Method of separating carbinol

 

(57) Abstract:

The present invention relates to a method of primary obtain enantiomer (R)-(+)-5-(phenyl) hydroxymethyl-1-methyl-1H-pyrazole (R-(+)-1) high yield allocation from the racemic mixture of ()-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole of formula 1, characterized by the consistent implementation of the method, which involves the use of a lipase having enzyme activity in the reaction of selective transesterification, using a complex ester of the formula 3: R1R2where R1represents methyl or ethyl, R2- vinyl or Isopropenyl. As a result of transesterification get a mixture containing unreacted R-(+)-1 and ester (S)-(-)-5-(phenyl) alkylcarboxylic-1-methyl-1H-pyrazole of the formula 4, where1represents methyl or ethyl. Unreacted enantiomer R-(+)-1 is separated from the ether by chromatography or by crystallization in an appropriate solvent with recovery of R-(+)-1 and carry out the hydrolysis of ester obtained. 5 C.p. f-crystals.

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The present invention relates to a new method of separation of carbinol of the formula 1, its enantiomers, and also to racemization of one of them. stereoisomer formula 1 are the main compounds for the synthesis of enantiomers of compounds of formula 2.

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The compound of formula 2 ()-5-{[(N,N-dimethylaminoethoxy)- phenyl]methyl}-1-methyl-1H-pyrazole is a compound having analgesic effect, and which is currently in clinical trials; it is described in the European patent EP 289380. Synthesis and study of both enantiomers of 2 as analgesics described in the literature (J. A. Hueso, J. Berrocal, B. Gutierrer, A. J. Farre u J. Frigola. Bioorganic & Medicinal Chemistry Letters, 1993, 3, 269-272); the results of these studies indicate that programalso the most active enantiomer.

The enantiomers (+) and (-) of the compounds of formula 2 receive, respectively, the alkylation of (+) and (-) stereoisomers of the compounds of formula 1. Stereoisomer (+) connection 1 receive with a very low yield of (R)-atlandilt that identified thus the absolute configuration of (R)-(+) connection 1. Enantiomers 1 you can also get complicated methods of separation through column chromatography or by fractional kristallizatsii of complex diastereoisomeric esters formed by the reaction of compound 1 with (+)-O-acetylindole acid. Output is 22% for enantiomer (-) connection of biocatalysts by separation of racemic mixtures is described in detail in the document:

[a) "Microbial reagents in organic synthesis" Stefano Servi, Kluwer Academic Publishers, London, 1992;

b) "Enzymes in synthetic organic chemistry", C. H. Wong u G. M. Whitesides, Elsevier Science, Oxford 1994;

c) "Biotransformations in Organic Chemistry", K. Faber, Lange and Springer, 1995].

There are many different classes of enzymes used for the separation of stereoisomers, including hydrolases (in particular, lipase, protease and esterase), LiAZ and oxidoreductase. Hydrolases are one of the most attractive for use in the separation of enantiomers because they are available at low prices, and some of them have demonstrated sufficient stability to organic solvents.

The use of organic solvents in reactions catalyzed by enzymes, has a number of advantages:

a) most organic substrates more soluble in organic solvents than in water;

b) recovery of the reaction products is greatly facilitated;

C) enzymes are easy to recover and reuse;

d) in some cases there is a high enantioselectivity.

Despite the advantages of using enzymes in organic solvents has some disadvantages:

a) search for a suitable solvent;

b) passive nature [see a) A. M. Klibanov. Trends Biochem.Sci 1989, 14, 141;

b) C. S. Chen, C. J. Sih, Angew. Chem. Int. Ed.Engl., 1989, 28, 695]. Confirmation of the fact that some enzymes can act in organic solvents, was one of the main reasons for the sharp increase over the last decade, the use of reactions of Bioperine to obtain products having therapeutic and industrial interest. [see: a) A. N. Collins, G. N. Sheldrake, S. Crosby "Chirality in Industry" Wiley, London, 1992;

b) S. C. Stinson, Chem. & Eng. News, 1994, 38;

c) A. C. Margolin, Enzyme Microb. Techol. 1993, 15, 266].

The present invention is to develop a cost-effective method of obtaining programalso stereoisomer (R)-(+) connection 1, which could be useful for obtaining levogyrate stereoisomer (S)-(-) of the same connection 1.

The method applies the present invention is based on Biocatalysis using the biocatalyst to ensure the election of transesterification between racemic alcohol 1 and a complex ester of formula 3, where R1represents methyl or ethyl and R2represents a vinyl or Isopropenyl. With the help of the enzyme, providing appropriate stereoselectivity, you can get the reaction mixture, steili ethyl, obtained from the other enantiomer 1.

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For separation and recovery of unreacted alcohol and derived complex ester can, therefore, relatively easy to apply the well-known chemical methods, such as chromatography or crystallization. Another aspect of the invention is to carry out the hydrolysis of ester obtained using acidic or basic catalyst so as to obtain compound 1 with racemizations last or with retention of configuration. In the case when you get a racemic mixture of compounds 1, it can then be processed with the specified part of the biocatalyst for the implementation of the above transesterification, and so several times. Thus achieve almost complete transformation of racemic substrate 1 with the formation of the desired enantiomer.

The strategy used in the present invention, is to consistently combine the enzymatic transesterification carbinol 1 and chemical transformation with racemizations. Enzymes, the most suitable for the implementation of transesterification are hydrolases, mainly lipases secreted by ICRI agents, are complex enol ethers of formula 3, where R1represents methyl or ethyl and R2represents a vinyl or Isopropenyl. The reaction of transesterification proceeds in the absence of solvent or in an appropriate solvent, such as hexane, cyclohexane, toluene, acetone, dioxane, tetrahydrofuran, ethanol, etc. at temperatures between 20oC and reflux temperature in the course of time, necessary to implement the transformation, this time can vary from 6 to 48 hours. The addition of molecular sieves in the middle of the reaction may increase activity and reduce the water content. The reaction of acylation is easily controlled by the nuclear magnetic resonance of the proton. Unreacted enantiomer 1 is separated from the other esterified enantiomer 4 by chromatography on a column of silica gel or by crystallization in an appropriate solvent. Optical purity analyzed by chiral high-performance liquid chromatography (HPLC).

Esterified enantiomer 4 hydrolyzing to obtain racemic carbinol 1 or the corresponding homochiral carbinol. The hydrolysis is carried out respectively in acidic or basic medium under eat alkylation of stereoisomers (+) and (-) connections 1 dimethylaminoethanol in phase transition and subsequent processing citric acid, receive, respectively, the stereoisomers (+) citrate and (-) citrate connections 2.

The above method of transesterification of racemic carbinol 1 for homochiral carbinol and formed by hydrolysis of homochiral complex ester to obtain the corresponding homochiral alcohol or racemic alcohol, as well as a detailed description of the examples, data below is for illustrative purposes only and should not limit the scope of the present invention.

Example 1

Split ()-5-(phenyl)-hydroxymethyl-1-methyl - 1H-pyrazole, ()-1, lipase PS:

A mixture of 100 g of the above racemic carbinol, 50 g of activated lipase PS manufactured by AMANO PHARMACEUTICAL COMPANY Ltd. (NACOYA-JP), 50 g of activated molecular sieve with cells 3 and 1000 ml of vinyl acetate is shaken at a temperature of 60oC for 24 hours. By analysis of the 1H-NMR determines that the substrate acetiminophen 55%, are filtered to separate the lipase and molecular sieve, and under reduced pressure to evaporate the vinyl acetate. The residue is dissolved in cyclohexane, and from him obtained by crystallization 36 g(72%) (+)-5-(phenyl) hydroxymethyl-1-methyl-1H-pyrazole, (+)-1, with an optical purity of more than 96% (excess enantiomer, CHCl3). Evaporation of solvent gives a 76.5 g mainly (-)-5-(phenyl) methylcarbamoylmethyl-1-methyl-1H-pyrazole, (-)-4, where R1represents methyl.

Example 2

Hydrolysis and racemization (-)-5-(phenyl)methylcarbamate-methyl-1 - methyl-1H-pyrazole, (-) -4:

of 76.5 g of (-)-5-(phenyl)methylcarbamoylmethyl-1-methyl-1H-pyrazole, (-)-4, heated under reflux in 300 ml of 6 N. hydrochloric acid for 12 hours, filtered under heating and alkalinized solution of ammonium hydroxide, to get to 61.4 g of racemic carbinol ()-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, ()-1, melting point 105-106oC; IR (KBr) 3225, 1457, 1398, 1208, 1200, 1018, 1009, 794, 751, 702 cm-1; enantiomerically excess defined HPLC=0.

Example 3

Split ()-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, ()-1, lipase PS:

A mixture of 61.4 g of the carbinol ()-1 obtained in example 2, a 30.7 g of activated lipase PS, manufactured by AMANO PHARMACEUTICAL COMPANY (NACOYA-JP), a 30.7 g of activated molecular sieve with cells and 600 ml of vinyl acetate is shaken with 56oC for 36 hours. Using NMR analysis of the proton determines that the substrate acetiminophen at 53%, followed by filtration to separate the lipase and molecular sieve, and evaporated under reduced tableitemstyle-1-methyl-1H-pyrazole, (+)-1, with an optical purity higher than 95%, melting point: 79-85oC []D= +16,0 (c= 1, CHCl3). Evaporation of the solvent gives the 45.8 g mainly (-)-5-(phenyl)methylcarbamoylmethyl-1-methyl - 1H-pyrazole and (-)-4, where R1represents methyl.

Example 4

Split ()-5-(phenyl)hydroxymethyl-1-methyl - 1H-pyrazole, (+)-1, lipase PS:

A mixture of 3.5 g of the carbinol ()-1, 7,4 g activated lipase PS manufactured by AMANO PHARMACEUTICAL COMPANY Ltd. (NACOYA-JP) and 100 ml of validatedata shaken when 62oC for 13 hours. By analyzing the NMR proton determines that the substrate acetiminophen 50%, followed by filtration to separate the lipase and molecular sieve, and vinyl acetate is evaporated under reduced pressure. The residue is subjected to chromatography on a column of silica gel with a mixture of diethyl ether:hexane (2:1) as eluant, and obtain 2.1 g(98%) (-)-5-(phenyl)methyl-carbonyloxy - 1-methyl-1H-pyrazole, (-)-4, where R1represents methyl. Subsequent elution with diethyl ether to obtain 1.7 g(98%) (+)-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, (+)-1 with enantiomerically excess defined HPLC=94%.

Example 5

Hydrolysis with retention of configuration of (-)-5-(phenyl)methylcarbamoylmethyl-1-methyl-1H-pyrazole, (-)-4:
D= -16,1 (C=1, CHCl3).

Example 6

Getting citrate (+)-5-{[N,N-dimethylaminoethoxide]methyl}- 1-methyl-1H-pyrazole, (+)-2 citrate.

Heated under reflux for 7 hours a mixture of 12.7 g of (+)-5-(phenyl) hydroxymethyl-1-methyl-1H-pyrazole, (+)- 1, 250 ml of toluene, 125 ml of 50% sodium hydroxide, 3 g of chloride triethylmethylammonium and 14.6 g of the hydrochloride of dimethylaminoborane. The cold mixture is extracted with toluene 16.2 g(92,6%) (+)- 5-{[N,N-dimethylaminoethoxy)-phenyl]methyl}-1-methyl-1H-pyrazole, (+)-2.

Shaken at 40oC a mixture of 15 g of (+)-5-{[N,N-dimethylaminoethoxy)-phenyl] methyl} -1-methyl-1H-pyrazole, (+)-2, and 13.5 g of citric acid monohydrate in ethanol until complete dissolution. From this solution produce crystallization of 24.7 g (94,5%) citrate (+)-5-{[N,N-dimethylaminoethoxy)-phenyl]methyl}-1-methyl-1H - pyrazole, (+)-2, the melting point of 129-131oC []D= +8,3 (C=1, H2O).

Example 7

Getting citrate (-)-5-{ [N, N-dimethylaminoethoxy)phenyl]methyl} -1-methyl-1H-pyrazole, (-)-2-pyrazole, (-)-1 as a product of the separation, receive (-)-5-{[N,N-dimethylaminoethoxy)-phenyl]methyl} -1-methyl-1H-pyrazole, (-)-2 citrate, melting point 128-130oC []D= -8,2 (C=1, H2O).

1. The method of obtaining, in General, the enantiomer R-(+)-5-(phenyl)-hydroxymethyl-1-methyl-1H-pyrazole, denoted by (R)-(+)-1, the selection of the racemic mixture of ()-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole of the formula I

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characterized in that the conduct of the election the transesterification between a complex ester of the formula 3

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where R1represents methyl or ethyl;

R2represents a vinyl or Isopropenyl,

and enantiomer carbinol S-(-)-5-(phenyl) hydroxymethyl-1-methyl-1H-pyrazole, S-(-)-1, specified racemic mixture using a lipase catalyst having enzyme activity in the reaction of transesterification, which results in obtaining a reaction mixture containing unreacted enantiomer R-(+)-1 and S-(-)-5(phenyl)alkylcarboxylic-1-methyl-1H-pyrazole of formula 4

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where R1represents methyl or ethyl, denoted by S-(-)-4,

unreacted enantiomer R-(+)-1 is separated from the obtained complex ester of S-(-)-4 chromatography or crystallization in the corresponding dissolve the derived complex ester of S-(-)-4.

2. The method according to p. 1, characterized in that the vinyl acetate formula 3, where R1represents methyl and R2represents a vinyl, is used as a reagent and as a solvent in the reaction of transesterification.

3. The method according to PP.1 and 2, characterized in that the polar solvent, for example cyclohexane, used for crystallization of enantiomer (R) - (+)-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, (R) - (+)-1, from a solution also containing an ester of (S)-(-)-5-(phenyl)methylcarbamoylmethyl-1-methyl-1H-pyrazole, (S)-(-)-4, formula 4, where R1represents methyl.

4. The method according to one of paragraphs.1 and 2, characterized in that exercised by chromatography on a column of silica gel to separate the carbinol (R)-(+)-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, (R)-(+)-1, of ester (S)-(-)-5-(phenyl)methylcarbamoylmethyl-1-methyl-1H-pyrazole, (S)-(-)-4, where R1represents methyl.

5. The method according to p. 1, characterized in that carry out the hydrolysis of ester (S)-(-)-5-(phenyl)alkylcarboxylic-1-methyl-1H-pyrazole, (S)-(-)-4, where R1represents methyl or ethyl, in an acidic medium to obtain a racemic mixture of ()-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole of formula 1, which may, in its octreotide.

6. The method according to p. 1, characterized in that carry out the hydrolysis in a basic medium with retention of configuration of ester (S)-(-)-5-(phenyl)alkylcarboxylic-1-methyl-1H-pyrazole, (S)-(-)-4, where R1represents methyl or ethyl, to obtain (S)-(-)-5-(phenyl)hydroxymethyl-1-methyl-1H-pyrazole, (S)-(-)-1.

 

Same patents:

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The invention relates to an improved process for the preparation of pyrazole and its derivatives of the formula I

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in which the radicals R1-R4have the meanings specified below,

from,- unsaturated carbonyl compounds of the formula II

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and hydrazine or hydrazine derivatives of formula III

H2N-OTHER4

The invention relates to pyrazole derivative of the General formula I

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in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

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R3is phenyl, substituted lower alkylthio, lower alkylsulfonyl, or lower alkylsulfonyl, provided that when R1is phenyl, substituted lower alkoxy, then R2represents halogen or halo(lower)alkyl,

or their pharmaceutically acceptable salts

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26 cl, 518 ex, 3 tbl

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3 cl, 1 tbl, 4 ex

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7 cl, 6 tbl, 3 ex

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8 ex

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EFFECT: valuable medicinal properties of compounds and compositions.

59 cl, 10 tbl, 54 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, medicine, pharmacy.

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EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

22 cl, 23 sch, 4 tbl, 501 ex

FIELD: medicine; pharmacology.

SUBSTANCE: subjects of invention are also pharmaceutical drugs or agents for prophylaxis and treatment of neuropathy, increase of production and treatment of the neurotrophic factor, for pain relief, for nerve protection, for prophylaxis and treatment of the neuropathic pain containing compound of the formula or of the formula . In the compounds of the formulas (I) and (II) symbols and radicals have the meanings mentioned in the invention formula. The specified agents have an excellent effect and low toxicity. There are also proposed ways of treatment and prophylaxis of the abovementioned conditions by means of the compounds of the formula (I) or (II) and application of these compounds for production of the abovementioned agents. Besides, one has proposed methods for production of the specified compounds and intermediate pyrazol compounds.

EFFECT: compound has an effect increasing production and secretion of the neurotrophic factor.

46 cl, 1 tbl, 233 ex

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