PROCESS FOR PREPARING (2R,3S)-3-(4-LOWER ALKOXYPHENYL)GLYCIDIC ACID ESTERS

Abstract: A novel process for preparing a (2R,3S)-3-(4-lower alkoxyphenyl)glycidic acid ester and a process for preparing a (2S,3S)-1,5-benzothiazepine compound, which is useful as a medicine, using the same are provided; and the (2R,3S)-3-(4-lower alkoxyphenyl)glycidic acid ester can be prepared by permitting a racemic trans-3-(4-lower alkoxyphenyl)glycidic acid ester to act on an amine compound in the presence of an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S,3R)-3-(4-lower alkoxyphenyl)glycidic acid ester thereby stereoselectively amidating the (2S,3R) isomer, and then, separating and collecting a remaining (2R,3S)-3-(4-lower alkoxyphenyl)glycidic acid ester from a reaction mixture; and also the (2S,3S)-1,5-benzothiazepine compound can be prepared by permitting the resulting (2R,3S)-3-(4-lower alkoxyphenyl)glycidic acid ester to act on a 2-aminophenol compound, hydrolyzing a resulting compound, if necessary, then subjecting to intramolecular cyclization and O-alkanoylation, and, if desired, N-alkylation.

Description: DESCRIPTION PROCESS FOR PREPARING (2R, 3S) -3- ( 4-LO ER ALKOXYPHENYL) - GLYCIDIC ACID ESTERS Field of the invention This invention relates to a process for preparing (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid esters by asymmetric amidation of racemic trans-3- (4-lower alkoxyphenyl) glycidic acid esters and a process for preparing (2S, 3S) -1, 5-benzothiazepine derivatives using the same . Background art It has been known that (2S, 3S) -1, 5-benzothiazepine derivatives such as diltiazem hydrochloride (chemical name: (2S, 3S) -2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2 , 3-dihydro-l, 5-benzothiazepin- 4(5H)-one hydrochloride), etc. which are widely used as a calcium channel blocker for treatment of angina or essential hypertension can be advantageously prepared by using (2R, 3S) -3-phenylglycidic acid ester compounds (see Japanese Provisional Patent Publications No. 13776/1985 and No. 145174/1986 and U.S. Patent No. 4,885,375). It has also been known that (2S, 3R) -3- (4-methoxy- phenyl) glycidic acid methyl ester is subjected to asymmetrical amidation by acting lipase SP523 (trade name, available from Novo Nordisk, Denmark) on racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester (PCT publication No. WO 95/07359), but in this method, activity and selectivity of the enzyme were not sufficient. The present inventors have earnestly studied to amidate racemic trans-3- (4-lower alkoxyphenyl) glycidic acid esters with a rapid reaction rate and good stereo- selectivity. According to the present inventors' studies, it has been found that racemic trans-3- (4-lower alkoxyphenyl) - glycidic acid esters are subjected to asymmetric amidation by reacting with ammonia or a lower alkyl amine in the presence of an enzyme produced by a microorganism belonging to the genus Serra tia , and the remaining esters are separated and collected from the reaction mixture, (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid esters can be produced within a short period of time with good efficiency to accomplish the present invention. Summary of the invention The present invention is to provide a process for preparing a (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound represented by the formula (III) : wherein R 1 represents a lower alkyl group and R represents an ester residue, which comprises (a) permitting a racemic trans-3- (4^1ower alkoxyphenyl) glycidic acid ester compound represented by the formula (I) : wherein R 1 and R have the same meanings as defined above, to act on an amine compound represented by the formula (II) : R 2 NH 2 (II) wherein R 2 represents hydrogen atom or a lower alkyl group, in the presence of an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S, 3R) -3- (4-lower alkoxyphenyl) - glycidic acid ester compound thereby stereoselectively amidating the (2S,3R) isomer, and then (b) separating and collecting a remaining (2R,3S)-3- (4-lower alkoxyphenyl) glycidic acid ester compound from a reaction mixture. Description of the preferred embodiments In the following, embodiments of the present invention are described. In the process of the present invention, the lower alkyl group of R 1 in the formula (I) preferably includes an alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, n-butyl group, etc., more preferably methyl group. The ester residue repre- sented by R may include an alkyl group, which may have a substituent (s) . The substituent for the alkyl group may include an alkoxy group having 1 to 4 carbon atoms, a halogen atom, etc. The alkyl group of R may include an alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, hexyl group, etc. R is preferably a lower alkyl group such as methyl group, ethyl group, etc., particularly preferably methyl group. The lower alkyl group of R 2 in the formula (II) preferably includes an alkyl group having 1 to 4 carbon atoms such as methyl group, ethyl group, propyl group, n- butyl group, etc., more preferably methyl group. The amine compound of the formula (II) is preferably those in which R 2 is hydrogen atom. In the present invention, as the racemic trans-3-(4- lower alkoxyphenyl) glycidic acid ester compound (I) which is the starting material, not only one ' containing equal amounts of (2R,3S) isomer and (2S,3R) isomer, but any one containing both of these optically active isomers with an optional ratio can be employed. As the enzyme which can be used in the process of the present invention, there may be mentioned those derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S,3R)-3- (4-lower alkoxyphenyl) glycidic acid ester compound, such as lipase, esterase, etc., produced by Serra tia marces- cens, etc. These microorganisms belonging to the genus Serratia may be either wild strains or mutant strains, and further may be those derived from these microorganisms according to the bioengineering methods such as gene recombination and cell fusion. These enzymes can be used generally by separating and purifying from culture broth of microorganisms producing the enzyme. In place of using these separated enzymes, a culture broth of these microorganisms, a cell, an extract of a cell, a cell treated by ultrasonic wave, etc. may be used. The enzyme derived from a microorganism belonging to the genus Serra tia to be used in the present invention can be used after immobilizing it by the conventionally known method such as a polyacrylamide method, a. sulfur-containing polysaccharide gel method (e.g., a carrageenan gel method) , an alginic acid gel method, an agar gel method, a photocross-linkable resin method, a polyethylene glycol method, a Celite (trade name, available from Celite Corporation in U.S.A.) immobilizing method or the like. The asymmetric amidation according to the present invention is shown by the following reaction scheme. wherein R, R 1 and R 2 have the same meanings as defined above . That is, by permitting a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester compound (I) to act on an amine compound (II) in a suitable solvent in the presence of an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S, 3R) -3- (4-lower alkoxyphenyl) glycidic acid ester compound thereby stereoselectively amidating the (2S,3R) isomer, and then, separating and collecting a remaining (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound from the reaction mixture whereby the desired (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound can be obtained. The concentration of the racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester compound (I) in the reaction mixture, which is one of the substrates in the process of the present invention, is generally about 0.1 to 80 % (w/w) , particularly preferably 1 to 20 % (w/w) . Also, the amine compound (II) , which is the other substrate, is preferably used in an amount of 0.5 to 3.0 mole, particularly 0.6 to 2.0 mole per mole of the racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester compound (I) . Moreover, the concentration of the amine compound (II) in the reaction mixture is generally about 0.1 to 5 % (w/w), particularly preferably 0.2 to 2 % (w/w). When the amount of the amine compound (II) in the reaction mixture is reduced, it may be added successively or consecutively. The reaction suitably proceeds at room temperature or under heating, preferably 10 to 50°C, particularly preferably 20 to 40 °C. As the solvent, there may be mentioned aromatic hydrocarbon solvents which may be halogenaced such as benzene, toluene, xylene, chlorobenzene, etc.; aliphatic hydrocarbon solvents which may be halogenated such as hexane, cyclohexane, heptane, isooctane, dichloroe hane, trichloroethane, carbon tetrachloride, etc.; ester solvents such as ethyl acetate, butyl acetate, etc.; ketone. solvents such as methyl isobutyl ketone, etc.; ether solvent such as t-butyl methyl ether, isopropyl ether, 1,4-dioxane, tetrahydrofuran, etc.; nitrile solvents such as acetonitrile, etc.; and alcoholic solvents such as isopropanol, t-butanol, etc. Among these solvents, aromatic hydrocarbon solvents, ether solvents and ester solvents are preferably used, particularly preferably toluene, t-butyl methyl ether, ethyl acetate, butyl acetate. In the process of the present invention, the reaction is preferably carried out in an organic solvent containing substantially no water co prevent from hydrolysis of the racemic trans-3- (4-lower alkoxyphenyl) - glycidic acid ester compound (I) . Separation and collection of the thus obtained (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound (III) from the reaction mixture car. be easily carried out according to the conventional manner. For example, after completion of the enzymatic reaction, an enzyme was filtered off, and the filtrate was concentrated under reduced pressure. Then, the residue was dissolved in an aromatic hydrocarbon solvent (e.g., oluene) and the precipitate was filtered off whereby (2S, 3R) -3- (4-lower alkoxyphenyl) glycidic acid amide compound was removed. Thereafter, the solvent was removed from the filtrate and an alcoholic solvent (e.g., methanol) was added to the residue whereby crystallizing the resulting material and filtering the crystal to obtain the (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound (III). The thus obtained (2R, 3S) -3- (4-lower alkoxyphenyl) - glycidic acid ester compound (III) is reacted with a 2- aminothiophenol compound represented by the formula (IV) : wherein the ring A represents a benzene ring which may be substituted; and R 3 represents hydrogen atom or a di-lower alkylamino-lower alkyl group, and, if necessary, after hydrolyzing an ester portion of the product, the resulting compound is subjected to intramolecular cyclization to obtain a (2S,3S)-1,5- benzothiazepine compound represented by the formula (V) : where same meanings as defined above. The reaction of the (2R, 3S) -3- (4-lower alkoxyphenyl) - glycidic acid ester compound (III) and the 2-aminothio- phenol compound (IV) can be carried out in a suitable organic solvent in the presence or absence of an iron catalyst. As the solvent, there may be mentioned aromatic hydrocarbon solvents which may be halogenaued (e.g., benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, trichlorobenzene) ; and alcoholic solvents (e.g., methanol, ethanol, propanol) , particularly preferably methanol, xylene, chlorobenzene and dichlorobenzene. As the iron catalyst, there may be mentioned an inorganic or organic salt or complex having a divalent or trivalent iron ion. Specific examples of such an iron catalyst may include ferric nitrate, iron (III) hydroxide oxide [FeO(OH)], ferric chloride, ferrous chloride, iron sulfate, ferrous iodide, iron sulfide, iron 4-cyclohexyl- butyrate, ferric oxide, ferric bromide, ferrous fluoride, ferric fluoride, etc., particularly ferric chloride, iron sulfate, ferric nitrate, etc., are preferably used. The reaction suitably proceeds at 60 to 200 °C, particularly at 100 to 150 °C. Hydrolysis of the ester portion of the product can be carried out according to the conventionally known hydrolysis method of an ester, for example, the product is subjected to hydrolysis by using a base such as an alkali metal hydroxide (e.g., sodium hydroxide, potassium hydroxide), and an alkaline earth metal hydroxide (e.g., calcium hydroxide), etc. or an acid such as a mineral acid (e.g., hydrochloric acid, nitric acid, sulfuric acid). The subsequent intramolecular cyclization can be carried out in a suitable solvent in the presence or absence of an acid or a base at 0 to 250 °C, particularly at 80 to 200 °C. As the solvent, any solvent may be used so long as the reaction is not prohibited. Such a solvent may include aromatic hydrocarbon solvents which may be halogenated (e.g., benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, trichlorobenzene, naphthalene) ; aliphatic hydrocarbon solvents which may be halogenated (e.g., methylene chloride, carbon tetra- chloride, dichloroethane, cyclohexane) ; aprotic polar solvents (e.g., N,N-dimethylformamide, dimethylsulfoxide) ; ketone solvents (e.g., acetone, methyl ethyl ketone); ester solvents (e.g., ethyl acetate, butyl acetate); ether solvents (e.g., dioxane, tetrahydrofuran) ; nitrile solvents (e.g., acetonitrile) ; alcoholic solvents (e.g., methanol, ethanol, propanol) or the like. These solvents may be used in combination of two or more kinds with an appropriate ratio in the form of a single phase or a double phase, if necessary. Among these solvents, alcoholic solvents, aromatic hydrocarbon solvents, which may be halogenated, and ether solvents are preferred, and chlorobenzene, dichlorobenzene, toluene, xylene and mesitylene are particularly preferred. The intramolecular cyclization is preferably carried out in the absence of water to avoid hydrolysis. As the acid, either of a Brønsted acid or a Lewis acid can be used. As the Brønsted acid, either of an organic or inorganic acid can be used, and there may be mentioned mineral acids (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, phosphonic acid, hydrofluoric acid, hydrobromic acid, perchloric acid) ; lower alkanoic acids (e.g., formic acid, acetic acid, propionic acid, butyric acid) ; hydroxy group-substituted lower alkanoic acids (e.g., citric acid); halogeno lower alkanoic acids (e.g., trifluoroacetic acid); lower alkanesulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid) ; arylsulfonic acids (e.g., p-toluenesulfonic acid, benzenesulfonic acid); oxalic acid or the like. As the Lewis acid, there may be used, for example, titanium tetrachloride, aluminum chloride, boron trifluoride, tin chloride or the like. Among these acids, mineral acids, lower alkanoic acids or arylsulfonic acids are preferred, and methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid and hydrobromic acid are particularly preferred. As the base, either of an inorganic or organic base can be used. As such a base, there may be mentioned alkali metal hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate) ; alkali metal carbonates (e.g., sodium carbonate, potassium carbonate); alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide); alkali metal amides (e.g. /sodium amide, lithium amide, potassium amide) ; alkali metal alkoxides (e.g., sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide); alkali metals (e.g., metal lithium, metal sodium, metal potassium) ; alkaline earth metals (e.g., calcium): organic bases (e.g., 1,8-diaza- bicyclo [5.4.0]undec-7-ene, diisopropylamine, triethyl- amine, pyridine) or the like. The reaction between the (2R, 3S) -3- (4-lower alkoxy- phenyl) glycidic acid ester compound (III) and the 2-amino- thiophenol compound (IV) and the intramolecular cyclization can be carried out in one pot reaction. That is, after the reaction of the (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester compound (III) and the 2-amino- thiophenol compound (IV) , an acid or a base is directly added to the reaction mixture to carry out the intramolecular cyclization. In the above-mentioned process, the case where R is a lower alkyl group (e.g., methyl group, ethyl group) and the ring A is an unsubstituted benzene ring or a halogen- substituted benzene ring is preferred, and the case where R and R 1 are methyl groups, R 3 is hydrogen atom and the ring A is an unsubstituted benzene ring is particularly preferred. The thus derived (2S, 3S) -1, 5-benzothiazepine compound is subjected to O-alkanoylation and, when R 3 is hydrogen atom, to N-alkylation to introduce a di-lower alkylamino- lower alkyl group, by a conventional method, and, if desired, by converting the product to a pharmaceutically acceptable salt, to obtain a (2S, 3S) -1, 5-benzothiazepine compound represented by the formula (VI) : wherein R 4 represents a di-lower alkylamino-lower alkyl group; R s represents a lower alkanoyl group; R 1 and the ring A have the same meanings as defined above, or a pharmaceutically acceptable salt thereof. The O-alkanoylation mentioned above can be easily carried out in accordance with the methods described in, for example, Japanese Patent Publications No. 16749/1971, No. 13994/1988 and No. 28594/1990, and Japanese Provi- sional Patent Publication No. 99471/1983 or the like. Also, the introduction of the di-lower alkylamino- lower alkyl group by N-alkylation when R 3 is hydrogen atom can be easily carried out in accordance with the methods described in, for example, Japanese Patent Publications No. 16749/1971, No. 13994/1988 and No. 28594/1990; Japanese Provisional Patent Publications No. 99471/1983, No. 118377/1986, No. 78673/1990, No. 228117/1994 and No. 269026/1996. In the above-mentioned converting method, the case where R 1 is methyl group, R 3 is hydrogen atom, R 4 is dimethylaminoethyl group, R 5 is acetyl group and the ring A is an unsubstituted benzene ring is preferred. Incidentally, in the present specification, a lower alkyl group may include a straight or branched alkyl group having 1 to 4 carbon atoms, and a lower alkanoyl group may include a straight or branched alkanoyl group having 2 to 5 carbon atoms . Utilizability in industry In the process of the present invention, a (2S,3R) isomer of a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester can be amidated with a markedly rapid rate and excellent stereoselectivity as compared with the process described in PCT Publication No. WO 95/07359 by using an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S, 3R) -3- (4-lower alkoxyphenyl) glycidic acid ester, and a (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester can be separated and collected with good efficiency. The thus obtained (2R, 3S) -3- (4-lower alkoxyphenyl) - glycidic acid ester is useful for preparation of a (2S, 3S) -1, 5-benzothiazepine compound such as diltiazem hydrochloride. Thus, when the process of the present invention is employed, a (2S, 3S) -1, 5-benzothiazepine compound can be prepared from a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester with good efficiency. Examples Example 1 In 200 ml of an eggplant type flask were charged toluene (86 ml), racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester (hereinafter abbreviated to as "racemic ester", 5 g) , a t-butanol solution of ammonia (2.65 mole/1, 14 ml) and 1 g of lipase (hereinafter abbreviated to as "lipase SM" ) derived from Serratia arcescens Sr 41 (International Deposition No. FERM BP-487 deposited on February 20, 1984 at Fermentation Research Institute Agency of Industrial Science and Technology, Japan which is now National Institute of Bioscience and Human- Technology (NIBH) at 1-3, Higashi 1-chome, Tsukuba-shi, IBARAKI-KEN 305 Japan) . After the flask was airtight, the mixture was reacted at 30 °C at 300 rp for 4.5 hours. Incidentally, the lipase SM used in the above reaction was prepared by culturing according to the method described in Reference example of Japanese Provisional Patent Publication No. 78790/1994, sterilizing with an MF film (EMP-313, trade name, available from Asahi Kasei) and then, subjecting to lyophilization. Also, an olive oil decomposition activity described in Reference example of said Japanese Patent was 4.95 x 10 5 unit/g (hereinafter the same). The t-butanol solution of ammonia (2.65 mole/1) was prepared by bubbling an ammonia gas into t-butanol under ice-cooling for 4 hours, and an ammonia concentration was measured by using a potentiometric automatic titration device (available from Kyoto Denshi Kogyo) . The reaction mixture was analyzed by an apparatus and conditions for the following high performance liquid chromatography (HPLC) and quantitated by comparing the results with that of the pure product. As the results, it was found that 50.4 % (the molar number of the substrate was made 100 %, hereinafter the same) of the racemic ester substrate was decomposed, and 49.4 % of (2R, 3S) -3- (4- methoxyphenyl) glycidic acid methyl ester (hereinafter referred to as "(\2R,3S) ester") and 49.6 % of (2S,3R)-3- (4-methoxyphenyl) glycidic acid amide (hereinafter referred to as "(2S,3R) amide") were contained in the reaction mixture . Column: CHIRALCEL OB-H available from Daicel Chemical Industries, Ltd. Mobile phase: n-Hexane : Isopropanol ' = 9 : 1 Flow Rate: 1.0 ml/min Temperature: 40°C Detection: 235 nm The enzyme was filtered from the thus obtained reaction mixture, the filtered materials were washed with acetone, the filtrate and the washing were combined and the solvent was removed under reduced pressure. Toluene (26 ml) was added to the residue to dissolve it, the solution was filtered by a glass filter and the filtered materials were washed with toluene. The filtrate and the washing were combined and toluene was removed from the mixture, and the obtained amber-like product was crystal- lized by adding methanol (10 ml) thereto. The crystals were filtered by a glass filter and washed twice with methanol (5 ml) to obtain the (2R,3S) ester (2.07 g, yield: 41 %) as crystals. The filtrate and the washing were combined and ice-cooled, and precipitated crystals were collected by filtration, (2R,3S) ester (0.15 g, yield: 3 %) was obtained as crystals. Isolated total yield: 44 % . When the both crystals were analyzed in the same manner as mentioned above, it was found that its optical purity was 99.9 % or higher. Example 2 In test tubes (6 test tubes) each having a diameter of 1.5 cm and a length of 12.3 cm were each charged toluene (1.72 ml), racemic ester (100 mg) , a t-butanol solution of ammonia (2.65 mole/L, 0.28 ml) and lipase SM (20 mg) , each of the test tubes was airtight with a screw cap, and the mixture was reacted at 30 °C at 300 rpm. One of test tubes was taken out at 0 min, 15 min, 30 min, 1 hour, 2 hours or 5 hours from initiation of the reaction, and N,N-dimethylformamide was added to the test tube to stop the enzymatic reaction. When the resulting materials were quantitated by HPLC in the same manner as mentioned above by sampling from each of the reaction mixtures, it was found that 49.3 % of the racemic ester of the substrate was decomposed after 2 hours from initiation of the reaction, and 49.9 % of the (2R,3S) ester, 0.8 % of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester (hereinafter referred to as "(2S,3R) ester") and 46.7 % of the (2S,3R) amide were contained in the reaction mixture. When an E value representing a stereoselectivity of an enzyme was calculated by the following formula based on the above results, the E value calculated from the compositional ratio after 2 hours from initiation of the reaction was 3457. ln[(1-C)(1-θθ)] E = in[(1-C)(1+ee)] wherein 1-C is an amount of trans-3- (4-methoxy- phenyl) glycidic acid methyl ester (containing either of the optical isomers, hereinafter referred to as an amount of the remaining ester(s)) (calculated based on an amount of the used racemic ester as 1) ; and ee is an optical purity (calculated based on a material with an optical purity of 100 % as 1) of the (2R,3S) ester in the remaining ester. Change in amounts of the respective compounds in the reaction mixture with a lapse of time is shown in Table 1. Table 1 Example 3 In a test tube having a diameter of 1.5 cm and a length of 12.3 cm were charged toluene (1.72 ml), racemic ester (100 mg) , a t-butanol solution of ammonia (2.65 mole/L, 0.28 ml), 1, 3-dimethoxybenzene (internal standard, 5 uL) and lipase SM (50 mg) , the test tubes was airtight with a screw cap, and the mixture was reacted at 40 °C at 300 rpm for 15 minutes. N,N-dimethylformamide was added to the test tube to stop the enzymatic reaction and the resulting material was quantitated by HPLC in the same manner as mentioned above by sampling part of the reaction mixture. As . the results, it was found that 49.4 % of the racemic ester used as the substrate was decomposed, and 48.2 % of the (2R,3S) ester was contained in the reaction mixture whereas only 2.3 % of the (2S,3R) ester was contained therein. Example 4 In a test tube having a diameter of 1.5 cm and a length of 12.3 cm were charged an organic solvent (1.72 ml) , racemic ester (100 mg) , a t-butanol solution of ammonia (3.0 mole/L, 0.28 ml), 1, 3-dimethoxybenzene (internal standard, 5 μL) and lipase SM (10 mg) , the test tubes was airtight with a screw cap, and the mixture was reacted at 30 °C at 300 rpm for 4 hours. N,N-dimethyl- formamide was added to the test tube to stop the enzymatic reaction and the resulting material was quantitated by HPLC in the same manner as mentioned above by sampling part of the reaction mixture. Amounts of the (2R,3S) ester and the (2S,3R) ester contained in the reaction mixture are as shown in Table 2. Table 2

Claims: Claims 1. A process for preparing a (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid ester represented by the formula (III) : wherein R 1 represents a lower alkyl group and R represents an ester residue, which .comprises (a) permitting a racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester represented by the formula (I): wherein R 1 and R have the same meanings as defined above, to act on an amine compound represented by the formula (ID : R 2 NH 2 (ID wherein R 2 represents hydrogen atom or a lower alkyl group, in the presence of an enzyme derived from a microorganism belonging to the genus Serratia having the ability to asymmetrically amidate a (2S, 3R) -3- (4-lower alkoxyphenyl) - glycidic acid ester thereby stereoselectively amidating the (2S,3R) isomer, and then (b) separating and collecting a remaining (2R,3S)-3- (4-lower alkoxyphenyl) glycidic acid ester from a reaction mixture . 2 : The process according to Claim 1, wherein R is a lower alkyl group. 3. The process according to Claim 1, wherein R 2 is a hydrogen atom. 4. The process according to Claim 1, wherein R 1 and R are both methyl groups . 5. The process according to Claim 1, wherein the enzyme is lipase or esterase. 6. The process according to Claim 1, wherein the microorganism belonging to the genus Serra tia is Serra tia marcescens . 7. A process for preparing a (2S, 3S) -1, 5-benzothiazepine compound represented by the formula (V) : wherein the ring A represents a benzene ring which may be substituted; R 1 represents a lower alkyl group; and R 3 represents hydrogen atom or a di-lower alkylamino-lower alkyl group, which comprises permitting the (2R, 3S) -3- (4-lower alkoxy- phenyl) glycidic acid ester obtained by the process according to Claim 1 to act on a 2-aminothiophenol compound represented by the formula (IV) : wherein R 3 and the ring A have the same meanings as defined above, and, if necessary, after hydrolyzing an ester portion of the product, the resulting compound is subjected to intramolecular cyclization. 8. A process for preparing a (2S, 3S) -1, 5-benzothiazepine compound represented by the formula (VI) : wherein the ring A represents a benzene ring which may be substituted; R 1 represents a lower alkyl group; R 4 represents a di-lower alkylamino-lower alkyl group; R 5 represents a lower alkanoyl group, or a pharmaceutically acceptable salt thereof, which comprises subjecting the (2S, 3S) -1, 5-benzothiazepine compound represented by the following formula (V) : wherein R 3 represents hydrogen atom or a di-lower alkylamino-lower alkyl group; and the ring A and R 1 have the same meanings as defined' above, obtained by the process according to Claim 7 to O-alkan- oylation, and when R 3 is hydrogen atom, to N-alkylation to incorporate a di-lower alkylamino-lower alkyl group, and if desired, converting the resulting compound to a pharmaceutically acceptable salt. 9. The process according to Claim 8, wherein the ring A is an unsubstituted benzene ring; R 1 is methyl group, R 4 is dimethylaminoethyl group; and R 5 is acetyl group.

Inventors: IDEI AKIKO, MATSUMAE HIROAKI, SHIBATANI TAKEJI, YOSHIOKA RYUZO, IDEI, AKIKO, MATSUMAE, HIROAKI, SHIBATANI, TAKEJI, YOSHIOKA, RYUZO
Applicants: IDEI AKIKO, MATSUMAE HIROAKI, SHIBATANI TAKEJI, TANABE SEIYAKU CO, YOSHIOKA RYUZO, IDEI, AKIKO, MATSUMAE, HIROAKI, SHIBATANI, TAKEJI, TANABE SEIYAKU CO., LTD., YOSHIOKA, RYUZO
Application year: 1998
Main classification: C12P41
IPC codes: C07D281, C07D303, C12P17, C12P41