GB2299332A - Esters of (R) 2-(2-hydroxybutyl)-3-chlorothiophene and a process for the resolution of (S) 2-(2-hydroxybutyl)-3-chlorothiophene - Google Patents

Abstract

A process for the resolution of (S) 2-(2-hydroxybutyl)-3-chlorothiophene comprises reacting a mixture of the (R) and (S) stereoisomers of 2-(2-hydroxybutyl)-3-chlorothiophene with a esterifying agent under substantially anhydrous conditions in the presence of an immobilised hydrolase enzyme (eg a lipase such as Lipozyme 1M), whereby the (R) alcohol is selectively esterified and the (S) alcohol is left unchanged. Esters of (R) 2-(2-hydroxybutyl)-3-chlorothiophene include those from C 2-6 -alkanoic and optionally substituted aryl-carboxylic and arylacetic acids which are claimed per se. The (S) alcohol, resolved in the process above, may be stereospecifically converted in one or more steps, optionally in the presence of the esterified (R) alcohol, into (R) 2-(2-aminobutyl)-3-chlorothiophene which is then separated from the reaction mixture. (R) 2-(2-Aminobutyl)-3-chlorothiophene is useful as an intermediate in the preparation of adenosine derivatives which may be used in the treatment of hypertension.

Description

RESOLUTION PROCESS This invention relates to biochemical and chemical processes, and in particular to processes for preparing the R enantiomer of 2-82-aminobutyl)-3-chlorothiophene.

(R) 2-(2-Aminobutyl)-3-chlorothiophene is useful, inter alia, as an intermediate in the preparation of a derivative of adenosine potentially useful in the treatment of hypertension (see C.A. Fink et al, Nucleosides and Nucleotides, 1992, volume 11, 1077-1088).

According to the present invention there is provided a process which comprises: (a) reacting a mixture of the (R) and (S) stereoisomers of 2-(2 hydroxybutyl)-3-chlorothiophene with a esterifying agent under substantially anhydrous conditions in the presence of an immobilised hydrolase enzyme, whereby the (R) alcohol is selectively esterified and the (S) alcohol is left unchanged, (b) in one or more steps, stereospecifically converting the (S) alcohol, optionally in the presence of the esterified (R) alcohol, into (R) 2-(2-aminobutyl)-3-chlorothiophene, and (c) separating the (R) 2-(2-aminobutyl)-3-chlorothiophene from the reaction mixture.

The term substantially anhydrous means that the liquid phase of the reaction mixture contains no more than 2 grams of water per litre.

Step (a) of the process may be carried out in the presence or the absence of a reaction medium. Suitable reaction media include ethers, and a specific example of a reaction medium is methyl tertiary butyl ether (TBME). When a reaction medium is used, the reaction is preferably carried out at a relatively high concentration, e.g. from 100 to 400 grams of the (R) and (S) mixture per litre of reaction medium.

The reaction is preferably carried out under a inert atmosphere, for example an atmosphere of nitrogen.

The hydrolase enzyme is preferably a lipase, and the preferred lipase is Lipozyme 1M, an immobilised enzyme commercially available from "Novo Industri". This enzyme is highly enantioselective and can be re-used. Other enzymes which may be used, but appear to work less well include Mucor miehi lipase (Biocatalysts), Pseudomonas alkaliaines lipase (Biocatalysts), and Novozyme 435 (Novo Industri) (Novozyme is a Trade Mark).

The esterifying agent may conveniently be a vinyl alkanoate, for example a vinyl ester of an alkanoic acid containing from 2 to 6 carbon atoms (e.g. vinyl propionate or vinyl butyrate). Other vinyl esters may also be used, for example vinyl esters of optionally substituted arylacetic acids (e.g. phenylacetic acid), or aryl carboxylic acids (e.g. benzoic acid). Under the influence of the enzyme used in the process of the invention, the acyl group (e.g. the propionate or butyrate residue) is transferred to the hydroxy group of the (R) alcohol to give the corresponding ester (e.g. the propionate or butyrate ester), while the vinyl alcohol is released as acetaldehyde.

Step (a) of the process is preferably carried out at a temperature from 10 to 750C and more preferably from 25 to 30"C.

In Step (b) of the process, the conversion of the (S) hydroxy-butylthiophene to the (R) aminobutylthiophene may be carried out, if desired, in the presence of the esterified (R) hydroxybutyl thiophene. If this procedure is adopted, the esterified (R) hydroxy compound is carried through to the end of the process as an impurity, and the desired (R) aminobutyl compound separated from it and from other unwanted constituents of the reaction mixture as the last step of the process. Alternatively the (S) hydroxybutyl compound may be separated from the esterified (R) hydroxybutyl compound before its conversion to the (R) aminobutylthiophene. The separation may be carried out for example by column chromatography (e.g. on silica gel using methanol/dichloromethane mixture as the eluent).Chemical procedures are known for the stereo specific conversion of a hydroxy group into an amino group; for example, the procedure described by Mitsunobu, in which the hydroxy compound is treated with triphenyl phosphine, phthalimide, and DEAD (DEAD has the formula EtO2CH=NCO2Et), to form a compound in which the hydroxy group is replaced by a phthalimido group, and this phthalimido compound is then treated with hydrazine to form the required amino derivative. (see review by Mitsunobu in Synthesis, 1981, volume 1, page 1 et seq, and in particular the description of the conversion of (S)-2-octanol to (R)-2-octylamine on page 6).

This conversion procedure takes place under mild reaction conditions; the reaction of the hydroxy compound with triphenylphosphine, DEAD and phthalimide proceeds at ambient temperatures (e.g. 20 to 250C), and is preferably performed in an ether (e.g. tetrahydrofuran) as solvent. The subsequent reaction of the phthalimido derivative with hydrazine may be carried out at a moderately elevated temperature (e.g. in boiling ethanol).

In Step (c) of the process, the required 2-(2-aminobutyl)-3chlorothiophene may be separated from the reaction mixture by acidifying the reaction mixture with a aqueous acid (e.g dilute hydrochloric acid) and extracting the mixture with an organic solvent immiscible with water. The 2-(2-aminobutyl)-3-chlorothiophene is retained in the aqueous acid solution while the esterified (R) alcohol is removed in the organic solvent. The 2-(2-aminobutyl)-3-chlorothiophene is then recovered by making the aqueous solution alkaline and extracting the aminobutyl thiophene with an organic water-immiscible solvent. The organic extract is then dried and evaporated to obtain the aminobutyl thiophene, which may be further purified by standard procedures.

The mixture of esterified (R) alcohol and unchanged (S) alcohol prepared by Step (a) of the process of the invention may be generally useful in the preparation of enantiomeric forms of thienyl compounds corresponding to the starting material but in which the hydroxy group of the (S) alcohol is replaced by a different functional group. Step (a) of the process of the invention therefore forms a further feature of the invention.

The C26-alkanoic, optionally substituted arylacetic and optionally substituted aryl carboxylic esters of (R) 2-(2-hydroxybutyl)3-chlorothiophene are novel and are a further feature of the present invention.

Example 1 Racemic 2- (2-hydroxybutyl) -3-chlorothiophene (24.3g), dissolved in methyl tertiary butyl ether (100ml) was stirred at 250C with vinyl butyrate (15.7g) and granular Lipozyme 1M (12.2g). The progress of the reaction was monitored by gas-liquid chromatography (GLC) and chiral high-performance liquid chromatography (HPLC). After 7 hours, less than 2 percent of the (R) alcohol remained. The reaction was stopped by filtering off the enzyme, and the enzyme washed twice with 25ml portions of TBME. The filtrate and washings were combined and evaporated under reduced pressure to a volume of l00ml, giving a solution containing a mixture of (S) 2-(2-hydroxybutyl)-3chlorothiophene and (R) 2-(2-butyroxybutyl)-3-chlorothiophene.

Example2 This Example illustrates the conversion of (S) 2-(2hydroxybutyl)-3-chlorothiophene to (R) 2-(2-aminobutyl)-3chlorothiophene.

To a mixture of DEAD (9.98g; 0.057 moles) and (S) 2-(2hydroxybutyl)-3-chlorothiophene (10.93g; 0.057 moles) in tetrahydrofuran (25ml) was added phthalimide (8.44g; 0.057 moles) and triphenylphosphine (15g; 0.057 moles) in tetrahydrofuran. The mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure, and ether was added to precipitate triphenylphosphine oxide and diethylhydrazine dicarboxylate, which were then filtered off.

Evaporation of the ether filtrate and column chromatography of the residue gave the (R) phthalimido derivative. The phthalimide derivative is treated with hydrazine hydrate (one molar proportion in solution in refluxing ethanol) to give the required (R) 2-(2aminobutyl)-3- chlorobutylthiophene.

Claims (3)

1. A process which comprises: (a) reacting a mixture of the (R) and (S) stereoisomers of 2-(2hydroxybutyl)-3-chlorothiophene with an esterifying agent under substantially anhydrous conditions in the presence of an immobilised hydrolase enzyme, whereby the (R) alcohol is selectively esterified and the (S) alcohol is left unchanged, (b) in one or more steps, stereospecifically converting the (S) alcohol, optionally in the presence of the esterified (R) alcohol, into (R) 2-(2-aminobutyl)-3-chlorothiophene, and (c) separating the (R) 2-(2-aminobutyl)-3-chlorothiophene from the reaction mixture.

2. A process which comprises reacting a mixture of the (R) and (S) stereoisomers of 2-(2-hydroxybutyl)-3-chlorothiophene with an esterifying agent under substantially anhydrous conditions in the presence of an immobilised hydrolase enzyme, whereby the (R) alcohol is selectively esterified and the (S) alcohol is left unchanged.

3. C26-alkanoic, optionally substituted arylacetic, and optionally substituted aryl carboxylic esters of (R) 2-(2-hydroxybutyl)3-chlorothiophene.