MXPA98001569A - Procedure to prepare ester of glycic acid trans-3-substituted optically act - Google Patents

Abstract

A process for preparing a trans-3-substituted glycidic acid ester compound of the formula (1) :( See Formula) characterized in that ring A is a substituted or unsubstituted benzene ring, and R 1 is a ester residue, comprising: prepare a solution of an isomeric (A) and the other isomeric (B) of the ester compound (I), which are optical isomers due to the asymmetric carbons in the 2- and 3- positions, and a ester compound (B ') which is different to isomer (B) only in the ester residue R1, crystallize the isomeric (A) from the solution to the extent that the isomeric (A) is crystallized without the precipitation of the isomeric (B) due to the presence of the ester compound (B ') although the isomeric (B) would precipitate if the ester compound (B') is not present, and isolate the crystals of the isomeric (A), by means of which a desired isomer (A) with high purity can be obtained and with re high concentration, so that the desired isomer can be crystallized until the concentration of the desired isomer in the stock solution is very low compared to conventional methods

Description

PROCEDURE FOR PREPARING OPTICALLY ACTIVE TRANS-3- SUBSTITUTION GLYCEDIC ACID ESTER BACKGROUND OF THE INVENTION The present invention relates to a process for preparing optically active trans-3-substituted glycidic acid esters. More particularly, the present invention relates to a process for preparing optical isomers of trans-3-substituted or unsubstituted phenyl glycidic acid esters which are useful as intermediates for the synthesis of pharmaceutical compounds, as well as to the use of optical isomers. Diltiazem hydrochloride, whose chemical name is (2S, 3S) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-2- (4-methoxyphenyl) -l, hydrochloride benzothiazepin-4 (5H) -one, is a pharmaceutical compound that is widely used as a calcium channel blocker for the treatment of angina pectoris, essential hypertension, and the like (Merck Index, XII Ed., page 541 ). To prepare diltiazem, a conventionally known method is where the racemic trans-3- (4-methoxyphenyl glycidic acid ester is used as the starting material, and an optical resolution is carried out at a later stage in the synthesis, as is disclosed in Japanese Patent Publication Kokoku No. 46-16749, No. 53-18038 and No. 61-52142. In the same way, a method using a methyl ester of (2R, 3S) -3- acid is proposed. (4-methoxyphenyl glycid) obtained by optical resolution of the racemic trans-glycidic acid ester to prepare diltiazem in the Japanese Patent Publication Kokai No. 60-13776. Thus, several processes for preparing optically active trans-3- (4-methoxyphenyl glycidic acid esters) have been investigated and, for example, the following procedures are proposed: (a) a process comprising hydrolyzing methyl ester racemic trans-3- (4-methoxyphenyl glycidic acid) to form an alkali metal salt, form its reomeric diastede salt with an optically resolving agent such as (-) - a-methylbenzylamine, resolve the salt and re-esterify the salt obtained optically active (Japanese Patent Publication Kokai No. 61-145174 and No. 2-231480), (b) a process comprising carrying out a Darzens reaction of a chloroacetic acid ester having an asymmetric ester residue such as (-) - Methyl group, (-) - 2-phenylcyclohexyl group or (-) - 8-phenylmethyl group with p-anisaldehyde (Japanese Patent Publication Kokai No. 61-268663, No. 2-17170 and No. 2- 17169), (c) a method comprising hid enzymatically and asymmetrically isomerically isomerized (2S.3R) in racemic trans-3- (4-methoxyphenyl glycidic acid) methyl ester and recover the remaining (2R, 3S) isomer (Japanese Patent Publication Kokai No. 2-109995 and No. 3-15398 and WO 90/04643), (d) a process for the asymmetric synthesis of (2R, 3S) -3- (4-methoxyphenyl glycidic acid) methyl ester, which comprises subjecting the methyl ester of trans-4 acid -metoxycinnamic to oxidation with osmium in the presence of an asymmetric catalyst to give an optically active diol, and subjecting the diol to intramolecular ring closure to give the desired compound (WO 89/02428 and WO 89/10350), and (e) a Process comprising subjecting the (2S.3R) isomer in racemic trans-3- (4-methoxyphenyl glycidic acid) methyl ester to asymmetric enzymatic transesterification with butanol to give (2R, 3S) -3- (4-) methyl ester methoxyphenyl glycidic) (Japanese Patent Publication Kokai No. 4-228095 and No. 6-78790). It is also known that some 1,5-benzothiazepine derivatives other than dialzem have excellent pharmacological activities. For example, Japanese Patent Publication Kokai No. 60-202871 discloses that benzothiazepine derivatives having an inverse absolute configuration of diltiazem in the 2- and 3- positions have platelet aggregation inhibiting activity, and the like. It is also known that the methyl ester of acid (2S, 3R) -3- (4-methylphenyl glycidic acid), which is useful in the synthesis of this derivative, is prepared by enzymatic asymmetric hydrolysis of racemic trans-3- (4-methylphenyl glycidic acid) methyl ester (Japanese Patent Publication Kokai No. 3-175995). Japanese Patent Publication Kokai No. 8-259552 discloses a process for obtaining both isomers of methyl ester of trans-3- (4-methoxyphenyl glycidic acid) with high optical purity from racemate by enzymatically and asymmetrically transesterifying the (2S. 3R) thereof with butanol, recovering the methyl ester of (2R, 3S) -3- (4-methoxyphenyl glycoside non-transesterified, and chemically transesterifying the transesterified product, ie, butyl ester of (2S, 3R) acid). -3- (4-methoxyphenyl glycid) to convert it to the corresponding methyl ester Japanese Patent Publication Kokai No. 4-217969 describes a process for obtaining isomer crystals (2R.3S) of methyl ester of trans-3- (4-methoxyphenyl glycidic acid) by dissolving an equimolar mixture of the isomer (2R.3S), the isomer (2S.3R) and the isomer (2R.3S) in a solvent of methyl t-butyl ether under heating, adding a crystalline seed of isomer (2R, 3S), and crystallizing the isomer (2R, 3S), thus giving the crystalline (2R, 3S) isomer in a slightly larger amount than that of the isomer (2R, 3S) initially dissolved together with the equimolar mixture. Similarly, Japanese Patent Publication Kokai No. 5-301864 discloses a process for obtaining (2R.3S) isomer crystals of 4-chloro-3-methylphenyl ester of trans-3- (4-methoxyphenyl glycidic acid) by dissolving thermally an equimolar mixture of isomer (2R, 3S) and isomer (2S.3R) and isomer (2R, 3S) in tetrahydrofuran, adding a crystalline seed of isomer (2R, 3S), and crystallizing the isomer (2R, 3S) at 30 ° C, thus obtaining the crystalline (2R, 3S) isomer in a slightly higher amount than that of the (2R, 3S) isomer initially dissolved together with the equimolar mixture. In addition, Japanese Patent Publication Kokai No. 8-259552 describes a method for obtaining the isomer (2R, 3S) of the methyl ester of trans-3- (4-methoxyphenyl glycidic acid) from an equimolar mixture of (2R, 3S) isomer and (2S, 3R) isomer transesterifying enzymatically and asymmetrically the isomer (2S.3R) ) thereof with butanol until the molar ratio of ester (2S, 3R) -butyl ester / ester (2S, 3R) -methyl is 7.8 / 1, and crystallizing the isomer (2R, 3S) ap ri r thereof. However, in this procedure, to prevent contamination of the desired methyl ester (2R.3S) due to crystallization of the remaining unesterified methyl ester (2S, 3R) in a small amount, the crystallization was stopped at a stage where the The methyl ester of (2R, 3S) -3- (4-methoxyphenyl glycidic acid) still remains in the stock solution in an amount greater than that of the non-transesteri fi ed isomer (2S.3R). Thus, despite the fact that the (2R, 3S) -3- (4-methoxyphenyl glycidic) methyl ester is transesterified sparingly in this transesterification reaction and the conversion rate by transesterification of the isomer (2S.3R) is high, the yield of (2R, 3S) -3- (4-methoxyphenyl glycidic acid methyl ester obtained in the form of crystals is not satisfactory.) An objective of the present invention is to provide a method for optically resolving phenyl glycidic acid esters trans-3-substituted or unsubstituted in a simple manner with high yield and high optical purity Another object of the present invention is to provide a process for crystallizing a desired optical isomer of the trans-3-substituted phenyl glycidic acid ester or unsubstituted from a solution containing a mixture of optical isomers thereof with high purity and high yield, since the desired optical isomer can be crystallized to the extent that the concentration of the desired optical isomer remaining in the stock solution is extremely low compared to known methods. A further object of the present invention is to provide a process for crystallizing a desired optical isomer of trans-3-substi tuted or unsubstituted phenyl glycidic acid ester with high purity from a reaction mixture of an asymmetric transesteri? Cation of racemate, to the extent that the concentration of the desired optical isomer remaining in the stock solution is extremely low compared to known methods. These and other objects of the present invention will become apparent from the following description.

BRIEF DESCRIPTION OF THE INVENTION The inventors of the present invention have found that yes, in a solution containing a trans-3-substituted or unsubstituted racemic phenyl glycidic acid ester and an ester compound that is different from an isomer of the racemic ester only in the ester residue and having a greater solubility than the isomers of the trans-3-substituted or unsubstituted phenyl glycidic acid ester, the crystallization of an isomer having the same absolute configuration as the ester compound is prevented. Thus, in accordance with the present invention, there is provided a process for preparing an optically active isomer of a trans-3-substituted glycidic acid ester compound of the formula (I): wherein ring A is a substituted or unsubstituted benzene ring, and R1 is an ester residue, comprising: preparing a solution of an optical isomer (A) and the other optical isomer (B) of the ester compound (I) , which are the optical isomers due to the asymmetric carbons in the 2- and 3- positions, and an ester compound (B ') that is different from the (B) isomer only in the ester residue R *, crystallize the optical isomer (A) of the solution to the extent that the optical isomer (A) is crystallized without the precipitation of the optical isomer (B) due to the presence of the ester compound (B '), although the optical isomer (B) would precipitate if the ester compound (B ') is not present, and isolate the crystals of the optical isomer (A). The solution from which the optical isomer (A) is crystallized can also contain a small amount of an ester compound (A ') which is different from the optical isomer (A) only in the ester residue R *, and has the same ester residue as the ester compound (B). The solution from which the optical isomer (A) is crystallized can be a solution obtained by subjecting a solution of the optical isomers (A) and (B) and an alcohol to transesterification in the presence of an enzyme having a transesterification capacity stereoselective to transesterify the isomer (B) with the alcohol, thus producing the ester compound (B ').

Thus, the present invention also provides a procedure for the repair of an optically active isomer of the compound of this t-3-substi tuted glycidic acid of formula (I): wherein ring A is a substituted or unsubstituted benzene ring, and R1 is an ester residue, comprising: subjecting a mixture of an optical isomer (A) and the other optical isomer (B) of the ester compound (I) , which are the optical isomers due to the asymmetric carbons in portions 2- and 3-, to transesterification in the presence of an alcohol and an enzyme having a stereoselective transesterification capacity, thus transesterifying the optical isomer (B) with alcohol to produce an ester compound (B ') which is different from isomer (B) only at the ester residue R1, until the molar ratio of the ester compound (B') / isomer (B) is within the range of 13 / 7 to 7.8 / 1, crystallize the optical isomer (A) of the resulting solution containing the isomer (A), the non-transesterified isomer (B) and the ester compound (B '), and isolate the isomer (A) that has optical purity of at least 99% with a yield of at least minus 75% based on the initial amount of the optical isomer (A). The other optical isomer (B) can also be obtained with high purity and high yield, then isolating the isomer (A), chemically transesterifying the ester compound (B ') in the mother solution to convert it to the isomer (B), and crystallizing the isomer (B) followed by isolation thereof. In accordance with the present invention, an optical isomer of trans-3-substituted glycidic acid ester (I) can be crystallized from and obtained with high purity from a solution of a mixture of optical isomers of the ester (I) and a compound of ester which is different from one of the isomers only in the ester residue, to the extent that the concentration of the desired optical isomer in the stock solution becomes very low compared to that in conventional processes. In addition, from a racemic trans-3-substituted glycidic acid ester, the desired high purity isomer can be obtained in a simple manner with a high yield, carrying out the asymmetric transesterification of the racemic ester and subsequently crystallizing the desired isomer from the resulting reaction mixture.

BRIEF DESCRIPTION OF THE DRAWING Figure 1 illustrates the condition under which an optical isomer (A) is crystallized from a solution (a) containing the optical isomers (A) and (B) and an ester compound (B '), but the isomer optical (B) does not precipitate due to the presence of the ester compound (B '), although the optical isomer (B) would precipitate in the absence of the ester compound (B') by using the parameters of temperature and time. In this regard, it is assumed that the ratio of the optical isomers (A) and (B) and the ester compound (B ') in said solution (a) is sufficient for the inhibition of the crystallization of the optical isomer (B).

DETAILED DESCRIPTION OF THE INVENTION In the present invention, a solution wherein one optical isomer (A) and the other optical isomer (B) of a trans-3-substituted glycidic acid ester of the formula (I): wherein the ring A is a substituted or unsubstituted benzene ring and R1 is an ester residue, which are the optical isomers due to the asymmetric carbons in the 2- and 3- positions of the ester (I), and a compound ester (B ') which is different from the optical isomer (B) only in the ester residue, are dissolved in a solvent (referred to later as "ABB solution'"), used in crystallization. The solution of the isomers (A) and (B) and the ester compound (B ') may further contain a small amount of an ester compound (A') which is different from the (A) isomer only in the ester residue R 1 , and has the same ester residue R1 as the ester compound (B ') (hereinafter referred to as "solution AA'BB'"). The trans-3-substituted glycidic acid esters (I), namely a mixture of the optical isomers (A) and (B) thereof used in the present invention, are the compounds of the formula (I), wherein the ring A is a substituted or unsubstituted benzene ring, and Ri is an ester residue which allows the trans-3-substituted glycidic acid esters (I) to crystallize in a solvent for crystallization. Said trans-3-substituted glycidic acid esters are, for example, compounds of the formula (I), wherein the ring A is a phenyl group which can be substituted by (a) a linear or branched lower alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-hexyl group, 2-hexyl group or 3-hexyl group; (b) a linear or branched lower alkoxy group, for example, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, n-butoxy group, sec-butoxy group, t-butoxy group, n-hexyloxy group, 2-hexyloxy group or 3-hexyloxy group; or (c) a halogen atom, eg, fluorine atom, chlorine atom, bromine atom or iodine atom, and R1 is (a) a linear or branched lower alkyl group, eg, methyl group, ethyl group , propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-hexyl group, 2-hexyl group or 3-hexyl group; (b) a substituted cycloalkyl group, for example, 2-phenylcycloalkyl group; or (c) a substituted or unsubstituted aryl group, for example, 4-chloro-3-methylphenyl group. Preferable examples of the trans-3-substituted glycidic acid ester (I) are, for example, compounds of the formula (I), wherein the ring A is ethylphenyl group or methoxyphenyl group, and R 1 is methyl group, ethyl group, group 2-phenylcyclohexyl or 4-chloro-3-methylphenyl group. In particular, the compounds of the formula (I), wherein ring A is 4-methylphenyl group or 4-methoxyphenyl group and R 1 is methyl group or ethyl group, are the most preferred examples. Any ester residue can be used for the ester residue of the ester compound (B), while giving the ester compound (B ') a good solubility in the solvent used in the crystallization. The ester residues of the ester compound (B ') are, for example, (a) a linear or branched alkyl group which may have a substituent and has more carbon atoms than that of the ester residue R1 of an optical isomer (B), for example, propyl group, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-pentyl group, 2-pentyl group, 3-pentyl group, n-hexyl group, 2-hexyl group, group 3-hexyl, n-heptyl group, 2-heptyl group, 3-heptyl group, 4-heptyl group, n-octyl group, 2-octyl group, 3-octyl group, 4-octyl group, n-nonyl group, group 2-nonyl, 3-nonyl group, 4-nonyl group, 5-nonyl group, n-decyl group, 2-decyl group, 3-decyl group, 4-decyl group, or 5-decyl group; (b) an alkoxyalkyl group which may have a substituent, for example, methoxymethyl group, ethoxymethyl group, propyloxymethyl group, methoxyethyl group, methoxypropyl group, methoxybutyl group, ethoxyethyl group or propyloxypropyl group; and (c) an arylalkyl group which may have a substituent, for example, benzyl group, phenethyl group, phenylpropyl group or naphthylmethyl group. The substituent for the linear or branched alkyl group (a) and the alkoxyalkyl group (b) includes, for example, a halogen atom such as a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. The substituent for the arylalkyl group (c) includes, for example, a linear or branched lower alkyl group, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, sec-butyl group, t group -butyl, n-hexyl group, 2-hexyl group or 3-hexyl group; a linear or branched lower alkoxy group, for example, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, n-butoxy group, sec-butoxy group, t-butoxy group, n-hexyloxy group, 2-hexyloxy group or group 3 -hexyloxy; a halogen atom, for example, fluorine atom, chlorine atom, bromine atom or iodine atom; and similar. Preferable examples of the ester residue of the ester group (B ') are, for example, isopropyl group, n-butyl group, sec-butyl group, t-butyl group, n-pentyl group, n-hexyl group, n-octyl group , n-nonyl group, n-decyl group, benzyl group and phenethyl group, if the ester residue of the trans-3-substituted glycidic acid ester (I) is methyl group or ethyl group. In addition, the absolute configuration of the ester compound (B ') can be any of (2R, 3S) and (2S.3R). If the ester compound (2R, 3S) (B ') is dissolved in the solution, the (2S, 3R) isomer (A) can be crystallized to give crystals of high purity until the concentration of the isomer (2S.3R) ( A) in the mother solution becomes very low compared to conventional procedures. On the other hand, if the ester compound (2S, 3R) (B ') is dissolved in the solution, the (2R, 3S) isomer (A) can be crystallized to give crystals of high purity until the concentration of the isomer (2R) , 3S) (A) in the mother solution becomes very low compared to conventional procedures. Therefore, in any case, the desired product can be obtained with an extremely superior performance, comparatively with conventional methods. Any solvent that can be used in the recrystallization of the trans-3-substituted glycidic acid esters (I) can also be used as the crystallization solvent of the present invention. Examples of said crystallization solvents are, for example, an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol or n-butanol; an ether solvent such as diethyl ether, t-butyl methyl ether, diisopropyl ether, tetrahydrofuran or dioxane; an aromatic hydrocarbon solvent which can be substituted by a halogen atom, such as benzene, toluene, xylene, chlorobenzene or dichlorobenzene; an aliphatic hydrocarbon solvent which can be substituted by a halogen atom, such as hexane, cyclohexane, n-heptane, n-octane, dichloromethane, chloroform, 1,2-dichloroethane or carbon tetraeloride; an ester solvent such as methyl acetate or ethyl acetate; and similar. The solvents can be used alone or in a mixture thereof. A suitable solvent can be selected depending on the ester residues of the trans-3-substituted glycidic acid ester (I) and the ester compound (B ') and the substituent on the phenyl group of the ester (I). It is preferable to use solvents in which the solubility of the optical isomer (A) of the trans-3-substituted glycidic acid ester (I) varies widely depending on the temperature, and the solubility of the ester compound (B ') is larger than that of the optical isomer (TO). For example, when trans-3- (4-methoxyphenyl glycidic acid) methyl ester is used as the ester (I), and the n-butyl ester thereof is used as the ester compound (B '), it is preferred methanol, ethanol, xylene and the like as the solvent to dissolve these compounds. The suitable amount of the solvent can be determined within the scale in which the optical isomers (A) and (B) and the ester compound (B ') can be dissolved once, and the (A) isomer can be crystallized by lowering the temperature of the solution. Thus, a suitable scale of the amount of solvent according to the type of optical isomers (A) and (B) and the ester compound (B '), the proportion thereof, the crystallization temperature, etc. can be found experimentally. In general, when the solvents in which the solubility of the optical isomers (A) and (B) is large and the solubility is largely modified according to the temperature change used, it may be possible to decrease the amount of the solvent. For example, in the case where the following mixture of trans-3- (4-methoxyphenyl glycidic acid esters) is dissolved in 100 ml of xylene, and the resulting solution is cooled to -OT, only methyl ester can be efficiently crystallized ( 2R, 3S) of the solution even in the scale where the concentration of the methyl ester (2R, 3S) in the solution is lower than that of the methyl ester (2S.3R).

Mixture of glycidic acid esters dissolved in 100 ml of xylene methyl ester (2R, 3S) 49 g methyl ester (2S.3R) 14 g n-butyl ester (2S, 3R) 39 g Composition of the glycidic acid esters remaining in the solution after crystallization of the methyl ester (2R.3S) methyl ester (2R, 3S) 9 g methyl ester (2S, 3R) without n-butyl ester exchange (2S, 3R) ) without changes The concentration of the optical isomer (A) in the solution before crystallization can vary, depending on the types of the isomer (A) and the solvent, the temperature of the crystallization and the like, but is usually 0.5 to 4 moles / liter. In a solution in the process of the present invention, the ratio of the optical isomer (A) / the optical isomer (B) is required to be within a scale in which the optical isomer (A) is more easily crystallized than the isomer optical (B), whose crystallization is inhibited by the ester compound (B '). Even under the relation (A) / (B), where the optical isomer (B) would precipitate if the ester compound (B ') were not present, the optical isomer (A) can be obtained as crystals by the process of present invention. In fact, the solution containing the optical isomer (A) in an amount greater than the optical isomer (B) can be used and is preferred in the process of the present invention, since said additional large amount of the optical isomer (A) can also obtain as the crystals in addition to the crystals of the optical isomer (A) obtained by inhibiting the crystallization of the isomer (B) due to the presence of the ester compound (B '). Thus, the process of the present invention can be initiated from a solution containing a greater amount of the isomer (A) than of the isomer (B). In addition, the inhibitory effect of the ester compound (B ') on the crystallization of the optical isomer (B) increases according to the increase in the ratio of the ester compound (B') / the optical isomer (B), so it can obtain the increased amount of the optical isomer (A). Thus, the higher the ratio of the ester compound (B ') / the isomer (B), the more preferable is the process of the present invention. The ratios of these compounds in the initial solution for the crystallization of the present invention varies, depending on the types of the ester residues of the ester compound (B ') and the solvent used in the crystallization. In general, the molar ratio of the optical isomer (A) / optical isomer (B) is from about 4/6 to about 10/1, and the molar ratio of the ester compound (B ') / optical isomer (B) is from about 5/3 to about 10/1. Preferably, the molar ratio of isomer (A) / isomer (B) is from about 1/1 to about 4/1, and the molar ratio of ester compound (B ') / isomer (B) is about 2. / 1 to approximately 7.8 / 1. In the process of the present invention, the crystallization can also be carried out from a solution containing other components than the isomers (A) and (B) and the ester compound (B '). For example, in addition to these three components, the solution may contain an optical isomer (ester compound (A ')) different from the optical isomer (A) only in the ester residue. In case the ester compound (A ') is contained in the solution, the molar ratio of the ester compound (A') / the isomer (A) is preferably at most 9/35 of the molar ratio of the compound of ester (B ') / the isomer (B), so that the inhibiting effect of the ester compound (A') on the crystallization of the isomer (A) can be minimized, whereby the (A) isomer can be obtained in large quantity and with high purity. This means that the ester compound (A ') can be present in the solution for the crystallization of the present invention, while the optical isomer (A) is only crystallized due to the inhibitory effect of the ester compound (B') on the crystallization of the optical isomer (B), although the crystallization of the optical isomer (A) can be inhibited by the presence of the ester compound (A '). When the inhibiting effect of the ester compound (B ') present in the solution on the crystallization of the isomer (B) is greater than that of the ester compound (A') on the crystallization of the isomer (A), the isomer (A) it can crystallize more easily than isomer (B), whereby isomer (A) can be obtained by the process of the present invention. In the process of the present invention, it is required that at least three isomers, namely, the optical isomers (A) and (B) and the ester compound (B '), are present in the solution. In this regard, the process of the present invention is clearly different from a preferential crystallization process from a solution containing only the isomers (A) and (B). In the same way, the process of the present invention takes advantage of the inhibitory effect of the ester compound (B ') on the crystallization of the isomer (B), whereby the isolation of the desired isomer (A) can be achieved by a crystallization process -isolation. In this regard, the process of the present invention is also different from the preferential crystallization process, in which it is necessary to repeat the following steps (i) and (ii): (i) seeding crystals of the optical isomer (A) in a solution containing only the isomers (A) and (B) to crystallize and isolate the optical isomer (A) and (ii) seeding crystals of the optical isomer (B) in the solution resulting from step (i) to crystallize and isolate the optical isomer (B). In addition, the process of the present invention differs from preferential crystallization, wherein the crystallization of an optical isomer should be carried out using a solution containing a greater amount of an optical isomer and a smaller amount of the other optical isomer. In contrast to this, in accordance with the process of the present invention, the crystallization of an optical isomer (A) is possible on a wide scale from the optical isomer (A) > > the optical isomer (B) in the solution with respect to the optical isomer (A) < the optical isomer (B) in it. Concomitantly, the method of the present invention includes the embodiment in which the crystallization is carried out from a solution in which the crystals of the optical isomer (A) are also included. However, crystallization of the optical isomer (A) from a solution that does not include at least one of the optical isomer (B) and the ester compound (B '), is excluded from the present invention because it is not possible inhibition of the crystallization of the optical isomer (B). The crystallization according to the process of the present invention must be carried out at a temperature at which the optical isomer (A) of the trans-3-substituted glycidic acid ester (I) is crystallized, but the optical isomer (B) and the ester compound (B ') are not precipitated. The temperature at which the crystallization of the optical isomer (B) begins only after the solution is allowed to settle for some time is included within the temperature scale of the present invention. Said crystallization temperature varies, depending on the type of trans-3-substituted glycidic acid ester (I), the type of solvent and the composition of the solution to be crystallized. Considering the stability of the oxirane ring of the trans-3-substituted glycidic acid ester (I), it is not convenient to prepare the crystallization solution by dissolving the optical isomers (A) and (B) and the ester compound (B ') a higher temperature. It is preferable that the solution be carried out at a temperature not higher than 70 ° C, and that the crystallization be carried out at a temperature not higher than room temperature. Similarly, in general, when the amount of the solvent is large, the crystallization of isomer (A) does not proceed, unless the solution is cooled to a low temperature, and when the amount of the solvent is small, the crystallization still proceeds at a relatively high temperature. Therefore, when the process of the present invention is carried out on an industrial scale it is preferable, from the viewpoints of the amount of the solvent, installation and energy, that the amount of the solvent be reduced and the crystallization carried out. from a concentrated solution at about room temperature. On the other hand, when the crystallization is carried out from a concentrated solution, the product generally tends to contain an increased amount of impurities. Therefore, from the purity point of view, it is preferable to use a large amount of a solvent and carry out the crystallization at a low temperature. For these reasons, in order to efficiently perform the crystallization of the optical isomer (A), an optimal temperature scale must be determined experimentally depending on the type of trans-3-substituted glycidic acid ester (I), the ester residue of the ester compound (B '), of the type of solvent used and of the composition of the solution to be subjected to crystallization. For example, when the optical isomers (A) and (B) are methyl esters and the ester compound (B ') is an n-butyl ester and the crystallization is carried out from methanol, it is preferable to carry out the crystallization at a temperature of -30 ° to + 15 * C. A similar temperature scale can be applied for other cases.

In the process of the present invention, since the crystallization of the optical isomer (B) is inhibited by the ester compound (B '), the optical isomer (A) free of any contamination of the optical isomer (B) can be obtained without no very strict temperature control, which is necessary for preferential crystallization, taking advantage of the difference in precipitation speed between optical isomers that have the same solubility. Therefore, the allowable temperature scale of the present invention is broader than the preferential crystallization process. In accordance with the process of the present invention, the crystallization of the optical isomer (B) is inhibited by the ester compound (B '). When the precipitation of the optical isomer (B) occurs, the optical isomer (B) is precipitated together with the ester compound (B ') in a form similar to the amorphous one. The crystallization of the optical isomer (A) is visually distinguished from said precipitation. Concomitantly, the crystallization of the optical isomer (A) according to the present invention can be carried out from a solution containing the optical isomer (A) and (B) and the ester compound (B ') to the degree wherein the optical isomer (B) is precipitated if the ester compound (B ') is not present. Since, whether said degree is reached or not depends on the solubility of the optical isomers (A) and (B) and the ester compound (B '), even if the degree is not reached at a temperature, said degree is it can reach another temperature, and vice versa. In the following lines, the condition under which the optical isomer (A) is crystallized from a solution containing the optical isomers (A) and (B) and the ester compound (B '), but the optical isomer ( B) is not precipitated by the presence of the ester compound (B ') although the optical isomer (B) would be precipitated in the absence of the ester compound (B'), it is explained by the use of figure 1 which illustrates the extent to which it must be achieved by the process of the present invention by using the temperature and time parameters. In connection with this, it is assumed that the initial concentration of the optical isomer (A) in the solution is greater than that of the optical isomer (B) and the amount of the ester compound (B ') in the solution is sufficient for the inhibition of the crystallization of the optical isomer (B). Solution (a) is a completely homogeneous solution. If solution (a) is cooled, isomer (A) begins to crystallize at point (b). If the cooling of the solution is further continued, the isomer (A) in excess of the isomer (B) in the solution is crystallized to reach point (c) at which the molar ratio of the isomer (A) / the isomer (B) It's 1/1. From the theoretical point of view, it is possible that only the isomer (A) crystallizes during the cooling of the solution (a), that is, from point (b) to point (c). However, in a process described in Japanese Patent Application Kokai No. 8-259552, isomer (A) is crystallized only to the extent that the molar ratio of isomer (A) / isomer (B) in the stock solution after crystallization it is about 1.3 / 1. This is because, according to the knowledge of the general crystallization technique, if solution (a) is cooled from point (b) to point (c), the ratio of the optical isomer (B) / the optical isomer (A) in the solution increases through the precipitation of the crystals of the optical isomer (A) and the solubility of the optical isomer (B) decreases. Therefore, the fluctuation of the solution (ie, partial non-uniformity of temperature, concentration, etc., of the solution) exerts an influence on the crystallization of the isomer (B). The solution in point (c) contains isomers (A) and (B) in equal amounts. Therefore, when the solution is cooled from point (c), it is considered that the optical isomers (A) and (B) are crystallized in the form of an equimolar mixture thereof. Nevertheless, in the present invention, since the ester compound (B ') is present in the solution, the crystallization of the isomer (B) is inhibited by it. In this way, even when the solution is cooled further from point (c), isomer (A) is crystallized, but isomer (B) is not crystallized, whereby the yield of isomer (A) can be increased. After passing through point (c), if the solution is cooled further to a lower temperature, the solution finally reaches point (d) at which the entire solution becomes turbid and not only isomer (A) is crystallized, but a similar to the amorphous form of the isomer (B) and the ester compound (B ') is also precipitated. Therefore, it is necessary to carry out the process of the present invention at a temperature greater than point (d). After passing through point (c), if the solution is cooled more, for example, to reach point (e) and the solution is maintained for a certain time at that temperature, the solution reaches point (f) after that a certain time t elapses, in which the whole solution becomes cloudy and the same phenomenon appears in point (d). That is, the isomer (B) which has been inhibited from the precipitation by the ester compound (B ') is precipitated together with the ester compound (B') as a form similar to the amorphous one. Therefore, the method of the present invention is required to complete the crystallization and isolation of the optical isomer (A) before time t at which the solution becomes turbid. As indicated above, the degree of crystallization achieved by the process of the present invention is within the region "the degree to be achieved by the process of the invention" shown in Figure 1. This region varies depending on several factors , for example, the type and ratio of the isomers (A) and (B) and the ester compound (B '), and the type and amount of the solvent. Thus, the right region can be determined according to these factors. For example, in the case that the amount of isomer (A) in solution (a) as shown in figure 1 is smaller than that of isomer (B), the starting point of the crystallization of the isomer (A) ) is a little between points (d) and (c) and it is possible to crystallize and isolate isomer (A) in pure form up to point (d). The isolation of the crystalline isomer (A) can be carried out in a usual manner such as decanting and filtration. If crystallization is carried out on a large scale, a long time for isolation is required, although small-scale isolation can be achieved in a short time. In the case of laboratory scale isolation, even immediate isolation is possible. If the insulation requires a long time as in the case of industrial production, it is preferable to interrupt the crystallization, for example, at point (e), so that the insulation can be completed without any contamination within the length of time until the point t. In accordance with the process of the present invention, if the crystallization is carried out, for example, from a solution containing racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester and n-butyl acid ester (2S, 3R) -3- (4-methoxyphenyl) glycidic acid, the amount at which it is sufficient to inhibit the precipitation of the (2S.3R) isomer of the methyl ester, is possible to catalyze the methyl ester of acid (2R, 3S ) -3- (4-methoxyphenyl) glycidic acid until the concentration of (2S, 3R) -3- (4-methoxyphenyl) glycidic acid in the stock solution after crystallization becomes at least twice that of the methyl ester of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid. In addition, it is also possible to obtain the crystals of the (2R, 3S) isomer having an optical purity of at least 99%. Therefore, in accordance with the present invention, after carrying out the crystallization of the optical isomer (A) without any precipitation of the optical isomer (B) until the amount of the isomer (A) in the stock solution is equal to the of the isomer (B), it is possible to continue the crystallization of isomer (A) in high purity until the amount of isomer (A) in the stock solution becomes smaller than that of isomer (B). Japanese Patent Publication Kokai No. 8-259552 discloses that crystals of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester having at least 99% optical purity are obtained by asymmetrically transesterifying methyl ester of trans-3- (4-methoxyphenyl) glycidic acid in the presence of an esterase derived from Serratia marcescens to convert 7.8 / 8.8 (approximately 88.6%) of the isomer (2S.3R) to the n-butyl ester, removing the enzyme, distilling the solvent under reduced pressure and then conducting the crystallization from isopropanol.

However, the crystallization is interrupted at the stage where the amount of the desired (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester in the stock solution after crystallization is about 1.3 times that of the ester (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester. This is because it was considered necessary to interrupt the crystallization to avoid contamination by crystallization of the unwanted (2S.3R) isomer. In contrast, according to the present invention, the crystallization can be carried out until the amount of the desired methyl (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester is the mother solution after crystallization it becomes approximately half of the undesired (2S, 3R) -3- (4-methoxyphenyl) glycidic acid methyl ester. The degree to which the isomer (A) is crystallized, that is, the degree to which the crystallization is continuous, varies depending on the ratio of trans-3-substituted glycidic acid ester (I) / ester compound (B ') , solvent for crystallization, crystallization temperature and the like. However, since the solution subjected to the crystallization becomes turbid at a stage when a shape similar to the amorphous form of the isomer (B) and the ester compound (B ') begins to precipitate, it is possible to recognize the end point of the crystallization of the isomer (A) monitoring the appearance of turbidity in the solution.

The purity of crystals can be affected generally by the concentration of a solution that is going to be subjected to crystallization (or the ratio of the solvent / the amount of the optical isomers), the ratio of the optical isomer (A) / optical isomer (B) , temperature, amount of crystals obtained and the like. Generally speaking, the purity of the crystals of the optical isomer (A) tends to be high if the crystallization is carried out to the extent that the isomers (A) and (B) are difficult to be crystallized and the amount of Precipitated crystals of the optical isomer (A) is small. For example, if the concentration of the isomers (A) and (B) in the crystallization solution is low, the ratio of the isomer (A) / isomers (A) and (B) is high, the crystallization temperature is high and the amount of crystals of the optical isomer (A) is small, the purity of the crystalline isomer (A) is high. In contrast to this, the performance of the optical isomer crystals generally tends to be low if the concentration is low. However, in accordance with the present invention, the precipitation of the optical isomer (B) is inhibited by considering the presence of the ester compound (B ') and therefore it is possible to obtain an optical isomer (A) having purity greater than 99. % in high performance. The crystallization process is very simple in that it merely comprises conducting the crystallization of the optical isomer (A) from a solution of optical isomers (A) and (B) and the ester compound (B ') to the extent that the optical isomer (B) is not precipitated due to the presence of the ester compound (B '), although the optical isomer (B) would precipitate in the absence of the ester compound (B'), so crystallization is continued until the scale wherein the amount of the optical isomer (A) is smaller than that of the optical isomer (B) in the mother liquor of the crystallization. In conventional crystallization, the crystals of the optical isomer (A) are obtained by crystallizing from a solution (AB) containing the optical isomers (A) and (B) to the extent that the amount of the optical isomer (A) in the mother solution is greater than that of the isomer (B). In said crystallization, the solvent, temperature and concentration were carefully selected in a respective manner in order to obtain the optical isomer (A) in high purity without any crystallization of (B), but the performance of the optical isomer (A) had to be sacrificed to a certain degree. However in accordance with the method of the present invention, the optical isomer (A) can be crystallized without precipitation of the optical isomer (B) even to the extent that both optical isomers (A) and (B) would crystallize in conventional crystallization wherein the ester compound (B ') is absent in the crystallization solution. The preparation of the solution (ABB ') and the solution (AA'BB') that is to be subjected to the crystallization is explained below. The ester compound (A ') can act to reduce the performance of the optical isomer (A) and, therefore, it is preferable that a solution to be subjected to crystallization does not contain the ester compound (A '). Since the ester compound (A ') is not a component that will be added positively to the solution although said contamination in some cases may not be avoidable in the preparation of the solution, the solution (ABB') is more preferable than the solution (AA'BB '). The solution (ABB ') can be prepared, for example, by adding the ester compound (B') to a solution (AB) containing the optical isomers (A) and (B) or transesterifying the optical isomer (B) in the solution (AB) to an ester compound (B ') in the presence of an enzyme having a stereoselective transesterification capacity by the use of an alcohol (R3-0H wherein R3 is a linear or branched alkyl group that can be substituted, alkoxyalkyl group which may be substituted or an arylalkyl group which may be substituted). In the case of enzymatic transesterification, the solution (ABB ') is obtained only when the stereoselectivity of the enzyme is 100%, and an enzyme having a stereoselectivity of less than 100% gives the solution (AA'BB'). Therefore, it is preferable to use an enzyme that has good stereoselectivity. The solution (AB) is generally obtained by chemical synthesis since the product thereof is an equimolar mixture of the optical isomers with the exception of asymmetric synthesis. The ester compound (B ') remains at a high concentration in the stock solution from which the optical isomer (A) has been crystallized and isolated according to the present invention and can be removed therefrom if necessary. The ester compound (B ') can also be obtained by enzymatically and selectively hydrolyzing an ester compound (A') in a mixture of ester compounds (A ') and (B'). In the case of preparing the solution (ABB '), the ester compound (B') is generally added to a solution (AB) so that the resulting solution (ABB ') satisfies the condition that the isomer (A) is crystallized, but the isomer (B) is not crystallized by the presence of the ester compound (B '). The solution (AB) to which the ester compound (B ') is added, is not limited to a solution of an equimolar mixture of the optical isomers (A) and (B) and can be a solution containing the isomers ( A) and (B) in different quantities. For example, shower solution (AB) can be prepared by an asymmetric synthesis as described, for example, in Japanese Patent Publication Kokai No. 61-268663, No. 2-17170 and No. 2-17169, WO 89 / 02428 and WO 89/10350.

The solution (AB) containing the isomers (A) and (B) in different amounts can also be a solution prepared by subjecting a racemic solution to the enzymatic and asymmetric hydrolysis described, for example, in Japanese Patent Publication Kokai No. 2 -109995 and No. 3-15398, and Japanese Kohyo Patent Publication No. 4-501360, or by subjecting a racemic solution to optical chemical resolution as described, for example, in Japanese Patent Publication Kokai No. 61-145174 and No. 2-231480. As mentioned above, the process of the present invention can be carried out in combination with known methods, for example, asymmetric synthesis, optical, chemical or enzymatic resolution, etc. In these cases, even when the asymmetric induction or the speed of optical resolution in the known methods is insufficient, the optical isomer (A) having a high purity can be recovered in a good yield by combining said insufficient procedure with the method of the present invention. Also, the process of the present invention can be applied to a solution prepared by subjecting a solution (AB) to an enzymatic transesterification instead of adding the ester compound (B ') to the solution (AB). For example, the method hereof is applicable to a solution (ABB ') obtained in the process described in Japanese Patent Publication Kokai No. 4-228095, No. 6-78790 and No. 8-259552 wherein the ester (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester is obtained by subjecting racemic trans-3- (4-methoxyphenyl) glycidic acid methyl ester to enzymes asymmetric transesterification with n-butanol to convert the (2S, 3R). Various applications and modifications of the method of the present invention are possible. For example, the optical isomers (A) and (B) can be obtained in high purity by means of a recirculation process comprising: (a) preparing a solution of one optical isomer (A) and the other optical isomer (B) of the ester compound (I), which are the optical isomers due to the asymmetric carbons in positions 2 and 3, and an ester compound (B ') which is different from the (B) isomer only in the ester residue R 1 , (b) crystallizing the optical isomer (A) from the solution to the extent that the optical isomer (A) is crystallized without the precipitation of the optical isomer (B) due to the presence of the ester compound (B ') , although the optical isomer (B) is precipitated if the ester compound (B ') is not present. (c) isolating the crystals of the optical isomer (A), (d) chemically transesterifying the ester compound (B ') included in the resulting stock solution together with the remaining optical isomers (A) and (B) to convert the compound of ester (B ') in the optical isomer (B) followed by crystallization and isolation of isomer (B), (e) adding a racemic trans-3-substituted glycidic acid ester (I) and an ester compound (B) ') to the resulting stock solution to provide a solution to be subjected to the crystallization of step (b), and (f) to represent steps (b), (c), (d) and (e) above mentioned in this order. In the recirculation process, the concentration of the isomer (B) in the reaction mixture of the chemical transesterification in step (d) is greater than that of the isomer (A) and, therefore, only the isomer (B) is it can be obtained by conducting a conventional crystallization and isolation. If an ester compound (A ') is added to the reaction mixture of the chemical transesterification before crystallizing the isomer (B) in step (d), the (B) isomer can be more efficiently crystallized by an inhibitory effect of the ester compound (A ') on the crystallization of the isomer (A). In case the ester compound (A ') is added in step (d), said ester compound (A') included in the resulting stock solution is chemically transesterified to isomer (A) in step (e). It is preferable that the amount of the ester compound (A ') added to step (d) corresponds to that of the ester compound (B') included in the solution in step (a). The amount of the ester compound (A ') varies depending on the ester residues of the isomers (A) and (B) and the ester compound (A') and the solvent used for the crystallization, but in general the amount of ester compound (A ') can be adjusted so that the molar ratio of the ester compound (A') / isomer (A) is about 5/3 to about 10/1. The chemical transesterification adopted in the recirculation process is carried out by adding an organic amine and an alcohol corresponding to the ester residue of an optical isomer to be obtained to the stock solution obtained in step (c), and conducting the transesterification followed by distillation of the organic alcohol amine. The chemical transesterification of the ester compound (A ') is carried out in the same manner. The amount of the alcohol to be used in the chemical transesterification may preferably be from 1 to 1,000 moles, especially 2 to 10 moles, per mole of an ester to be transesterified. Alcohols having a low boiling point, for example methanol or ethanol, can preferably be used for chemical transesterification in view of the recirculation of isomers (A) and (B). Examples of the amine used in the chemical transesterification are, for example, a monoalkylamine (for example, methylamine, ethylamine, propylamine, butylamine); a dialkylamine (for example, dimethylamine, diethylamine, dipropylane, diisopropylamine); a trialkylamine (for example, trimethylamine, triethylamine); a cyclic amine (eg, morpholine); and an aromatic amine (e.g., pyridine). The use of a dialkylamine having a low boiling point, for example diethylamine, dipropylamine or diisopropylamine is particularly preferred. The organic amine is preferably used in an amount of 0.01 to 1,000 moles, especially 0.1 to 10 moles, per mole of the ester to be transesterified. When the above recirculation process is conducted, the isomers (A) and (B) can be obtained in high purity in one cycle. Since the process can be carried out practically infinitely if the organic amine and the alcohol can be sufficiently distilled after the chemical transesterification, the isomers (A) and (B) which have a high purity can be obtained in a manner efficient only recirculating the procedure without conducting an asymmetric chemical reaction. In addition, the decrease in optical purity due to antipode contamination as a result of the fluctuation (partial non-uniformity in solution temperature, concentration etc.) of a crystallization solution can be suppressed and the amounts of the optical isomers obtained in a cycle it is big. Therefore, the recirculation process is industrially advantageous. Next, a method is explained in which a solution containing an optical isomer (A) and (B) and ester compound (B ') is prepared by means of a transesterification process and then applied to the process of the present invention .

It is preferable to prepare a solution to be used for the crystallization of optical isomer (A) by enzymatic transesterification of the isomer (B) in a solution of optical isomers (A) and (B) in the ester compound (B '), since it is possible to obtain in a single reaction step a solution containing a larger amount of the isomer (A) and a smaller amount of the isomer (B) together with the ester compound (B ') which inhibits the crystallization of the isomer ( B). In the process of the present invention, it is preferable that the ratio of the isomer (A) / the isomer (B) in the reaction mixture resulting from the transesterification be as great as possible. In other words, it is preferable that the ester compound (B ') be abundant in the reaction mixture. In this case, in order to reduce the amount of the isomer (B) therein, it is necessary, for example, to increase the amounts of the enzyme and the alcohol used for the transesterification and to conduct the reaction for a longer time. However, these procedures increase the cost and produce side reactions. In accordance with the method of the present invention, even when the degree of transesterification is low, the resulting solution can be used successfully for optical resolution unlike conventional methods. This is because the ester compound (B ') inhibits the precipitation of the isomer (B). The isomer (A) can be obtained in high purity in a high yield provided that the molar ratio of the isomer (A) / isomer (B) is 4/6 to 10/1 and the molar ratio of the ester compound (B) ') / isomer (B) is from 5/3 to 10/1. It is particularly preferable that the molar ratio of isomer (A) / isomer (B) is 3/1 to 4/1 and the molar ratio of ester compound (B ') / isomer (B) is 2/1 to 7.8. /1. The alcohols used for the transesterification are those corresponding to the aforementioned ester residue of the ester compound (B '). Any enzymes that have the ability to stereoselectively transesterify trans-3-substituted glycidic acid ester (I) with alcohol can be used in transesterification. Said enzymes capable of selectively transesterifying the (2S, 3R) isomer of the trans-3-substituted glycidic acid ester (I) include, for example, esterases derived from the microorganisms belonging to the genera Serratia, Candida, Mucor, Pseudomonas, Aspergillus, Alcaligenes, Absidia, Fusarium, Giberella, Neurospora, Trichodeerma, Rhizopus, Archromobacter, Bacillus, Brevibacterium, Corynebacteriu, Providencia, Saccharomycopsis, Nocardia and Arthrobacter, a-chemitrippin, porcine heper-esterase, pancreatic esterase of porcine and similar. Representative examples of the aforementioned enzymes are, for example, esterases derived from Absidia corymbifera IFO 4009 and IF0 4010, Aspergillus ochraceus IF0 4346, Aspergillus Terreus IFO 6123, Fusarium oxysporum IFO 5942, Fusarium oxysporum ATCC 659, Fusarium solani IFO 5232, Gibberella fujikuroi. IFO 5368, Mucor anguli acrosporus IAM 6149, Mucor circinelloides IFO 6746, Mucor flavus IAM 6143, Mucor fragilis IFO 6449, Muero genevensis IAM 6091, Mucor globosus IFO 6745, Mucor janssenii IFO 5398, MUcro javanicus IFO 4569, IFO 4570, IFO 4572 IFO 5382, Mucor lamprosporus IFO 6337, Mucor petrinsularis IFO 6751, Muero plumbeus IAM 6117, Muero praini IAM 6120, Muero pusilus IAM 6122, Muero racemosus IFO 4581, Muera ramannianus IAM 6128, Muero recurvus IAM 6129, Muero silvaticus IFO 6753, Muero spinescens IAM 6071, I die subtilissimus IFO 6338, Neurospora crassa IFO 6068, Rhizopus arrhizus IFO 5780, Rhizopus dele ar ATCC 34612, Rhizopus japonicus IFO 4758, Trichoderma viride IF O 4847, Achromobacter eyeloelastes IAM 1013, Bacillus sphaericus IFO 3525, Brevibacterium ketoglutamicum ATCC 15588, Corynebacterium alkanolyticum ATCC 21511, Corynebaterium hydrocarboclastum ATCC 15592, Corynebacterium pri orioxydans ATCC 31015, Providencia alcalifaciens JCM 1673, Pseudomonas utabilis ATCC 31014, Pseudomonas putida ATCC 17426, ATCC 17453 and ATCC 33015, Serratia liquefaciens ATCC 27592, Serratia marcescens ATCC 13880, ATCC 14764, ATCC 19180, ATCC 21074, ATCC 27117 and ATCC 21212, Serratia marcescens Sr41 FERM BP-487, Candida parapsilosis IFO 0585, Saccharomycopsis lipolytica IFO 0717, IFO 0746, IFO 1195, IFO 1209 and IFO 1548, Nocardia asteroides IFO 3384, IFO 3424 and IFO 3423, Nocardia gardneri ATCC 9604, Arthrobacter ureafaciens nov. var., Arthrobacter blobiformis and Candida cylindracea. Commercially available enzymes are also useful, for example, alkaline lipase from Achromobacter, Wako Pure Chemical Industries, Ltd,), Lipase B (from Pseudomonas fragi 22-39B, Wako Pure Chemical Industries, Ltd.), Lipase M AMANO "10 (from Mucor javanicum, Amano Seiyaku Kabushiki Kaisha), Lipase type XI (from Rhizopus arrhizus, Sigma Chemical Co., Ltd.), Talipase (from Rhizopus delemar, Tanabe Seiyaku Co., Ltd.), Lipase NK-116 (from Rhizopus japonicus, Nagase Sangyo Kabushiki Kaisha), Lipasa N (from Rhizopus niveus, Amano Seiyaku Kabushiki Kaisha), Lipasa SP 435 &; 535 (from Candida Antarctica, Novo), Alcalase (from Bacillus licheniformis, Novo), Lipase type VII (from Candida cylindracea, Sigma Chemical Co., Ltd.), Lipase (from porcine pancreas, Wako Puré Chemical Industries, Ltd.) , esteraea (from porcine, Sigma Chemical Co., Ltd), cholesterol esterase (from Candida rugosa, Nagase Sangyo Kabushiki Kaisha), Lipase OF (from Candida cylindracea, Meito Sangyo Kabushiki Kaisha), Lipase OL (from Alcaligenes sp., Meito Sangyo) Kabushiki Kaisha), Lipasa AL (from Achromobacter sp., Meito Sangyo Kabushiki Kaisha), and Lipasa PL (from Alcaligenes sp., Meito Sangyo Kabushiki Kaisha). Among these enzymes, esterases derived from microorganisms belonging to the genera Serratia, Candida, Alcaligenes and Achromobacter are preferred, particularly esterases derived from microorganisms such as Serratia marcescens and Candida cylindracea. On the other hand, enzymes capable of selectively transfecting the (2D, 3S) isomer of the trans-3-substituted glycidic acid ester (I) include, for example, esterases derived from microorganisms belonging to the genera Micrococcus, Agrobacterium, Microbacterium, Rhizobium. , Citrobacter, Debaryomyces, Hanseniaspora, Hansenula, Pichia, Rhodosporidium, Schizosaccharomyces, Sporobolomyces, Kloeckera, Torulaspora and Streptomyces and the like. Representative examples of said microbial enzymes capable of selectively transfecting the (2R, 3S) isomer are, for example, esterases derived from Micrococcus ureae IAM 1010 (FERM BP-2996), Agrobacterium radiobacter IAM 1526 and IFO 13259, Microbacterium sp. ATCC 21376, Rhizobium melioti IFO 13336, Citrobacter freundii ATCC 8090, Debaryomyces hansenii var. fabryi IFO 0015, Devaryomyces nepalensis IFO 0039, Hanseniaspora valbyens IFO 0115, Hansenula polymorpha IFO 1024, Hansenula saturnus HUT 7087, Pichia farinosa IFO 0607, Pichia pastoris IFO 0948, IFO 1013 and IAM 12267, Pichia wickerha ii IFO 1278, Rhodosporidium toruloides IFO 0559 , Schizosaccharomyces pmbe IFO 0358, Sporobolomyces gracillis IFO 1033, Kloeckera corticis IFO 0633, Torulaspora delbrueckii IFO 0422, Streptomyces griseus subsp, griseus IFO 3430 and IFO 3355, and Streptomyces lavendulae subsp. lavendulae IFO 3361, IFO 3415 and IFO 3146. The enzymes used in the present invention can be commercially available enzymes or enzymes obtained from a culture broth of microorganism cells. Also, the enzymes may be those obtained from wild or mutant strains, or those obtained from microorganisms obtained by a biotechnological technique such as gene recombination or cell fusion. Microbial enzymes can be obtained, as mentioned above, by culturing a microorganism in a conventional manner, for example, in a medium containing carbon sources, nitrogen sources and inorganic salts customary at room temperature, or an elevated temperature under aerobic conditions, a pH of 5 to 8, removing the cells from the culture broth in the usual manner, such as by centrifugation or filtration, and optionally removing impurities with a resin adsorbent. The culture broth of a microorganism can be used directly as the enzyme. The solution thus obtained can be used directly as the enzyme, or it can be lyophilized. Also, the enzymes can be immobilized by means of a known method such as a polyacrylamide method, a sulfur-containing polysácaride gel method, (e.g., the carrageenan gel method), an agar gel method, a Photo-interlacing resin method, a polyethylene glycol method, a celite method or a membrane adsorption method. A column can be filled with the immobilized enzymes and used in transesterification.

Meanwhile, enzymes with a high E-value have a high stereoselectivity. With such enzymes, the optical isomer (A) is transesterified into the ester compound (A ') in a smaller amount, while the optical isomer (B) is transesterified into a ester compound (B') in a larger amount. Since the amount of the ester compound (A '), which inhibits the precipitation of the desired isomer (A), must be decreased to increase the amount of crystallized isomer (A) while the precipitation of isomer (B) is inhibited by the ester compound ( B '), enzymes having a high E value are preferred among the enzymes mentioned above. The E-value is one of the popular indications for representing the esteroselectivity of the enzymes, and E is a relationship of the enzymatic reaction rate with respect to repective steroisomeres per unit of concentration (for example, the rate ratio of transesterification of the isomer ( 2R, 3S) to that of the isomer (2S.3R) .In general, in case the reaction has proceeded haeta a greater degree, the E value is strongly influenced by the inactivation of the enzyme, the lateral reaction, the error of In this way, the E value as it is in the present, is a measured value when the conversion speed is 10% (the time in which 10% of the trane-dl form has been traced) in The lateral reaction, the reverse reaction and the measurement error are light, the E value is represented by the following equation, and is a unique value for each of the enzymes. _ln [(lc) (l-ee (optical aomer A))] ln [(lc) (l + ee (optical aomer A))] in which Amount of ester A '+ amount of ester B' Amount of isomer A + amount of isomer B + amount of ester A '+ amount of ether B' ee (optical isomer A) Amount of isomer A - amount of ether A 'Amount of aomer A + amount of ether A' In this way, the E value and the conversion rate of traeneterification can be determined, the ratio of optical origin and thickness of the tracer can be determined, and the type of enzyme can be imported, and it is possible to expect the optical purity and yield obtained therefrom. . Preferably, the value E for the preparation of the solution which is subjected to crystallization according to the present invention is at least 20, especially at least 50. Enzymes having a preferred E value as mentioned above , they can select adequately in an experimental way. The amount of the enzyme varies depending on the type of enzyme used, the manner of use and the like. But it is convenient to use an enzyme in an amount having an olive oil hydrolysis activity of 1 x 10 to 1 x 105U, especially 1 x 10 * to 1 x 10 * U, per g of isomer (B). The olive oil hydrolysis activity is calculated by measuring the amount of fatty acid generated by the breakdown of the ester bond in the olive oil by the esterase, in accordance with the graea digestion potency test reported in Iyakuhin Kenkyu, Vol. 11, No. 3, 505-506 (1980). The transesterification reaction can be carried out in an appropriate solvent or in the absence of a solvent. Examples of solvent are aromatic organic solvents such as benzene, toluene or xylene; halogenated aromatic organic solvents, such as chlorobenzene or dichlorobenzene; aliphatic organic solvents, such as hexane, heptane or cyclohexane; a halogenated aliphatic organic solvent such as dichloromethane, chloroform, carbon tetraeloride, or trichloroethane; ketone solvents such as acetone, methyl ethyl ketone or methyl isobutyl ketone; ether solvents such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran or 1,4-dioxane; ether solvent such as ethyl acetate or butyl acetate; and eimilaree. In particular, it prefers toluene, xylene, hexane, carbon tetraeloride, tert-butyl methyl ether and diieopropyl ether, since the activation of the enzyme is small and the reaction proceeds at high speed. The concentration of the subetratoe, that is, the isomers (A) and (B), preferably from about 0.02 to about 3 moles / liter, especially about 0.02 to about 2 moles / liter, may cause the reaction rate to be high and The inetalacionee for the reaction of tranneterificación can be released iniaturized. The amount of the alcohol for the transesterification is preferably 0.6 to 10 moles, especially 0.8 to 5 moles, per mole of the omer (B), so that the enzyme can be prevented from being de-activated and the reaction rate can increase. The contamination of the reaction system with water causes hydrolysis at the same time as the transesterification, resulting in a reduction in the efficiency when the solution obtained is applied to the process of the present invention. Therefore, it is preferable to carry out the reaction by avoiding, as much as possible, the presence of more water than required for an enzyme to exhibit the transesterification activity. In addition, the hydrolysis product is not soluble in some solvents and this leads to decreased purity of the desired product due to contamination of such by-product. The transesterification reaction ee is carried out at room temperature or a high temperature, preferably at a temperature of 10 to 50 ° C, especially 20 to 40 ° C.

The conversion rate in the trane-esterification reaction can be suitably selected in accordance with the stereoselectivity of the enzyme, yield of the optical isomer (A) and eimilar. This conversion rate can be freely adjusted by changing the activity of the enzyme, the reaction temperature, the reaction time and similar according to the substrate, trane-3-eubstituted glycidic acid ester (I), and ether redox. of the ether composet (B '). To obtain the high purity optical isomer (A) in a high yield by a conventional method, it is generally preferred to increase the conversion rate in the transesterification and to use an enzyme having a very high selectivity. However, to raise the conversion rate, to a degree where the reaction has proceeded to a greater degree, the omer (B), which remains in a small amount in the reaction mixture, must additionally be etherified. Therefore, it is indisputably impossible to raise the conversion rate to a high level considering the facts that a large amount of expensive enzyme would be needed, the enzyme is easily activated during the long reaction time, the glycidic acid ester -3-substituted ineetable (I) can be decomposed during the long reaction and some enzymatic transesterification of isomer A is inevitable due to insufficient selectivity of the enzyme.

For example, the Japanese patent publication Kokai No. 8-259552 teaches that asymmetric trane-etherification of racemic trans-3- (4-methoxyphenyl) -glycidic acid methyl ester is performed using eeteraea derived from Serratia arceecene, to convert the (2S, 3R) omomer of the racemic methyl ether into the (2S, 3R) -n-butyl ester until the molar ratio of (2S, 3R) -butyl ester / ester (2S, 3R) -methyl is made 7.8 / 1 [ether (2S, 3R) -methyl 10.8 g , and ether (2S, 3R) -n-butyl, 101.85 g]. However, this transesterification is carried out in such a way that the reaction is carried out first for 24 hours using 5 × 10 5U stearate per mole of the eublock, and then the solvent is removed by distillation under reduced pressure, until the volume of the The reaction mixture is made 1/3, 5 × 105 uae is added to the reaction, and the reaction is continued for 16 hours. Said process is substantially inapplicable to industrial production, since the reaction time is too long, the process is too complicated, and the amount of expensive enzyme is too large. In contrast, according to the present invention, the optical isomer (A) of high purity can be obtained in a high yield, even if the conversion rate in the transesterification is not raised to a high level. For example, methyl acid ether can be obtained (2R, 3S) -3- (4-methoxyphenyl) glycidic having a purity of 99% or more, in a yield of at least 80% of the reaction mixture obtained by the transesterification of methyl ester of trans-3 acid - racemic (4-methoxyphenyl) glycid using eeteraea derived from Serratia marceecene Sr41 FERM BP-487 (1 x 105U, 24 hours), where only 70% of the ioomer (2S, 3R) is converted into n-butyl ether (ester) of compound B '/ optical isomer B = 7/3). The present invention encompasses a mode in which crystals of the sub-layer remain in the reaction mixture during the trane-esterification reaction, because the solubility of the substrate is low in the solvent. In this case, after the trane-esterification reaction in which the undesired ioomer is converted into a soluble ether compound, the resulting product can be obtained from the reaction mixture by: filtering the mixture of the enzyme and the chosen ioomer crietalee, and removal of the contaminated enzyme from the selected ioomer, while the filtrate is cooled and the resulting crystals are obtained by filtration, or direct cooling of the reaction mixture, filtration of the mixture of the enzyme and the desired isomer in crystals, and removal of the enzyme thereof. The present invention also encompasses a mode in which no crystals precipitate during trane-esterification when the reaction is conducted in a normal procedure, but the crystals precipitate by positively distilling off the solvent in the course of the reaction. The separation of the crystals precipitated by deacelation of the solvent can be done in the same manner as before. In order to remove a large part of the solvent by deethylation and add a different solvent to the reaction mixture, the separation of the crystals can also be carried out in the same manner mentioned above. In that case, an alcohol resulting from the transesterification can also be removed to the outside of the reaction system, at the same time as the distillation of the solvent and, therefore, the efficient trane-etherification proceeds easily. As mentioned before, the process of the present invention is advantageous, since the optical isomer (A) of the trans-3-substituted acidic glycidic ester (1) is preferably manufactured on an industrial scale. This is because the isomer (A) can be obtained in high purity and in a high yield, coupling the crystallization and the transeeterification, which by itself was considered industrially inapplicable, even if the transesterification of the racemate stops at a stage in which The conversion speed is low. The above explanation has been made with respect to a process in which the optical isomer (A) is isolated by crystallization of the isomer (A) to the extent that isomer B is not crystallized due to the presence of the ester compound (B) '), although the optical isomer (B) would precipitate if the ester compound (B') were not present. However, in accordance with the process of the present invention, it is also possible to obtain the crystals of the optical isomer (A) in a larger amount compared to the conventional method, in which the (A) isomer is crystallized from a solution (AB) under the condition that the isomer (A) crystallizes, but not the isomer (B). This is because the ester component (B ') in the solution (AA 'BB') or (ABB '), inhibits the precipitation of the optical isomer (B) thereof. In addition, the optical aomer (A) can be obtained in high purity and in high yield in comparison with the conventional methods, including the solution (ABB ') or the (AA' BB ') obtained by the transesterification at a low conversion rate . For example, the isomer (A) of the trans-3-sub-substituted glycidic acid ether (1) is obtained in the form of crietalee having an optical purity of more than 99% in a yield of more than 75% (in particular, 80%) by means of: transforming the mixture of the ioomers (A) and (B) with an alcohol corresponding to the ester composition (B ') using an enzyme having a capacity to stereoselectively transeeterify the (B) isomer in the ester composition (B ') (especially having the E value of more than 20, for example, steraea derived from Serratia marcescens Sr41 FERM BP-487), until the molar ratio of ester compound (B') / isomer ( B) ee do 13/7 to 7.8 / 1 (especially 2/1 to 8/2) and: crystallize the isomer (A) of the resulting reaction solution (the solvent from which it can be exchanged). Concomitantly, the aforementioned reaction solution, the solvent from which it is exchanged, includes, for example, that obtained by partially or totally exchanging the solvent of the reaction solution, by way of removing the resulting alcohol during the transesterification or by partially exchanging or The solvent is completely removed after the transesterification, so that the transesterification is carried out in a suitable solvent and the crietalization is carried out in an appropriate solvent for this purpose. The solution obtained by traneetherification can be a solution obtained by conventionally eliminating the enzyme from the reaction mixture resulting from traneetherification, such as by filtration or decantation. Derivatives of (2S, 3S) -1,5-benzothiazepine or pharmaceutically acceptable saltse can be prepared from the (2R, 3S) ieromer of the trane-3-eubstituted glycidic acid ether, which was previously obtained as the optical isomer (A ), by means of various procedures, for example, which are described in Japanese Patent Publication Kokoku No. 46-16749, Kokoku No. 63-13994, Kokai No. 5-201865, Kokai No. 2-289558 and Kokoku No. 2-28594, Chem Pahrm Bull., 18 (109, 2028-2037 (1970), and Publication Patent No. Kokai No. 2-17168, No. 4-234866, No. 5-222016, No. 4-221376, No. 2-202013, No. 2-17170, No. 2-286672, No. 6- 279398, No. 58-99471, No. 8-269026, No. 61-118377, No. 6-228117, and No. 2-78673, European Patent Publication No. 796853 and Holandeea Patent Publication No. 1006293. Especially The derivatives of (2S, 3S) -1,5-benzothiazepine or pharmaceutically acceptable salts can be prepared by means of: the reaction of the isomer (2R.3S) with an aminothiophenol derivative of the formula (IV): in which ring B is as defined before river, and R * ee a hydrogen atom, a 2- (dimethylamino) ethyl group or a group of the formula: for example, 2-aminothiophenol, 2-amino-chlorothiophenol, 2-amino-5-benzylthiophenol, 2- (dimethylaminoethylamino) -thiophenol, or a compound of the formula: wherein the ring B is as defined above, or the reaction of the ioomer (2R, 3S) with a nitrothiophenol derivative of the formula (V): wherein the ring B ee as defined above, for example, 2-nitro-5-chlorothiophenol or 2-nitro-5-benzylthiophenol, followed by reduction of the nitro group to give an ether of the acid (2S.3S) -3 - (2-amy nofenyl thio) -3-f eni 1-2-hydroxypropionic of the formula (VI): wherein two rings A and B, R1 and R4 are as defined above, subjecting the re-compounding compound (VI) to intramolecular ring closure directly, or after carrying out hydrolysis thereof, to give a derivative (2S, 3S) - 2-phenyl-3-hydroxy-l, 5-benzothiazapine of the formula (VII): wherein the rings A and B, and R * are as defined above, and subjecting the resulting compound (VII) to dimethylaminoethylation at the nitrogen atom of the poem , and acetylation of the hydroxyl group substituted on the 3-poem in arbitrary order to give a (2S, 3S) -1,5-benzothiazepine derivative of the formula (II): wherein the rings A and B and R2 are as defined above, or a pharmaceutically acceptable salt thereof. The total reaction scheme of the conversion mentioned above is shown below. form (2B, 3S) (II) Examples of derivatives of (2S, 3S) -1,5-benzothiazepine (II) and pharmaceutically acceptable salts of the same, for example, (2S, 3S) -2- (4-methoxyphenyl) - 3-Acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-l, 5-benzothiazepin-4- (5H) -one (diltiazem), (2S, 3S) -2- (4-methoxyphenyl) ) -3-acetoxy-5- [2- (dimethylamino) ethyl 3 -8-chloro-2,3-dihydro-1, 5-benzothiazepin-4- (5H) -one, (2S, 3S) -3-acetoxy -5- [3- [4- (2-methoxyphenyl) -l-piperazinyl] propyl] -2,3-dihydro-2- (4-methoxyphenyl) -8-chloro-l, 5-benzothiazepin-4 (5H) -one, (2S, 3S) -3-acetoxy-8-benzy1-2.3-dihydro-5- [2- (dimethylamino) ethyl)] - 2- (4-methoxyphenyl) -1,5-benzothiazepin-4 (5H) -one, and pharmaceutically acceptable salts thereof. While both of the isomer (2S.3R) of the trans-3-substituted glycidic acid ester, which was obtained before as the optical addomer A, can be prepared from (2R, 3R) -1,5-benzothiazepine, or ealee pharmaceutically aceptablee de loe miemoe, in a manner similar to the previous one in accordance with known procedures. Especially, (2R, 3R) -1,5-benzothiazepine derivatives, or pharmaceutically acceptable salts thereof, can be prepared by: reaction of the (2S, 3R) isomer with the aminothiophenol derivative (IV), or the reaction of the nitrothiophenol derivative (V) followed by reduction of the nitro group, in the same manner as the aforementioned preparation of the (2S, 3S) -l, 5-benzothiazepine (II) derivatives from the (2R. 3S), to give an (2R, 3R) -3- (2-aminophenylthio) -3-phenyl-2-hydroxypropionic acid ester of the formula (VIII): wherein the ring A, the ring B and R1 are as defined above, eome the resulting compound (VIII) to intramolecular ring closure, directly or after carrying out the hydrolysis of the mole, to give a derivative (2R, 3R) -2-phenyl-3-hydroxy-l, 5-benzothiazepine of the formula (IX): in which ring A and ring B are as defined above, and erect the reagent composition (IX) to dimethylaminoethylation at the nitrogen atom of section 5 and acetylation of the substituted hydroxyl group on position 3 in arbitrary order to give a (2R, 3R) -1,5-benzothiazepine derivative of formula (III): wherein ring A and ring B are as defined above, or a pharmaceutically acceptable salt thereof. The total reaction scheme of the confection mentioned above is shown below. shape (2R, 3S) Examples of the derivatives of (2R, 3R) -1,5-benzothiazepine (III) and pharmaceutically acceptable salts of the same, for example, (2R, 3R) -cie-2- (4-methylphenyl) -3 -acetoxy-5- [2- (dimethylamino) ethyl] ~ 8-methyl-2,3-dihydro-l, 5-benzothiazepin-4 (5H) -one and pharmaceutically acceptable salts thereof. In addition, an optically active threo-nitrocarboxylic acid compound of the formula can be prepared: in which the ring A and the ring B eon as defined previously and * denotes atom of carbon dioxide; which is useful as an optical resolution agent, from the optical isomer A of the trans-3-sub-substituted glycidic acid ester obtained by the process of the present invention. In the preparation of said optically active threo-nitrocarboxylic acid compounds, ring A and B are, for example, the same rings mentioned in the aforementioned preparation of 1,5-benzothiazepine derivatives. Preferably, ring A is a lower 4-alkoxyphenyl group and ring B is a substituted benzene ring of the formula: in which, Hal is a halogen atom. Preferably, ring A is a 4-methoxyphenyl group and ring B is the substituted benzene ring shown by the above formula in which Hal is a chlorine atom. The preparation of the threo-nitrocarboxylic compound can be practiced, for example, by reacting the optical isomer A of the trane-3-substituted acidic glycide ether with a nitrothiophenol compound of the formula: in which ring B is as defined above; in a manner as described in Japanese Patent Publication Kokoku No. 61-18549, and after hydrolyzing the product in accordance with a method described in Chem. Pharm. Bull., 18 (10), 2028-2037 (1970). According to said methods, the (2S.3S) isomer of the threo-nitrocarboxylic acid compound can be obtained and the (2R, 3S) isomer of the trans-3-eubstituted glycidic acid ester (I) is used, and the isomer (2R, 3R) of the threo-nitrocarboxylic acid compound if the (2S.3R) isomer of the trans-3-sub-substituted glycidic acid ester (I) is used. Concomitantly, the term "linear or branched lower alkyl group", as used in the foregoing, denotes a linear or branched alkyl group having from 1 to 6 carbon atoms. Also, the term "linear or branched lower alkoxy group", as used in the preamble, means a linear or branched alkoxy group having from 1 to 6 carbon atoms. In addition, the term "cycloalkyl group", as used herein, means a cycloalkyl group having from 3 to 6 carbon atoms, and the term "aryl group", as used in the preamble, means an aryl group which It has 6 to 10 carbon atoms. Also, the term "linear or branched alkyl group", as used in the preamble, denotes a linear or branched alkyl group having from 1 to 12 carbon atoms. The term "alkoxyalkyl group", as used in the foregoing, denotes an alkoxyalkyl group in which the alkoxy group has from 1 to 6 carbon atoms and the alkyl group has from 1 to 6 carbon atoms. Also, the term "arylalkyl group", as used herein, means an arylalkyl group in which the aryl group has from 6 to 10 carbon atoms, and the alkyl group has from 1 to 6 carbon atoms.

The present invention is described and explained more specifically by means of the following examples. It is understood that the present invention is not limited to these examples.

EXAMPLE 1 In a 300 ml eggplant-type flask, (2R, 3S) -3- (4-methoxyphenyl) glycidic acid methyl ester (hereinafter referred to as "MPGM"), (2S, 3R) -MPGM and (2S, 3R) -MPGR3 [ether R3 of (2R, 3S) -3- (4-methoxyphenyl) glycidic acid, ie, a compound in which the methyl group of (2S, 3R) -MPGM was changed to group R3; R3 = n-propyl group, n-butyl group, n-octyl group, n-decyl group, benzyl group, cyclohexyl group or 2-octyl group] in the number of samples shown in Table 1, together with 30 ml of methanol. They were dissolved in methanol at an elevated temperature. The solution was cooled to -15 ° C, with stirring by means of a magnetic stirrer, and allowed to stand at -15 ° C for 5 minutes. The concentrations of the respective components in the resulting copolymer were measured by means of HPLC. *: HPLC conditions: column, CHIRALCEL 0D (Daicel Chemical Co.); Detection, UV at 237; Temp., 40 ° C; Flow rate, 1.0 ml / min; Solvent of development, Hexane / Isopropanol = 20/1. From the concentrations, the amounts of the respective components included in the supernatant were calculated. In addition, the amount of the crystals was calculated according to the equation: (amount of (2R, 3S) -MPGM before crystallization) - (amount of (2R, 3S) -MPGM in the supernatant). The results are shown in Table 1. A small portion of the crietal loles was obtained by filtration, washed with methanol (-15 ° C) in an amount equal to the portion, and dried under vacuum; the purity of the crystals was measured by means of HPLC. It was found that the content of (2R, 3S) -MPGM in the crystals was 99% or more in all cases.

TABLE 1 R3 Coaposition before Amount in the Amount of crystals of crystallization (g) supernatant deposited (g) (2R.3S) -HPGN: 9.8 (2R.3S) -HPGH: 1.1 (2R, 3S) -HPGH: 8.7 N-propyl group (2S.3R) -HPGH: 2.0 (2S.3R) -HPGH: without caibium (2S.3R) -HPGR3: 8.3 (2S.3R) -HPGRJ: without caibium (2R.3S) -HPGH: 9.9 (2R.3S) -HPGH: 1.0 (2R, 3S) -HPGH: 8.9 N-Butyl group (2S.3R) -HPGH: 2.7 (2S.3R) -HPGH: without caibium (2S.3R) -HPGR3: 8.5 (2S.3R) -HPGR3: without caibium (2R.3S) -HPGH: 9.4 (2R.3S) -HPGH: 1.4 (2R, 3S) -HPGH: 8.0 N-Octyl group (2S.3R) -HPGH: 2.2 (2S.3R) -HPGH: without caibium (2S.3R) -HPGR3: 6.7 (2S.3R) -HPGRJ: without caibium (2R.3S) -HPGH: 10.3 (2R.3S) -HPGH: 1.6 (2R, 3S) -HPGH: 8.7 N-decyl group (2S.3R) -HPGH: 2.8 (2S.3R) -HPGH: without caibium (2S.3R) -HPGR3: 8.6 (2S.3R) -HPGR3: without caibium (2R, 3S) -HPGH: 9.6 (2R.3S) -HPGH: 1.6 (2R, 3S) -HPGH: 8.0 Benzyl group (2S.3R) -HPGH: 2.2 (2S.3R) -HPGH: without caibium (2S.3R) -MPGR3: 7.7 (2S.3R) -HPGRJ: without caibium (2R.3S) -HPGH: 9.7 ( 2R.3S) -HPGH: 1.5 (2R, 3S) -HPGH: 8.2 Cyclohexyl group (2S.3R) -HPGH: 2.5 (2S.3R) -HPGH: without caibium (2S.3R) -HPGRí: 6.6 (2S.3R) -HPGR3: without caibium (2R.3S) -HPGH: 9.3 ( 2R.3S) -HPGH: 1.4 (2R, 3S) -HPGH: 7.9 2-octyl group (2S.3R) -HPGH: 2.0 (2S.3R) -HPGH: without caibium (2S.3R) -HPGR3: 5.1 (2S.3R) -HPGR3 without caibium EXAMPLE 2 In a 300 ml aubergine-type flask was placed (2R, 3S) -MPGM, (2S, 3R) -MPGM and (2S, 3R) -MPGnBu [(2S, 3R) -3- ( 4-methoxyphenyl) glycidic acid] in the amounts shown in tables 2 to 7, together with 30 ml of methanol. They were dissolved by stirring the mixture with a 2.5 cm magnetic stirrer at 300 rpm. The solution was cooled to a temperature shown in tables 2 to 7, and after a predetermined time (0, 0.5 or 1 hour) the agitation was stopped. A small portion of the copolymer was taken and the concentration of the respective components in the supernatant was determined by means of HPLC. From the concentrations, the quantities of the respective components included in the supernatant were calculated. In addition, the amount of the crystals was calculated according to the equation: (amount of (2R, 3S) -MPGM before crystallization) - (amount of (2R, 3S) -MPGM in the supernatant). The clouding time denotes the time in which a solution becomes cloudy, after reaching the crystallization temperature. The quantity of reagent material in the copolymer was determined by HPLC with respect to the material taken before the turbidity occurred.

TABLE 2 (2S.3RHPGnBu / (2S.3R) -HPGH = 1.7 by lol Coaposition Te y rature Type of Quantity in the Amount of before clouding supernatant (g) crystals (g) crystallization (g) crystallization (linuto) CC) (2R.3SHPGH: 10.3 (2R, 3S) -HPGH: 2.7 (2R, 3S) -HPGH: 7.6 (2S, 3R) -HPGH: 3.6 10> 60 (2S, 3R) -HPGH: without caibium (2S, 3R) -HPGnBu: 7.5 (2S, 3R) -HPGnBu: without caibium TABLE 3 C2S.3R) -HPGnBu / (2S.3RHPGH 2.0 by lol Composition Teat rater Amount of Quantity in the Amount of before turbidity supernatant (g) crystals (g) crystallization (g) crystallization (linuto) CC) (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 2.5 (2R, 3S) -HPGH: 7.8 (2S, 3R) -HPGH: 3.4 10 > 60 (2S, 3R) -HP6H: without caibium (2S, 3R) -HPGnBu: 7.9 (2S, 3R) -HPGnBu: without caibium TABLE 4 (2S.3RHPGnBu / (2S.3RHPGH - 2.2 per tol Co-deposition Teiperature Type of Quantity in the Amount of before turbidity *) supernatant (g) crystals (g) crystallization (g) crystallization (linuto) CC) (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 2.2 (2R, 3S) -HPGH: 8.1 (2S, 3R) -HPGH: 3.2 10 > 60 (2S, 3R) -HPGH: without caibium (2S, 3R) -HPGnBu: 8.3 (2S, 3R) -HPGnBu: without caibium (2R, 3S) -HPGH: 10.3 (2R, 3S) -HP6H: 1.6 (2R .3SHPGH: 8.7 (2S, 3R) -HPGH: 3.1 0 35 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 8.2 (2S, 3R) -HPGnBu: without caibium (2R, 3S) - HPGH: 10.3 (2RP3S) -HPGH: 0.9 (2R, 3S) -HPGH: 9.4 (2S, 3R) -HPGH: 3.1 -10 5 (2S, 3R) -HPGH: without caibium (2S, 3R) -HP6nBu: 8.2 (2S, 3R) -HPGnBu: without caibio TABLE 5 (2S, 3R) -HP6nBu / (2S.3RHP6H - 2.4 per lol Composition Teiperature Amount of Quantity in the Amount of before turbidity supernatant (g) crystals (g) crystallization (g) crystallization (linuto) (§C) (2R, 3S) -HPGH: 10.4 (2R, 3S) -HPGH: 2.2 (2R, 3S) -HPGH: 8.2 (2S, 3R) -HPGH: 3.0 10 > 60 (2S, 3R) -HPGH: unchanged (2S, 3R) -HPGnBu: 8.7 (2S, 3R) -HPGnBu: no change (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 2.0 (2R , 3S) -HPGH: 8.3 (2S, 3R) -HPGH: 2.9 0 55 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 8.4 (2S, 3R) -HPGnBu: no change (2R. 3SHPGH: 10.3 (2R, 3S) -HPGH: 1.1 (2R, 3S) -HPGH: 9.2 (2S, 3R) -HPGH: 2.9 -10 50 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu : 8.4 (2S, 3R) -HPGnBu: no change TABLE 6 (2S.3R) -HPGnBu / (2S.3R) -HP6H: 2.7 per mole Composition Temperature Time of Quantity in the Amount of before clouding supernatant (g) crystals (g) crystallization (g) crystallization (minute) CC) (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 2.3 ( 2R, 3S) -HPGH: 8.0 (2S, 3R) -HPGH: 2.7 10 > 60 (2S, 3R) -HPGH: unchanged (2S, 3R) -HPßnBu: 8.7 (2S, 3R) -HPGnBu: unchanged (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 1.4 (2R , 3S) -HPGH: 8.9 (2S, 3R) -HPGH: 2.7 0 > 60 (2S, 3R) -HPGH: unchanged (2S, 3R) -HPGnBu: 8.7 (2S, 3R) -HPGnBu: unchanged (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 0.8 (2R , 3S) -HPGH: 9.5 (2S, 3R) -HPGH: 2.7 -10 55 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 8.7 (2S, 3R) -HPGnBu: no change TABLE 7 2S.3R) -HP6nBu / (2S, 3R) -HPGH: 3.8 per mole Composition Temperature Time of Quantity in the Amount of before clouding supernatant (g) crystals (g) crystallization (g) crystallization (minute) (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 1.4 (2R, 3S) -HPGH: 8.9 (2S, 3R) -HPGH: 2.0 > 60 (2S, 3R) -HPGH: unchanged (2S, 3R) -HPGnBu: 9.2 (2S, 3R) -HPGnBu: unchanged (2R, 3S) -HPGH: 10.3 (2R, 3S) -HPGH: 0.8 (2R , 3S) -HPGH: 9.5 (2S, 3R) -HPGH: 2.0 -10 > 60 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 9.2 (2S, 3R) -HPGnBu: no change EXAMPLE 3 In an aubergine-type flask, 1,000 ml of (2R, 3S) -MPG, (2S, 3R) -MPGM and (2S, 3R) -MPGnBu were placed in the amounts shown in table 8, together with an amount of a solvent shown in table 8. They were dissolved in the solvent by stirring the mixture with a magnetic stirrer of 2.5 cm at 300 f. The solution was cooled to a temperature shown in Table 8, and stirring was immediately stopped. A small portion of the supernatant was taken and the concentrations of the respective components in the supernatant were measured by means of HPLC. From the concentrations, the amounts of the respective components included in the supernatant were calculated. In addition, the amount of crystals was calculated according to the equation: (amount of (2R, 3S) -MPGM before crystallization) - (amount of (2R, 3S) -MPGM in the supernatant). The results are shown in Table 8. A small portion of the crystals was obtained by filtration, washed with methanol (-10ßC) in an amount equal to the portion and dried under vacuum; the purity of the crystals was measured by HPLC. It was found that the content of (2R, 3S) -MPGM in the crystals was 99% or more in all cases.

TABLE 8 Solvent Amount Tempera- Composition before Quantity in Amount of crystalline crystallization sol- der (g) supernatant crystals (g) crystallizing crystallization (ml) (2R, 3S) -HPGH: 49 (2R, 3S) -HPGH: 9 (2R, 3S) -HPGH: 40 Xylene 100 -10 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: unchanged (2S, 3R) -HPGnBu: 39 (2S, 3R) -HPGnBu: no change (2R, 3S) -HPGH: 49 (2R, 3S) -HPGH: 9 (2R, 3S) -HPGH: 40 Toluene 100 -10 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 39 (2S, 3R) -HPGnBu: no change Ether (2R, 3S) -HPGH: 49 (2R, 3S) -HPGH: 8 (2R, 3S) -HPGH: 41 isopro100 -10 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: no change pill (2S, 3R) -HPGnBu: 39 (2S, 3R) -HPGnBu: no change Ether (2R, 3S) -HPGH: 49 (2R.3SHPGH: 9 (2R, 3S) -HPGH: 40 t -butyl- 150 -10 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: without Methyl change (2S, 3R) -HPGnBu: 39 (2S, 3R) -HPGnBu: no change (2R, 3S) -HPGH: 49 (2R, 3S) -HPGH: 8 (2R, 3S) -HPGH: 41 Isopro150 3 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: no panol change (2S, 3R) -HPGnBu: 39 (2S, 3R) -HPGnBu: no change (2R, 3S) -HPGH: 50 (2R, 3S) -HPGH: 6 (2R, 3S) -HPGH: 44 Ethanol 150 -10 (2S, 3R) -HPGH: 14 (2S, 3R) -HPGH: no change (2S, 3R) -HPGnBu: 42 (2S, 3R) -HPGnBu: no change EXAMPLE 4 In a 300 ml eggplant-type flask was placed (2R, 3S) -MPGM, (2S, 3R) -GMP and (2S, 3R) -MPGnBu in the amounts shown in Table 9, together with methanol in an amount shown in Table 9. They were dissolved in methanol by stirring the mixture with a 2.5 cm magnetic stirrer at 300 rpm. The solution was cooled to -10 ° C. After stirring at that temperature for one hour, the stirring was stopped immediately. A small portion of the supernatant was taken and the concentrations of the respective components in the supernatant were measured by means of HPLC. From the concentrations, the amounts of the respective components included in the supernatant were calculated. In addition, crystals were obtained by filtration, washed with methanol (-10 ° C) in an amount equal to the crystals and dried under vacuum, the composition of the crystals was measured by means of HPLC. The results are shown in table 9.

TABLE 9 Amount Tempera- Composition before Quantity in Quantity of Composition of the crystallization solids (g) the supernatant crystals crystals (% by glass) (g) obtained (g) mol) (ml) (2R, 3S) -HPGH: 10.0 (2R, 3S) -HPGH: 0.8 8.5 (2R, 3S) -HPGH: 99.8 30 -10 (2S, 3R) -HPGH: 2.5 (2S, 3R) -HPGH: no change (2S, 3R) -HPGH: 0.1 (2S, 3R) -HPGnBu: 9.3 (2S.3R) -MPGnBu: no change (2S, 3R) -HPGnBu: 0.1 (2R, 3S) -HPGH: 10.0 (2R, 3S) -HPGH: 0.7 9.2 (2R, 3S) -HPGH: 99.2 20 -10 (2S, 3R) -HPGH: 2.5 (2S, 3R) -HPGH: no change (2S, 3R) -HPGH: 0.3 (2S, 3R) -HPGnBu: 9.3 (2S, 3R) -HPGnBu: no change (2S, 3R) -HPGnBu: 0.5 EXAMPLE 5 In a 300 ml aubergine-type flask was placed (2R, 3S) -MPGM, (2S, 3R) -MPGM, (2R.3S) -MPGnBu and (2S, 3R) -MPGnBU in the amounts shown in Table 10 , together with 30 ml of methanol. They were dissolved in the methanol by stirring the mixture with a 2.5 cm magnetic stirrer at 3000 rpm. The solution was cooled to -15 ° C for 30 minutes. After stirring at that temperature for two more hours, stirring was stopped, and a small portion of the supernatant was taken to measure the concentrations of the respective components in the supernatant by means of HPLC. The amounts of the respective components included in the supernatant were calculated from the concentrations. In addition, the amount of crystals was calculated according to the equation: (amount of (2R, 3S) -MPGM before crystallization) - (amount of (2R, 3S) -MPGM in the supernatant). In addition, the crystals were obtained by filtration, washed with methanol (-15'C) in an amount equal to the crystals and dried under vacuum, and the composition of the crystals was determined by HPLC. The results are shown in table 10.

TABLE 10 (2R, 3S) -HPGnBu (Ratio Composition Amount of Molar Composition) before crystals crystals (2R, 3S) -HPG positivity tallation (g) (\ per mol) 0. 01 (2R, 3S) -HPGH: 9.9 (2R, 3S) -HPGH: 8.9 (2R, 3S) -HPGH: 99.7 (2S, 3R) -HPGH: 2.7 (2S, 3R) -HPGH: 0.1 (2R, 3S) ) -HPGnBu: 0.1 (2R, 3S) -HPGnBu: 0.1 (2S, 3R) -HPGnBu: 8.5 (2S, 3R) -HPGnBu: 0.1 0. 01 (2R, 3S) -HPGH: 8.1 (2R, 3S) -HPGH: 6.5 (2R, 3S) -HPGH: 96.1 (2S, 3R) -HPGH: 2.1 (2S, 3R) -HPGH: 0.5 (2R, 3S) ) -HPGnBu: 1.0 (2R, 3S) -HPGnBu: 2.5 (2S, 3R) -HPGnBu: 5.5 (2S, 3R) -HPGnBu: 0.9 0. 25 (2R, 3S) -HPGH: 7.6 (2R, 3S) -HPGH: 6.0 (2R, 3S) -HPGH: 96.6 (2S, 3R) -HPGH: 2.1 (2S, 3R) -HPGH: 0.2 (2R, 3S) ) -HPGnBu: 2.3 (2R, 3S) -HPGnBu: 2.9 (2S, 3R) -HPGnBu: 7.1 (2S, 3R) -HPGnBu: 0.3 0. 50 (2R, 3S) -HPGH: 6.5 (2R, 3S) -HPGH: 5.0 (2R, 3S) -HPGH: 93.8 (2S, 3R) -HPGH: 1.7 (2S, 3R) -HPGH: 0.2 (2R, 3S) ) -HPGnBu: 3.8 (2R, 3S) -HPGnBu: 5.5 (2S.3R) -HPGnBu: 9.0 (2S, 3R) -HPGnBu: 0.5 EXAMPLE 6 A solution of 10.4 g of (2R, 3S) -MPGM, 10.4 g of (2S, 3R) -MPG and 40.5 g of (2S, 3R0) -GPnBu in 150 ml of methanol in a round flask was placed and stirred at 300 rpm by means of a 2.5 cm magnetic stirrer. The solution was cooled to -10 ° C for 30 minutes and further stirred for 10 minutes. The crystals were obtained by filtration, washed with 10 ml of methanol (-10ßC) and dried in vacuo. The composition of the crystals was measured by HPLC. It was found that the content of (2R, 3S) -MPGM in 4.5g of crystals (43% yield based on the amount of (2R, 3S) -MPGM before crystallization) is 99% or more. After obtaining the crystals, 10 ml of methanol, which correspond to the washing liquid in the filtrate mixture and the washes, was distilled off. The concentrated mixture was cooled to -10 ° C, and seed crystals of (2S, 3R) -GMP were added thereto. When the mixture was stirred at that temperature for 30 minutes, it became a hazy and amorphous precipitated material. The amorphous type material was obtained by filtration and the composition thereof was measured by means of HPLC. The amorphous type material was found to be a solid containing (2S, 3R) -MPG having the same configuration as the seed crystals in the largest amount together with almost the same amount of (2R, 3S) -MPGM and about two thirds of the amount of (2S, 3R) -MPGnBu.

EXAMPLE 7 In a mixed solvent of 500 ml of xylene, 80 ml of n-butanol and 0.25 ml of water was dissolved 104 g (0.5 mol) of (2RS, 3SR) -MPGM [52 g of (2R, 3S) -MPGM and 52 g of (2S, 3R) -MPGM]. In the resulting solution, 200 mg of esterase derived from Serratia marcescens (olive oil hydrolysis activity: 4 x 10 * U) was suspended, which was obtained in the reference example l- (2-b) described later, the solution was stirred at 30 ° C for 24 hours, and the reaction mixture was analyzed by HPLC.The product was found to be composed of 50 g of (2R, 3S) -MPGM, 13.5 g of (2S, 3R) -MPGM and 44 g of (2S, 3R) -MPGnBu The enzyme was removed from the reaction mixture by filtration, and the complete solvent was distilled off from the filtrate under reduced pressure to give an oily residue. residue was added 150 ml of methanol and stirred during crystallization.In order to further increase the production, the mixture was cooled to -15 ° C and stirred at the same temperature for 30 minutes.The crystals were obtained by filtration with 40 ml of methanol (-15ßC) and dried under vacuum to give 44.2 g of (2R, 3S) -MPGM. After analyzing the filtrate obtained at that time, it was also found that the stock solution contained 6 g of (2R, 3S) -MPGM, 13.5 g of (2S, 3R) -MPGM and 44 g of (2S.3R) -MPGnBu . The production of the crystals was 85.0% (percentage in the base that (2R, 3S) -MPGM in the changed racemic compound was 100%). the content of (2R, 3S) -IPGM in the crystals was found to be 99% or more.

EXAMPLE 8 .8 g of (2RS, 3SR) -MPGM [10.4 g of (2R, 3S) -MPGM and 10.4 g of (2S, 3R) -MPGM], 100 ml of xylene, 16 ml of n-butanol, 25 μl of water and 10 mg of esterase derived from Serratia marcescens (olive oil hydrolysis activity: 2 x 103U) which was obtained in the reference example l- (2-b) described below. The mixture was subjected to an enzymatic transesterification reaction at 30 ° C until the transesterification conversion shown in Table 11 was obtained. The enzyme was removed from the reaction mixture by filtration, and the complete solvent was distilled off from the filtrate. and a temperature of 60 to 70 ° C under reduced pressure to give an oily residue. 30 ml of methanol was added to the residue and stirred in a round-bottom flask at 300 r.p.m. with a 2.5 cm magnetic stirrer. After cooling the mixture to -10 ° C, stirring was stopped. A small portion of the supernatant was removed and the concentrations of the components in the supernatant were measured by HPLC. The amounts of the compounds included in the retentate were calculated from the concentrations. A small portion of the crystals was obtained by filtration, washed with methanol of -10 ° C in an amount equal to that of the crystals, dried on the vacuum and analyzed by CLAR: The content of (2R, 3S) -MPGM in the crystals was found to be 99% or more in all cases.

CUflPRQ 11 Conversion Composition Quantity in Quantity before cris. crystallization supernatant crystals < g > deposited < 9 > < 2R, 3S > MPGM: 10.2 (2R, 3S) -MPGM: 0.9 (2R, 3S) -MPGM: 0. 36 < 2S, 3R > • MPGM: 3.1 < 2S, 3R) -MPGM: s.c. 9.3 < 2R, 3S > MPGnBu: .03 (2R, 3S) -MPGnBu: s. c. < 2S, 3R > • MPGnBu: 8.2 < 2S, 3R) -MPGn: s.c. < 2R, 3S > MPGM: 10.2 < 2R, 3S) -MPGM: 1.1 < 2R, 3S) -MPGM: 0. 37 < 2S, 3R > MPGM: 2.9 < 2S, 3R > -MPGM: S.C. 9.1 < 2R, 3S > MPGnBu: .03 (2R, 3S) -MPGnBu: S. C. < 2S, 3R > MPGnBu: 8.3 < 2S, 3R) -MPGnBu: S.C. < 2R, 3S > MPGM: 10.2 (2R, 3S) -MPGM: 0.β < 2R, 3S) -MPGM: 0. 38 < 2S, 3R > MPGM: 2.7 (2S, 3R) -MPGM: s.C 9.4 < 2R, 3S > MPGnBu: .03 < 2R, 3S > -MPGnBu: s.c. < 2S, 3R > MPGnBu: 8.6 < 2S, 3R > -MPGnBu: S.C. < 2R, 3S > - MPGM: 10.2 < 2R, 3S) -MPGM: 0.8 < 2R, 3S) -MPGM: 0. 41 < 2S, 3R > - MPGM: 2.0 < 2S, 3R > -MPGM: S.C 9.4 < 2R, 3S > MPGnBu: .03 < 2R, 3S > -MPGnBu: S.C. < 2S, 3R > MPGnBu: 9.2 < 2S, 3R > -MPGnBu: s.c. s.c. : without changes EXAMPLE 9 In a mixed solvent of 500 ml of xylene and 80 ml of n-butanol was dissolved 104 g (0.5 mole) of (2RS, 3SR) -MPGM [52 g of (2R, 3S) -MPGM and 52 g of (2S, 3R) - PGM]. In the resulting solution was suspended 3.0 g of immobilized esterase on Celite (2.5 x 104U olive oil hydrolysis activity) which was obtained in the reference example l- (2-a) described below. The solution was stirred at 30 ° C for 24 hours and the reaction mixture was analyzed by HPLC. The product was found to be composed of 51 g of (2R, 3S) -MPGM, 14.7 g of (2S, 3R) -MPGM and 38 g of (2S.3R) -MPGnBu. The esterase immobilized with Celite was removed from the reaction mixture by filtration, and the complete solvent was removed by distillation from the filtrate at a temperature of 60 to 70 ° C under reduced pressure to give an oily residue. To the residue was added 150 ml of methanol, and stirred for crystallization. In order to further increase the yield, the mixture was cooled to -10 ° C and stirred at the same temperature for 30 minutes. The crystals were obtained by filtration, washed with 40 ml of methanol of -10 ° C and dried in vacuo to give 43.Q g of (2R.3S) -MPGM. From the analysis of the filtrate obtained at the same time, it was also found that the stock solution contained 7 g of (2R, 3S) -MPGM, 14.7 g of (2S, 3R) -MPGM and 38 g of (2S.3R) -MPGnBu . The yield of the crystals was 82.9% (percentage on the basis that (2R, 3S) -MPGM in the loaded racemic compound was 100%). It was found that the content of (2R, 3S) -MPGM in the crystals was 99% or more.

EXAMPLE 10 (1) In 150 ml of methanol, 20 g of (2RS, 3SR) -MPGM and 41 g of (2S, 3R) -MPGnBu were dissolved at a temperature of 30 to 40 ° C. The solution was cooled with stirring, and 10 mg seed crystals of (2R, 3S) -MPGM at 0ßC were added to the solution. The solution was further cooled to -10 ° C for 30 minutes and stirred at that temperature for 10 minutes. The crystals were obtained by filtration with a glass filter, washed with 20 ml of -10 ° C methanol and dried under vacuum to give (2R, 3S) -MPGM. Filtering and washing were combined to give a methanol solution containing (2R, 3S) -MPGM, (2S, 3R) -MPGM and (2S, 3R) -MPGnBu. (2) To the above methanol solution was added 100 ml of methanol and 10 ml of diisopropylamine. The solution was stirred at 30 ° C for 16 hours to convert (2S.3R) -MPGnBu to (2S, 3R) -MPGM. (3) The reaction mixture obtained in step (2) was allowed to stand at 0 ° C for 30 minutes. The (2S, 3R) -MPGM crystals were obtained by filtration and washed with 40 ml of methanol at 5 ° C. The filtrate was concentrated under reduced pressure to give a residue containing (2S, 3R) -MPGM and (2R, 3S) -MPGM in approximately equal amounts. (4) To the residue was added (2RS, 3SR) -MPGM so that the total amount of (2RS, 3SR) -MPGM became about 20 g. To it was added (2S, 3R) -MPGnBu and methanol. The resulting solution was applied to the previous step (1). The procedure of steps (1) to (4) was repeated three times, and the results thereof are shown in table 12.

CURPRQ 12 (Change in composition of components in methanol solution) Procedure (2R, 3S > -MPGM (g) (2S, 3R) -MPGM (g) (2S, 3R) -MPGnBu <9> R10 ratio (+10 addition) 10 (+10 addition) 4K + 41 addition) racemic compound CristaLi- 4.4 (-5.6 deposi10 41 ation) Transeste44 rification 4.4 («• 34.1 transes- 0 (~ 41 transes chem- icalization-0.1») »terification) CristaLi- 3.6 (-0.ß ***) 3.9 (-37.9 deposition 0 -2.2 **) Ride of 10 (+6.4 addition) 10.3Í + 6.4 adi4K +41 addition) compound) racemic CristaLi- 4.2 ( -5.β deposi10.3 41 ation) Transeste4.2 44Í + 34.1 transOÍ-4 transesrification esterification terificación) chemistry -0.4 *) CristaLi- 4.2 4.4 (-35.8 deposi 0ación) 10 (+ S.ß addition ) 10.2Í + 5.8 adi4K + 41 addition) compound) racemic CristaLi- 5.2C-4.8 deposi10.2 41 a tion) Transeste5.2 44 (+34.1 trans0 (-4l transesrification esterification terification) chemical -0.3 *) CristaLi- 5.2 6.2Í-37.0 deposition 0 -ß.ß **) * Loss at the time of transesterification ** Loss at the time of washing the crystals *** Loss caused by washing and others 16.2 g of (2R) was obtained, 3S) -MPGM in total by means of the above procedure of three cycles. The purity and optical purity of (2R, 3S) -MPGM obtained in each cycle was 98% or more and 97% or more, respectively. Since (2S, 3R) -MPGM can be obtained as crystals in a molar amount greater than (2S, 3R) -MPGnBu used as an ester compound, it is also possible to obtain (2S, 3R) -MPGM having high purity if the (2S, 3R) -MPGM thus obtained is chemically transesterified to (2S, 3R) -MPGnBu only in an amount necessary for (2S, 3R) -MPGnBu in the next cycle.

EXAMPLE 11 In a 2 liter reactor equipped with a stirrer, 187 g (.09 mole) of (2RS, 3SR) -MPGM [93.5 g of (2R.3S) -MPGM] was dissolved in a mixed solvent of 720 ml of xylene and 57.6 g. ml (0.9 mole) of n-butanol. In the resulting solution was suspended 3. 0 g of esterase immobilized with Celite (to which 0.81 ml of purified water was previously added and which had an olive oil hydrolysis activity of 2.5 x 10 * U) which was obtained in the reference example l- (2 -a) described later. The solution was stirred at 30 ° C for 4 hours under a reduced pressure of 15 mmHg, and the reaction mixture was analyzed by HPLC. The product was found to be composed of 91.6 g of (2R, 3S) -MPGM, 24.3 g of (2S, 3R) -MPGM and 83.2 g of (2S.3R) -MPGnBu.

The esterase immobilized with Celite was removed from the reaction mixture by filtration, and the filtrate was concentrated at a temperature of 60 to 70 ° C under reduced pressure to give an oily residue. To the residue was added 150 ml of methanol and cooled to -10 ° C with further stirring or agitation at that temperature for 30 minutes. The crystals were obtained by filtration, washed with methanol of -10 ° C and dried under vacuum to give 82.3 g of (2R, 3S) -MPGM. The stock solution and the washings were combined and analyzed by means of CLAR. The mixture was found to contain 9.1 g of (2R, 3S) -MPGM, 24.1 g of (2S, 3R) -MPGM and 83.1 g of (2S, 3R) -MPGnBu.

REFERENCE EXAMPLE 1 (1) In a 30-liter jar fermentor, 18 liters of a pH 7.0 liquid medium containing 1% dextrin, 0.2% ammonium sulfate, 2% Meast S (made by Asahi Brewers, Ltd.) was placed. ), 0.2% dihydrogen phosphate, 0.05% magnesium sulfate, 0.001% ferrous sulfate, 1.5% w / v% of a sorbitan trioleate surfactant (Rheodol SP-030, made by Kao Corporation) and 0.2 v / v% of a polyalkylene glycol derivatized surfactant (trademark Karanin 102, made by Sanyo Chemical Industries, Ltd.). After sterilizing the medium, as before, sterilized medium was inoculated with 200 ml of a precultured broth of Serratio marcescens Sr41 FERM BP-487 obtained by previously cultivating with reciprocal agitation at 27.5 ° C for 20 hours in the same culture medium. The mixture was cultivated at 25 ° C for 28 hours with the continuous addition of 1.5% L-proline to the medium under the conditions of 0.33 vvm, 0.5 kg / cm2 G and 300 r.p.m. Ten liters of the culture broth was centrifuged to remove the cells, and the impurities were removed from the supernatant by the use of an absorbent resin SP207 (made by Mitsubishi Chemical Corporation). The supernatant thus obtained was concentrated to 1 liter using an ultrafiltration membrane (SLP1053 made by Asahi Chemical Industry Co., Ltd.) to give 1.080 ml of a concentrated esterase liquid having an oil hydrolysis activity of 1.0 x 10 * U / ml. (2-a) After impregnating 30 ml of the concentrated enzyme liquid obtained in (1) in 30 g of Celite (made by Celite Corporation, California, USA) placed in a 500 ml round-bottomed flask, they were mixed uniformly and dried at an external temperature of 30 ° C under reduced pressure using a rotary evaporator to give 36.5 g of esterase immobilized with Celite having an activity of 8.2 U / mg. (2-b) The lyophilizate was 1,000 ml of the concentrated enzyme liquid obtained in (1) to give 54 g of esterase having an olive oil hydrolysis activity of 1.96 x 105U / g.

REFERENCE EXAMPLE 2 A mixture of 225 ml of a 2% aqueous solution of polyvinyl alcohol (trademark Poval 117, made by Kuraray Co., Ltd.) and 75 ml of olive oil at a temperature of 5 to 10 ° C for 10 minutes was stirred. minutes at 14,500 rpm to form an emulsion. Subsequently, 5.0 ml of the obtained olive oil emulsion and 4.0 ml of a 0.25 M tris-HCL pH buffer (pH 8.0, containing 2.5 mM calcium chloride) was preheated at 37 ° C for 10 minutes, and to it was added 1 ml of an enzyme liquid. The reaction was conducted at 37 ° C for 20 minutes, and 20 ml of a mixed solvent of acetone-ethanol (1: 1) was added to the reaction mixture to terminate the reaction. The reaction mixture was titrated with a 0.05 N solution of NaOH using phenolphthalein as an indicator. The amount of enzyme that released 1 μmol of a fatty acid per minute was defined as a unit (U) by the above procedure. As explained above, in accordance with the present invention, a desired optical isomer having high purity can be crystallized from a solution containing a mixture of optical isomers of trans-3-substituted glycidic acid esters until the concentration of the desired optical isomer in the stock solution is very low compared to conventional methods. Further, after transesterifying in an asymmetric and enzymatic manner the trans-3-substituted racemic glycidic acid esters, a desired optical isomer having high purity can be crystallized from the reaction mixture until the concentration of the desired optical isomer is desired. in the mother solution is very low compared to conventional procedures.

Claims (26)

NOVELTY OF THE INVENTION CLAIMS

1. - A procedure for preparing a compound of this optically active substituted rans-3-substituted glycidic acid of formula (I): wherein ring a is a substituted or unsubstituted benzene ring, and R1 is an ester residue, which comprises: preparing a solution of one optical isomer (A) and the other optical isomer (B) of the ester compound (I), both are optical isomers due to the asymmetric carbons in the 2- and 3- positions, and an ester compound (B ') that is different to the (B) isomer only in the ester residue Ri, crystallize the isomer optical (A) from the solution to the extent that the optical isomer (A) is crystallized without the precipitation of the optical isomer (B) due to the presence of the ester compound (B ') although the optical isomer (B) would precipitate if the ester compound (B ') is not present, and isolate the crystals of the optical isomer (A).

2. The process according to claim 1, further characterized in that the solution contains a small amount of an ester compound (A ') that is different to the isomer (A) only in the ester residue R1 and has the same residue of ester than the ester compound (B ').

3. The process according to claim 1 or 2, further characterized in that the ester residue of isomer (B) is methyl or ethyl group, and the ester residue of ester compound (B ') is a member selected from starting from the group consisting of: (a) a linear or branched alkyl group having more carbon atoms than the ester residue of isomer (B) and which can be substituted with a halogen atom; (b) an alkoxyalkyl group which can be substituted with a halogen atom, and (c) an arylalkyl group which can be substituted with a linear or branched lower alkyl group, a linear or branched lower alkoxy group or a halogen atom.

4. The process according to claim 1, further characterized in that the molar ratio of isomer (A) / Isomer (B) in the solution is 4/6 to 10/1, and the molar ratio of ester compound ( B ') / isomer (B) in the solution is from 5/3 to 10/1.

5. The process according to claim 2, further characterized in that the molar ratio of the ester compound (A ') / isomer (A) is when more than 9/35 that of the ester compound (B') / isomer (B) ,

6. - The method according to any of claims 5, further characterized in that the solvent of the solution is a member selected from the group consisting of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent that can be substituted with a halogen atom, an aliphatic hydrocarbon solvent which can be substituted with a halogen atom and an ether solvent.

7. The process according to any of claims 1 to 6, further characterized in that the concentration of the isomer (A) in the solution before crystallization is 0.5 to 4 moles / liter, and the crystallization is carried out at a temperature from -10 to + 15 ° C.

8. The process according to any of claims 1 to 7, further characterized in that the solution to be subjected to crystallization is a solution obtained by transesterifying the optical isomer (B) in the solution of the isomers (A) and ( B) to an ester compound (B ') in the presence of an enzyme having a stereoselective transesterification capacity by the use of an alcohol.

9. The process according to claim 8, further characterized in that the enzyme has an E value of at least 20 measured when the conversion rate of the transesterification reaction is 10%.

10. The process according to claim 8, further characterized in that the transesterification is conducted such that the molar ratio of the ester compound (B ') / isomer (B) is from 5/3 to 10/1.

11. The method according to any of claims 1 to 10, further characterized in that the isomer (A) has an absolute configuration of (2R.3S) and the isomer (B) has an absolute configuration of (2S.3R).

12. The process according to any of claims 1 to 11, further characterized in that the ring A is 4-methoxyphenyl group, the ester residue of the isomer (B) is methyl group and the ester residue of the ester compound ( B ') is n-butyl group.

13. A process for preparing an optical active isomer of a trans-3-substituted glycidic acid ester compound of the formula (I): wherein ring A is a substituted or unsubstituted benzene ring, and R1 is an ester residue comprising: subjecting a mixture of an optical isomer (A) and the other optical isomer (B) of the ester compound (I) ), both are optical isomers due to asymmetric carbons in the 2- and 3- positions, for transesterification in the presence of an alcohol and an enzyme having a stereoselective transesterification capacity, thereby transesterifying the optical isomer (B) with the alcohol to produce an ester compound (B ') that is different from isomer (B) only at the ester residue R1 until the molar ratio of the ester compound (B') / isomer (B) falls within the scale of 13/7 to 7.8 / 1, crystallize the optical isomer (A) from the resulting solution containing the isomer (A), the non-transesterified isomer (B) and the ester compound (B '), and isolate the isomer (A) that has optical purity of at least 99% in a po r at least 75% based on the initial amount of isomer (A).

14. The method according to claim 13, further characterized in that the enzyme has an E value of at least 20 measured when the conversion rate of the transesterification reaction is 10%.

15. The process according to claim 13 or 14, further characterized in that the isomer (A) has an absolute configuration of (2R.3S) and the isomer (B) has an absolute configuration of (2S, 3R).

16. The method according to claim 13, further characterized in that the enzyme is an esterase derived from Serratia marcescens. the molar ratio of the ester compound (B ') / isomer (B) is 2/1 to 8/2, and the yield of the isomer (A) is at least 80%:

17. The process according to Any of claims 13 to 16, further rotated because the ring A is 4-methoxyphenyl group, the ester residue of the isomer (B) is methyl group and the ester residue of the ester compound (B ') it is n-butyl group.

18. - A process for isolating each of the optically active isomers of a t rans-3-substituted glycidic acid ester compound of the formula (I): wherein ring A is a substituted or unsubstituted benzene ring, and R1 is an ester residue, comprising: (a) preparing a solution of one optical isomer (A) and the other optical isomer (B) of the compound of ester (I), both are optical isomers due to the asymmetric carbons in the 2- and 3- positions, and an ester compound (B ') which is different to the (B) isomer only in the ester residue R, ( b) crystallizing the optical isomer (A) from the solution to the extent that the optical isomer (A) is crystallized without the precipitation of the optical isomer (B) due to the presence of the ester compound (B ') although the optical isomer ( B) would be precipitated if the ester compound (B ') was not present, (c) isolate the crystals of the optical isomer (A), (d) chemically transesterify the ester compound (B') included in the resulting stock solution together with the remaining optical isomers (A) and (B) to convert the ester compound (B ') to the is optical mer (B) followed by crystallization and isolation of isomer (B), (e) adding a racemic trans-3-substituted glycidic acid ester (I) and an ester compound (B ') to the resulting mother liquor to provide a solution that will undergo the crystallization of step (b), and (f) repeat steps (b), (c), (d) and (e) above in this order.

19. The process according to claim 18, further characterized in that in step (d), an ester compound (A ') is added to the resulting mother liquor which is different to isomer (A) only in the residue R1 and it has the same ester residue as the isomer (B '), and in step (e) the added ester compound (A') is chemically transesterified to give the optical isomer (A).

20. The method according to claim 18 or 19, further characterized in that the solution in step (a) further contains a small amount of an ester compound (A ') that is different only in the ester residue R1 of the isomer (A) and has the same ester residue as the ester compound (B ').

21. The process according to claims 18, 19 or 20, further characterized in that the ester residue of isomer (B) is methyl or ethyl group, and the ester residue of ester compound (B ') is a member selected from the group consisting of a linear or branched alkyl group having carbon atoms larger than those of the ester residue of isomer (B) and which can be substituted with a halogen atom, an alkoxyalkyl group which can be substituted with a halogen atom and an arylalkyl group which can be substituted with a linear or branched lower alkyl group, a linear or branched lower alkoxy group or a halogen atom.

22. The process according to claim 18, further characterized in that in the solution in step (a), the molar ratio of isomer (A) / isomer (B) is 4/6 to 10/1 and the ratio molar of ester compound (B ') / isomer (B) is from 5/3 to 10/1.

23. The process according to claim 19, further characterized in that in the solution in step (a), the molar ratio of isomer (A) / isomer (B) is 4/6 to 10/1 and the ratio molar of ester compound (B ') / isomer (B) is from 5/3 to 10/1 and the amount of the ester compound (A') is such that the molar ratio of isomer (A ') / isomer (A ) in the resulting solution is 5/3 to 10/1.

24. The process according to claim 20, further characterized in that in the solution in step (a), the molar ratio of ester compound (A ') / isomer (A) is when more than 9/35 of the molar ratio of the ester compound (B ') / isomer (B).

25. - The method according to any of claims 18 to 24, further characterized in that the solvent used is a member selected from the group consisting of an alcohol solvent, an ether solvent, an aromatic hydrocarbon solvent which can be substituted with a halogen atom, an aliphatic hydrocarbon solvent that can be substituted with a halogen atom and an ester solvent.

26. The process according to any of claims 18 to 25, further characterized in that the solution before crystallizing the isomer (A) in step (a) contains the isomer (A) in a concentration of 0.5 to 4 moles / liter, and the crystallization of the isomer (A) is carried out at a temperature of -30 to + 15 ° C. 27.- In a procedure to prepare a derivative of (2S, 3S) -l, 5-benzothiazepine of the formula (II): wherein Ring A and Ring B are independently a substituted or unsubstituted benzene ring, and R 2 is 2- (dimethylamino) ethyl group or a group of the formula: or a pharmaceutically acceptable salt thereof, the improvement comprises using as the starting material a (2R.3S) isomer of trans-3-substituted glycidic acid ester (I) obtained as the optical isomer (A) in the compliance process with any of claims 1 to 26. 28.- The process according to claim 27, further characterized in that ring A is 4-methoxyphenyl group, ring B is an unsubstituted benzene ring and R2 is group 2- ( dimethylamino) ethyl. 29.- In a procedure to prepare a derivative of (2R, 3R) -l, 5-benzothiazepine of the formula: wherein ring A and ring B are independently a substituted or unsubstituted benzene ring, or a pharmaceutically acceptable salt thereof, the improvement comprises using as a starting material a (2S, 3R) isomer of transglycidyl ester -3-substituted (I) obtained as the optical isomer (A) in the process according to any of claims 1 to 26. 30.- In a process for preparing a reactive active carboxylic acid compound of the formula: wherein ring A and ring B are independently a substituted or unsubstituted benzene ring, and * denotes asymmetric carbon atoms, the improvement comprises using as the starting material the optical isomer (A) obtained in the process according to any of claims 1 to 26. SUMMARY OF THE INVENTION A process for preparing a compound of this trans-3-substituted glycidic acid of formula (I): characterized in that the ring A is a substituted or unsubstituted benzene ring, and R1 is an ester residue, comprising: preparing a solution of one optical isomer (A) and the other optical isomer (B) of the ester compound (I) ), which are optical isomers due to the asymmetric carbons in the 2- and 3- positions, and an ester compound (B ') that is different to the (B) isomer only in the ester residue R1, crystallize the optical isomer (A) from the solution to the extent that the optical isomer (A) is crystallized without the precipitation of the optical isomer (B) due to the presence of the ester compound (B ') although the optical isomer (B) would precipitate if the ester compound (B ') is not present, and the crystals of the optical isomer (A) are isolated, by means of which a desired optical (A) isomer can be obtained with high purity and high yield, so that the isomer desired can be crystallized until the concentration of the isome The desired solution in the mother solution is very low compared to conventional procedures. MG / JJ / EA / IV / apm * blm * fac * amm * elt * lpm * mmm. P98-163