauses (J. Am. Chem. Soc. 1998, 120, 8340-8347 and Tetrahedron 56, 2000, 6339-6344).

Table 1.
Stereoisomers nebivolol

the General formula isomers nebivolol
SRRS
Stereoisomer 1
SRRR
The stereoisomer 2 d-nebivolol
SRSR
Stereoisomer 3
meso-form 1
SRSS
Stereoisomer 4
RRRS
The stereoisomer 2 d-nebivolol
RRRR
Stereoisomer 5
RRSR
Stereoisomer 6
RRSS
Stereoisomer 7
meso-form 2
RSRS
Stereoisomer 3
meso-form 1
RSRR
Stereoisomer 6
RSSR
Stereoisomer 8
RSSS
Stereoisomer 9 l-nebivolol
SSRS
Stereoisomer 4
SSRR
Stereoisomer 7
meso-form 2
SSSR
Stereoisomer 9 l-nebivolol
SSSS
Stereoisomer 10

Ways to get nebivolol described in the above references, are briefly summarized below.

A. U.S. patent No. 4654362 (and its counterpart EP 0145067 U.S) (Janssen Pharmaceutica N. V.)

Synthetic path asteroseismology get nebivolol described on the basis of 6-fluoro-4-oxo-4H-1-benzopyran-2-carboxylic acid a1 (Scheme 1a).

To get nebivolol in Scheme 1A in U.S. patent No. 4654362 and its equivalent EP 0145067 contains detailed examples of the synthesis of components a1, a2, a3, a4 and a8. All other examples are the analogues of methods that describe the receipt of the related derivatives (such as derivatives without fluorine substituent in the aromatic ring). The General strategy for obtaining nebivolol or its related derivatives based on the synthesis of 2-oxiranylmethyl (a6 and a7) as key intermediates for the final stages of the mix. Due to the presence of two asymmetric carbon atoms, these compounds can be formed from racemic aldehydes a5 in the form of two diastereomeric racemate ("form" a7 = RS/SR and "In shape"a6 = SS/RR), which can be separated using chromatography. In the above link for the desired intermediate products are not given a description of the processing methods, crystallization and purification or separation of the stereoisomers, outputs, etc.

p> The racemates a6 or a7 can be converted into the corresponding benzylidene aminoalcohols A8 and A9 interaction with benzylamine. Protected by benzyl AV mixture of nebivolol a10 can be obtained by the interaction of the racemate a8 (RS/SR) racemate epoxide a6 (RR/SS) or by the interaction of the racemate a9 (RR/SS) racemate epoxide a7 (RS/SR). The protective group can be removed at the last stage catalytic hydrogenation, which leads to the formation of AB mixture nebivolol a11.

Scheme 1b shows additional methods of synthesis of the analogous 2-romaniaalgeria (a14) and 2-oxiranylmethyl (a16) as key intermediates for the synthesis of derivatives of nebivolol, containing different substituents in the aromatic group.

The aldehyde (a14) can be obtained by low-temperature recovery imidazoline a12 or the same recovery of ester a13. Aldehyde a14 then converted into 2-oxiranylmethyl a16 interaction with sodium hydride and potassium iodide trimethylsulfoxonium in dimethyl sulfoxide by a reaction similar to that described above. Another possibility of the synthesis of 2-oxiranylmethyl a16 is the oxidation of 2-vinylchloride a15 3-chloroperoxybenzoic acid (source 2-vinylchloride a15 is not specified in these patents, but according to EP 0334429 (see also below), the compound (a14) can be transformed into a compound A15 R the action of the Wittig).

In scheme 1c shows that diastereomer a mixture of desired and undesired diastereomers (i.e. RSSS/SRRR and RSRR/SRSS), can be obtained by the method presented in scheme 1a.

The strategy of synthesis described in U.S. patent No. 4654362 and its equivalent EP 0145067, has the following disadvantages:

1. Synthesis of aldehydes a6 and a14 requires very low temperatures and therefore requires special equipment, which complicates and increases the cost method.

2. Aldehyde A5 is a very unstable compound, as set forth in the PCT-application WO 2004/041805.

3. Synthesis a6/a7 from a5 can be dangerous, since it is known that the use of sodium hydride in solvents like DMSO, dimethylformamide (DMF), dimethylacetamide (DMA) and DMI can cause an exothermic reaction and, consequently, can cause uncontrolled reaction (see UK Chemical Reaction Hazards Forum: "Sodium Hydride/DMF process stopped").

4. Compound a6 and a7 were characterized as oily substances (see publication of the PCT-application WO 2004/041805). Since the acquisition in accordance with the described method leads to the formation of diastereomeric mixture a6 and a7 may require chromatographic purification, which is commercially unprofitable.

5. Connection a10 and A11 can be obtained by the reaction of racemic intermediate A8 (isomer A) with the racemate a6 ("isomer B") is whether the alternative reaction of racemic intermediate a9 ("isomer B") with the racemate A7 (isomer A) with subsequent removal of the protection. In U.S. patent No. 4654362 and its equivalent EP 0145067 not explicitly describe whether the individual isomers or mixture of isomers of compounds a10 and A11 (described only as "AB" isomeric form). Not presented any thoughts on the separation of such mixtures. Obviously, such techniques may lead to the formation of diastereomeric mixtures, consisting of desirable RSSS/SRRR of diastereoisomer and unwanted RSRR/SRSS of diastereoisomer (scheme 1c; cf. also table 1, showing the combination of different fragments, which gives all possible diastereomers). In addition, prior art it is known (see WO 2004/041805)that racemic nebivolol obtained by the method described in U.S. patent No. 4654362 (and its equivalent EP 0145067) (scheme 1a and 1c) in the form diastereomers of the racemate with SRSS/RSRR configuration failed successfully to separate by fractional crystallization; and

6. Loss of expensive substances due to the formation of undesirable isomers of nebivolol, especially during the last stages of the method.

b. Publication of the European patent application EP 0334429 and U.S. patent No. 6545040 (Xhonneux et al., Janssen Pharmaceutica N.V.)

A similar strategy for the synthesis of nebivolol described in EP 0334429 and U.S. patent No. 6545040, but the difference is that l-nebivolol get enantioselective synthesis, in which the key intermedi the tov use enantioface fragments b6 and b11 (Scheme 2).

For this technique it is necessary to separate racemic 6-ferroman-2-ylcarbonyl acid b2 through education diastereomeric amide b3 with (+)-dehydroabietylamine followed by fractional crystallization of diastereomers and hydrolysis of amides. The following stages of synthesis fragments b6 and b11 provide convergent paths, using (S)-form and (R)-form 6-ferroman-2-ylcarbamate acids b4 and b8. First, (S)-6 - ferroman-2-ylcarbonyl acid b4 is transformed into aldehyde b5 according to the methods already mentioned in scheme 1b. You can then obtain the epoxide b6 interaction b5 with sodium hydride and potassium iodide trimethylsulfoxonium in dimethyl sulfoxide. In the case of the second path (R)-6-ferroman-2-ylcarbonyl acid b8 first etherification education b9. Epoxide b10 synthesize methodology “without selecting” restore b9 to the corresponding aldehyde followed by reaction with sodium hydride and potassium iodide trimethylsulfoxonium in dimethyl sulfoxide. The epoxide ring b10 disclose the reaction of substitution of benzylamine, which gives the second key fragment b11, the latter is then subjected to interaction with the epoxide b6 and receive protected by benzyl l-nebivolol b12. The last stage unprotect catalytic hydrogenation b12 gives l-nebivolol.

The strategy described in EP 0334429 and U.S. patent No. 6545040 has followed the s disadvantages:

1. The stage of obtaining compounds b5 from b4 and b10 from b9 require very low temperatures to restore diisobutylaluminium (DIBAH), which is more complicated and expensive method because of the need in special refrigeration equipment.

2. The stage of receiving connections from b6 b5 and b10 from b9 can be a security risk, since it is known that the use of sodium hydride in solvents like DMSO, DMF, DMA and DMI may cause an exothermic reaction and, consequently, can cause uncontrolled reaction (see UK Chemical Reaction Hazards Forum: "Sodium Hydride/DMF process stopped").

3. Compound b5, b6, b9 and b10 are oily substances and therefore they are difficult to clean; in the likely case when connections b6 and b10 contaminated with undesired diastereomers may require their separation column chromatography, which is not commercially viable method.

4. Low outputs, especially the outputs of the stages of obtaining compounds b2-b3-b4, b2-b7-b8 and b5-b6, b9-b10, result in very low yield (less than 0.5%) for the synthesis of l-nebivolol, which makes the considered methodology unprofitable.

5. As it turns out only l-nebivolol, and to get nebivolol required racemic mixture required an additional stage for the synthesis of the corresponding d-form (i.e., d-nebivolol); and

6. When interaction is tvii intermediate b2 are formed diastereomers b3 and b7, which then has to be split and processed separately, receiving b6 and b11, then combine to produce b12, therefore, for a method requires a lot of extra steps.

C. Publication of PCT patent application WO 2004/041805 (terms and regulations et al., EGIS GYOGYSZERGYAR RT)

WO 2004/041805 describes the enantioselective synthesis of d - and l-nebivolol (see Diagram 3a-c).

The strategy of this path is based on the synthesis and separation of protected isopropylidenebis group of isomers (1`,2`-dihydroxyethyl)-6-ferroman-4-she C11, c12, c13, C14 (Scheme 3a). These compounds are synthesized starting from the acylation of 4-fernicola C1 chloroacetylation by Friedel-Crafts c education chloracetophenone c2, which is further transformed under the action of triphenylphosphine followed by treatment with a weak base in a stable postenligaen derived c4. Connection c4 then subjected to interaction or protected glycerin c6 aldehydes (from vitamin C) obtaining C11 and c12; or c8 (derived from D-mannitol) to obtain the c13 and C14 after cyclization.

Each of these isomers was further transformed in four ways, and similarly (Scheme 3b and 3c), resulting in paths 1 and 2 get l-nebivolol using C11 and c12 as parent compounds (Scheme 3b).

The enantiomeric d-nebivolol get and the illogical way and as the original substances using S,R-isomer c13 and R,R-isomer C14 (1`,2`-dihydroxyethyl)-6-ferroman-4-it-protected isopropylidene group (paths 3 and 4, Scheme 3c).

A typical sequence of reactions for each path begins with unprotect C11 (path 1, Scheme 3b), C12 (path 2, Scheme 3b), C13 (path 3, Scheme 3c), C14 (path 4, Scheme 3c) and obtain the corresponding diols C15, c19, c25, s. Selective totalrevenue primary alcohol group gives compound c16, c20, c26, c30, which can then be converted into epoxides c17, c21, c27, c31 processing base. After transformation of these epoxides action benzylamine in c18, c22, c28, c32, and the substitution of the desired epoxides (c18+c21, c22+c17, c28+c31, c32+c27) are formed dichloroethane C23 and is protected benzyl group. Removing the protection and restoration of the carbonyl groups can be carried out in one reactor catalytic hydrogenation to obtain or l-nebivolol, or d-nebivolol.

Racemic nebivolol get, preparing a mixture (1:1) intermediates c23 and c33 before the last stage hydrogenation (yield 52%).

The strategy described in WO 2004/041805, has the following disadvantages:

1. Although the strategy is based on the use of all stereoisomers for synthesis or l-nebivolol or d-nebivolol, the main disadvantage is the fact to obtain the racemic mixture must perform 30 stages, using all the intermediates that makes such a synthesis of a long and unprofitable; and

2. The stage of obtaining compounds c23 from cl8, c23 from c22, c33 of c28 and c33 of c32 carried out without the use of solvent at 145°C (mostly after melting reagent). This technique is not suitable for use on a large scale.

d. Johannes et al., J. Am. Chem. Soc. (1998), 120, 8340-8347

In article Johannes c co-authors described the enantioselective receipt of d-nebivolol (Scheme 4).

The strategy is based on the synthesis of chiral fragments chromane d12 (R,R-configuration) and d21 (S,S-configuration) as key intermediates in convergent ways, all of which are connected and give after removal of the protection of d-nebivolol. An essential stage in the synthesis mentioned chiral Romanov is Zr-catalyzed kinetic resolution of racemic intermediates d7 and d16.

In accordance with the first through the original substance to obtain a fragment chromane d12 is salicylic aldehyde d3, which synthesize or formirovanie connection d1, or reaction litoraneo connection d2 with DMF at -60°C. Then the allyl epoxide of cycloheptene, which can be obtained by epoxydecane of cycloheptadiene, is subjected to the interaction with the aldehyde d4, receiving racemic compound d7 by regioselective and Starosel the active nucleophilic opening of epoxide cycle d8. Protection of the hydroxyl group d7 using TBSOT followed by treatment with 5 equivalents. EtMgCl and 10 mol.% (R)-(EBTHI)Zr-biphenol gives d8 with the release of 44% and >98%ee. Mo-catalyzed reaction metathesis in the atmosphere of ethylene with subsequent oxidation of the terminal double bond by Wacker (Wacker) and subsequent catalytic hydrogenation gives d10 with a total yield of 83%. To synthesize d11 from d10 need photochemical splitting of Norrish type II. The following sequence of three stages: sonalities cleavage, reaction Mitsunobu, which use tributylphosphine and ftaid, and subsequent hydrazinolysis to remove telemedicine group gives intermediate d12. The second path begins with the synthesis of the racemate d16 with CIS-configuration, which is then divided in the presence of zirconium catalyst (S)-(EBTHI)Zr-biphenol. Connection d17 make in connection d18 Mo-catalyzed metathesis reaction. Oxidation by Wacker (Wacker) terminal double bond and subsequent catalytic hydrogenation to give the intermediate of d19, which further photochemical splitting of Norrish type II and ozonolysis converted into aldehyde d21. D-Nebivolol get then by reductive amination of compounds of d12 and d21 with the subsequent removal silylating protective groups.

The strategy described in the article Johannes with co-authors, has the following disadvantages:

1. Getting aldag is Yes d3 is or with low yield by the reaction of formirovaniya d1, using chloroform in the presence of a base, or requires a low temperature to literarure and formirovaniya derivative d2. In addition, working with n-BuLi in an industrial scale requires special precautions.

2. The stage of obtaining derivatives from d8 d7 and d16 and d17 of d13/d14 also require low temperature (-78°C) for sililirovanie. In addition, it takes hard separation stage, which uses a special commercially available Zr-catalyst.

3. The stage of obtaining compounds d10-d11 and d19-d20 require special equipment for carrying out photochemical reactions (cleavage by Norris, type 2).

4. Stage receiving connections from d12 d11 requires low temperature (-78°C) and special equipment for ozonolysis.

5. For the synthesis of a single enantiomer of nebivolol (d-form) must 16-20 stages, but requires a racemic mixture; therefore an additional stage to synthesize the corresponding l-form (i.e. l-nebivolol).

e. Chandrasekhar et al., Tetrahedron (2000), 56, 6339-6344

In article Chandrasekhar and co-authors described another technique enantioselective synthesis of d-nebivolol (see scheme 5).

The basis for these enantioselective strategy is asymmetric ignoreaction epoxidation of allyl alcohol e7 on he sang sharpless, in which the use of (-)-DET and (+)-DT, to obtain both enantiomeric diols e8 and e12 after the cyclization stage.

The reference compound is 4-terfenol e1, which is first converted into a simple allyl ether of e2. Rearrangement of Clausena at 210°C With subsequent protection of the phenolic group (e3) TBDMS-Cl leads to the formation of intermediate e4. Primary alcohol e5 receive gidroborudovaniya and subsequent oxidative treatment of H2O2. Product e5 converted into α,β-unsaturated ester e6 dorectory oxidation by periodnum dessa-Martin and rafinirovannom by Wittig. Then the connection e6 restore DIBAL-H in allyl alcohol e7. At this stage, the path splits into two paths, each of which begins with asymmetric epoxidation on he sang sharpless and cyclization in the same reactor. According to the first way diol e8 can be obtained with a yield of 65% (- )- DET. Selective totalrevenue primary alcohol e8 and substitution e9 azide, followed by catalytic regeneration E10 gives amerosport E11. The second path synthesize diol e12, almost similar dialu e8, except that the use of (+)-DET for epoxidation on he sang sharpless, receiving the corresponding enantiomeric compound. Inversion at carbon atom C2under the reaction conditions, Mitsunobu the action of n-nitrobenzoic acid leads to the formation of compound e13 protected TLDs what I PNB groups. After removal of the protective groups can be obtained diastereomeric diol e14. Selective totalrevenue e14 and processing of the received e15 base gives epoxide e. Synthesis of hydrochloride of d-nebivolol can be accomplished by reaction of a combination of amerosport E11 with the epoxide e with subsequent transformation into cleaners containing hydrochloride salt.

The strategy described in the article Chandrasekhar and co-authors, has the following disadvantages:

1. The stage of obtaining compounds of e3 from e2 requires a high temperature to regroup Clausena, which is practically unattainable on an industrial scale.

2. For the synthesis of only one enantiomer of nebivolol requires up to 16 stages, but necessary racemic mixture.

3. The last stage combination gives d-nebivolol with low yield (20%).

4. Asymmetric epoxidation on he sang sharpless, as we know, does not enantioface products. Therefore, the likely contamination of other stereoisomers. To identify such possible contamination is not well described method of measuring optical purity, as mentioned in WO 2004/041805.

5. Almost all intermediates purified column chromatography, as most of the intermediates are oily compounds.

Thus, numerous stage (more than 13), low output, using unusual catalysts, conditions reacts and, special equipment and column chromatography for purification predominantly oily intermediates make their strategy and most of the stages are too time-consuming and economically unacceptable for commercial method.

In spite of the above work, there is a need for new, effective and practicable on an industrial scale method of obtaining racemic nebivolol with increased output.

All references cited here included in this application in its entirety by reference.

The INVENTION

The present invention relates to new compounds and intermediates, and methods that can be used directly for the selective synthesis of nebivolol or racemic ([2S*[R*[R[R*]]]]- ([2R*[S*[S[S*]]]]-(±)-α,α`- [iminobis(methylene)]bis[6-ferroman-2-methanol] of the formula (I)

and its clean ([2S[2R*[R[R*]]]]- ([2R*[S*[S[S*]]]]-enantiomeric forms and pharmaceutically acceptable salts.

Accordingly, the method of obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts include

(a) providing a compound of formula (VIII)

as diastereomeric pure compounds, containing less is th least 95% of the RS/SR configuration or RR/SS configuration, where PG represents hydrogen or aminosidine group, and aminosidine group represents at least one allyl group, or aryl-C1alkyl groups;

(b) providing a racemic compound of the formula (V)

where LG is selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate;

(c) N-alkylation of compounds of formula (VIII) with a compound of the formula (V), where the specified N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain the compounds of formula (IX),

the compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX),

or mixtures thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereoisomers;

(d) separation of the diastereomers of the compounds of formula (IX) or the compound of formula (IX') at least one of (d1) or (d2) methods, where

(d1) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% RS/SRR or RRS/SSR configuration;

(d2) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') to give the essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% of RSS/SRR or RRS/SSR configuration, at the stage of simultaneous epimerization-crystallization stage where the epimerization-crystallization includes:

(1) the epimerization of the compounds of formula (IX) or formula (IX') RSR/SRS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration and RSR/SRS configuration or

the epimerization of the compounds of formula (IX) or (IX') RRR/SSS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RRS/SSR configuration and RRR/SSS configuration, provided that the specified epimerization is carried out in the presence of a base and an organic solvent, where the mixture is optionally cooled, using a temperature gradient and where the diastereomers RSS/SRR configuration or RRS/SSR configuration in the mix get at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration; and

(2) crystallization of essentially pure diastereomers of formula (IX) or formula (IX') with RSS/SRR configuration or RRS/SSR configuration of at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration;

separation of the mixture by fractional crystallization optional the part after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX') with RSS/SRR or RRS/SSR configuration;

(e) recovering essentially pure diastereomers of formula (IX) or formula (IX') with RSS/SRR or RRS/SSR configuration with obtaining the compounds of formula (X)

as RSSS/SRRR diastereomeric mixture in which the ratio of the RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration is at least 1;

(f) removing the protection of the compounds of formula (X), provided that PG is H (and if G represents H, then cancel the stage unprotect) to obtain the compounds of formula (I) or its pharmaceutically acceptable salts; and

(g) removing the compounds of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration, if any, by recrystallization or suspendirovanie obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)[α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salt.

Additionally, there is racemic ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-(±)-α,α`-[imino-bis(methylene)]bis[6-ferroman-2-methanol] the compounds of formula (I)obtained by the method described above.

A preferred variant of the method shown in scheme 6A

The reference compound is 6-ferroman-2-carboxylic acid II, which make the relevant tra what spermaceti (stage 1, 2 and 3) in connection V, containing a suitable leaving group (LG). Selective reduction of compound V with the subsequent formation of epoxide and override protected amine gives compound VIIIa after fractional crystallization. In this case, the order of transformations can be changed without requiring the formation of epoxide. The reaction mix compounds VIIIa connection V gives diastereomer mixture of compounds IXa and Xb, then the connection IXa selectively isolated and almost selectively restore in a mixture of compounds Xa (main product) and Xb (minor product). The resulting mixture is then subjected to unprotect and after the formation of the salt with HCl racemic nebivolol hydrochloride I selectively crystallized. The total yield is 8%, but additional quantities of compound V used on stage 7, are ignored.

In a preferred embodiment of the invention, the protective group is a benzyl group. In some embodiments the invention, the leaving group is a chlorine or bromine.

In some embodiments, the method at the stage (b), the compound of formula (V) are obtained in an amount of from about 1.0 to about 1.5 equivalents.

In some embodiments, the method at the stage (c) the organic solvent is a polar aprotic Rast is oritel, selected from the group consisting of DMF, DMA and NMP.

In some embodiments, the method at the stage (c) base represents at least one of the tertiary amines, carbonates of alkali metals or hydrogen carbonates of alkali metals. The preferred base is sodium bicarbonate. It is preferable to use from about 1.5 to about 2.5 equivalents of base.

In some embodiments, the method at the stage (c) catalyst consists of at least one of the bromides of alkali metals, iodides of alkali metals, of tetraalkylammonium bromides or iodides of tetraalkylammonium. The preferred catalyst is sodium bromide. It is preferable to use from about 0.1 to about 0.25 equivalent of catalyst and most preferably 0.15 equivalent catalysts.

In some embodiments of the invention at the stage (c) the specified N-alkylation is carried out at a temperature from about room temperature up to about 80°C.

In some embodiments, the implementation stage (d) fractional crystallization was carried out in a solvent. The preferred solvent is acetonitrile. It is preferable to use the free amine for fractional crystallization. In some embodiments, the implementation of the use from about 0.4/n to about 0.6/n equivalent sillero the corresponding reagent and n denotes the number of transferred silyl groups, per similarbuy reagent. Preferably, similarbuy reagent represented by at least one of tributyltinchloride, HMDS or BSU.

In some embodiments of the invention at the stage (d1) similarbuy the reagent is used for the modification to fractional crystallization from a solvent. The modification is carried out preferably in the presence of from about 1.0 to about 2.0 equivalents of base. The preferred base is imidazole.

In some embodiments, the implementation stage (d1) this separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') is carried out in acetonitrile, methyl tert-butyl ether (MTBE), cyclohexane or their mixtures.

In some embodiments, the method stage (d2) is carried out for the compounds of formula (IX) or (IX`) RSR/SRS configuration. Configuration RSS/SRR in the mix get preferably at about nine-fold excess of RSR/SRS.

In some embodiments, the method at the stage (d2) the mixture is cooled at the temperature gradient from about 70°C to about 20°C. In a preferred embodiment of the invention the temperature gradient ranges from 70° to 40°C.

In some embodiments, the method at the stage (d2) mentioned the epimerization is carried out in the presence of at least 0.1 equivalent of base. In some of the options which implement the epimerization is carried out in the presence of at least 0.25 equivalents of base.

In some embodiments, the implementation stage (d2) base is a compound selected from the group consisting of alkoxide, amidine, guanidine and phosphazene. The preferred base is amidin. In a preferred embodiment of the invention the base is databaseconnect.

In some embodiments, the implementation stage (d2) the water content, if any, may not exceed 1.0%. In some embodiments, the implementation stage (d2) the water content, if any, may not exceed 0,1%.

In some embodiments, the implementation stage (e), referred to the restoration carried out for the compounds of formula (IX) or the compound of formula (IX') RSS/SRR configuration in the solvent by the action of alkali metal borohydride, tetrabutylammonium borohydride, selectride (SELECTRIDE) an alkali metal borohydride or zinc optional in the presence of Lewis acid. In some embodiments, the implementation of a Lewis acid represents at least one substance from Ti(Alkyl)4, ZnCl2, the halide of alkali metal or alkali earth metal halide. Preferably, the solvent is represented by at least one of ether, alcohol or a halogenated hydrocarbon. In some embodiments of the invention mentioned the restoration ol the lead at temperatures from about -20°C to about room temperature.

In some embodiments, the implementation stage (f) referred to unprotect carried out by catalytic hydrogenation.

In some embodiments, the implementation stage (g) mentioned cleaning the compounds of formula (I) is carried suspendirovanie his cleaners containing hydrochloride salt in a solvent. The suspension preferably carried out in methanol as solvent.

In some embodiments of the invention, the above provision of the compounds of formula (VIII) include:

(i) recovery of racemic compounds of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG represents a bromine or chlorine, with the formation of diastereomeric mixture of compounds of the formula (VI)

(ii) formation of a mixture of diastereoisomers of the compounds of formula (VII)

;

(iii) the interaction of diastereomers of compounds of formula (VII) with NH2PG with the formation of a mixture of diastereoisomers of the compounds of formula (VIII)

and

(iv) separation of the diastereomers of the compounds of formula (VIII) mixture of diastereoisomers by fractional crystallization is not necessary after the formation of the salt. In a preferred variant of the invention, the PG is a benzyl group.

In some embodiments of the invention distinguish what about the at least one of the diastereomers of the compounds of formula VIII, with RR/SS or RS/SR configuration.

Another aspect of the present invention relates to a method of recycling unwanted diastereomers obtained during the method, which reduces costs and makes the method of obtaining nebivolol more effective. Specifically, during the selective obtaining compounds VIIIa and Xa undesired diastereomers are formed as minor products. Therefore, recycling of waste is an economic and environmental advantage compared with previous methods of obtaining nebivolol.

Alkylation of compound VIIIa connection V also forms diastereomers blend (mixture of IXa and IXb, 1:1), where stage recirculation makes possible the transformation of unwanted form IXb or by selective cleavage with the formation of compound VIIIa, or by conducting an appropriate stage of epimerization in the mixture of compounds IXa and IXb, followed by selective allocation of the desired diastereoisomer IXa.

In some embodiments of the method are recycling the compounds of formula (VIII) RR/SS configuration, which includes:

the provision of the compounds of formula (VIII) with a protective group RR/SS configuration; and

inversion of the configuration of the alcohol with the formation of the compounds of formula VIII SR/RS configuration.

In some embodiments of the invention at stage i) vos is canonical choose from a borohydride of an alkali metal, of of tetraalkylammonium borohydride, zinc borohydride, triacetoxyborohydride alkali metal, SUPERHYDRIDE, RED-AL, selectride (SELECTRIDE) alkali metal or coordination borhydride. In some embodiments of the invention at stage i) referred to the restoration carried out under the reaction conditions of Meerwein-Ponndorf-Verley. In some embodiments, the implementation of stage i) referred to the restoration carried out by catalytic hydrogenation. In some embodiments, the implementation of stage i) Lewis acid is an acid selected from the group consisting of chlorides of alkali or alkaline earth metals, zinc chloride, alkoxide of titanium (IV) and tralkoxydim aluminum. In some embodiments, the implementation of stage i) referred to the restoration carried out in conditions that lead to the formation of the compounds of formula (VI) RR/SS isomer in excess. In some embodiments, the implementation of stage i) referred to the restoration carried out at a temperature from about -78°C to about room temperature. Preferably the said recovery at temperatures from -20°C to room. In some embodiments, the implementation of stage i), the solvent is a solvent selected from the group consisting of alcohols, ethers, halogenated hydrocarbons and aromatic solvents.

In some the options for implementation in phase ii) mentioned the formation of a mixture of diastereomers of compounds of formula (VII) is carried out in a solvent and in the presence of a base. The solvent is preferably an alcohol and a base is an alcoholate of an alkali metal. Use preferably 1.0 to 2.0 equivalent basis.

In some embodiments, the implementation of stage ii) mentioned the formation of a mixture of diastereomers of compounds of formula (VII) is carried out at temperatures from 0°C to 40°C.

In some embodiments, the implementation of the on stage iv) fractional crystallization was carried out in toluene, acetonitrile, C1-C3-alcohol, simple ester or their mixtures. Preferred C1-C3-alcohol is 2-propanol, and a simple ether represents at least one of diisopropyl ether, or MTBE.

In some embodiments of the invention mentioned the provision of racemic compounds of formula (V) includes:

(1) the conversion of compounds of formula (II)

in the activated acid derivative;

(2) the interaction of the activated derivative of the acid with the acid Meldrum in the presence of a base to form compounds of formula (III)

;

(3) the conversion of compounds of formula (III) in a compound of the formula (IV)

where R represents hydrogen or COOR` where R` represents a C1-C6alkyl or aryl-C1alkyl; and

(4) haloge the licensing of compounds of formula (IV), and optionally carrying out hydrolysis and decarboxylation to form compounds of formula (V).

In some embodiments of the invention at the stage of (1) carboxylic acid is transformed into the corresponding acid chloride acid.

In some embodiments of the invention at the stage (2) the base is a tertiary amine. In some embodiments, the implementation of the use of 1-3 equivalents of acid Meldrum. In some embodiments, the implementation stage (2) the reaction temperature is from about -10°to about +30°C.

In some embodiments, the implementation stage (3), the compound of formula (III) hydrolyzing in a mixture of organic acid and water and get the connection formula (IV), where R represents H. In a preferred variant of the invention, the organic acid is an acetic acid and the hydrolysis is carried out at the boiling point. In some embodiments, the implementation stage (3), the compound of formula (IV), containing R as OOR' and R` in the form of C1-C6the alkyl or aryl-C1of alkyl, produced by alcoholysis of the compound of formula (III). Alcoholysis is conducted preferably ethanol and tert-butanol. Alcoholysis is conducted preferably at temperatures from about 70°C to about 80°C.

In some embodiments of the invention at the stage (3) the solvent represents at least one alcohol or toluene.

In some embodiments, the implementation of the ISO is retene on stage (4) before carrying out the halogenation of the compound of formula (IV), in which R represents H, turn sellerbuyer in the appropriate selenology ether containing a terminal double bond. In some embodiments of the invention similarobama carried out by kinetically controlled deprotonation by diisopropylamide lithium (LDA) followed by sellerbuyer at a temperature from about -78°C to about -40°C. Preferably similarobama at a temperature of from -78°C to -70°C. In a preferred embodiment of the invention silylium agent is TMSCl.

In some embodiments of the invention at the stage (4) after transformation into simple selenology ether conduct halogenoalkane using pomeroyi reagent. Preferred brainwashin reagent is N-bromosuccinimide.

In some embodiments of the invention at the stage (4), the compound of formula (IV), where R represents COOR`, first halogenous, and then converted into the compound of the formula (V) hydrolysis of the ester followed by decarboxylation. Preferably halogenoalkane in the presence of a catalyst. In some embodiments, the implementation as halogenation reagents used from about 1.0 to about 1.5 equivalents of N-bromosuccinimide, N-chlorosuccinimide or SO2Cl2. In some embodiments, the implementation as a cat is of Isadora use about 0.2 to 0.4 equivalent of Mg(ClO 4)2.

In some embodiments of the invention at the stage (4) mentioned halogenoalkane carried out at temperatures from 0°C to about room temperature.

In some embodiments of the invention at the stage (4) after the above-mentioned halogenation carry out the hydrolysis of ester followed by decarboxylation in an aqueous solution of an organic acid. The organic acid preferably represents at least one of triperoxonane acid, formic acid and acetic acid. Preferably the hydrolysis and decarboxylation at temperatures from about 75°to about 90°C.

In some embodiments, the implementation of the method further include the recycling of the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration where the above-mentioned recycling includes:

the epimerization of the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration, with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration containing diastereomers RSR/SRS configuration, or a mixture of diastereomers of formula (IX) or formula (IX') RRS/SSR configuration containing diastereomers RRR/SSS configuration, and

separation of the mixture by fractional crystallization after the formation of salts or after modification, resulting in essentially pure diastereomers of formula (IX) or formula (IX')having RSS/SRR and the and RRS/SSR configuration.

In some embodiments, the implementation of the method further include the recycling of the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration where the above-mentioned recycling includes:

cleavage of compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration, which gives a mixture of diastereomers of the formula (VIII) RS/SR or RR/SS configuration; and

the separation of the RS/SR or RR/SS configuration of the diastereomers of the formula (VIII).

An additional aspect is a compound of formula (III)

An additional aspect is a compound of formula (IV)

where R represents hydrogen or COOR' and R` represents a C1-C6alkyl or aryl-C1alkyl.

An additional aspect is a compound of formula (V)

where LG represents bromine or chlorine.

An additional aspect is a compound of formula (VI)

where LG represents bromine or chlorine.

An additional aspect is a compound of formula (IX)

or cyclic policealna form of formula (IX'),

where PG is a protective group selected from hydrogen, allyl, and aryl-C1the alkyl.

An additional aspect is the connection is their formula (IX) with RSS/SRR configuration

or cyclic policealna form of formula (IX')

where PG is a benzyl group.

Aspect of the invention is also a method of obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts comprising: providing a compound of formula (IX); and recovering the compounds of formula (IX) with a compound formula (X)containing not more than 50% of the stereoisomer having RSRS configuration. The method further includes obtaining the compounds (VIII) and compounds of formula (V).

According to the present invention can also be obtained enantiomerically pure nebivolol (l-nebivolol or d-nebivolol), for example, after the separation of compound II (see Scheme 6b and 6c). Each of the enantiomers (S-II and R-II) can be transformed in the same way as described for the corresponding racemic compound (II) (cf. scheme 6a) to obtain the first key intermediates S-V and R-V. Hydrochloride of l-nebivolol (scheme 6b) can then be obtained by synthesis of R-VIIIa, on the basis of R-V, followed by reaction mix with S-V (stage 11), selective recovery (stage 12), removing the protection and education of salt (stage 13). The hydrochloride of d-nebivolol can be obtained in the same manner and on the Ohm, except that unlike the synthesis of l - nebivolol, enantiomeric intermediate S-VIIIa receive from the S-V and then injected into the reaction mix with R-V (scheme 6c, stage 11). Selective recovery (stage 12) with subsequent removal of the protection and education of salt gives the hydrochloride of d-nebivolol.

To a person skilled in the art it is obvious that various changes and modifications discussed ways can be used for enantioselective syntheses of l - or d-nebivolol. Therefore, the use of intermediates for the enantioselective synthesis of l - or d-nebivolol received on circuits 6b and 6c, is not limited to the described ways. For example, epoxides R-VIIa, R-VIIb, S-VIIa and S-VIIb (obtained from the key intermediates R-V or S-V) can also be used directly for the synthesis of each enantiomer of nebivolol, for example, in the way described in scheme 2. From the reducing agent depends happen epoxides R-VIIa, R-VIIb, S-VIIa and S-VIIb as a major or minor connection.

The method of obtaining the compounds of formula (I) in the form of a racemic mixture or an enantiomerically pure form and its pharmaceutically acceptable salts include:

(a) separation of the compounds of formula (II)

obtaining the compounds of formula (II) S configuration or R configuration is;

(b) the conversion of compounds of formula (II) S configuration in the compound of formula (V) S configuration

where LG is a Deputy selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate, through the formation of the compound of formula (III) S configuration and the compounds of formula (IV) S configuration;

(c) the conversion of compounds of formula (II) R configuration in the compound of formula (V) R configuration through the formation of the compound of formula (III) R configuration and the compounds of formula (IV) R configuration;

(d) the provision of the compounds of formula (VIII)

where PG represents hydrogen or aminosidine group, where aminosidine group represents at least one allyl group, or aryl-C1alkyl groups and where the compound of formula (VIII) represents the enantiomeric connection with RS or SR configuration;

(e) conducting N-alkylation of (i) the compounds of formula (VIII) RS configuration compound of formula (V) S configuration, or (ii) of the compound (VIII) SR configuration compound of formula (V) R configuration, provided that the said N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst to obtain the RSS or SRR enantiomers is connected to the I of the formula (IX)

or SRR RSS or enantiomeric form of the compound (IX`), which is a cyclic polyethalene form the compounds of formula (IX)

(f) recovering at least one of the RSS or SRR enantiomeric forms of the compounds of formula (IX) or formula (IX') obtaining at least one RSSS or SRRR enantiomeric forms of compounds of formula (X)

(g) removing the protecting at least one of the RSSS or SRRR enantiomeric forms of the compounds of formula (X), provided that PG is H (and if PG is a N, then the specified stage unprotect cancel)to obtain the compound of formula (I) or its pharmaceutically acceptable salt; and

(h) removing the compounds of formula (I) or its pharmaceutically acceptable salts RSRS diastereomeric configuration, if any, as a by-product, recrystallization or suspendirovanie obtaining at least one of ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-enantiomers of the compounds of formula (I) and its pharmaceutically acceptable salts; and

(i) optional Association ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]- enantiomers of the compounds of formula (I) and its pharmaceutically acceptable salts for the formation of racemic ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-(±)α,α`-[imino-bis(methylene)]bis[6-ferroman-2-methanol] of the formula (I) and its pharmaceutically acceptable salts.

Another aspect of the invention is a method for racemic [2S*[R*[R*[R*]]]]and [2R*[S*[S*[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:

(a) providing a compound of formula (VIII) in the form of a diastereoisomer with RR/SS configuration, where PG represents hydrogen or aminosidine group, where aminosidine group represents at least one allyl group, or aryl-C1alkyl groups;

b) providing a racemic compound of the formula (V), where LG represents a Deputy selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate;

(c) N-alkylation of compounds of formula (VIII) with a compound of the formula (V)where the above-mentioned N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst and obtain the connection formula (IX), the compound of formula (IX'), which is cyclic polyethalene form the compounds of formula (IX), or a mixture thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereomers, with RRR/SSS and RRS/SSR configuration;

(d) separation of the diastereomers of the compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of the salt or the Les modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX'), having at least 50% RRR/SSS or RRS/SSR configuration;

(e) recovering essentially pure diastereomers of formula (IX) or formula (IX') RRS/SSR configuration that gives compound of formula (X) in the form of RSSS/SRRR diastereomeric mixture in which the ratio of the RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration, is at least 1;

(f) removing the protection of the compounds of formula (X), provided that PG is H with obtaining the compounds of formula (I) or its pharmaceutically acceptable salts; and

(g) removing the compounds of formula (I) or its pharmaceutically acceptable salts RSRS diastereomeric configuration, if any, by recrystallization or suspendirovanie, leading to the formation of racemic [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts.

In some embodiments of the invention the method further includes splitting the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with the formation of the compounds of formula (VIII) in the form of a diastereoisomer RR/SS configuration.

In one embodiment, the method further includes the epimerization of the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with the formation of the above-mentioned mixtures of diastereomers of compounds of formula (IX) or connected to the I of the formula (IX') RRR/SSS and RRS/SSR configuration. In yet another embodiment, the above-mentioned variant, the method further includes splitting the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with the formation of the compounds of formula (VIII) in the form of a diastereoisomer RR/SS configuration.

Also provided is a method of obtaining the compounds of formula (VIII)

the method includes

(i) providing a racemic compound of the formula (V)

;

(i) recovery of racemic compounds of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG represents a bromine or chlorine, with getting diastereomeric mixture of compounds of formula (VI)

;

(ii) formation of a mixture of diastereoisomers of the compounds of formula (VII)

;

(iii) the interaction of diastereomers of compounds of formula (VII) with NH2PG, where PG represents hydrogen or aminosidine group and where aminosidine group represents at least one allyl group, or aryl-C1alkyl groups, which gives compound of formula (VIII) as a mixture of diastereoisomers; and

(iv) optional separation of diastereomers of compounds of formula (VIII) of the mixture of diastereoisomers by fractional crystallization.

Also provided is a method of obtaining racemic [2S*[*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:

(a) providing a compound of formula (IX), compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX) or a mixture thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereoisomers;

(b) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') at least one of (b1) or (b2) methods, where

(b1) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% of RSS/SRR or RRS/SSR configuration; (b2) the separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') to give the essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% RSS/SRR or RRS/SSR configuration stage simultaneous epimerization-crystallization stage where the epimerization-crystallization includes:

(1) the epimerization of the compounds of formula (IX) or (IX') RSR/SRS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration and RSR/SRS configuration or

the epimerization of the compounds of formula (IX) or (IX') RRR/SSS configuration, with a mixture of diastereomers of formula (IX) or formula (IX') RRS/SSR configuration and RRR/SSS configuration, provided that the specified epimerization is carried out in the presence of a base and an organic solvent, where the mixture is optionally cooled, using a temperature gradient and where RSS/SRR configuration or RRS/SSR configuration in the mix get in at least twofold excess relative to the RSR/SRS configuration and RRR/SSS configuration; and

(2) crystallization of essentially pure diastereomers of formula (IX) or formula (IX')having RSS/SRR configuration or RRS/SSR configuration at least twofold excess relative to the RSR/SRS configuration and RRR/SSS configuration;

separation of the mixture by fractional crystallization is not necessary after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX') RSS/SRR or RRS/SSR configuration;

(c) recovering essentially pure diastereomers of formula (IX) or formula (IX') RSS/SRR or RRS/SSR configuration with obtaining the compounds of formula (X) in the form of RSSS/SRRR diastereomer mixture with respect RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration, which is at least 1;

(d) removing the protection of the compounds of formula (X), provided that PG is H (and if PG represents H, then cancel the stage unprotect) to obtain the compounds of formula (I)

or pharmaceutically acceptable what's salts; and

(e) removing the compounds of formula (I) RSRS or RRSS diastereomeric configuration or its pharmaceutically acceptable salts, if any, by recrystallization or suspension from receiving racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α`-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or pharmaceutically acceptable salts.

The new compounds obtained by the authors of the present invention, include the following

and

A BRIEF DESCRIPTION of SEVERAL VIEWS of the DRAWINGS

The invention will be described together with the following drawings, in which similar item numbers denote like elements and where:

Figure 1A shows the structural formula of d-nebivolol, figure 1B shows the structural formula of racemic nebivolol.

Figure 2 is a schematic representation of molecules of compound VIIIa with numbered atoms (50% probability ellipsoids; given an arbitrary parameters displacement of atoms N for clarification).

Figure 3 is an image13C-NMR spectrum of compound IXa in cyclic polyethalene form.

Figure 4 is an image13C-NMR spectrum of compound IXb in cyclic polyethalene form.

Figure 5 represents the FDS is th a schematic representation of the molecules of compound IXb in cyclic polyethalene form.

Figure 6 is a diagram illustrating a method of obtaining racemic nebivolol and its pharmaceutically acceptable salts.

Figure 7 is a diagram illustrating a method for simultaneous epimerization-crystallization according to the invention.

Figure 8 is a diagram illustrating a preferred example of the method for simultaneous epimerization-crystallization according to the invention, where the protecting group is a benzyl group.

Figure 9 is a diagram illustrating a method of obtaining racemic nebivolol and its pharmaceutically acceptable salts, in which stage 7b represents the simultaneous epimerization-crystallization according to the invention.

DETAILED description of the INVENTION

The present invention relates to new compounds and methods of synthesis of racemic nebivolol and its pharmaceutically acceptable salts, as well as enantiomerically pure nebivolol and its pharmaceutically acceptable salts. The present invention stimulated by the desire to create a more efficient way, containing a smaller number of reaction stages, to avoid stages of separation of the enantiomers to obtain a racemic mixture. One example of the separation of enantiomers is described in WO 2004/041805 (Scheme 3b). Since all enantiomers share during the earlier stages of the way, to receive the of racemic nebivolol need up to 30 stages in four convergent paths. Therefore, the method of obtaining racemic nebivolol based on such a strategy is difficult and inefficient. The present invention offers a solution that makes possible the selective obtaining intermediates, as shown in figure 6a, where each of the intermediates obtained as racemic mixtures without prior separation of the enantiomers, which are formed during the method.

In addition, the present invention provides the possibility of obtaining enantiomerically pure nebivolol, for example, after separation of the selected racemic compounds, such as compound II (Scheme 6b and 6c).

The invention also relates to a method for producing racemic nebivolol in which the formation of undesired diastereomers (e.g SRSS/RSRR) in the final stages is minimized by promoting the clearance and increase efficiency. The authors of the present invention surprisingly found that in order to effectively get nebivolol can take advantage of differences in solubility of other diastereomeric derivative of nebivolol in the form of their salts with HCl. Specifically, the inventors have observed that the meso-form of racemic nebivolol (as HCl-salt) configuration RSRS has a high solubility compared to nebivolol hydrochloride, while the second meso-form Conf the configuration RRSS has a solubility comparable to the solubility of nebivolol hydrochloride. The solubility of the HCl-salt in MeOH 1.5% for nebivolol, 1.0% for RRSS-meso-forms and more than 15% for RSRS-meso-forms. In a preferred embodiment, the present invention provides selective receiving racemic nebivolol, which may contain only the selected diastereoisomer (for example RSRS-meso-form) as a possible impurities that can be removed easily by simple recrystallization due to the higher solubility. Therefore, by using this synthetic strategy can avoid the difficult and inefficient (low output) purification of the final product, so as to prevent the formation of poorly soluble diastereomers of nebivolol (SRRS/RSSR, RRSS, SRSS/RSRR and RRRR/SSSS).

Another aspect of the present invention relates to a diastereoselective synthesis of intermediate VIIIa, containing the preferred SYN-configuration. The specified connection is a useful intermediate in the above synthetic strategy of selective receiving racemic nebivolol because it can be formed as impurities only diastereoisomer RSRS configuration, which can be easily removed at the final stage (figure 6a, stages 8 and 9).

Another aspect of the present invention relates to an efficient method of selectednodestyle compounds IXa, in which the formation of undesired isomer RSRS is minimized.

The authors of the present invention have found that the efficiency of the method increases additionally ways of recycling for re-use of unwanted diastereomers, which can be obtained during the synthesis of intermediates.

The method of obtaining racemic nebivolol (as shown in figure 6a) will now be described in detail.

The starting material of this method is the connection II, racemic acid, which can be obtained in various ways according to the methods described in U.S. patent No. 5171865 (see also patent-analogue EP 0331078) and U.S. patent No. 4985574 (see also patent-analogue EP 0264586).

Stage 1 includes obtaining (±)-5-[6-ferroman-2-carbonyl]-2,2-dimethyl[1,3]dioxane-4,6-dione (compound III) from compound (II), as shown in figure 7.

First of racemic acid II is converted into an activated derivative of the acid, which then reacts with acid Meldrum in an organic solvent gives the corresponding acylated Meldrum III, which is a new compound and is a useful intermediate for the synthesis of nebivolol.

Acylation with acid Meldrum can be performed according to the method similar to the traditional, for example the method described in J. Org. Chem. 43(10), 1978, 2087).

5, PHaI3, SOHaI2, (COHaI)2in the form of a carboxylic acid anhydride, an activated complex ether, etc. Activation of obtaining gelegenheid preferred, and the acid chloride is the most preferred galogenangidridy, which is obtained using 1-5 equivalents SOl2, preferably 1-3 equivalents in the presence of catalytic amounts of DMF. The above reaction can be conducted without using any solvent or in a solvent, such as benzene, alkyl - or halogen-substituted benzene, halogenated hydrocarbons and the like. Alkyl substituted or halogen-substituted benzenes are preferred solvents, toluene is the preferred solvent.

The reaction temperature can vary in the range from room temperature up to the boiling point of the solvent. In a preferred variant of the invention, the temperature range is from 60°C to 90°C in toluene as solvent. Acylchlorides can be obtained in almost quantitative yield by evaporation of the solvent together with the excess glorieuses reagent.

The acylation acid Meldrum can be carried out in the same solvent, which is used to activate the carboxylic acid. Halogen is consistent hydrocarbons are the preferred solvents, while methylene chloride is most preferred. Usually the acid Meldrum used in a molar ratio of 1-3 mol per mole of compound II, preferably about 1-1 .5 moles per mole of compound II. The reaction is carried out in the presence of organic or inorganic bases, preferably in the presence of organic bases, such as tertiary amine, and most preferably in the presence of pyridine. In some embodiments of the invention as the basis of use 1-5 equivalents, preferably 1.5 to 3 equivalents of pyridine. The reaction temperature can vary in the range from -10°C (but not below the melting temperature of the pure solvent, e.g. benzene) to about +30°C, preferably in the range from 0°C to room temperature. The reaction is carried out in the specified temperature range (0°C-connemarathon), usually completed within 2 hours.

At the end of the reaction the mixture was hydrolized and extracted with water or a dilute aqueous solution of inorganic acid, preferably 5%-10% aqueous solution of hydrochloric acid.

After separating layers, the organic solvent is evaporated and the residue can be used directly in the next stage, or can be cleaned by recrystallization or suspendirovanie in an organic solvent. It is preferable to clean the residue with what spenderorganen in the air, and most preferably in methyl tert-butyl ether (MTBE) or diisopropyl ether.

If you want to obtain enantiomerically pure nebivolol, it is possible to obtain the separation of the compound (II), using, for example, (+)- dehydroabietylamine, as described in U.S. patent No. 6545040.

Stage 2 includes obtaining compounds IV, scheme 6a, where R represents H, then obtain (±)-1-(6-ferroman-2-yl)-Etalon (compound IVa, scheme 8, path A), or COOR', where R' is an alkyl or substituted alkyl, then get alkilany ether (±)-3-(6-ferroman-2-yl)-3-oxopropanoic acid (compound IVb, scheme 9, path B).

Acylated acid Meldrum are suitable intermediates to produce the corresponding ketone after hydrolysis and decarboxylation or to obtain the appropriate beta-ketoacids after alcoholysis and decarboxylation. The reaction can be performed similarly to the standard technique, such as described in J. Org. Chem. 43(10), 1978, 2087 and Synth. Commun., 10, 1980, 221).

The path And

Hydrolysis and decarboxylation of compound III with the formation of compound IVa (scheme 8) as a new connection and a useful intermediate for the synthesis of nebivolol, can be carried out in aqueous acid solution at boiling point. It is possible to use inorganic or organic acid, vinegar is the second acid is preferred. Water can be used in excess; preferred equal volume amounts of water and acetic acid. The connection can be used directly as a crude product or it can be clear column chromatography.

Path B

The reaction of compound III with alcohols gives the corresponding beta ketoester IVb as a new connection and a useful intermediate for the synthesis of nebivolol in which R' represents an alkyl or substituted alkyl. This alcoholysis can be primary, secondary or tertiary alcohols, preferably primary and tertiary alcohols, and most preferably ethanol or tert-butanol. As a solvent, you can use the alcohol or inert aromatic solvent. The preferred solvent for the synthesis of the corresponding ethyl ester is ethanol, and toluene is the preferred solvent for the synthesis of tert-butyl methyl ether. The reaction temperature may vary from the boiling point of the low-boiling alcohols up to the boiling point of toluene or the boiling point of the corresponding azeotrope of toluene/alcohol. The preferred temperature to obtain beta-ketoacidosis ether, and beta-keto-tert-butyl ether in the range from about 70°to about 80°C. In the Le completion of the reaction, the reaction mixture can be processed in the usual way, for example, the extraction, the crude product can either be used directly in the next stage, or clear column chromatography.

Stage 3 includes obtaining connection V from compound IV, for example (±)-2-bromo-1-(6-ferroman-2-yl)ethanone (compound Va) and (±)-2-chloro-1-(6-ferroman-2-yl)ethanone (compound Vb) (schemes 10 and 11 a-c).

Compound IV obtained in stage 2, can be used for the synthesis of compound V, which contains a suitable leaving group (LG). Non-limiting examples of suitable leaving groups include substituted and unsubstituted alkyl and aryl derivatives of sulfonic acid and halogen atoms. In a preferred variant of the invention, the leaving groups are halogen atoms, and most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb).

Compounds Va and Vb can be obtained by way of A scheme of 10 or path B circuits 11a, as described below.

Path As:

Synthesis of brometea (compound Va) direct bromirovanii of ketone (compound IVa) bromine or NBS leads in most cases to a competitive bromirovanii aromatic ring. However, after preliminary conversion of the ketone IVa in the appropriate selenology ether containing a terminal double bond, allowing selective connection of Va (see diagram 10).

According to the General method selenology ether can be obtained kinetically controlled deprotonation with strong base followed by sellerbuyer. Examples of the solvent include ethers or mixtures of ethers with such solvents, which are usually available solutions of strong bases. In a preferred embodiment, receiving similaralcohol ether as the basis use diisopropylamide lithium (LDA), as cilleruelo agent use trimethylsilane (TMSCl), and tetrahydrofuran (THF) is used as a simple ether. The reaction begins at -78°C by addition of compound IVa to a mixture of 1-1 .5 equivalent of LDA and 1-2 equivalents of TMSCl. Preferred 1.2 equivalent of LDA and 1.6 equivalent of TMSCl. Then the reaction mixture is allowed to warm to room temperature, the mixture is first extracted and then concentrated. Bromination can be carried out in a suitable solvent with N-bromosuccinimide (NBS), 1,3-dibromo-5,5-dimethylhydantoin or perbromide hydrobromide pyridine at a temperature from 0°C to room. Suitable solvents include, for example, halogenated hydrocarbons, preferably methylene chloride. After completion of the reaction the mixture is extracted, and the product can be cleaned column chromatography or recrystallization. As with the non-selective bromirovanii observed is by the formation of by-products, what complicates the purification was developed more selective and effective method of obtaining compounds of V (see path B, Scheme 11a).

Path B:

Path B represents an alternative way of obtaining halogenated compounds Va and Vb, which is more selective than the path A (see figure 11a).

The advantage of the way In is the possibility of carrying out the reaction at a higher, more comfortable temperatures consistent halogenoalkanes beta keeeper IVb, followed by hydrolysis and decarboxylation. Halogenoalkane can be performed with a suitable halogenation reagent with catalyst or without catalyst. Typical halogenation reagent to obtain the corresponding bromides or chlorides include, for example, NBS, NCS, and SO2Cl2. A non-limiting example, the catalyst includes Mg(ClO4)2. Suitable solvents for this reaction include acetonitrile, esters or halogenated hydrocarbons, acetonitrile, ethyl acetate and methylene chloride are preferred. In some embodiments, the implementation can be used 1.0 to 1.5 equivalent of halogenation reagent and 0.3 equivalent of catalyst. The reaction is carried out at a temperature of from 0°C. to room to complete the conversion within 3-4 hours. A higher temperature for the halogenation trail is t be avoided because of possible adverse reactions, and at lower temperatures may increase the duration of the reaction. Subsequent hydrolysis of the ester and decarboxylation with the formation of compound V can be carried out in aqueous or non-aqueous solutions of acids at higher temperatures. You can use organic and inorganic acids.

Compound IVb as ethyl or tert-butyl methyl ether can be used as initial substances, and tert-butyl methyl ether is preferred. In the case of ethyl ester hydrolysis and decarboxylation of the corresponding halogenated beta-keeeper can preferably aqueous solution triperoxonane acid. When using the form tert-butyl ester hydrolysis and decarboxylation of the corresponding halogenated beta-keeeper preferably carried out in a mixture of formic acid and acetic acid, preferably in the presence of water. The temperature for the hydrolysis reaction of the ester and decarboxylation is in the range from about 60°to about 100°C., preferably 75-90°C. Purification of compounds V can be performed as described above for compounds Va. Because the connection Vb is also more stable during storage than the connection Va, compound Vb is preferred.

The connection V, containing as leaving g the PP substituted and unsubstituted derivatives of alkyl - and arylsulfonic acids, can be obtained, for example, the transformation of compound IVb` or Ivb" (LG = halogen) salts of carboxylic acids in the compound Ivb"' followed by hydrolysis of ester, followed by decarboxylation and sulfonylamine under the action of the corresponding acid chlorides alkyl - or arylsulfonic acids (see figure 11b). Alternatively, the Vc connection can be obtained by a similar transformation, starting directly from halogenated Va or Vb (see Scheme 11c)

Stage 4 includes obtaining compound VI as shown below in scheme 12. Non-limiting examples of compounds VI include (±)-2-chloro-1-[6-fluoro-(2R*)-chroman-2-yl]-(1R*)-Ethan-1-ol (intermediate VI), (±)-2-chloro-1-[6-fluoro-(2R*)-chroman-2-yl]-(1S*)-Ethan-1-ol (intermediate VIb), (±)-2-bromo-1-[6-fluoro-(2R*)-chroman-2-yl]-(1R*)-Ethan-1-ol (intermediate VIc) and (±)-2 - bromo-1-[6-fluoro-(2R*)-chroman-2-yl]-(1S*)-Ethan-1-ol (intermediate VId).

A number of reducing agents can be used to obtain halogenation alcohols (compound VI) of racemic halogenoalkanes (compound V) (see scheme 12). Generally can be formed of two racemic diastereoisomer with sin(RR/SS) or anti(RS/SR) configuration. Regarding the strategy for the synthesis of nebivolol, as shown in figure 6(a), the preferred restoration methods, which lead to the formation of excess halogenosilanes alcohol with sin(RR/SS) to the nfiguration. Surprisingly, there is very little research on the selective recovery of halogenoalkanes containing alkoxy-substituted chiral center in the alpha-position (for example, Tetrahedron Letters, 40 (1999), 2863-2864). Until the present invention no clear influence of alkoxy-substituted chiral center in the alpha position halogenoalkanes on the formation of a new chiral center in the alpha position, and the diastereoselectivity for such reactions is uncertain.

Usually there are no restrictions on the use of reducing agents, for example borhydride and aluminiumhydride reducing agents and reagents, which are applicable for the recovery Meerwein-Pondorf-Verley. Non-limiting examples of reducing agents include LiBH4, NaBH4, KBH4N(nBu)4BH4, Zn(BH4)2, NaH(Oac)3, Superhydride®, Red-Al, Li-selectride (Li-Selectride), BH3SMe2or like them. In the case of catalytic hydrogenation of suitable catalysts are the catalysts that do not give adverse reactions with halogenoalkane compounds (for example, the catalysts described and cited in WO 03/064357). Recovery can be performed in the absence or in the presence of a Lewis acid such as MgCl2, CaCl2, BaCl2, ZnCl2Al(Alkyl)3, Ti(Alkyl) BF3OEt2etc. Suitable solvents include ethers, alcohols, halogenated hydrocarbons, halogenated or alkylated aromatic solvents and the like, except that the halogenated solvents are not suitable for reactions of catalytic reduction. Preferred halogenoalkane connection V contain chlorine or bromine as a substituent "LG". Recovery is conveniently carried out at temperatures from about -78°C to about room temperature, preferably at a temperature of from -20°C. to room. Table 2 shows representative results of recovery chloromethylketone Vb (LG = Cl).

56,3//43,7*
Table 2
Reagent (equiv.)The catalyst (equiv.)SolventTemperature [°C]Time [h]Attitude
RR/SS/RS/SR
LiBH4(1)noTHF-20 to -15158,3//41,7
LiBH4(1)no -20 to -15160,2//39,8
LiBH4(1)noiPrOH-20 to -15151,0//49,0
LiBH4(1)noCH2Cl2-20 to -15342,8//57,2
LiBH4(1)notoluene-20 to room Temperature.During the night41,5//58,5
LiBH4(1)noDME-20 to -15153,8//46,2
LiBH4(1)ZnCl2(2)THF-20 to -15156,9//43,1
LiBH4(1)ZnCl2(2)MeOH -20 to -15163,7//36,3
LiBH4(1)ZnCl2(2)iPrOH-20 to -15160,3//39,7
LiBH4(1)ZnCl2(2)CH2Cl2-20 to rooms. Temperature.During the night59,3//40,7
LiBH4(1)ZnCl2(2)toluene-20 to room Temperature.During the night53,0//47,0
LiBH4(1)ZnCl2(2)DME-20 to -15246,7//53,3
LiBH4(1)Ti(OiPr)4(2)THF-20 to -15148,8//51,2
LiBH4(1)Ti(OiPr)4(2)MeOH -20 to -15159,3//40,7
LiBH4(1)Ti(OiPr)4(2)iPrOH-20 to -15147,3//52,7
LiBH4(1)Ti(OiPr)4(2)CH2Cl2-20 to -15135,6//64,4
LiBH4(1)Ti(OiPr)4(2)toluene-20 to -15138,1//61,9
LiBH4(1)Ti(OiPr)4(2)DME-20 to -15143,4//56,6
LiBH4(1)MgCl2(2)THF-20 to -15357,8//42,2
LiBH4(1)MgCl2(2)MeOH-20 to -15 59,5//40,5
LiBH4(1)MgCl2(2)iPrOH-20 to -151,541,1//58,9
LiBH4(1)MgCl2(2)CH2Cl2-20 to -152,544,3//55,7
LiBH4(1)MgCl2(2)toluene-20 to -152,542,9//57,1
LiBH4(1)MgCl2(2)DME-20 to -15152,4//47,6
LiBH4(1)Al(OiPr)3(2)THF-20 to -15154,7//45,3
LiBH4(1)Al(OiPr)3(2)MeOH-20 to -15159,7//40,3
LiBH4(1)Al(OiPr)3(2)iPrOH-20 to -15150,5//49,5
LiBH4(1)Al(OiPr)3(2)CH2Cl2-20 to -15141,9//58,1
LiBH4(1)Al(OiPr)3(2)toluene-20 to -15139,6//60,4
LiBH4(1)Al(OiPr)3(2)DME-20 to -15151,1//48,9
LiBH4(1)BF3xOEt2(2)THF-20 to room Temperature.During the night61,5//38,5*
LiBH4(1)BF3xOEt2(2)MeOH-20 to room Temperature.During the night
LiBH4(1)BF3xOEt2(2)iPrOH-20 to room Temperature.During the night55,4//44,6*
LiBH4(1)BF3xOEt2(2)CH2Cl2-20 to -15344,9//55,1
LiBH4(1)BF3xOEt2(2)toluene-20 to room Temperature.During the night45,6//54,6*
LiBH4(1)BF3xOEt2(2)DME-20 to -15146,0//54,0
NaBH4(1)noTHF-20 to -15151,8//48,2
NaBH4(1)noMeOH-20 to -15 160,2//39,8
NaBH4(1)noiPrOH-20 to room Temp.22,2559,1//40,9
NaBH4(1)noCH2Cl2-20 to room Temp.2150,9//49,1*
NaBH4(1)notoluene-20 to room Temperature.2151,7//48,3*
NaBH4(1)noDME-20 to -15154,7//45,3
NaBH4(1)noEtOH-78°C to comtainer.356,8//43,2
NaBH4(0,5)noiPrOHbr Rate. 0,550,4//49,6
NaBH4(1)ZnCl2(2)THF-20 to -15158,3//41,7
NaBH4(1)ZnCl2(2)MeOH-20 to -15163,4//36,6
NaBH4(1)ZnCl2(2)iPrOH-20 to room Temp.1859,7//40,3
NaBH4(1)ZnCl2(2)CH2Cl2-20 to room Temp.2163,8//36,2*
NaBH4(1)ZnCl2(2)toluene-20 to room Temperature.2161,5//38,5*

NaBH4(1)ZnCl2(2)DME -20 to -15249,3//50,7
NaBH4(1)Ti(OiPr)4(2)THF-20 to -15142,8//57,2
NaBH4(1)Ti(OiPr)4(2)MeOH-20 to -15158,8//41,2
NaBH4(1)Ti(OiPr)4(2)iPrOH-20 to -15346,4//63,6
NaBH4(1)Ti(OiPr)4(2)CH2Cl2-20 to room Temp.1838,4//61,6
NaBH4(1)Ti(OiPr)4(2)toluene-20 to room Temperature.1841,4//58,6
NaBH4(1)Ti(OiPr)4(2)DME-20 to -15 244,9//55,7
NaBH4(1)MgCl2(2)THF-20 to COMNAP.1844,4//55,6*
NaBH4(1)MgCl2(2)MeOH-20 to -15258,1//41,99
NaBH4(1)MgCl2(2)iPrOH-20 to -15253,4//46,6
NaBH4(1)MgCl2(2)CH2Cl2-20 to room Temp.1858,2//41,8*
NaBH4(1)MgCl2(2)toluene-20 to room Temperature.1847,9//52,1
NaBH4(1)MgCl2(2)DME-20 to -15 147,8//52,2
NaBH4(1)Al(OiPr)3(2)THF-20 to COMNAP.46,5//53,5
NaBH4(1)Al(OiPr)3(2)MeOH-20 to -15159,6//40,4
NaBH4(1)Al(OiPr)3(2)iPrOH-20 to -15348,6//51,4
NaBH4(1)Al(OiPr)3(2)CH2Cl2-20 to -15355,0//45,0*
NaBH4(1)Al(OiPr)3(2)toluene-20 to -15352,0//48,0*
NaBH4(1)Al(OiPr)3(2)DME-20 to -151 50,4//49,6
NaBH4(1)BF3xOEt2(2)THF-20 to COMNAP.2052,3//47,7*
NaBH4(1)BF3xOEt2(2)MeOH-20 to COMNAP.2057,0//43,0*
NaBH4(1)BF3xOEt2(2)iPrOH-20 to COMNAP.2053,4//46,6*
NaBH4(1)BF3xOEt2(2)CH2Cl2-20 to COMNAP.2060,0//40,0*
NaBH4(1)BF3xOEt2(2)toluene-20 to COMNAP.2061,5//38,5*
NaBH4(1)BF3xOEt2(2)DME-20 to-15 141,47//58,3
NaBH4(1)MgCl2(2)Meon0 to 50,554,0//46,0
NaBH4(1)MgCl2(2)Meon-78 to COMNAP.0,565,9//34,1
NaBH4(1)MgCl2(2)THF0 to COMNAP.2241,0//59,0
NaBH4(1)Cl2(2)Meon0 to 50,547,0//53,0

NaBH4(1)Cl2(2)Meon0 to 50,550,0//50,0
NaBH4
(11.1)
Cl3(2)Meon 0 to 5236,9//63,1
NaBH4(1)ZnCl2(2)Meon0 to 50,561,0//39,0
NaBH4(1)ZnCl2(2)Meon-78 to COMNAP.264,7//35,5
NaBH4(1)ZnCl2(2)THF-100,2557,0//43,0
NaBH4(1)ZnCl2(2)Et2O-100,2556,0//44,0
NaBH4(1)ZnCl2(2)DME-100,2550,0//50,0
NaBH4(1)ZnCl2(2)EtOH-20 to -151 64,0//36,0
NaBH4(1)ZnCl2(1,5)EtOH-20 to -151,564,2//35,8
NaBH4(1)ZnCl2(1,0)EtOH-20 to -151,564,7//35,3
NaBH4(1)ZnCl2(0,5)EtOH-20 to -151,564,9//35,1
NaBH4(1)ZnCl2(0,3)EtOH-20 to -151,563,8//36,2
NaBH4(1)ZnCl2(0,2)EtOH-20 to -151,563,2//36,8
NaBH4(1)ZnCl2(0,1)EtOH-20 to -151,563,0//37,0
NaBH4() noEtOH-20 to -151,054,7//45,3
Bu4NH4(1)ZnCl2(0,3)MeOH-20 to -15163,9//36,1
Bu4NH4(1)Al(OiPr)3(2)MeOH-20 to -15160,5//39,5
Bu4NH4(1)ZnCl2(2)EtOH-20 to -15162,7//37,3
Zn(BH4)2
(1,0)
noEt2O-78 to kamnem.364,9//34,1
Zn(BH4)2
(1,4)
noEt2O-780,559,1//40,9
Zn(BH4 )2
(1,4)
noTHF/Et2O
(1/1)
-780,559,4//40,6
Zn(BH4)2
(1,4)
noTHF/Et2O
(1/2)
-780,558,4//41,6
Zn(BH4)2
(1,4)
noTHF/Et2O
(2/1)
-780,562,2//37,8
Bu4NH4
(1.1)
noTHF-78259,8//40,2
Bu4NH4
(1,3)
noCH2CL2-78239,2//60,8
Bu4NH4
(1,1)
noTHF/CH2Cl2
(1/1)
-78 266,7//33,3
Bu4NH4
(1,1)
noTHF/CH2Cl2
(1/1)
0252,2//47,8
Bu4NH4
(1,1)
ZnCl2(2)THF/CH2Cl2
(1/1)
-78260,7//39,3

NaH(Oac)3
(2)
ZnCl2(2)THF/Et2O
(2/1)
0 to comtem.2252,2//47,8*
NR3xSMe2
(1,1)
noTHF/CH2Cl2
(1/1)
-78257,7//42,3
NR3xSMe2
(1,1)
ZnCl2(2)THF/CH2Cl2
(1/1)
-78261,8//38,2
Red-Al (1,3)noCH2Cl2/toluene (1/1)-78352,9//48,0
Red-Al (1,3)ZnCl2(2)CH2Cl2/toluene (1/1)-78354,1//45,9*
Superhydride®
(1,1)
noTHF/CH2Cl2(1/1)-78235,5//64,4
Superhydride®
(1,1)
ZnCl2(2)THF/CH2Cl2(1/1)-78237,4//62,6
DIBAH
(1,1)
noTHF/CH2Cl2(1/1)-78260,1//39,9*
Li(tBuO)3AlHnoTHF/CH2Cl2(1/1)-782 44,4//55,6
Li(tBuO)3AlHZnCl2(2)THF/CH2Cl2(1/1)-78256,6//43,4
Al(OiPr)3(0.5)
iPrOH (7.0)
CH3SO3H (0,5)toluene35-451,527,9//72,1
Al(OiPr)3(0,5)
BINAPHTHOL
iPrOH (5,0)
notoluene20-251625,6//74,4
DIBAH (2,0)
Acetone (2,0)
noTHF20-251627,6//72,4
DIBAH (2,0)
Acetone (2,0)
noTHF/toluene
(1/1)
20-251627,6//72,4
Al(OtBu)3(0,5)
D/L-finitely alcohol (2,0)
notoluene228,0//72,0
Al(OtBu)3(0,1)
D/L-finitely alcohol (2,0)
notoluene20-25628,0//72,0
Al(OsBu)3(0,5)
sBuOH (7,0)
CH3SO3H
(0,5)
toluene20-25125,7//74,3
Al(OiPr)3(0,5)
The cyclohexanol
(7,0)
CH3SO3H (0,5)toluene20-25519,6//80,4
Al(OtBu)3(0,5)
The cyclohexanol
(7,0)
CH3SO3H (0,5)toluene20-25318,4//81,6
Al(OtBu)3(0,5)
The cyclohexanol
(7,0)
CH3SO3H (0,5)toluene0-5614,5//85,5
Al(OtBu) (0,5)
3-pentanol
(7,0)
CH3SO3H (0,5)toluene0-5318,0//82,0
Al(OtBu)3(0,5)
9-hydroxyfuran
(3,4)
CH3SO3H (0,5)toluene0-54,527,1//72,9
Al(OtBu)3(0,5)
9-diphenylcarbinol
CH3SO3H (0,5)toluene0-comnen.3111,7//88,3

In table 2 incomplete conversion is indicated by the symbol "*".

The ratio of the diastereomeric configurations RR/SS to the RS/SR ranges from about 0.3 to about 2, preferably 1.1 to 2, most preferably 1.2 to 2.

Found that the best ratio of diastereomers (connection VIa SYN-configuration of the RR/SS) diastereoselective reduction reaction of give at temperatures above -20°C, when the recovery is carried out, for example, NaBH4in MeOH or EtOH in the presence of a catalyst, such as ZnCl2(0.1 to 2.0 equivalent). The formation of diastereoisomer having anticonspiracy (compound VIb, RS/SR), promotes recovery for Me is Ruano-Pondorf-Verley. In this case, the ratio of RS/SR to RR/SS is 9.

After almost complete conversion of the reaction can be subjected to processing similar to that described in the prior art, the concentration of the reaction mixture and dissolving the residue in a solvent not miscible with water, preferably in toluene or MTBE, then successive washing with an aqueous solution of acid, preferably 2N HCl solution, followed by washing with water and/or an alkaline solution, preferably a solution of NaHCO3. A mixture of the diastereomeric products can be cleaned column chromatography or used directly for the next stage.

It was found that in contrast to reconnect Vb, reconnecting Va occurs with partial cyclization to the corresponding epoxides (compounds VIIa and VIIb, see below).

Stage 5 involves obtaining compound VII from the compound VI as shown in scheme 13. Non-limiting examples of compounds VII include (±)-6-fluoro-[(2R*)-oxiran-2-yl]-(2S*)-chroman (compound VIIa) and (±)-6-fluoro-[(2R*)-oxiran-2-yl]-(2R*)chroman (compound VIIb).

The formation of epoxides compounds VII of halogenation alcohols compounds VI is conveniently carried out in solvents, such as ethers or alcohols, with base, such as hydroxides of alkaline is s and alkaline earth metals, alkoxides of alkali and alkaline earth metals, carbonates of alkali and alkaline earth metals, tertiary amines or hydrides of alkali metals. The use of alkoxides of alkali metals in alcohols, used as a solvent is preferred, and most preferred is the use of sodium methoxide in methanol as solvent. The temperature for this reaction can vary in the range of from about 0°C to 40°C, preferably from 15°C to 25°C. Approximately 1.0 to 2.0 equivalents of a base can be used, preferably 1.1 equivalent. After completion of the reaction the excess of base is usually neutralized by adding acid, preferably acetic acid. The mixture was then concentrated and the residue is dissolved in a suitable solvent, for example ether or halogenated hydrocarbon. Washing the resulting solution polysystem aqueous solution of sodium chloride and the concentration of the organic layer gives epoxides compounds VII. If the reaction is carried out using a mixture of diastereomeric halogenation alcohols of the formula VI, then formed a mixture of the corresponding diastereomeric epoxides VII. Diastereomer mixture of epoxides can be used directly in the next stage or split column chromatography. In the preferred embodiment, implemented the program this way the mix is used in the next stage without separation diastereoisomers.

Stage 6 includes a connection is obtained from compound VIII VII, as shown in figure 14, and separation of diastereomers. Non-limiting examples of compounds VIII include (±)-2-benzylamino-1-[6-fluoro-(2R*)-chroman-2-yl]-(1S*)-Ethan-1-ol (compound VIIIa) and (±)-2-benzylamino-1-[6-fluoro-(2R*)-chroman-2-yl]-(1R*)-Ethan-1-ol (compound VIIIb).

Examples of suitable protective groups (PG) include hydrogen or a suitable aminosidine group. Preferred are protective groups, which allow for a subsequent stage of alkylation (stage 7) and can be easily removed at the final stage simple way to remove the protection. Therefore, the preferred PG represents an allyl group, a substituted or unsubstituted arylmethyl group. If PG is a benzyl group, obtaining compounds VIII can be performed in the same manner as described in EP 0145067, but without pre-separation diastereomeric mixture of compounds VIIa and VIIb. The authors of the present invention found that the chromatographic separation of the oily compounds VIIa and VIIb is not necessary in the present method, and that diastereomer mixture can be divided by fractional crystallization after transformation into VIII and VIIIb. Therefore, in a preferred embodiment of the invention the mixture VIIa and VIIb subject ot modestia with benzylamine with the formation of the corresponding diastereomeric mixture of compounds VIII and VIIIb, which then separated by fractional crystallization. Since connections VIII and VIIIb have basic properties, fractional crystallization can be carried out not only with the free amine, but also with the corresponding salt. Connection VIII and compound VIIIb represent intermediates applicable to get nebivolol and, therefore, the method can be used for selective receipt of these two isomers in industrial scale.

In relation to this strategy get nebivolol, most preferred is a selective receipt and allocation of connection VIII.

In a typical equimolar or enriched diastereomer mixture of compounds VII (SYN) and VIIb (anti) with the ratio of SYN/anti, equal to 1 or more is obtained at stages 4 and 5, is treated with excess benzylamine (≥ 3 equivalents) in C1-C3alcohol as a solvent at temperatures from about room temperature up to about 50°C. In a preferred embodiment of the invention the reaction is carried out at 40°C with 3 equivalents of benzylamine in 2-propanol.

After complete conversion the reaction mixture is cooled to cause crystallization. It was shown that the solvent preferred for the reaction, suitable for fractional crystallization. Additional servings can be obtained by additional to the stallization concentrated mother solutions of the same alcohol or of a mixture of this alcohol ethers, preferably diisopropyl ether. Additional increase diastereomeric relations regarding the connection VIII can be obtained by recrystallization or suspension in C1-C3alcohols, ethers, toluene, acetonitrile or their mixtures.

Based on diastereomeric mixture of compounds VIIa and VIIb with the ratio of diastereoisomers about 57/43, the above-mentioned method it is possible to obtain a connection VIII, containing 5% or less of the compound VIIIb.

The relative configuration is preferred compounds VIIIa (see figure 2) confirmed by x-ray analysis on single crystal, as shown below in table 3.

Table 3.
Crystallographic data for compounds VIII
Crystallization fromdiisopropyl ether/CH2Cl2
Empirical formula
Molecular weight [g-1·mol]
Crystal color, appearance
The size of the crystal [mm]
Temperature [K]
Crystal system
space group
Z
Reflection to determine the cell
2θ-interval to determine cell [°]
With18H20FNO2
301,6
the devil is Vatan prism
0,15×0,20×0,25
160(1)
monoclinically
P21/C (#14)
4
4489
4-60
The unit cell parametersa [Å]4,5882(1)
b [Å]26,3162(5)
c [Å]12,4357(3)
α [°]90
β [°]92,288(1)
γ [°]90
V [Å3]1500,34(6)
F(000)640
Dx[g·cm-3]1,334
µ(Mo Kα) [mm-1]0,0947
Scan typeϕ and ω

2θ (max) [°]60
The total number of measured reflections35736
Symmetrically independent reflections4388
Rint0,061
Reflections with I > 2σ(I)3005
Reflections used in the refinement4386
Refined parameters208
The final R(F)[I > 2σ(I)reflections]0,0480
wR(F2) (all data)0,1162
Weight:w=[σ2(Fo2)+(0,0419P)2+0,2604P]-1where P=(Fo2+2Fc2)/3
The matching criteria1,036
The coefficient of secondary extinction0,012(2)
Final Δmax0,001
Δρ (max; min) [e Å-3]0,24; -0,19
σ(d(C-C))[Å]0,002

Stage 7 includes receiving connection IX of compounds VIII and V and separation of diastereomers of compound IX. Non-limiting examples of compounds IX include (±)-2-{benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxyethyl]amino}-1-(6-fluoro-(2S*)-chroman-2-yl)alanon (compound IXa) (scheme 15) and (±)-2-{benzyl-[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxyethyl]amino}-1-(6-fluoro-(2R*)-chroman-2-yl)alanon (compound IXb) (see Scheme 17).

The preferred reaction of racemic diastereoisomer connection VIII with the racemic compound V, containing an appropriate reactive leaving group (LG), gives diastereomer mixture of new compounds IXa and IXb. The resulting mixture can be divided column chromatography or by fractional crystallization to obtain the desired compound IXa as a suitable intermediate for the synthesis of racemic nebivolol. As compounds IXa and IXb possess basic properties of fractional crystallization can be performed using the free amine or the corresponding salt.

As described above in stage 3, a suitable leaving group (LG) connection V include halogen, alkylsulfonate, substituted or n is substituted arylsulfonate or the like. Preferred leaving groups are halogen and the most preferred leaving groups are bromine (compound Va) and chlorine (compound Vb). The protective group (PG) is described in the consideration stage 6; the preferred protecting group is a benzyl group.

Alkylation reaction is conveniently performed in a suitable inert organic solvent or in mixtures of such solvents and in the presence of a base and an appropriate quantity of catalyst. Typical solvents include substituted or halogenated hydrocarbons, such as methylene chloride, dichloroethane and the like; ethers, such as THF, dioxane, dimethoxyethane, and polar aprotic solvents such as DMF, DMA, N-organic (NMP), dimethylsulfoxide (DMSO) and the like. Preferred solvents are polar aprotic solvents. You can use 1.0 to 1.5 equivalent of compound V, preferably 1.1 equivalent. Typical bases include tertiary amines, such as triethylamine, pyridine, carbonates of alkali metals, carbonates of alkali metal or sodium hydride. Preferred bases are carbonates of alkali metals, and the most preferred base is sodium bicarbonate. You can use 1.5 to 2.5 equivalents of a base, preferably 2.0 EQ is Valens. Typical catalysts to speed up reactions include the halides of alkali metals or of tetraalkylammonium halides. If the leaving group is chloride, then the preferred catalysts are the bromides and iodides, and the most preferred is sodium bromide and sodium iodide. You can use at least 0.1 equivalent of catalyst, preferably 0.15 equivalent. In a preferred embodiment of the invention the reaction can be conducted at temperatures from about room temperature up to about 80°C. lower temperatures can increase reaction times and higher temperatures may cause adverse reactions. After completion of the reaction, the mixture can be treated with the extraction method known in the art. Evaporation of the solvent after extraction and crystallization diastereomeric mixture using a suitable antibacterial gives diastereomeric compounds IXa and IXb, you can select column chromatography or by fractional crystallization from a suitable solvent. As compounds IXa and IXb possess basic properties of fractional crystallization can be performed with a mixture of free amines or the corresponding salts. Separation of a mixture of compounds IXa and IXb can be effectively implemented by fractional crystallization of the free amines of acetonitrile in quality is the firmness of the solvent.

A suitable modification of compounds IXa and IXb may also be applicable for the separation diastereomeric mixture. The authors of the present invention surprisingly found that the diastereoisomer IXb can be selectively similarbut in the presence of diastereoisomer IXa. Due to the higher solubility similarvideo compound IXb compared to nesselroade connections efficiency of fractional crystallization can be increased considerably. Usually similarobama can be carried out in organic solvents or mixture of solvents, such as ethers, esters, halogenated hydrocarbons, aromatic solvents (e.g. toluene, chlorobenzene and the like), polar aprotic solvents such as DMF, DMSO), silylium reagent, if necessary, in the presence of a base. Preferred organic solvents include acetonitrile, THF, MTBE and mixtures thereof. If the Foundation is required, then it is possible to use amines, such as triethylamine, pyridine, imidazole and the like, carbonates of alkali metals or hydrogen carbonates of alkali metals. Amines are the preferred organic solvents, and the most preferred is imidazole. You can use 1.0 to 2.0 equivalents of a base, preferably 1.5 equivalents. As cilleruelo reagent can be used TMSCl, HMDS, BSU, etc., TMSCl preferred. For successful separation of the diastereomers is important to use similarbuy reagent in a molar relationship of 0.40/n - 0,60/n relative to the total numbers of both diastereomers, where n denotes the total number of portable silyl groups per similarbuy reagent. Fewer equivalents may lead to a lack of division, and a greater number of equivalents may lead to a reduction in output. The reaction is usually conducted in the temperature range from about 0°C. to about room temperature. Lower temperatures can increase reaction times and higher temperatures can lead to lack of selectivity.

For this strategy to get a nebivolol is preferred allocation of compounds IXa of a mixture consisting of IXa and IXb, by fractional crystallization or selective modification IXb with subsequent crystallization IXa. The term "essentially pure diastereomers", as used here, denotes the diastereomers at least 50%purity, preferably 80%purity, and more preferably 95%purity.

Data of NMR spectra recorded for the selected diastereomers, indicate that both isomers cyclists in polyethalene form.13C NMR spectra show that instead of the peaks of the carbonyl group, in the spectra have peaks at 94,616 and 94,707, matched with the public, which indicate the carbon atom cyclic polyethalene form (see scheme 16 and 17 and figures 3 and 4).

The relative configuration of the preferred connection Ib` confirmed by x-ray analysis on single crystal, as shown below in table 4.

Table 4.
Crystallographic data connection Ib`
Crystallization fromMeCN
Empirical formulaWith29H29F2NO4
Molecular weight [g·mol-1]493,55
Crystal color, appearancecolorless prisms
The size of the crystal [mm]0,25 x 0,25×0,28
Temperature [K]160(1)
Crystal systemmonoclinically
space groupP21/n (#14)

Z4
Reflection to determine cell5882
2θ-interval to determine cell [°]4-55
The unit cell parametersa[Å]14,0502(3)
b[Å]11,3937(3)
c [Å]15,5302(3)
α[°]90
β[°]100,145(1)
γ[°]90
V3]2447,3(1)
F(000)1040
Dx[g·cm-3]1,339
µ(Mo Kα) [mm-1]0,0986
Scan typeϕ and ω
2θ(max) [°]55
The total number of measured reflections54789
Symmetrically independent reflections5601
Rint0,057
Reflections with I > 2σ(I)4092
Reflections used in the refinement5598
Refined parameters330
The final R(F)[I > 2σ(I)reflections]0,0468
wR(F2) (all data)0,1252

Weight:W=[σ2(Fo2)+(0,0616P)2+0,3697P]-1where P=(Fo2+2Fc2)/3
The matching criteria 1,052
The coefficient of secondary extinction0,012(2)
Final Δmax0,001
Δρ(max;min) [e Å-3]0,27; -0,21
σ(d(C-C))[Å]0,002

Stage 8 includes obtaining compound X, as shown in figure 18. Non-limiting examples of compounds include X (±)-[2R*[R*[R*(S*)]]]-α,α`-[[(phenylmethyl)imino]bis(methylene)]bis[6-ferroman-2-methanol] (intermediate Xa) and (±)-[2R*[S*[R*(S*)]]]-α,α`-[[(phenylmethyl)imino]bis(methylene)]bis[6-ferroman-2-methanol] (compound Xb). A number of reducing agents can be used to restore the connection IXa, two racemic diastereoisomer can be formed RSSS/SRRR configuration (connection Xa) or RSRS configuration (connection Xb). Regarding the strategy for the synthesis of nebivolol, as shown on figures 6(a) and 18, the preferred restoration methods, which lead to the formation of excess Xa connection. There is quite a bit of research on selective restoration of chiral 1-hydroxy-5-catasetinae, adjustable stereogenic centers in remote positions of the chain (length 4 or more atomic the of introw; Tetrahedron Letters, 35 (1994), 4891-4894), Tetrahedron Letters 40 (1999) 593-596, J. Org. Chem. 63 (1998) 7964-7981). In contrast to the compounds described in these works, the connection IXa contains three asymmetric center, especially in positions 1-2 and in positions 1-5 and 1-6, which can adjust the diastereoselectivity when restoring ketogroup.

PG can be a hydrogen or aminosidine group, as defined above. Preferred are the same as those of the protective groups, which have been already described for stages 6a-c and 7.

In principle there are no restrictions on the use of borhydride or aluminiumhydride reducing agents that can be selected, for example from LiBH4, NaBH4, KBH4N(nBu)4BH4, Zn(BH4)2, NaH(Oac)3, Superhydride® (triethylborohydride sodium), Red-Al® (sodium bis(2-methoxyethoxy)aluminiumhydride), Li-Selectride® (three-second-butylbromide, Li, K), BH3SMe2or the like, or such reagents, which are applicable for the recovery Meerwein-Pondorf-Verley. Note, however, that the reduction reaction of Meerwein-Pondorf-Verley reversible Oxidation of Oppenauer). Since the Xa connection contains two secondary alcohol groups, which may be in equilibrium oxidation/restore with a reducing agent, may form a mixture of three diastereomers (anilinophenol nebivolol (RSSS/SRRR) and two meso forms (RSRS and RRSS)).

To prevent such adverse reactions, it is possible to protect the hydroxyl group of compound IXa before recovery Meerwein-Pondorf-Verley. Another possibility consists in a continuous distillation of the ketone (e.g. acetone, if isopropanol is used as a hydride donor).

Catalytic hydrogenation of compounds IXa may be optional, but if PG is a protective group, an unstable during recovery (e.g., benzyl), then you should consider removing the protection.

Of reduction reaction can be carried out in the absence or in the presence of Lewis acids selected from the MgCl2, CaCl2, BaCl2, ZnCl2Al(Alkyl)3, Ti(Alkyl)4BF3OEt2etc. Suitable solvents are ethers, alcohols, halogenated hydrocarbons and the like, except that the halogenated solvents are not suitable for reactions of catalytic reduction. Recovery is conveniently carried out at temperatures from -20°C to room. Although lower temperatures may increase the selectivity, the reaction time will increase, and higher temperatures may lead to a reduction in selectivity. Table 5 presents typical results of selective reduction of compound IXa.

Table 5
Reagent (equiv.)The catalyst (equiv.)SolventTemperature [°C]Time [h]Attitude
RSSS/SRRR
//RSRS
NaBH4(1)noTHF/EtOH/H2OComnen.350//50
LiBH4(1)noTHF0-5570//30
LiBH4(1)Ti(OiPr)4(2)THF-20 to comtainer.378//22
LiBH4(1)Ti(OiPr)4(2)THF0-5282//18
Zn(BH4)2(1)noEt2O/THF comtainer.377//23*
KBH4(1)ZnCl2(2)MeOH/THF0-5283//17*
K-selectride (2)noTHF0-5384//16
K-selectride (4)Ti(OiPr)4(2)DCM/THF0-5383//17*
KBH4(1)LiClTHF0-51870//30
Bu4BH4(1)noTHF0-comnen.2494,4//5,6
KBH4(1)Ti(OiPr)4(2)
Diglyme (3)
THF0-comnen.26 94,5//4,5
KBH4(1)Ti(OiPr)4(2)DME0-comnen.2694,5//4,5

In table 2 incomplete conversion is indicated by the symbol "*".

The ratio of the diastereomeric configurations RSSS/SRRR to RSRS is from about 1 to about 20, preferably 2-20, most preferably 4 to 20.

After complete conversion, the reaction mixture can be processed in a standard way. Diastereomers the mixture of products can be divided column chromatography or fractional crystallization. As compounds Xa and Xb have basic properties, the formation of salt before carrying out fractional crystallization is an optional feature. A mixture of the diastereomeric products can also be used on the next stage in the form of a crude product without further purification.

Stage 9 includes obtaining hydrochloride (±)-[2R*[R*[R*(S*)]]]-α,α`-[iminobis(methylene)]bis[6-ferroman-2-methanol] (compound I) and separation from the byproduct hydrochloride (±)-[2R*[S*[R*(S*)]]]-α,α`-[iminobis-(methylene)]bis[6-ferroman-2-methanol]as shown in figure 19.

The final stage of obtaining racemic hydrochloride nebivolol include removing protection, education is salt and purification by fractional crystallization to remove by-products, mainly undesired diastereoisomer having RSRS configuration.

PG may represent the same group, which have already been described above, and if PG is a group that is different from hydrogen, removing the protection can be performed by known methods. As benzyl group are preferable, removing protection can be performed by catalytic hydrogenation. If the connection Xa contains the connection Xb as a by-product, then the cleaning can be accomplished by fractional crystallization. As compounds Xa and Xb after removing the protection possess basic properties of fractional crystallization can be performed after the formation of the corresponding salt. It was found that a mixture consisting of nebivolol and its RSRS of diastereoisomer, you can easily separate by fractional crystallization after the formation of the salt with HCl or any other pharmaceutically acceptable salt.

Compound I can be converted into its pharmaceutically acceptable non-toxic acid additive salt, which is formed as a result of processing corresponding acids such as, for example, inorganic acids such as halogenation acid, e.g. hydrochloric, Hydrobromic and the like, sulfuric acid, nitric acid, phosphoric acid and the like; or organic acids such, for example the EP, as acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, o, preventiva, Balandina, (Z)-2-Buendia, (E)-2-Buendia, 2-hydroxybutanone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

The formation of the salt with HCl is preferred for fractional crystallization, providing a pharmaceutically acceptable cleaners containing hydrochloride salt of nebivolol. Fractional crystallization usually can be carried out in suitable solvents, in which the nebivolol soluble worse than it RSRS a diastereoisomer. As solvents for fractional crystallization preferred alcohols, and methanol is the preferred solvent.

RECYCLING STAGE of DIASTEREOMERS

The present invention also includes the recycling stage of the diastereomers formed during the implementation of the method.

I. Opportunities for recycling intermediates formed at stage 5 and stage 6

A non-limiting example of recycling is illustrated by figure 20, where the leaving groups use Cl.

Stage recirculation can be performed using, for example, reaction of Mitsunobu for the inverter is AI secondary alcohol groups for recycling undesired diastereoisomer VIIIb, appearing on stage 6. However, you might need a suitable protective group (PG`) for nitrogen-containing group. The person skilled in the art it is clear that the examples of the introduction of suitable protective groups PG` include the formation of the corresponding carbamates, for example, under the action of alkylchlorosilanes, or the formation of the corresponding amides by the action of acid chlorides or anhydrides of carboxylic acids. The protective group can be entered after separation diastereomeric mixture by fractional crystallization followed by separation of undesired diastereoisomer of mother solutions.

II. The possibility of recirculation of the compounds produced in stage 7

On stage 7 is formed a mixture of two diastereomers (compound IXa and IXb), which is shared by fractional crystallization. There are two possible recycling of undesired diastereoisomer IXb (figure 21, table 6, 7, 8). The first possibility is the epimerization of undesired diastereoisomer IXb again with the formation of a mixture of IXa and IXb, which can be divided as described above.

Solvent
Table 6.
Studies of epimerization in different solvents, containing 10% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), from relations IXa/IXb about 23/77.
Temperature [°C]the ratio of connections
IXa/IXb
the ratio of connections
IXa+IXb/VIIIa
MeOHComtainer.69/3120/80
DMFComtainer.53/4785/15
AcnComtainer.53/4771/29
THF4053/4761/39
AcOEt4054/4674/26
Toluene4055/4581/19

The mixture analyzed HPLC after 40 hours the Results presented in table 6, show that the splitting of compounds IXa/IXb in methanol with the formation of compound VIIIa is faster than the epimerization. All other solvents after 40 h, the epimerization gave a mixture of diastereomers IXa and IXb (almost 1/1), whereas the tendency to cleavage with the formation of the soedineniya VIIIa explicitly suppressed especially in such solvents, as DMF and toluene. The results of additional studies of epimerization in DMF and toluene are shown in tables 7 and 8.

Table 7.
Studies of epimerization in DMF containing 5% 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 30°C, ranging from relationships IXa/IXb about 23/77. The mixture was analyzed by HPLC.
Time [h]the ratio of connections
IXa/IXb
the ratio of connections
IXa+IXb/VIIIa
128/7298,3/1,7
2,531/6997,4/2,6
5,537/6395,6/4,4
22,550/5091,3/8,7
45,554/4687,8/12,2

Table 8.
The epimerization in toluene containing 5% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) at 30°C, ranging from relationships IXa/IXb about 23/77. The mixture was analyzed by HPLC.
Time [h] the ratio of connections
IXa/IXb
the ratio of connections
IXa+IXb/VIIIa
124/7699,7/0,3
5,527/7399,4/0,6
22,533/6798,3/1,7
45,543/5896,0/4,0

The second possibility recycling involves the splitting of the undesired diastereoisomer IXb with the formation of a mixture of compound VIIIa and some by-products. Splitting can be done tautomeric transformation of aminoketone in enamine form with subsequent hydrolysis by known methods. Compound VIIIa can then select and re-enter in the process, as shown in scheme 21.

III. Alternative synthesis of nebivolol using the diastereoisomer VIIIb

Although in accordance with the above strategy of synthesis, it is preferable to receive diastereoisomer VIIIa as an intermediate, the undesired diastereoisomer VIIIb can also be used as an intermediate to obtain racemic nebivolol, as shown in figure 22.

For the other similar ways of recycling. For example, in contrast to the way in which use the preferred compound VIIIa, using compound VIIIb network after phase alkylation diastereomer mixture of compounds IXc and IXd. Reconnection IXd after removing the protection gives nebivolol and second meso-form, having RRSS configuration (as opposed to the preferred route, which leads to the formation of meso-shape having RSRS configuration). As mentioned above, the meso-form, having RSRS configuration has a higher solubility than the second meso-form, having RRSS configuration, and therefore nebivolol contaminated RSRS diastereoisomer (preferred path), can be easily cleaned by recrystallization. In case of contamination nebivolol meso-form RRSS configuration purification can also be carried out by recrystallization, but due to the fact that the solubility of RRSS diastereoisomer and nebivolol close, cleaning much more difficult and you have to take into account the decrease in the output.

IV. Recycling meso-forms of nebivolol (RSRS and RRSS)

Both meso-forms nebivolol obtained by the above methods, can be converted directly into nebivolol after appropriate protection (e.g., cyclic carbamate, cyclic silyl group and the like), the subsequent inversion of the secondary alcohol group (for example, by reaction of Mitsunobu) and remove the protection, as shown n the scheme 23.

Reaction to protect, unprotect and inversion can be accomplished by methods known in the art.

Although considered ways to reduce costs and increase efficiency by recycling unwanted diastereoisomer, they still require additional stages for recycling and highlight the desired compounds. To reduce costs and the environmental impact was made further improvement of the method of obtaining compounds IXa/IXa`, as described below.

In addition, it was found that in some circumstances, additional enrichment, contributing to the formation IXa, can be achieved by epimerization of equimolar mixture of IXa and IXb, which leads to a more efficient way than recycling methods described above. This increase of the ratio of desired to undesired diastereoisomer of the diastereoisomer mixture leads to an increase in yield and volumetric output and promotes the release IXa by fractional crystallization. Finally, this method also reduces waste and reduces the time of receipt.

Thus, the invention relates to new methods and conditions to increase the ratio of diastereomers IXa and IXb in stage 7 (figure 6) from about 1:1 to 9:1 before allocation IXa (see figure 7-9).

Increase diastereomeric against the Oia can be obtained using the method of simultaneous epimerization-crystallization, including epimerization of a mixture of compounds IXa and IXb in a ratio of about 1:1, in the presence of a suitable base and in an organic solvent in which the solubility of compounds IXa slightly worse than the solubility of compound IXb. Figure 7 shows the simultaneous epimerization-crystallization, which is a dynamic process of increasing diastereomeric relations and obtain the desired diastereoisomer (compound IX is shown in acyclic forms).

The protective group (PG) can be any appropriate aminosidine group. PG is preferably selected from allyl group or a substituted or unsubstituted arylmethylidene group; most preferred (PG) is a benzyl group(Bn). Suitable bases for the epimerization can be selected from alkoxides, amidino, guanidino or phosphazenes, the preferred bases are amidine, such as databaseconnect (DBU), diazabicyclo (DBN), and the most preferred base is DBU. The base can be used in amounts of at least 0.05 and 0.25 equivalent equivalent preferred. The epimerization is preferably carried out in the temperature range from 20°C to 70°C and most preferably in the range from 40°C to 70°C. lower temperatures can also be used, but they increase the societal reaction time, while higher temperatures can lead to high degradation rate. The epimerization can also be carried out in isothermal conditions, but it is preferable to slow cooling of the mixture at the specified temperature range. The organic solvent may be selected from solvents which can form a suspension in the specified temperature range for carrying out the simultaneous crystallization of the epimerization of the invention. Suitable solvents are usually chosen from aprotic solvents, for example aromatic solvents, ethers, esters, amides or NITRILES or proton solvents, such as alcohols. Acidic solvents that inactivate the base through the formation of salts, preferable to exclude. Preferred are aprotic solvents, and the most preferred solvent is acetonitrile. Since the presence of water can cause degradation of compounds IXa and IXb, preferably, in addition, to use solvents in which the water content is less than 1.0% and most preferably less than 0.1%.

The reaction is conveniently carried out at slow cooling of the suspension, containing equimolar amounts of compounds IXa and IXb in the presence of a base. Compound IXa, in which the number of undesired diastereoisomer composition is employed, less than 1%, you can select exit to 74% and only in one stage, without the need for multiple crystallization, selective modifications or additional stages of recirculation, as described above.

Thus, the simultaneous epimerization-crystallization involves the simultaneous (a) the epimerization of a mixture of compounds IXa and IXb in the presence of a suitable base and in an organic solvent and (b) promotes crystallization IXa of the mixture. It is necessary that during the epimerization compound IXa removed from the equilibrium system of simultaneous crystallization. Research the epimerization was performed in solution and not in suspension.

The technique of simultaneous epimerization-crystallization for the synthesis of compounds IXa exceeds the above methods crystallization and recycling, as a way of selective modification get IXa with only 41% compared with the yield 74% according to the method of simultaneous epimerization-crystallization. To get the same output using other methods, it is necessary to carry out several stages of recycling, which requires more time, reagents and produces more waste. In addition, a small number of compounds IXa/IXb, which is lost in a new way during the selection IXa, can be easily removed from the mother liquor and reused for the next experience of epimerization. Remove the giving of the lost substance and use it in the next experience additionally increases the efficiency of the method for simultaneous epimerization-crystallization.

The technique of simultaneous epimerization-crystallization will now be described using figure 8 as an example. The figure 8 shows the epimerization of a mixture of compounds IXa and IXb, where PG is a benzyl group (Bn). Compounds IXa and IXb shown in the form of an open-chain (acyclic form). The solution is a balance of acyclic forms IXa and IXb with the corresponding cyclic forms A' and Ib'. For the epimerization is required acyclic form, which contains an acidic proton on a chiral center in the alpha-position to a carbonyl group.

Suspension of a mixture of compounds IXa and IXb in almost equimolar ratio, heated in acetonitrile to an internal temperature of 70°C. After cooling to 60°C was added DBU (0.25 EQ.) and spend the epimerization, cooling the mixture to 40°C using the temperature gradient described in table 9.

Table 9
Time [h]the internal temperature [°C]
060
0,555
1,550
5,550
of 5.7545
8,545
8,7540
13,540

The reaction is stopped by addition of acetic acid (0.25 EQ.) and the mixture is cooled to 25°C. the Crude product is produce by filtration and additionally cleaned by suspendirovanie in acetonitrile. Filtering is carried out after the end of the simultaneous epimerization-crystallization to highlight IXa. The formation of a suspension in acetonitrile represents only an additional purification step to remove the remaining primecell and small amounts of undesired diastereoisomer. Table 10 shows the successful epimerization, controlled constant process control (IPC) (HPLC).

40
Table 10
IPCTime [h]Temperature [°C]attitude
IXa/IXb
10-50,8/49,2 (educt)
20,555,5 56,1/43,9
31,55062,9/37,1
42,55066,3/33,7
53,55071,0/29,0
64,55075,1/24,9
75,55078,7/21,3
87,54585,0/15,0
98,54587,3/a 12.7
109,54082,0/18,0
1110,540to 85.2/14,8
1211,54089,7/10,3
1313,589,2/10,8

Since the decomposition of IXa/IXb during the epimerization contributes to H2O, it is preferable that the original substance, and acetonitrile were nearly anhydrous (table 11). The mixture IXa/IXb incubated at 50°C in the presence of 0.25 EQ. DBU and various amounts of H2O. the Number of remaining IXa/IXb determined periodically by HPLC. The results are shown in table 11.

Table 11
% H2About in ACN (V/V)2 hours7 h22 h
0,0191%86%73%
0,291%86%75%
1,089%81%66%

Avoid temperatures above 70°C for more than 30 minutes, as IXa/IXb not quite stable at temperatures above 70°C. the Degradation and epimerization of control when conducting a stirring suspension IXa in ACN for 21 h at the appropriate temperature, as shown in table 12.

Table 12
Temperature [°C]Decomposition [%]The epimerization [%]1)
(IXa->IXb)
75-786,85,6
650,80,2
50Not definedNot defined

1)Because the rate of decomposition IXa and IXb may be different, it is unknown whether the attitude change is more rapid decomposition IXa, and not by epimerization.

The figure 9 shows the method of obtaining racemic nebivolol and its pharmaceutically acceptable salts, where stage 7b depicts stage simultaneous epimerization-crystallization according to the invention.

Options stage simultaneous epimerization-crystallization according to the invention is chosen based on the understanding that the solubility of compounds IXa below the solubility of compound IXb. Thus, we discovered that IXa may crystallize and therefore removed from equilibrium, while in solution the equilibrium of both diastereomers can be regenerated by epimerization of undesired diastereoisomer IXb in the presence of a base. The balance of IP who was ladoulis at different temperatures in the presence of a base in a solvent under certain cooling rates. Cooling is necessary to complete the crystallization and to optimize yield. As the cooling reduces the solubility of both diastereomers, create conditions for further crystallization, enabling the desired diastereoisomer. As the epimerization is slower at lower temperatures, the equilibrium is also regulated slower. Get a balanced relationship between the rate of epimerization to adjust the balance in the solution and cooling the mixture, promoting crystallization IXa. Therefore, the gradient of temperature (as shown in table 9 and below in examples 19 and 20), it is necessary to maintain a balanced relationship between the rate of epimerization and stages of crystallization. Because higher temperatures can also cause the degradation of compounds IXa and IXb, which contributes to the presence of water, the conditions for the epimerization of crystallization have to look for when degradation is minimized, to prevent a reduction in output.

The invention will be illustrated in more detail by reference to the following examples, but it should be understood that the present invention is not limited by them.

EXAMPLES

Example 1

Stage 1. Receive (+)-5-[6-ferroman-2-carbonyl]-2,2-dimethyl[1,3]dioxane-4,6-dione (compound III).

In nitrogen atmosphere thionyl chloride (109,21 g, 918 mmol) was added at 20-25°C. to a suspension of 6-ferroman-2-carboxylic acid (90,00 g, 459 mmol) and DMF (1.68 g, 23 mmol) in toluene (635 ml). Then the suspension is heated to an internal temperature of 60-70°C and receive a transparent yellow solution with simultaneous separation of gas. At this temperature the reaction is complete in 70 minutes, after which the mixture was concentrated in vacuo (bath temperature of 45-50°C, pressure ≤35 mbar) and get the acid chloride chroman-2-carboxylic acid as a yellow oil (112,65 g). The crude product is dissolved in methylene chloride (65 ml) and slowly added under nitrogen atmosphere to a solution of acid Meldrum (70,90 g, 482 mmol) and pyridine (72,62 g, 918 mmol) in methylene chloride (261 ml) at an internal temperature of 0-10°C. the Reaction mixture was allow to warm to 20-25°C for 50 min and stirred at this temperature for an additional 30 minutes and Then to the resulting brown suspension was added methylene chloride (325 ml) and water (325 ml). A two-phase mixture is stirred for 5 min, separated and the organic layer is then extracted with water twice (200 ml each time), then 2N aqueous solution of HCl (250 ml) and finally water (250 ml). After drying over Na2SO4the organic layer was filtered and concentrated in vacuo (≤50 mbar)to give a brown viscous oil (170,76 g), which crystallized after 10 minutes in to the room temperature. The solid is suspended in diisopropyl ether (500 ml) at 20-25°C for 2 hours After filtration of the suspension of the wet product was washed with diisopropyl ether (70 ml) and dried in vacuum (13 h at 40°C), receiving solid colors of yellow ochre (output: 114,71 g, HPLC purity: 96,98%).

Example 2

Stage 2, the path A. Obtain (±)-1-(6-ferroman-2-yl)ethanone (compound IVa).

Reproduce example 1 with 16 g of 6-ferroman-2-carboxylic acid and the residue obtained after the treatment and evaporation of methylene chloride, are used directly for stage 2, the path A. the Mixture thus obtained crude product (compound III) with water (40 ml) and acetic acid (40 ml) is heated for 70 min at boiling under reflux and then cooled to room temperature. The reaction mixture is extracted with methylene chloride (40 ml) and the organic layer twice washed with 1 N aqueous NaOH solution (each 20 ml). After drying over MgSO4the organic layer is filtered and evaporated. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate/cyclohexane (1/3 by volume). Collect the second fraction, the solvent is evaporated and get the product as yellow oil (yield: 11,89 g, HPLC purity: 98,76%).

Example 3

Stage 2, the path Century. Obtain ethyl ester (±)-3-(6-CFT is chroman-2-yl)-3-oxopropanoic acid (compound IVb in the form of ethyl ester)

Reproduce example 1 with 16 g of 6-ferroman-2-carboxylic acid and the residue obtained after the treatment and evaporation of methylene chloride, are used directly for stage 2, the path C. a Suspension of this crude product (compound III) in ethanol (150 ml) is heated at the boil under reflux for 75 min, the result is a clear solution. After cooling the solution to room temperature and the evaporation residue is distributed between methylene chloride (80 ml) and water (80 ml). The phases are separated and the organic layer is extracted with 1 N aqueous NaOH solution (40 ml). Solution in methylene chloride dried over MgSO4, filtered and evaporated. The residue is purified column chromatography on silica gel, using as eluent a mixture of ethyl acetate/cyclohexane (1/4 by volume). Collect the first fraction, the solvent is evaporated and get the product as a yellow-brown oil (yield: 11,89 g, HPLC purity: 92,45%).

Example 4

Stage 2, the path Century. Obtain tert-butyl ether (±)-3-(6-ferroman-2-yl)-3-oxopropanoic acid (compound IVb in the form of tert-butyl methyl ether)

tert-Butanol (83,90 g) was added at room temperature to a suspension of compound III (94,00 g) (obtained as described in example 1) in toluene (280 ml). The suspension is heated until the internal temperature is URS 70-80°C, the result is a clear solution with the simultaneous emission of the gas. The reaction completed in 80 minutes the Mixture is cooled to room temperature and extracted successively with a solution of NaHCO3(235 ml) and saturated NaCl solution. The organic layer is dried over Na2SO4, filtered and concentrated in vacuo, obtaining the product as an orange-brown oil (yield: 95,79 g, HPLC purity: 97,20%; the crude product contained a small amount of toluene). The crude product used in the next stage without additional purification.

Example 5

Stage 3, path A. Obtain (±)-2-bromo-1-(6-ferroman-2-yl)-ethanone (compound Va).

TMSCl (3.2 ml) was added to a solution of 2 M LDA (9.0 ml) in 20 ml of THF at -78°C for 10 minutes Then add a solution of compound IVa (3.0 g) (obtained as described above in example 2) in THF (3 ml), after 10 min the reaction mixture is allowed to warm to room temperature over 40 minutes of Precipitated white solid and the residue partitioned between cyclohexane (100 ml) and cold 10% solution of NaHCO3(60 ml). The aqueous layer was diluted with water (20 ml) and separated. The organic layer is extracted twice with 10% solution of NaHCO3each time (30 ml), dried over Na2SO4filter and concentrate. The residue is dissolved in methylene chloride (15 ml) and cooled to an internal temperature of 0°C. To the mixture was added a suspension of NBS (2,94 g) in methylene chloride (10 ml). After stirring for 1.5-2 h at the same temperature, the reaction mixture was poured into 10% solution of NaHCO3(15 ml), the organic layer is separated and concentrated. The residue is purified column chromatography on silica gel using a mixture of ethyl acetate/cyclohexane (1/5 by volume) as eluent. Collect the first fraction, evaporated the solvent and obtain a mixture of products consisting of compounds Va (78,1% according to HPLC) and the corresponding by-product (VaBP1),

which is formed by selective bromirovanii with subsequent elimination in the form of a yellow-brown oil (yield: 2.17 g, because the connection Va, apparently less stable than compound Vb, it should be stored preferably in the dark at -20°C).

Example 6

Stage 3, path B: Obtain (±)-2-bromo-1-(6-ferroman-2-yl)ethanone (compound Va).

N-Bromosuccinimide (NBS) (5,04 g) was added by portions at 5-10°C to a solution of tert-butyl methyl ether compound IVb (10.0 g) (obtained as described in example 4) and Mg(Cl4)2(2,32 g) in ethyl acetate (100 ml). Further reaction control HPLC. After the addition the mixture was stirred at 5-10°C for 45 minutes After remains 16% adduct, add on the additional number of NBS (1.0 g). The mixture is stirred for 20 min at 5-10°C, then allowed to warm to room temperature and stirred for 20 min at this temperature. The precipitate is filtered off and the mother liquor was concentrated in vacuo, obtaining tert-butyl ester 2-bromo-3-(6-ferroman-2-yl)-3-oxopropanoic acid in the form of a red oil (15.3 g). To conduct hydrolysis and decarboxylation red oil is dissolved in acetic acid (42 ml) and formic acid (49 ml) and the mixture is heated to an internal temperature of 80-85°C, while experiencing the allocation of gas. After 60 min the reaction is complete and the mixture was concentrated in vacuo, obtaining a brown oil. The oil is then dissolved in ethyl acetate (50 ml) and n-hexane (50 ml) and the solution is extracted successively twice polysystem NaCl solution each time (20 ml) and a saturated solution of NaHCO3(20 ml). The organic layer is dried over MgSO4, filtered and concentrated in vacuo, obtaining oil amber color, which is dissolved in the cyclohexane. The cause crystallization using a seed crystal at room temperature. After 45 min the suspension was filtered, getting after drying, the compound Va (2,98 g, beige solid). Additional quantities of compound Va (1.9 g) is obtained from the mother liquor after stirring at 6-7°C for 1.5 h, filtering off and drying (total yield: 4,88 g, HPLC purity: 98.5 per cent; that is how the connection Va, apparently less stable than compound Vb, it should be stored preferably in the dark at -20°C).

Example 7

Stage 3, path B: Obtain (±)-2-chloro-1-(6-ferroman-2-yl)ethanone (compound Vb)

At room temperature Mg(lO4)2(21,40 g) is slowly added to a solution of tert-butyl methyl ether compound IVb (105,59 g) (obtained as described in example 4) in ethyl acetate (800 ml). Then portions added NCS (41,80 g) at 20-25°C for 3.5-4 h and further reaction control HPLC. After completion of addition, the yellow suspension is stirred for 30 minutes at 20-25°C and then filtered. Layer on the filter is washed with ethyl acetate (100 ml) and the combined filtrates are extracted sequentially with saturated solution of NaCl (150 ml) and water (150 ml), then concentrated in vacuo (60 mbar) and get a brown oil (116,82 g). To conduct hydrolysis and decarboxylation brown oil dissolved in a mixture of acetic acid (420 ml), formic acid (390 ml) and water (80 ml). The solution is heated to an internal temperature of 80-90°C, while experiencing the allocation of gas. After completion of the reaction (within 2 h). the solution was concentrated in vacuo (<30 mbar)to give a dark orange oil (83,25 g)which was dissolved in ethyl acetate (400 ml). The resulting solution was sequentially extragear who have polysystem NaCl solution (300 ml), a saturated solution of NaHCO3(300 ml) and water (100 ml). After drying over Na2SO4the suspension is filtered and concentrated, obtaining the first red oil (80,00 g)which slowly crystallized at room temperature. For further purification the crude product (77.0 g) dissolved in isopropanol (240 ml) at an internal temperature of 45-50°C. In a solution put the seed in order to cause crystallization, and cooled to 0-5°C. After 75 min of stirring at 0-5°C, the suspension is filtered and the layer on the filter is washed with cold isopropanol (40 ml). The wet product is dried in vacuum at 35-40°C receives a yellowish solid (57,13 g, HPLC purity: to 99.00%).

Example 8

Stage 1-3. Obtain (±)-2-chloro-1-(6-ferroman-2-yl)ethanone (compound Vb) from 6-ferroman-2-carboxylic acid (II)

A mixture of 6-ferroman-2-carboxylic acid (to 114.4 g, analysis = 99%, 577 mmol), thionyl chloride (83,15 g, 692 mmol) and DMF (2,18 g, 30 mmol) in toluene (471 g) is slowly heated in a nitrogen atmosphere until the internal temperature of 70-80°C (internal temperature of 57°C begins the evolution of gas). When the reaction is completed within 40 min at 78°C. HPLC analysis shows 98.6% of the corresponding acid chloride), 208 g of the solvent is distilled off in vacuum (pressure: 220 (initial) - 155 (final) mbar, internal temperature: 73 (initial) - 69 (final)°C, the temperature of the vapors: 39 (primary) - 63 (final)°C) In the second flask is charged with acid Meldrum (89,1 g, 606 mmol), pyridine (89 ml, 1.11 mol) and methylene chloride (375 ml). The mixture is then cooled to an internal temperature of 0-5°C, slowly add the above previously prepared solution of chloride 6-ferroman-2-carboxylic acid in toluene at an internal temperature of 0-5°C. the Reaction mixture is allowed to warm to 20°C for 80 min (during the reaction HPLC shows 92.6% of product). To the mixture is slowly added tert-butanol (81,0 g at 1.08 mol) and the mixture slowly (over 4 hours) is heated to an internal temperature of 70-80°C with simultaneous distillation of the solvent and the allocation of gas. During heating (after 75 min and the internal temperature of 56°C) add an additional amount of tert-butanol (75 g, 1.00 mol). Distillation and gas is stopped when the internal temperature reaches 70-80°C (by this time Argonauts 370 g of solvent). When HPLC analysis of the process shows completion of the reaction, the mixture is cooled to 20°C. and add a solution of sulfuric acid (41.8 g) in water (200 ml). The organic layer is separated, extracted twice with saturated solution of NaHCO3(each 200 ml), then concentrated in vacuo to approximately 60% of the volume (pressure: 370-150 mbar; it is noted that during the distillation of water has to be removed completely) and diluted at room temperature with ethyl acetate (450 ml). After addition of Na3PO4(91,5 g), slow flashing, and than the but (within 3 h) added sulfurylchloride (53 ml) at an internal temperature of 10-20°C and continue mixing until until HPLC analysis of the process indicates completion of the reaction (approximately 1 hour). The mixture is extracted twice with water (each time 150 ml) and distilled in vacuum (pressure: 150 to 170 mbar) until and unless 305 g of distillate. Then add acetic acid (400 ml) and the mixture is again distilled in vacuum (pressure: 30-40 mbar) until then, until it receives an additional 292 g of distillate. Add concentrated hydrochloric acid (84 ml) and the mixture was stirred at an internal temperature of 40-50°C. until completion of reaction (hydrolysis and decarboxylation) (4 h, the control HPLC). After distillation, 100 g of the solvent in vacuum (pressure: 200-40 mbar; remove the remaining toluene and tert-butanol) emulsion is diluted with acetic acid (70 ml) at an internal temperature of 20°C and get the solution. Then add water (20 ml) and the crystals (seed)to induce crystallization. When crystallization starts slowly add more water (230 ml). The suspension is stirred at room temperature (15 h, then filtered and the layer on the filter is washed with a mixture of acetic acid and water (V/V = 1/1, 100 ml). The wet product is dried in vacuum at 40°C, receiving solid ochre (common output 101,84 g, purity (HPLC): 98.9 per cent).

Example 9

Stage 4. Obtain (±)-2-chloro-1-(6-fluoro-(2R*)-chroman-2-yl)-(1R*)-Ethan-1-ol (connection VIa) and (±)-2-chloro-1(6-fluoro-(2S*)-chroman-2-yl)-(1R*)-Ethan-1-ol (compound VIb)

Compound Vb (33,74 g) was added at 0-5°C to a solution of ZnCl2(40,3 g) in methanol (470 ml) and the mixture is stirred until complete dissolution of all solids (1 h). The solution is cooled to -10°C and add portions NaBH4within 35 minutes After completion of the reaction, controlled by HPLC, the mixture is concentrated to a volume of about 150 ml and then diluted with toluene (400 ml). The organic layer is extracted twice sequentially with 1.0 N HCl solution (each 200 ml) and a saturated solution of NaHCO3(100 ml). After drying over MgSO4the suspension is filtered and the solvent evaporated in vacuum, getting brownish oil (35,28 g, the ratio of the VIa/VIb = 61/39; crude mixture of products contains a small amount of toluene). The crude product used in the next stage without additional purification.

Example 10

Stage 5. Obtain (±)-6-fluoro-[(2R*)-oxiran-2-yl]-(2S*)-chroman (compound VIIa) and (+)-6-fluoro-[(2R*)-oxiran-2-yl]-(2R*)-chroman (compound VIIb)

A methanol solution of NaOMe (30%, of 30.9 g) was added at 20-25°C to a solution of the mixture of compounds VIa and VIb, or 37.9 g, the ratio of the VIa/VIb = 61/39) in methanol (380 ml). Reaction control HPLC and after stirring for 3.5 h at 20-25°C was added an additional amount of methanolic solution of NaOMe (30%, 1.4 g). After completion of the reaction (within 3.5 h), the mixture is neutralized with is the making of acetic acid and then concentrated in vacuo. The residue is distributed between methylene chloride (300 ml) and polysystem NaCl solution (200 ml). The phases are separated and the organic layer is dried over MgSO4. After filtration, the filtrate concentrated, getting brownish oil (32.1 g, attitude VIIa/VIIb = 61/39). The crude product is used directly in the next stage.

Example 11

Stage 6. Obtain (±)-2-benzylamino-1-(6-fluoro-(2R*)-chroman-2-yl)-(1S*)-Ethan-1-ol (compound VIII) and (±)-2-benzylamino-1-(6-fluoro-(2R*)-chroman-2-yl)-(1R*)-Ethan-1-ol (compound VIIIb) and separation of compounds VIIIa and VIIIb

The mixture of compounds VII and VIIb (ratio: 57/43) is slowly added (within 1.5 hours) at an internal temperature of 40°C to a solution of benzylamine (5,4 g) in 2-propanol (30 ml). After completion of the reaction, controlled by HPLC, the solution is cooled to room temperature and add substance seed. Then diastereoisomers VIIIa and VIIIb separated by fractional crystallization. The suspension is stirred at room temperature for 1 h and filtered, obtaining after drying in vacuum colourless solid (1.01 g). The mother liquor is concentrated until then, until you are left with 25 g of residue. Then the concentrated mixture is heated to 60°C and cooled for 3 h to 0-5°C. an Additional portion of product is obtained after filtration and drying the wet product in a vacuum (0.3 g). Fallopian will restaurantcenter until until there are 15 g of residue, and added diisopropyl ether (15 g). The third portion obtained after filtering and drying the wet product in a vacuum (0.33 g). The second and third portions of recrystallized from 2-propanol (3.7 g) and after filtration the wet product (0.6 g) is dissolved with the first portion in 2-propanol (10 g) by boiling under reflux. The mixture is cooled to 0-5°C and then filtered. The wet product is dried in vacuum, obtaining a colorless solid (yield: 1.1 g, attitude VIIIa/VIIIb = 96/4).

The diastereoisomer VIIIb can be obtained, for example, from the mother liquor after concentration to dryness, followed by extractive processing and crystallization.

Example 12

Stage 4-6. Obtain (±)-2-benzylamino-1-[6-fluoro-(2R*)-chroman-2-yl]-(1S*)-Ethan-1-ol (compound VIII) and (±)-2-benzylamino-1-[6-fluoro-(2R*)-chroman-2-yl]-(1R*)-Ethan-1-ol (compound VIIIb) of (±)-2-chloro-1-(6-ferroman-2-yl)ethanone (compound Vb) and separation of compounds VIIIa and VIIIb

Compound Vb (76,31 g, 324 mmol) and ZnCl2(22,53 g, 162 mmol) was dissolved in ethanol (648 ml) at an internal temperature of 20-30°C. the resulting solution was then cooled to an internal temperature of -15°C (-20)°C and slowly added a solution of NaBH4(12,77 g, 324 mmol) and NaOMe (4 ml 30% solution of MeOH) in MeOH (136 ml). During the addition maintain the internal temperature of -20 to -10°C and the reaction is s control HPLC. After the reaction mixture, allow to warm to 0-5°C and add hydrochloric acid (160 ml 2N HCl solution). The mixture allow to warm to 20-25°C and stirred at this temperature for 30 minutes. The solvent is almost completely removed in vacuum, obtaining a brown suspension (191,3 g). The residue is partitioned between hydrochloric acid (160 ml 2N HCl solution) and MTBE (450 ml). The organic layer is separated, extracted with hydrochloric acid (30 ml of 2N aqueous HCl, then twice with water (each time with 250 ml) and concentrated in vacuo, obtaining a brown oil (79,77 g, the ratio of the VIa/VIb = 63,5/36,5). After dissolution of the oil in 2-propanol was added a solution of NaOMe in MeOH (64,18 g, concentration: 30%) when the internal temperature of 20-25°C. the Reaction control HPLC. After completion of the reaction the mixture is cooled to 0-5°C. and neutralized by addition of acetic acid (1.9 ml). The suspension is filtered through celite and the layer on the filter is washed with 2-propanol (25 ml). The filtrate was concentrated in vacuo, getting policecontributing muddy brownish solution (115,97 g). The resulting mixture was again filtered and the layer on the filter is washed with 2-propanol (25 ml)to give a transparent brown solution, which is then slowly added (within 3 h) to a solution of benzylamine (105,2 g, 972 mmol) in 2-propanol (352 ml) at an internal temperature of 33-38°C. the Reaction it will trainout HPLC and add a seed crystal, to induce crystallization of the product during the reaction. After completion of the addition the mixture is stirred for 3.5 h at 25-30°C, then cooled to 0-5°C and stirred at the same temperature for 1.5 hours, the Suspension is filtered and the layer on the filter is washed with pre-cooled (0-5°C) 2-propanol (46 ml). The wet product is dried in vacuum at 50-55°C, receiving the solid is slightly beige color (42,23 g, attitude VIIIa/VIIIb = 92/8). The crude product is dissolved in acetonitrile (294 ml) is heated at the boil under reflux. The solution is slowly cooled 0-5°C (6-7 hrs), filtered and the layer on the filter is washed with acetonitrile (38 ml). The wet product is dried in vacuum at 50-55°C, getting a white solid (total yield: 38,2 g, attitude VIIIa/VIIIb = 98,8/1,2, purity (HPLC) product VIIIa: 98,62%).

Example 13

Stage 7. Obtain (±)-2-{benzyl[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)hydroxyethyl]amino}-1-(6-fluoro-(2S*)-chroman-2-yl)ethanone (compound IXa), (±)-4-benzyl-2-[6-fluoro-(2R*)-chroman-2-yl]-(6S*)-[6-fluoro-(2S*)-chroman-2-yl]morpholine-2-ol (compound IXa`), (±)-2-{benzyl[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxyethyl]amino}-1-(6-fluoro-(2R*)-chroman-2-yl)ethanone (compound IXb) and (±)-4-benzyl-(6S*)-2,6-bis-[6-fluoro-(2R*)-chroman-2-yl]-morpholine-(2S*)-ol (compound IXb`)and separation of diastereomers

Compound V (14,62 g) was added at an internal temperature of 40°C to suspense the compound VIIIa (17.5 g), NaHCO3(9.6 g) and NaBr (0.9 g) in DMF (70 ml). When the reaction is finished (for 3-3 .5 h, the control HPLC), the suspension cooled to room temperature and diluted with MTBE (400 ml) and water (200 ml). Then the phases are separated, the organic layer extracted with water (100 ml) and the combined aqueous layers are re-extracted with MTBE (100 ml). After evaporation of the combined organic layers remaining oil is amber in color (35,0 g) is dissolved in diisopropyl ether (400 ml) and make seed. The first suspension was stirred at room temperature for 1.5 h and then at 0-5°C for 0.5 hours After filtration of the wet product is dried in vacuum, obtaining a light yellow solid (yield: 23,95 g, HPLC purity of 97.5%, the ratio of IXa/IXa` to IXb/IXb` = 52/48).

The mother liquor is concentrated to 56 g, then cooled to 0-5°C and make seed. The second portion obtained after filtration and drying (yield: 2,62 g, HPLC purity of 92.6%, the ratio of IXa/IXa` to IXb/IXb` = 43/57).

Separation of the diastereomers carried out by fractional crystallization from acetonitrile.

Diastereomer mixture of compounds IXa/IXa` and IXb/IXb` (ratio: 55/45, 2,31 g) dissolved in acetonitrile at an internal temperature of 70°C. the light yellow solution make a seed crystal, cooled to room temperature (within 2-3 h) and stirred at the same temperature for 1.5-2 hours by Filtering the suspension and drying the wet product is ucaut first portion (yield: 0.26 g, the ratio of IXa/IXa` to IXb/IXb` = 95/5).

The mother liquor is concentrated to 30 g and stirred at room temperature after depositing the seed. Filtration of the suspension get wet product (1.12 g)which is recrystallized from acetonitrile (11.2 g). After drying the wet product in vacuum to get the second portion (0.50 g, the ratio of IXa/IXa` to IXb/IXb`=62/38). This portion is recrystallized from acetonitrile (10 ml), and get wet product (0,57 g), which was again dissolved in acetonitrile (8 ml) under heating. The solution is cooled to room temperature and make seed. After filtering the suspension and drying the wet product receive a third portion (yield: 0.16 g, the ratio of IXa/IXa` to IXb/IXb` = 98/2).

Separation of diastereoisomers also conduct selective sellerbuyer and fractional crystallization.

Methodology A.

The imidazole (0,417 g) was added at 0-5°C to a suspension of compounds IX (2.0 g, obtained by the above method, the ratio of IXa/IXa` to IXb/IXb` = 52/48) in a mixture of acetonitrile (13.5 ml) and THF (1.5 ml). Then slowly added TMSCl (0,228 mg) at the same temperature for 3.5-4 h, and when the control HPLC. After completion of addition, the mixture was concentrated in vacuo to 8-10 ml and then added acetonitrile (5 ml). Stirring the suspension at 0-5°C for 1-1 .5 h, followed by filtration gives white wet product (1.31 g), which is dried in the vacuum output: 0,82 g, the ratio of IXa/IXa` to IXb/IXb` = > 98/2).

Method B.

The imidazole (0.21 g) was added at 0-5°C to a suspension of compounds IX (1.0 g, obtained by the above method, the ratio of IXa/IXa` to IXb/IXb` = 52/48) in MTBE (10 ml). Then slowly added TMSCl (0,115 mg) at the same temperature for 3.5-4 h, and when the control HPLC. The reaction is completed by addition of 4 drops of TMSCl. Then the suspension is filtered and the wet product (0.87 g), dried in vacuum, obtaining a white crude product (0.51 g, the ratio of IXa/IXa` to IXb/IXb` = 98/2, the product contains imidazole hydrochloride). To remove imidazole hydrochloride crude product is suspended at room temperature in a mixture of acetonitrile and water (3.0 ml, 4/1 by volume) for 2.5-3 hours Filtering the suspension and drying the wet product (0.65 g) in vacuum to give white solid (yield: 0.31 g, the ratio of IXa/IXa` to IXb/IXb` = 98/2).

Example 14

Stage 7. Obtain (±)-2-{benzyl[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxyethyl]amino}-1-(6-fluoro-(2S*)-chroman-2-yl)ethanone (compound IXa), (±)-4-benzyl-2-[6-fluoro-(2R*)-chroman-2-yl]-(6S*)-[6-fluoro-(2S*)-chroman-2-yl]morpholine-2-ol (compound IXa`), (±)-2-{benzyl[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)-hydroxyethyl]amino}-1-(6-fluoro-(2R*)-chroman-2-yl)ethanone (compound IXb) and (±)-4-benzyl-(6S*)-2,6-bis-[6-fluoro-(2R*)-chroman-2-yl]-morpholine-(2S*)-ol (compound IXb`)and separation of diastereomers

A mixture of compound VIIIa (49,0 g, 162,6 mmol, obtained according to met the dick of example 12), compound Vb (42.5 g, 178,9 mmol, obtained according to the method of example 8), NaBr (1.68 g, 16.3 mmol) and NaHCO3(20.5 g, 243,9 mmol) in DMF (200 ml) is heated to an internal temperature of 60-65°C until HPLC analysis of the process shows almost complete conversion (approximately 1 hour). Then the suspension is filtered and the layer on the filter was washed with DMF (70 ml). To the filtrate was added water at 50°C (15 ml) and contribute crystals-crystal seed to induce crystallization. The product is then carefully precipitated by slow addition of water (within 4 h) at 50°C. ultimately, the complete precipitation by addition of water (25 ml) at 50°C. the Suspension is cooled to 20-25°C and filtered. The wet product was washed with 2-propanol (100 ml), dried in vacuum at 50°C and receive a white solid (yield: 70,15 g, purity (HPLC): 99,1%, the ratio of IXa/IXa` to IXb/IXb` = 52/48). To a suspension of the obtained solid (70,0) and imidazole (14.6 g, 214 mmol) in acetonitrile (385 ml) is slowly added (about 1.75 ml/h) TMSCl (7,56 g, 68.2 mmol) with an internal temperature-10-(-15)°C. Then the suspension is stirred for 2 h at-5-0°C, controlling HPLC. The reaction is completed by addition of TMSCl (1,34 g, 12.3 mmol). The suspension is filtered and the wet product is dried in vacuum at 40°C, getting a white solid (66,45 g, the ratio of IXa/IXa` to IXb/IXb` = 92/8). The resulting product is suspended in a mixture of cyclohexane (285 ml) and MTBE (95 ml) at an internal temperature of 60°C in those who tell 10 minutes. Then the suspension is cooled to 25°C. and filtered, the wet product was washed with cyclohexane (50 ml) and again suspended in cyclohexane (350 ml). The suspension is stirred at 60-65°C for 20 minutes, then cooled to 25°C and filtered. The wet product was washed with cyclohexane (50 ml) and dried in vacuum at 40°C, getting a white solid (total yield: 28,83 g, the ratio of IXa/IXa` to IXb/IXb` = 98,6/1,4).

Example 15

Stage 8. Obtain (±)-[2R*[R*[R*(S*)]]]-α,α`-[[(phenylmethyl)imino]bis(methylene)]bis[6-ferroman-2-methanol] (compound Xa) and (±)-[2R*[S*[R*(S*)]]]-α,α`-[[(phenylmethyl)imino]bis(methylene)]bis[6-ferroman-2-methanol] (connection Xb)

A solution of compound IXa/IXa` (0.40 g, containing 2% IXb) in THF (8.0 ml) cooled to an internal temperature -10 - (-15)°C. To the cooled solution was added Ti(OiPr)4(0,485 mg), then LiBH4(18 mg). After stirring at-10-(-15)°C for 1 h at 0-5°C for 1.5-2 h, the reaction mixture was poured into a mixture of methylene chloride (10 ml) and a saturated solution of NaHCO3(10 ml). The suspension is filtered through celite and the phases are separated. After drying over MgSO4the organic layer is concentrated and receive a colorless foam (418 mg ratio Xa/Xb = 78/22). The crude product used in the next stage without additional purification.

Example 16

Stage 8. Obtain (±)-[2R*[R*[R*(S*)]]]-α,α`-[[(phenylmethyl)imino]bis(methylene)]bis[6-ftorprom the-2-methanol] (compound Xa)

To a solution of compound IXa/IXa`(28,0 g, obtained as in example 14) and Ti(OiPr)4(32,9 g, 113,5 mmol) in DME (280 ml) was added KBH4(3.15 g, 56,73 mmol) at an internal temperature of 0°C. After stirring at the same temperature for 21 h (control HPLC), the mixture is allowed to warm to room temperature and slowly added hydrochloric acid (280 ml, 10% aqueous solution). The suspension is stirred for 2.5 hours, the Suspension is filtered and the wet product was washed first with a mixture of DME (25 ml) and hydrochloric acid (25 ml, 2N aqueous solution), then hydrochloric acid (50 ml, 2N aqueous solution) and twice with water (each time 50 ml). The wet product is suspended in ethanol (120 ml) and heated to 50°C. Then added an aqueous solution of NaOH (8,3 g, 30%), receiving the first clear solution, and the mixture is heated to 60°C. After the beginning of crystallization is added water (33 ml) and the suspension cooled to room temperature. The suspension is filtered and the wet product was washed with a mixture of EtOH/water (20 ml, V/V = 3/1). Next, the wet product was dissolved in EtOH (160 ml) by heating to 70-75°C and then cooled to 65°C. Add water (40 ml) and the crystals for starters, the mixture is cooled to room temperature and stirred at this temperature overnight. After filtration of the wet product was washed with a mixture of EtOH/water (30 ml, V/V = 31), dried in vacuum at 50°C and receive a white solid (yield: 21,66 g, HPLC purity: 99.85%of).

Example 17

Stage 9. Obtaining hydrochloride (±)-[2R*[R*[R*(S*)]]]-α,α`-[iminobis(methylene)]bis[6-ferroman-2-methanol] (compound I) and separation from the byproduct hydrochloride (±)-[2R*[S*[R*(S*)]]]-α,α`-[iminobis(methylene)]bis[6-ferroman-2-methanol]

Compounds Xa and Xb (418 mg, the ratio of Xa/Xb = 78/22 obtained by the method of example 11) are dissolved in a mixture of EtOH containing 14% HCl (0,665 g), and MeOH (10 ml). The resulting mixture hydronaut at normal pressure and at room temperature with a catalyst of 5% palladium on coal (100 mg). After completion of the reaction (within 3 hours) the mixture is diluted with MeOH (25 ml), heated to 40°C. and then filtered through celite. Layer on the filter is washed with hot MeOH (40°C, 30 ml), the combined filtrates concentrated in vacuo to number 7-8, the resulting suspension is filtered, getting a colourless solid after drying the wet product (yield: 0.17 g, the ratio of compound I/by-product = 95,5/4,5). The mother liquor is concentrated and the residue is dissolved in 2.0 ml of MeOH. The suspension is stirred at room temperature for 0.5 h, then filtered, receiving an additional portion (yield: 28 mg) after drying the wet product in a vacuum. The two portions recrystallized from MeOH (2.0 ml) and after drying receive going to be the solid substance (yield: 0,161 g, the connection I/by-product = 98/2).

Example 18

Stage 9. Obtaining hydrochloride (±)-[2R*[R*[R*(S*)]]]-α,α`-[iminobis-(methylene)]bis[6-ferroman-2-methanol] (compound I)

A mixture of compound Xa (21,0 g of 42.3 mmol, obtained according to the method of example 16) and of the catalyst is 5% palladium on coal (1.35 g) in acetic acid (150 ml) hydronaut at normal pressure and at an internal temperature of 40°C. After HPLC analysis shows the complete removal of protection, and the suspension filtered through celite. The filtrate is cooled to 20°C and added concentrated aqueous hydrochloric acid (4.59 g, 46.5 mmol). After filtration of the wet product is washed first with acetic acid (10 ml)and then ethanol (20 ml) and dried in vacuum, obtaining white solid (yield: 18,05 g, HPLC purity: 99,7 %).

Example 19

Obtain (±)-2-{benzyl[2-(6-fluoro-(2R*)-chroman-2-yl)-(2S*)hydroxyethyl]amino}-1-(6-fluoro-(2S*)-chroman-2-yl)ethanone (compound IXa) ⇔ (±)-4-benzyl-2-[6-fluoro-(2R*)-chroman-2-yl]-(6S*)-[6-fluoro-(2S*)-chroman-2-yl]morpholine-2-ol (compound IXa`)

In a glass reactor with double jacket volume of 1 L. the mixture was charged compounds IXa/IXb (100 g, 202,6 mmol, ratio of IXa/IXb = 50,8/49,2) and acetonitrile (311 g, water of 0.01% KF). The colorless suspension was heated to an internal temperature (IT) = 70°C and stirred at this temperature for 13 minutes. After a slow ohlord the ing the mixture to 60°C (30 minutes) was added DBU (7,79 g, at 50.7 mmol) and the reaction mixture is cooled with the following gradient:

Time [h]IT [°C]
060
0,555
1,550

Then the suspension is stirred for 1 h at 50°C and the ratio of IXa/IXb control HPLC (result: IXa/IXb = 66,3/33,7). Stirring is continued at 50°C up until the ratio of IXa/IXb won't 75/25 (control HPLC). In this case, the suspension is stirred for 4 h at 50°C (the ratio of IXa/IXb = 75,1/24,9). The mixture was then cooled to 45°C. and stirred at this temperature until such time as the ratio of IXa/IXb won't 84/16 (control HPLC). The suspension is stirred for 2 h at 45°C (the ratio of IXa/IXb = 85/15). The mixture was then cooled to 40°C. and stirred at this temperature until such time as the ratio of IXa/IXb won't 89/11 (control HPLC), but not longer than 8 hours (in this case, the reaction mixture should be processed in the same manner as described below). In this case, the suspension is stirred for 5 h at 40°C (the ratio of IXa/IXb = 89,2/10,8). The reaction mixture is neutralized with acetic acid (3,051 g of 50.7 mmol) and then cooled to 25°C. After stirring for 2 h at 25°C is Uspenskiy filtered off and the layer on the filter is washed four times with acetonitrile (each time 31 g) (the ratio of IXa/IXb in a layer on the filter after washing = 99,06/0,94). The mother liquor is amber color optional process (see below, extract, ML1). The wet product is suspended in acetonitrile (249 g) and the suspension heated to 70°C. After the suspension at this temperature for 1-10 minutes, the mixture is cooled to 20°C within 2 h 45 min) and stirred for 1.5 h at 20°C. After filtration of the wet product was washed twice with acetonitrile (each time 31 g) and dried in vacuum at 50°C, obtaining a colorless solid (yield: 74,09 g, 73,4%, HPLC purity: 99,33%, the ratio of IXa/IXb = 99,37/0,63, analysis = of 99.1%). The mother liquor from the mist (ML2) is used for extraction stages (see below).

Example 20

Removing the original substances from the mother liquor obtained in example 19.

Water (117 g) was added to the stock solution (ML1, 350,02 g) if IT = 24°C and the resulting mixture contribute seed IXa/IXb (0.05 g). Crystallization starts in a few minutes. After stirring for 1.5 h at 20°C - 25°C, beige suspension is cooled to 0°C-5°C and stirred at the same temperature for 3.5 hours the Suspension is filtered and the wet product was washed with a mixture of acetonitrile (31 g) and water (10 g). The mother liquor is amber in color and remove the wet product is suspended at 20°C-25°C in the second the mother solution (ML2, 279 g, see above). Then add water (93 g) and the mixture was stirred at 0°C(-5°C) for 1.5 hours After filtration of suspended matter in the most important product is washed with a mixture of acetonitrile (31 g) and water (10 g) and dried in vacuum at 50°C, getting not quite white solid (yield: 7,74 g and 7.6%, HPLC purity: 99,49%, the sum of the two diastereoisomers), the ratio of IXa/IXb = 39,1/60,9, analysis = of 98.2% (the sum of the two diastereoisomers)).

Although the invention is described in detail and with reference to specific examples, those skilled in the art it is obvious that can be made various changes or modifications not beyond being and scope of the invention.

1. The method of obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, comprising (a) providing a compound of formula (VIII)

as diastereomeric pure compounds containing at least 95% of the diastereoisomer RS/SR configuration or RR/SS configuration, where PG represents hydrogen or aminosidine group, and aminosidine group represents at least one allyl group, or aryl-C1alkyl group;
(b) providing a racemic compound of the formula (V)

where LG is selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate;
(C) N-alkylation of compounds of formula (VIII) with a compound of the formula (V), where the specified N-alkylation is carried out in an inert organic solvent in risotti base and optionally in the presence of a catalyst, obtaining the compounds of formula (IX)
,
the compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX)

or mixtures thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereoisomers;
(d) separation of the diastereomers of the compounds of formula (IX) or the compound of formula (IX') at least one means (dl) or (d2), where (d1) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX)containing at least 50% of RSS/SRR or RRS/SSR configuration;
(d2) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') to give the essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% of RSS/SRR or RRS/SSR configuration, at the stage of simultaneous epimerization-crystallization stage where the epimerization-crystallization includes:
(1) the epimerization of the compounds of formula (IX) or (IX') RSR/SRS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration and RSR/SRS configuration or
the epimerization of the compounds of formula (IX) or (IX') RRR/SSS configuration with obtaining a mixture of diaster the Mer of the formula (IX) or formula (IX') RRS/SSR configuration and RRR/SSS configuration, provided that the specified epimerization is carried out in the presence of a base and an organic solvent, where the mixture is optionally cooled, using a temperature gradient, and the diastereomers RSS/SRR configuration or RRS/SSR configuration in the mix get at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration; and
(2) crystallization of essentially pure diastereomers of formula (IX) or formula (IX') RSS/SRR configuration or RRS/SSR configuration of at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration;
separation of the mixture by fractional crystallization is not necessary after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX') with RSS/SRR or RRS/SSR configuration;
(e) recovering essentially pure diastereomers of formula (IX) or formula (IX') with RSS/SRR or RRS/SSR configuration, to obtain the compounds of formula (X)

as diastereomeric mixture RSSS/SRRR, in which the ratio of the RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration is at least 1;
(f) removing the protection from the compounds of formula (X), provided that PG is not N (if PG is a N, then stage unprotect exclude) to obtain the compound of the Fort the uly (I)

or its pharmaceutically acceptable salts; and
(g) removing the compounds of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration (if any) by recrystallization or suspendirovanie, obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)[α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts.

2. The method according to claim 1, where the protective group is a benzyl group.

3. The method according to claim 1, where the leaving group is a chlorine or bromine.

4. The method according to claim 1, where at stage (C) the organic solvent is a polar aprotic solvent selected from the group consisting of dimethylformamide, dimethylacetamide and N-methylpyrrolidone.

5. The method according to claim,1 wherein in stage (C) is based on at least one of the tertiary amines, carbonates of alkali metals or hydrogen carbonates of alkali metals.

6. The method according to claim 5, where the base is a sodium bicarbonate.

7. The method according to claim 6 where the use of from about 1.5 to about 2.5 equivalents of base.

8. The method according to claim 1, where at stage (C) catalyst consists of at least one alkali metal bromides, alkali metal iodides, of tetraalkylammonium bromides or iodides of tetraalkylammonium.

p> 9. The method of claim 8, where the catalyst is a sodium bromide.

10. The method according to claim 9 where the use of from about 0.1 to about 0.25 equivalent of catalyst.

11. The method according to claim 10, where the use of 0.15 equivalent of the catalyst.

12. The method according to claim 1, where at stage (C) the specified N-alkylation is carried out at a temperature from about room temperature up to about 80°C.

13. The method according to claim 1, where at stage (b), the compound of formula (V) is used in an amount of from about 1.0 to about 1.5 equivalents.

14. The method according to claim 1, where at stage (d1) fractional crystallization was carried out in a solvent.

15. The method according to 14, where at the stage (d1) use the free amine for fractional crystallization.

16. The method according to 14, where the solvent is a acetonitrile.

17. The method according to claim 1, where at stage (d1) use similarbuy reagent for modification before by fractional crystallization from a solvent.

18. The method according to 17, where similarbuy reagent represents at least one of tributyltinchloride, hexamethyldisilazane or bis-trimethylsilylacetamide.

19. The method according to 17, where use from about 0.4/n to about 0.6/n equivalents cilleruelo reagent and where n denotes the number of transferred silyl groups per similarbuy reagent.

20. The method according to 17, where the modification is carried out in the presence of from about 1.0 to about 2.0 equivalents based the project.

21. The method according to claim 20, where the base is an imidazole.

22. The method according to 17, where the specified separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') is carried out in acetonitrile, methyl tert-butyl ether, cyclohexane or their mixtures.

23. The method according to claim 1, where at stage (e), this recovery is carried out for the compounds of formula (IX) or the compound of formula (IX') RSS/SRR configuration in a solvent using an alkali metal borohydride, tetrabutylammonium borohydride, tri-sec-butylacrylamide alkali metal borohydride or zinc optional in the presence of Lewis acid.

24. The method according to item 23, where the Lewis acid is one of the compounds: Ti(Alkyl)4, ZnCl2the halide of alkali metal or alkali earth metal halide.

25. The method according to item 23, where the solvent represents at least one of the simplest ether, alcohol or a halogenated hydrocarbon.

26. The method according to item 23, where the specified restoration carried out in the temperature range from about -20°C. to about room temperature.

27. The method according to claim 1, where at stage (f) the removal of protection carried out by catalytic hydrogenation.

28. The method according to claim 1, where at stage (g) the purification of the compounds of formula (I) is carried suspendirovanie its hydrochloride in a solvent.

29. The method according to p where Aspandiyarova in methanol as solvent.

30. The method according to claim 1, where the specified provision of the compounds of formula (VIII) include:
(i) recovery of racemic compounds of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG represents a bromine or chlorine, with a mixture of diastereomers of compounds of formula (VI)

(ii) formation of a mixture of diastereoisomers of the compounds of formula (VII)

(iii) reaction of diastereomers of compounds of formula (VII) with NH2PG, obtaining a mixture of diastereoisomers of the compounds of formula (VIII)
and
(iv) separation of diastereomers of compounds of formula (VIII) from a mixture of diastereoisomers of the compounds of formula (VIII) by fractional crystallization is not necessary after the formation of the salt.

31. The method according to item 30, where isolated at least one of the diastereomers of the compounds of formula VIII with RR/SS or RS/SR configuration.

32. The method according to p, further comprising recycling the compounds of formula (VIII) RR/SS configuration where the specified recycling includes:
the provision of the compounds of formula (VIII) RR/SS configuration with a protective group; and
inversion of the configuration of the alcohol with obtaining the compounds of formula (VIII) SR/RS configuration.

33. The method according to item 30, where at stage i) reducing agent selected from alkali metal borohydride, the borohydride tetrault is ammonia, of zinc borohydride, triacetoxyborohydride alkali metal, triethylborohydride sodium bis(2-methoxyethoxy)aluminiumhydride sodium tri-sec-butylacrylamide alkali metal or coordination borhydride.

34. The method according to item 30, where at stage i) carry out the restoration in terms of Meerwein-Pondorf-Verley.

35. The method according to item 30, where at stage i) specified recovery is carried out by catalytic hydrogenation.

36. The method according to item 30, at the stage where i) a Lewis acid selected from the group consisting of chlorides of alkali or alkaline earth metals, zinc chloride, alkoxide of titanium (IV) and tralkoxydim aluminum.

37. The method according to item 30, where at stage i) specified recovery is carried out in conditions that lead to excess RR/SS isomer of compounds of formula (VI).

38. The method according to item 30, where at stage i) specified restoration carried out in the temperature range from about -78°C to about room temperature.

39. The method according to § 38, where the specified restoration carried out at a temperature from -20°C to room.

40. The method according to item 30, at the stage where i) a solvent selected from the group consisting of alcohols, ethers, halogenated hydrocarbons and aromatic solvents.

41. The method according to item 30, where PG is a benzyl group.

42. The method according to item 30, where stage ii) indicated the formation of a mixture of diastereomers of the compound fo the formula (VII) is carried out in a solvent and in the presence of a base.

43. The method according to § 42, where the solvent is an alcohol, and the base is an alcoholate of an alkali metal.

44. The method according to item 43, where the use of 1.0 to 2.0 equivalent basis.

45. The method according to item 30, where stage ii) indicated the formation of a mixture of diastereomers of compounds of formula (VII) is carried out at temperatures from 0 to 40°C.

46. The method according to item 30, where at stage iv) fractional crystallization was carried out in toluene, acetonitrile,1-C3-alcohol, simple ester or their mixtures.

47. The method according to item 46, where C1-C3-alcohol is 2-propanol, and a simple ether represents at least one of diisopropyl ether or methyl tert-butyl ether.

48. The method according to claim 1, where the specified provision of racemic compounds of formula (V) includes:
(1) the transformation of compounds of formula (II)

in an activated derivative of an acid;
(2) the interaction of the activated derivative of the acid with the acid Meldrum in the presence of a base to obtain the compounds of formula (III)

(3) the conversion of compounds of formula (III) in a compound of the formula (IV)

where R represents hydrogen or COOR' where R' represents a C1-C6alkyl or aryl-C1alkyl; and
(4) halogenoalkane the compounds of formula(IV), and optionally carrying out hydrolysis and decarboxylation to obtain the compounds of formula (V).

49. The method according to p, where at the stage of (1) carboxylic acid into the corresponding acid chloride.

50. The method according to p, where at stage (2) the base is a tertiary amine.

51. The method according to p, where at stage (2) use 1-3 equivalent acid Meldrum.

52. The method according to p, where at stage (2) the reaction temperature is from about -10°to about +30°C.

53. The method according to p, where at stage (3), the compound of the formula
(III) hydrolyzing in a mixture of organic acid and water, receiving the compound of formula (IV), where R represents N.

54. The method according to item 53, where the organic acid is an acetic acid and the hydrolysis is carried out at the boiling point.

55. The method according to p, where at stage (3), the compound of the formula
(IV)in which R represents a COOR' and R' represents a C1-C6alkyl or aryl-C1alkyl, produced by alcoholysis of the compound of formula (III).

56. The method according to § 55, where the alcoholysis is performed with ethanol and tert-butanol.

57. The method according to p, where at stage (3) the solvent represents at least one alcohol or toluene.

58. The method according to p, where at stage (3) the alcoholysis is carried out at temperatures from about 70°to about 80°C.

59. The method according to p, where at stage (4) before carrying out the halogenation of the compound of formula (IV), where R represents H, turn by sililirovanie to meet the speaker selenology ether, containing a terminal double bond.

60. The method according to p where similarobama carry through kinetically controlled deprotonation using sitedisability, followed by sellerbuyer at a temperature from about -78°to about 40°C.

61. The method according to p where similarobama carried out at a temperature from -78°C. to -70°C.

62. The method according to p, where as cilleruelo reagent use trimethylsilane.

63. The method according to p, where at stage (4) after transformation into selenology ether halogenoalkane performed using brainwashes reagent.

64. The method according to p where pomeroyi reagent is an N-bromosuccinimide.

65. The method according to p, where at stage (4), the compound of formula (IV)in which R represents a COOR', first halogenous, and then converted into the compound of the formula (V) hydrolysis of ester followed by decarboxylation.

66. The method according to p where halogenoalkane carried out in the presence of a catalyst.

67. The method according to p, where from about 1.0 to about 1.5 equivalents of N-bromosuccinimide, N-chlorosuccinimide or SO2Cl2used as halogenation reagents.

68. The method according to p, where from about 0.2 to about 0.4 equivalent of Mg(ClO4)2used as a catalyst.

69. The method according to p, where at stage (4) specified halogenoalkane is carried out at temperatures which x is between 0°C and to about room temperature.

70. The method according to p, where at stage (4) when the halogenation is conducted hydrolysis of ester followed by decarboxylation in an aqueous solution of an organic acid.

71. The method according to item 70, where the organic acid represents at least one of triperoxonane acid, formic acid and acetic acid.

72. The method according to p where hydrolysis and decarboxylation is carried out at temperatures from about 75°to about 90°C.

73. The method according to claim 1, further comprising recycling the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration where the specified recycling includes:
the epimerization of the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration containing diastereomers RSR/SRS configuration, or a mixture of diastereomers of formula (IX) or formula (IX') RRS/SSR configuration containing diastereoisomer RRR/SSS configuration, and
separation of the mixture by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX')having RSS/SRR or RRS/SSR configuration.

74. The method according to claim 1, further comprising recycling the compounds of formula (IX) or (IX') RSR/SRS or RRR/SSS configuration where the specified recycling includes:
cleavage of compounds of formula (IX) is whether (IX') RSR/SRS or RRR/SSS configuration, with the formation of a mixture of diastereoisomers of formula (VIII) RS/SR or RR/SS configuration; and
separation of the diastereomers of the formula (VIII) RS/SR or RR/SS configuration.

75. A compound selected from the following groups:
(a) compound of formula (III)

(b) a compound of the formula (IV)

where R represents a COOR' where R' represents a C1-C6alkyl or aryl-C1alkyl,
(C) a compound of the formula (V)

where LG represents a bromine or chlorine,
d) compound of formula (IX)

or cyclic policealna form of formula (IX')

where PG is a protective group selected from hydrogen, allyl, and aryl-C1of alkyl,
(e) compound of formula (IX), having RSS/SRR configuration

or its corresponding cyclic policealna form of formula (IX')

where PG is a benzyl group, or
f) a compound having the formula shown below
.

76. Connection on item 75, having the formula (IV)

where R represents a COOR' where R' represents a C1-C6alkyl or aryl-C1alkyl.

77. Connection on item 75, having the formula (V)

where LG represents bromine or chlorine.

78. Connection on item 75, having the formula (IX)

or cyclic policealna form of formula (IX')

where PG is a protective group selected from hydrogen, allyl, and aryl-C1the alkyl.

79. Connection on item 75, having the formula (IX), having RSS/SRR configuration

or its corresponding cyclic policealna form of formula (IX')

where PG is a benzyl group.

80. Connection on item 75, having the formula shown below

81. Connection on item 75, having the formula (III)

82. The method of obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
the provision of the compounds of formula (IX)

its salt or its derivative;
separation of the stereoisomers of the compound, salt or derivative of the formula (IX) by fractional crystallization to obtain essentially pure their diastereomers, which contain at least 50% of RSS/SRR or RRS/SSR configuration; and
the recovery of essentially pure diastereomers getting connection Faure the uly (X),

containing at most 50% of the stereoisomer with RSRS configuration.

83. The method according to p, in which the compound of formula (IX) is obtained by N-alkylation of compounds of formula (VIII) with a compound of the formula (V)as defined in claim 1.

84. The method of obtaining the compounds of formula (I) and its pharmaceutically acceptable salts,

including:
(a) separation of the compounds of formula (II)

obtaining the compounds of formula (II) with S-configuration or R-configuration;
(b) the conversion of compounds of formula (II) with S-configuration compound of formula (V) with S-configuration,

where LG is a Deputy selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate, through the formation of the compound of formula (III) with S-configuration and the compound of formula (IV) with S-configuration;
(c) the conversion of compounds of formula (II) with R-configuration compound of formula (V) with R-configuration through the formation of the compound of formula (III) with R-configuration and the compound of formula (IV) with R-configuration;
(d) the provision of the compounds of formula (VIII),

where PG represents hydrogen or aminosidine group, where aminosidine group represents at least one allyl group is whether aryl-C 1alkyl groups and where the compound of formula (VIII) is enantiomeric connection with RS or SR configuration;
(e) conducting N-alkylation of (i) the compounds of formula (VIII) with RS configuration compound of formula (V) with S-configuration or (ii) the compounds of formula (VIII) with SR configuration of the compound of formula (V) with R-configuration, provided that the N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, to obtain the RSS or SRR enantiomeric forms of compounds of formula (IX)

or SRR RSS or enantiomeric forms of compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX)

(f) recovering at least one of the RSS or SRR enantiomeric forms of the compounds of formula (IX) or formula (IX') obtaining at least one RSSS or SRRR enantiomeric forms of compounds of formula (X);

(g) removing the protecting at least one of the RSSS or SRRR enantiomeric forms of the compounds of formula (X), provided that PG is not N (if PG is a N, then cancel the specified stage unprotect), with compounds of the formula
(I) or its pharmaceutically acceptable salts; and
(h) removing the compounds of formula (I) or its headlight is asepticheski acceptable salts RSRS diastereomeric configuration, if they are present as a by-product, crystallization or suspendirovanie obtaining at least one of ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-enantiomers of the compounds of formula (I) and their pharmaceutically acceptable salts; and
(i) optional Association ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-enantiomers of the compounds of formula (I) and their pharmaceutically acceptable salts with the formation of racemic ([2S*[R*[R*[R*]]]]- ([2R*[S*[S*[S*]]]]-(±)α,α'-[imino-bis(methylene)]bis[6-ferroman-2-methanol] of the formula (I) and its pharmaceutically acceptable salts.

85. The method of obtaining racemic [2S*[R*[R*[R*]]]]and [2R*[S*[S*[S*]]]]-(±)-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
(a) providing a compound of formula (VIII)

in the form of a diastereoisomer having the RR/SS configuration, where PG represents hydrogen or aminosidine group, where aminosidine group represents at least one allyl group, or aryl-C1alkyl group;
(b) providing a racemic compound of the formula (V),

where LG is a Deputy selected from the group consisting of chlorine, bromine, iodine, alkylsulfonate, arylsulfonate;
(C) N-alkylation of compounds of formula (VIII) with a compound of the formula (V), where is the th N-alkylation is carried out in an inert organic solvent in the presence of a base and optionally in the presence of a catalyst, obtaining the compounds of formula (IX)

the compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX),

or mixtures thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereomers, with RRR/SSS and RRS/SSR configuration;
(a) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% stereoisomer RRR/SSS or RRS/SSR configuration;
(e) recovering essentially pure diastereomers of formula (IX) or formula (IX'), with RRS/SSR configuration with obtaining the compounds of formula (X)

as RSSS/SRRR diastereomeric mixture in which the ratio of the RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration is at least 1;
(f) removing the protection of the compounds of formula (X), provided that PG is not H, to obtain the compounds of formula (I)

or its pharmaceutically acceptable salts; and
(g) removing the compounds of formula (I) or its pharmaceutically acceptable salts, if any, RSRS diastereomeric configuration is rekristallizatsiei or suspendirovanie, obtaining racemic [2S[2R*[R[R*]]]] and [2R[2S*[S[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts.

86. The method according to p, further including:
the epimerization of the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with a mixture of diastereomers of compounds of formula (IX) or the compound of formula (IX')having the RRR/SSS and RRS/SSR configuration.

87. The method according to p, further comprising splitting the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with the formation of the compounds of formula (VIII) in the form of a diastereoisomer having the RR/SS configuration.

88. The method according to p, further comprising splitting the compounds of formula (IX) or the compound of formula (IX') RRR/SSS configuration with the formation of the compounds of formula (VIII) in the form of a diastereoisomer having the RR/SS configuration.

89. The method of obtaining RS/SR or RR/SS diastereomers of the compound (VIII),

including:
(i) providing a racemic compound of the formula (V)

(ii) recovery of racemic compounds of formula (V) in a solvent and optionally in the presence of a Lewis acid, where LG represents a bromine or chlorine, with getting diastereomeric mixture of compounds of formula (VI)

(iii) formation of a mixture of di is stereomono the compounds of formula (VII)

(iv) the interaction of diastereomers of compounds of formula (VII) with NH2PG, where PG represents hydrogen or aminosidine group, where aminosidine group represents at least one allyl group, or aryl-C1alkyl groups with obtaining the compounds of formula (VIII) as a mixture of diastereoisomers; and (v) the allocation of RS/SR or RR/SS diastereomers of compounds of formula (VIII) of the mixture of diastereoisomers by fractional crystallization.

90. The method according to claim 1, where the phase (d2) is carried out for the compounds of formula (IX) or (IX1with RSR/SRS configuration.

91. The method according to p, where the diastereoisomer RSS/SRR configuration in the mix get in about nine-fold excess relative to the diastereoisomer RSR/SRS configuration.

92. The method according to claim 1, where at stage (d2) the mixture is cooled, using a temperature gradient from about 70°to about 20°C.

93. The method according to p, where the temperature gradient is from about 70°to about 40°C.

94. The method according to claim 1, where at stage (d2) an organic solvent represents acetonitrile.

95. The method according to claim 1, where at stage (d2) specified epimerization is carried out in the presence of at least 0.1 equivalent basis.

96. The method according to claim 1, where the specified epimerization is carried out in the presence of at least 0.25 equivalent basis.

97. The method according to claim 1, where at stage (d2) base represents the t of a connection, selected from the group consisting of alkoxide, amidine, guanidine and phosphazene.

98. The method according to p, where the base is amidin.

99. The method according to p, where the base is databaseconnect.

100. The method according to claim 1, where at stage (d2) the water content, if present, may not exceed 1.0%.

101. The method according to claim 1, where at stage (d2) the water content, if present, may not exceed 0,1%.

102. The method of obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] and its pharmaceutically acceptable salts, including:
(a) providing a compound of formula (IX),

the compounds of formula (IX'), which is a cyclic polyethalene form the compounds of formula (IX),

or mixtures thereof, where the compound of formula (IX) and the compound of formula (IX') is a mixture of diastereoisomers;
(b) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') at least one of (b1) or (b2), where
(b1) separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') by fractional crystallization after the formation of salts or after modification of obtaining essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% of RSS/SRR is whether RRS/SSR configuration;
(b2) the separation of diastereomers of compounds of formula (IX) or the compound of formula (IX') to give the essentially pure diastereomers of formula (IX) or formula (IX')containing at least 50% of RSS/SRR or RRS/SSR configuration stage simultaneous epimerization-crystallization stage where the epimerization-crystallization includes:
(1) the epimerization of the compounds of formula (IX) or (IX') RSR/SRS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RSS/SRR configuration and RSR/SRS configuration, or
the epimerization of the compounds of formula (IX) or (IX') RRR/SSS configuration with a mixture of diastereomers of formula (IX) or formula (IX') RRS/SSR configuration and RRR/SSS configuration, provided that the specified epimerization is carried out in the presence of a base and an organic solvent, where the mixture is optionally cooled to a temperature gradient and where the diastereomers RSS/SRR configuration or RRS/SSR configuration in the mix get at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration; and
(2) crystallization of essentially pure diastereomers of formula (IX) or formula (IX') RSS/SRR configuration or RRS/SSR configuration of at least two-fold excess relative to the diastereomers RSR/SRS configuration and RRR/SSS configuration;
separation of the mixture by fractional crystallization is not necessary after the formation of the Oli or after modification of obtaining, essentially pure diastereomers of formula (IX) or formula (IX')having RSS/SRR or RRS/SSR configuration;
(C) recovering essentially pure diastereomers of formula (IX) or formula (IX')having RSS/SRR or RRS/SSR configuration with obtaining the compounds of formula (X)

as RSSS/SRRR diastereomeric mixture in which the ratio of the RSSS/SRRR diastereomeric configuration to SRSR or RRSS diastereomeric configuration is at least 1;
(d) removing the protection of the compounds of formula (X), provided that PG is not H, (and if PG is a N, then cancel the specified stage unprotect), obtaining the compounds of formula (I)

or its pharmaceutically acceptable salts; and (e) removing the compounds of formula (I) or its pharmaceutically acceptable salts RSRS or RRSS diastereomeric configuration, if any, by recrystallization or suspendirovanie, obtaining racemic [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±)α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] or its pharmaceutically acceptable salts.

103. The method according to 102, where stage (b) is carried out for the compounds of formula (IX) or (IX') RSR/SRS configuration.

104. The method according to p, where the diastereoisomer RSS/SRR configuration in the mix get in the approximately nine-fold excess relative to the diastereoisomer RSR/SRS configuration.

105. With the ESP on 102, where on the stage (b) the mixture is cooled at the temperature gradient from about 70°to about 20°C.

106. The method according to p, where the temperature gradient is from 70 to 40°C.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I , where R1 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl and lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl, which can be substituted with a halogen; R2 is selected from a group comprising hydrogen, lower alkyl, cycloalkyl or lower cycloalkylalkyl, where the cycloalkyl ring can be substituted with lower alkoxyalkyl, lower alkoxyalkyl, and tetrahydropyranyl or lower heterocyclylalkyl, where the heterocyclic ring is oxetanyl or tetrahydropyranyl which can be substituted with a halogen; or R1 and R2 together with the nitrogen atom to which they are bonded form a 4-, 5- or 6-member saturated or partially unsaturated heterocyclic ring which optionally contains the same heteroatom selected from oxygen or sulphur, where the said saturated or partially heterocyclic ring is unsubstituted or substituted with one or two groups independently selected from a group consisting of lower alkyl, halogen, halogenalkyl, cyano group, hydroxy group, lower hydroxyalkyl, lower alkoxy group, oxo group; A is selected from , and , where m equals 0 or 1; R3 is a lower alkyl; n equals 0; R4 is a lower alkyl; p equals 1; q equals 0, 1 or 2; R5 is hydrogen; and their pharmaceutically acceptable salts. The invention also relates to a pharmaceutical composition based on formula I compounds.

EFFECT: new quinoline derivatives are obtained, which have antagonistic effect on histamine 3 receptors (H3 receptors).

18 cl, 4 tbl, 86 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new 4-substituted 3-(3-dialkylaminomethyl-indol-1-yl)maleimide derivatives of general formula

and ,

where: X1-X4 denote C; Z denotes H; R1 denotes alkyl, H, -(CH2)3-N-(C2H5)2; R2 and R3 denote alkyl, or together with the nitrogen atom to which they are bonded form a C4-7-monocyclic ring containing 1 or 2 heteroatoms, selected from O and N, possibly substituted with an alkyl; R4 denotes H; Y denotes S, -N-(C2H5); where in formula I compounds R5 and R6 together with the nitrogen atom to which they are bonded form a C9-10 a condensed bicyclic ring containing an N heteroatom, possibly substituted with R, where R denotes -N-(R2)-R3; in formula II compounds R5 denotes phenyl, optionally substituted with OCH3.

EFFECT: obtaining new compounds which can be used as protein kinase inhibiting agents.

2 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to benzazepin derivatives of formula (I), where R1 is unsubstituted cyclobutyl, R2 is 3-pyrazinyl, substituted CON(H)(Me) or 2-pyridinyl-M-pyrrolidinyl, where the said pyrrolidinyl group is substituted with a =O group; which is: methylamide 5-(3-cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy) pyrazine-2-carboxylic acid

or 1-{6-[(3-cyclbutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-3-pyridinyl}-2-pyrrolidinone

EFFECT: obtaining compounds which have affinity to histamine H3 receptor and pharmaceutical compositons containing said compounds.

11 cl, 288 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

,

where the carbon atom denoted * is in R- or S-configuration; X is a concentrated bicyclic carbocycle or heterocycle selected from a group consisting of benzofuranyl, benzo[b]thiophenyl, benzoisothiazolyl, indazolyl, indolyl, benzooxazolyl, benzothiazolyl, indenyl, indanyl, dihydrobenzocycloheptenyl, naphthyl, tetrahydronaphthyl, quinolinyl, isoquinolinyl, quinoxalinyl, 2H-chromenyl, imidazo[1.2-a]pyridinyl, pyrazolo[1.5-a]pyridinyl, and condensed bicyclic carbocycle or condensed bicyclic heterocycle, optionally substituted with substitutes (1 to 4) which are defined below for R14; R1 is H, C1-C6-alkyl, C3-C6-cyclalkyl, C1-C3-alkyl, substituted OR11, -NR9R10 or -CN; R2 is H, C1-C6-alkyl, or gem-dimethyl; R3 is H, -OR11, C1-C6-alkyl or halogen; R4 is H, halogen, -OR11, -CN, C1-C6-alkyl, C1-C6-alkyl, substituted -NR9R10, C3-C6-cycloalkyl, substituted -NR9R10, C(O)R12; or R4 is morpholinyl, piperidinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, isoxazolyl, pyrrolidinyl, piperazinyl, 2-oxo-2H-pyridinyl, [1.2.4]triazolo[4.3-a]pyridinyl, 3-oxo-[1.2.4]triazolo[4.3-a]pyridinyl, quinoxalinyl, which are optionally substituted with substitutes (1 to 4) which are defined below for R14; R5 is H or C1-C6-alkyl; R6 is H, C1-C6-alkyl, or -OR11; R7 is H; R8 is H, -OR9, C1-C6-alkyl, -CN; R9 is H or C1-C4-alkyl; R10 is H or C1-C4-alkyl; or R9 and R10 taken together with the nitrogen atom to which they are bonded form morpholine; R11 is H, C1-C4-alkyl; R12 is C1-C6-alkyl; R14 in each case is independently selected from a substitute selected from a group consisting of halogen, -OR11, -NR11R12, C1-C6-alkyl, which is optionally substituted with 1-3 substitutes, in each case independently selected from a group consisting of C1-C3-alkyl, aryl; or to pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, to a method of obtaining formula (I) compounds, as well as to a method of treating disorders.

EFFECT: obtaining new biological active compounds having norepinephrine, dopamine and serotonin reuptake selective inhibitory activity.

90 cl, 162 ex, 2 tbl

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

Chemical method // 2386636

FIELD: chemistry.

SUBSTANCE: present invention relates to a method for synthesis of a compound of formula I , in which X1 is selected from O; and X2 is N; involving successive reaction of a formula II compound with (i) methyl- or optionally substituted aryl-lithium; then (ii) n-butyl-, sec-butyl-, tert-butyl- or n-hexyl-lithium; and then (iii) borate ester. The invention also relates to a method of obtaining formula IV compounds: , which involves combination of [4-(1,3,4-oxadiazol-2-yl)phenyl]boronic acid with a formula III compound, in which P is a nitrogen protecting group, and to a formula IV compound, where P is C1-6alkoxycarbonyl.

EFFECT: design of an efficient method of obtaining the said compound.

9 cl, 9 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to 3,3'-bis-(3,4-dihydro-3-phenyl-2H-1,3-benzoxazin-6-yl)-1(3H)-isobenzofuranone and analogues based on phenolphthalein, formaldehyde and a primary amine of formula 1: , in which R independently represents allyl or phenyl, and to a method of synthesising the said compounds. The invention also pertains to a method of making a refractory cast or layered material based on the said compounds and laminating compositions since through thermal hardening, these compounds form a net which does not catch fire easily and is resistant to high temperatures. The said compounds can be particularly useful in making printed circuit boards.

EFFECT: obtaining fire-resistant compounds.

5 cl, 4 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula Ia: and its pharmaceutically acceptable salt, where: p equals 0 or 1; n assumes values from 1 to 3, q equals 1; R5 is selected from hydrogen, -XNR7R8, pyrimidine-C0-4alkyl, pyridine-C0-4alkyl, phenyl, C3-10cycloalkyl-C0-4alkyl and C3-6heterocycloalkyl-C0-4alkyl, where C3-6heterocycloalkyl is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is hydrogen or C1-4alkyl; R7 and R8 represent C1-4alkyl; R6 denotes hydrogen; or R5 and R6 together with a nitrogen atom to which they are both bonded form morpholine or piperidine; where any piperdine-C0-4alkyl, piperidine-C0-4alkyl or C3-10cycloalkyl-C0-4alkyl of substitute R5 or a combination of radicals R5 and R6 can be optionally substituted with 1-2 radicals which are independently selected from -XNR7R8 and -XOR7, the said phenyl of substitute R5 is substituted with a -XR9 group, the said C3-6heterocycloalkyl-C0-4alkyl of substitute R5 is optionally substituted with a -XOR7 group, where X is a single bond or C1-4alkylene; R7 and R8 are independently selected from hydrogen and C1-4alkyl; R9 is selected from C3-10heterocycloalkyl which is a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R is as given above; R10 denotes hydrogen; R15 is selected from halogen, C1-6alkyl and C1-6alkoxy; and R16 is selected from halogen, methoxy, nitro, -NR12C(O)R13, -C(O)NR12R12, -NR12R12, -C(O)OR12 and -C(O)NR12R13; each R12 is selected from hydrogen and C1-6alkyl; R13 is selected from phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl, where any phenyl, thienyl, pyrazolyl, pyridinyl or isoxazolyl of substitute R13 can be optionally substituted with 1-2 radicals which are independently selected from halogen, C1-6alkyl, halogen-substituted C1-6alkyl, imidazole-C0-4alkyl, C3-10cycloalkyl, C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl; where the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl each represent a saturated monocyclic ring system containing the said number of atoms, provided that one or more of the said carbon atoms is substituted with O or NR, where R assumes values given above; and the said C3-10heterocycloalkyl-C0-4alkoxy and C3-10heterocycloalkyl-C0-4alkyl can each be optionally substituted with 1 radical independently selected from C1-6alkyl, hydroxyl-substituted C1-6alkyl and NR7R8, where R7 and R8 assume values given above. The invention also relates to pharmaceutical compositions containing the said compounds.

EFFECT: obtaining novel compounds and compositions based on the said compounds which can be used in medicine for treating and preventing diseases or disorders associated with abnormal or uncontrolled kinase activity, particularly diseases or disorders associated with abnormal activity of kinase c-Src, FGFR3, KDR and/or Lck.

12 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a group of novel chemical compounds pharmacologically acceptable salts thereof having formula , where A represents COOH; B represents H; n equals 0; V represents -CH2-, a single bond; W represents a 5-7-member heteroaromatic group with one heteroatom selected from N, O, S which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, when V represents a -CH2-group, where if V represents a single bond, W represents a bicyclic condensed a ring -member heterocyclic group with one heteroatom selected from O, S, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; X represents a 5-7-member heteroaromatic group with one O atom and one or two N atoms, which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Y represents C6-C10 aryl which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A, a 5-7-member heteroatomatic group with one S atom which can optionally be substituted with 1-3 substitutes selected from a group of substitutes A; Z represents C1-C8 alkyl, C3-C7 cycloalkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; C6-C10 aryloxy which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A, or C1-C12 aralkyl which can optionally be substituted with 1-5 substitutes selected from a group of substitutes A; group of substitutes A represents halogen, C1-C6 alkyl, halogen C1-C6 alkyl, C1-C6 alkoxy.

EFFECT: compounds exhibit inhibitory activity towards HvGR which enables their use to prepare a pharmaceutical composition used in therapy for autoimmune diseases.

33 cl, 6 tbl, 30 ex

FIELD: medicine.

SUBSTANCE: invention relates to compounds of general formula (I) and their pharmaceutically acceptable salts and pharmaceutically acceptable asters, possessing activity with respect to LXRα and/or LXRβ receptors. Compounds can be applied for treatment and prevention of diseases mediated by LXRα and/or LXRβ receptors, namely: increased level of lipids and cholesterol level, atherosclerotic diseases, diabetes, metabolic syndrome, dyslipidermia, sepsis, inflammatory diseases, pancreatitis, liver cholestasis/fibrosis, and diseases which include inflammatory component, such as Alzheimer's disease and reduced/improvable cognitive function. In general formula n represents integer number from 0 to 3; R1 is independently selected from group consisting of halogen, -CN, -NO2, -SO2Me, lower alkyl, -OR11, pyperidinyl and -N(R11)(R11), where R11 is independently selected from lower alkyl and H, X1, X2, X3 and X4 are independently selected from nitrogen and carbon, on condition that, not more than two of X1, X2, X3 and X4 can simultaneously represent nitrogen, and in case when two of X1, X2, X3 and X4 represent nitrogen, n represents 0,1 or 2; k represents integer number 0 or 1; R2 represents H; R3 represents H, lower alkyl or halogen; R4 represents aryl, heteroaryl, lower alkylaryl or lower alkylheteroaryl, each of which is optionally substituted with substituents in amount from one to five, which are independently selected from group consisting of halogen, lower alkyl, -OR41, lower alkinyl and NR42R43, where R41 represents lower alkyl, R42 and R43 independently on each other represent hydrogen or lower alkyl, or NR42R43 represents pyrrolidinyl, or R4 represents lower alkyl; R5 is selected from group, heteroaryl, consisting of and , said aryl and heteroaryl being optionally substituted in one or more positions with one or more substituents, independently selected from group consisting of H, halogen, lower alkyl and (CH2)VR53, where R51 is selected from group consisting of H, lower alkyl, lower alkenyl and lower alkylaryl, said lower alkylaryl is optionally substituted in one or more positions with one or more lower alkyl, -CN, halogen, group -COOR54 and group -CH2OR54, where R54 represents lower alkyl or H; R52 represents lower alkyl or -H; R53 represents H, lower alkyl, C3-C6-cycloalkyl, -COOR55, -N(R55)(R56), -CH2OH, -CN, CF3, -CONH2 or -CH2OR55, where R55 is independently selected from group consisting of lower alkyl, -H, -C(O)aryl or -C(O)-lower alkyl, and R56 is selected from group consisting of H, lower alkyl, -C(O)CF3, -C(O)aryl, -C(O)-lower alkyl and lower alkylaryl, and where said aryl and lower alkylaryl are optionally substituted in one or more positions with one or more lower alkyl, halogen, group COOR57 and group -CH2OR57, where R57 represents lower alkyl or -H, or R55 and R56 together with atom to which they are bound, form ring system; or R53 represents aryl, which can be optionally substituted with benzyloxy, carboxy, lower alkoxycarbonyl, hydroxy-(lower alkyl), halogen, carbamoyl, (lower alkyl)carbamoyl, di-(lower alkyl)carbamoyl, m represents integer number from 0 to 2; v represents integer number from 0 to 4; where term "lower alkyl" separately or in combination with other groups refers to branched or linear monovalent alkyl radical, containing from one to six carbon atoms, where term "aryl" separately or in combination with other groups refers to phenyl or naphthyl, and where term "hetyeroaryl" refers to aromatic 5- or 6-member ring, which can include 1-3 heteroatoms selected from nitrogen, oxygen and/or sulphur, and which can be condensed with phenyl group.

EFFECT: increase of compound application efficiency.

38 cl, 5 dwg, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 2H-1-benzopyran-2-methanol-α,α'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-[2R*[R*[R*(S*)]]]], i.e. a nebivolol base of formula (IX), or its hydrochloride salt

as well as to a method of producing an intermediate compound - benzylated nebivolol of formula (VIII),

EFFECT: invention also relates to a pharmaceutical composition with antihypertensive action without using a wetting agent, and to a tablet containing this pharmaceutical composition.

21 cl, 20 tbl, 21 ex

FIELD: medicine.

SUBSTANCE: invention relates to 2,4-pyrimidindiamins, such as N4-(4-Chlorine-3-methoxyphenyl)-5-fluorine-N2-[3-(N-ethylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-(3-Chlorine-4-methjopxycarbonylmethylenoxyphenyl)-5-fluorine- N2-[3-(N-methylamino)carbonylmethylenoxyphenyl]-2,4-pyrimidindiamin, N4-[3-Chlorine-4-(N-methylamino)carbonylmethylenoxyphenyl]-5-fluorine-N2-[3-(]N methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin, N4-[3-Chlorine-4-(2-hydroxyethylenoxy)phenyl]-5-fluorine-N2-[3-(N- methylamino)carbonylmethylenoxyphenyl]- 2,4-pyrimidindiamin and other compounds given in item 1 of claimed invention as Syk-kinase inhibitors, as well as to based on them pharmaceutical composition and their application.

EFFECT: claimed compounds can be applied for treatment of autoimmune diseases, systemic http://lingvo.yandex.ru/?text=lupus%20erythematosus, rheumatoid arthritis, etc.

12 cl, 27 dwg, 11 tbl, 1797 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new compounds with formula (I), their esters, carbamates and pharmaceutically used salts, which can be used as inhibitors of p38 kinase, which means they can be used for curing diseases and conditions for which p38 is the mediator. In formula (I): Q represents -C(R1R2R3); R1 is chosen from hydrogen, C1-C8 alkyl, hydroxyC1-C8alkyl, and C1-C8alkoxy C1-C8alkyl; R2 and R3 are chosen: (i) independently from: (a) hydrogen, under the condition that, if R1 represents hydrogen, then only one of R2 and R3 can be chosen from hydrogen; (b) C1-C8alkyl; C1-C8alkyl, substituted with one or two radicals halogen, -OR8, -S(O)pR10;(c) -OR8; or (ii) R2 and R3 together with the carbon atom to which they are bonded, form optionally substituted C3-C7cycloalkyl or substituted heterocyclic ring system; R4 and R5 are independently chosen from halogen; R8 and R9 are independently chosen from hydrogen, C1-C8alkyl; R10 represents C1-C8alkyl; m equals 0, n equals 0; and p equals 2; where the term "substituted cycloalkyl" stands for a cycloalkyl group, containing one or two substitutes, which are independently chosen from a group, consisting of -Y-ORs, -Y-S(O)0-2RS, C(=O)ORs, where Y is absent; Rs is independently chosen from hydrogen, C1-C8alkyl, except when the said substitute represents -Y-S(O)1-2Rs, then RS represents hydrogen; the term "heterocyclic ring system" stands for a saturated non-aromatic monocyclic fragment, consisting of 5 to 6 atoms, which are part of the ring system, from which one atom, which is part of the ring system, is a heteroatom, chosen from N, O, and the rest of the atoms in the ring system are carbon atoms; the term "substituted heterocyclic ring system" stands for a heterocyclic fragment mentioned above, containing one substitute, chosen from the group, -Y-Rs, -Y-ORs, -Y-C(O)2Rs, -Y-S(O)0-2Rs, where Y is absent or represents a C1-C4alkylene group, Rs represents the same as was defined above for the substituted cycloalkyl group.

EFFECT: used for treating diseases and conditions.

13 cl, 2 dwg, 5 tbl, 17 ex

FIELD: chemistry.

SUBSTANCE: invention concerns novel amidomethyl-substituted derivatives of 2-(4-sulfonylamino)-3-hydroxy3,4-dihydro-2N-chromen-6-yl of the general formula (I) where R1 is C1-C4alkyl, R2 is C1-C4alkyl, R3 is phenyl optionally once or twice substituted or substituted by halogen, C1-C4alkyl, C1-C4alkoxy group or trifluoromethyl, naphthyl or biphenyl, R4 is hydrogen, C1-C6alkyl or C3-C7cycloalkyl-C1-C4alkyl, R5 is hydrogen, and R6 is C1-C6 alkyl, phenyl-C1-C4alkyl, phenyl group optionally substituted by halogen, furyl-C1-C4alkyl or tetrahydronaphthyl, or R5 and R6 together with nitrogen atom linking them form piperazine ring optionally substituted by phenyl.

EFFECT: also invention claims method of obtaining claimed compounds, and intermediary products used in method implementation, as well as medicines containing compounds of the formula (I) with antiarrhythmic effect, and application of these medicines.

11 cl, 6 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds N-(2-furylalkyl)-NHR carbamides with formula 1: , exhibiting growth-regulating and immuno-modeling activity, and method of producing them. The method involves reacting furfuryl idenacetone with urea in hydroamination conditions in an autoclave, in the presence of skeletal nickel catalyst and an organic solvent at 70-90°C temperature, and ratio of substrate to reagent equal to 1:1 or 2:1.

EFFECT: invention can be used in agriculture.

2 cl, 9 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: in novel tocopherol-modified therapeutic drug compounds of formula 1 T-L-D, T is tocopherol, L is succinate, and D is camptotecin or its derivative, where all three fragments are bound covalently. Invention also relates to emulsions based on said compounds, formulations of micelles, including said compounds, methods of treating cell proliferative disease using said compounds and formulations, as well as to said compounds application for production of medication for treatment of cell proliferative disease.

EFFECT: increase of composition and treatment method efficiency.

18 cl, 17 dwg, 4 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of formula (I) as well as to synthesis procedure and application for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis where R1-R11, t, X, Y, Z and n have values specified in the description.

EFFECT: production of macrocyclic compounds used for treatment of various disorders, including inflammatory and autoimmune disorders, and disorders caused by malignant growths or by increased angiogenesis.

41 cl, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to the tetrahydroquinolin derivatives with the common formula (I) , or their pharmaceutically acceptable salts, where R1 and R2 are H, Me; R3 is (2-6C)-hetercycloalkyl(1-4C)alkyl, (2-5C)heteroaryl(1-4C)alkyl, (6C)aryl(1-4C)-alkyl, (2-6C)hetercycloalkylcarbonylamino(2-4C)alkyl, R5-(2-4C)alkyl or R5-carbonyl(1-4C)alkyl; R4 is (2-5C)heteroaryl (6C)aryl, not necessarily substituted with one or more substitutes selected from bromine, chlorine, nitro, phenyl, (1-4C)alkyl, trufluoromethyl, (1-4C)alkoxi or (1-4C)alkylamino; or (2-6C)hetercycloalkyl; R5 is (di (1-4C)alkylamino, (1-4C)alkoxi, amio, hydroxy, (6C)arylamino, (di)(3-4C)alkenylamino, (2-5C)heteroaryl(1-4C)alkylamino, (6C)aryl(1-4C)alkylamino, (di)[(1-4C)alkoxi(2-4C)alkyl]amino, (di)[(1-4C)alkylamino2-4C)alkyl]amino, (di)[amino(2-4C)alkyl]amino or (di)[hydroxy(2-4C)alkyl]amino. The invention also relates to the pharmaceutical composition based on the compound with formula (I) and to the application of the compound with the formula (I).

EFFECT: novel tetrahydroquinolin derivatives with follicle-stimulating hormone receptors modulating activity are obtained.

10 cl, 44 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new derivatives of benzo {b} {1, 4} dioxepin formulas (I) where B, X, Y, Z, R1 and R2 accept the value specified in the description of the invention, and also them pharmaceutically comprehensible salts.

EFFECT: pharmaceutical compositions containing these bonds, are applied to treatment and/or preventive maintenance of the diseases modulated by the ACCβ inhibitors.

20 cl, 1 tbl, 28 ex

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