MXPA97001992A - Procedure for preparing compounds of trans-3-phenylglicidamide optically acti - Google Patents

Abstract

A method for preparing a trans-3-phenylglycinamidaptically active compound, comprising subjecting a racemic trans-3-phenylglycidamide compound of the formula (I): wherein ring A is substituted or unsubstituted benzene, and R 1 is H or lower alkyl, for optical resolution using a microorganism which has the ability to hydrolyze preferably an isomer of (2S, 3R) or an isomer of (2R, 3S) thereof, and a process for preparing a derivative of 1,5- benzothiazepinaptically active from the compound of trans-3-phenylglycinamidaptically active asiobteni

Description

PROCEDURE FOR PREPARING OPTICALLY ACTIVE TRANS-3-PHENYLGLICIDAMIDE COMPOUNDS TECHNICAL FIELD OF THE INVENTION The present invention relates to a process for preparing an optically active trans-3-phenyl glycinamide compound, and to a process for preparing an optically active 1,5-benzothiazepine derivative using the optically active trans-3-pheniglycine damide compound.

PREVIOUS TECHNIQUE It is known that optically active 3-phenylglycid acids or esters are useful as intermediates for preparing 1,5-benzothiazepine derivatives having various pharmacological activities such as coronary vasodilator activity, platelet aggregation inhibiting activity, etc., and which are useful as medicines (see USP 4,590,188). It is also known that optically active 3-phenylglycidyl ester compounds, especially the optically active isomer (2S, 3R) thereof can be prepared by allowing a culture broth, cells or cells treated with a microorganism to have the ability to asymmetrically hydrolyze a compound of (2R, 3S) -3-phenylglycidic acid ester to act on the corresponding racemic 3-phenylglycidic acid ester compound, thereby hydrolyzing the optically active (2R, 3S) isomer thereof, and isolating and collecting the antipode from 22S, 3R) not hydrolyzed from the reaction mixture (EP-ñ-0417785).

BRIEF DESCRIPTION OF THE INVENTION The present inventors have intensively studied an improved method for preparing 1,5-benzothiazepine derivatives using 3-phenylglycinamide compounds in place of 3-phenylglycidic acid esters, and have also studied to obtain an improved method for preparing a composed of optically active 3-phenylglycidamide from which 1,5-benzothiazepine derivatives can be obtained in the optically active form which is most desirable. It is an object of the present invention to provide a process for preparing an optically active trans-3-phenylglycinamide compound by treating the corresponding racemic trans-3-phenylglycinamide compound of the following formula I: Where the ring A is a substituted or unsubstituted benzene ring and R 1 is a hydrogen atom or a lower alkyl group, with a microorganism having the ability to hydrolyse preferably one of the optically active isomers thereof, and isolate and collect the another antipode that is not hydrolyzed by said microorganism. Another object of the present invention is to provide a process for preparing an optically active 1,5-bezothiazepine derivative using said optically active trans-3-phenylglycinamide compound.

DETAILED DESCRIPTION OF THE INVENTION By the study of the present inventors it has been found that the desired 1,5-benzothiazene derivatives can be obtained by reacting a 3-phenylglycinamide compound with a 2-aminothiophenol derivative and subjecting the product to a reaction of intramolecular cyclization (Japanese Patent Application No. 35302/1996). In addition, the inventors of the present have found that some microorganisms show ability to preferably hydrolyze one of the (2S, 3R) isomer and the (2R, 3S) isomer of the trans-3-phenylglycinamide compound, and that the 3-phenylglycinamide compound The desired optically active compound can be prepared by treating the racemic trans-3-phenylglycinamide compound with said microorganisms to hydrolyze one of the optically active isomers, followed by isolation and collection of the non-hydrolyzed antipode from the reaction mixture, and have achieved the present invention. In accordance with the present invention, an optically active trans-3-phenylglycinamide compound of the formula I: F ® HxO "CONHR1 wherein the ring A is an unsubstituted benzene ring, and R * is a hydrogen atom or a lower alkyl group, is prepared by contacting a racemic trans-3-phenylglycidate compound of the formula I with a culture or a treated culture of a microorganism having the ability to hydrolyze preferably one of an isomer (2S, 3R) and (2R, 3S) isomer thereof, followed by isolating and collecting the non-hydrolyzed antipode from the reaction mixture. The process of the present invention can be applied to any 3-phenylglycinamide compound of the formula I wherein the O-ring is either an unsubstituted benzene ring or a benzene ring which is substituted by a lower alkyl group, a group lower alkoxy or a halogen atom. The substituent on ring A includes, for example, a methyl group, methoxy group, etc., at the position of the benzene ring. The lower alkyl group for l includes, for example, methyl group, ethyl group, isopropyl group or t-butyl group. The starting racemic trans-3-phenylglycinamide compound (I) of the present invention includes not only a mixture of (2S, 3R) isomer and (2R, 3S) isomer at a uniform ratio but also mixtures of these isomers at any ratio. The microorganisms used in the present invention include any microorganisms that have the ability to hydrolyze preferably one of a (2S, 3R) isomer and (2R, 3S) isomer of racemic trans-3-phenylglycididan compound (I), eg, microorganisms such as bacteria, yeasts, molds, etc. Suitable examples of the microorganisms are bacteria belonging to the genus Co amonas, the genus Achromobacter, the genus Rhodococcus, the genus Arthrobacter, the genus Rhodobacter, or the genus Flavobacteriu, yeasts belonging to the genus Candida, the genus Rhodosporidium, the genus Criptococcus, the genus Rhodotorula, or the genus Yarro ia, and molds that belong to the genus Mucor, the genus Aspergillus, the genus Penicillium, or the genus Aureobasidiu. Specific examples of said microorganisms may include, for example, bacteria, such as Comamonas acidovorans ATCC 11299a, Ditto IFO 13582, flchromobacter aguatilis OUT 8003, Thodococcus sp. ATCC 15592, fí throbacter for fineus ATCC 21219, Rhodobacter sphaeroides ATCC 21286, Flavobacterium rigense No. 35 (FERM BP-5289); yeasts such as Candida maltose IAM 12247, Ditto JCM 1504, Candida parapsilosis IFO 0708, Candida rugosa IFO 0591, Candida tropicalis IFO 1401, Rhodosporidiu toruloides IFO 0559, Thodotorula gulutinis OUT 6152, Rhodotorula rubra OUT 6158, Yarrowia lipolytica IFO 0717, Ditto IFO 1209 , Cryptococcus laurentii OUT 6027 (FERM P-14400); molds such as fispergillus oryzae IFO 5710, flspergillus flavus IFO 5839, Mucor racemosus IFO 6745, Mucor hiemalis IFO 6753, Ditto OUT 1047, Mucor janssenii OUT 1050, Mucor circinelloides IFO 6746, Penicilliu notatum IFO 4640, Aureobasidiu pullulans IFO 6405, etc. These microorganisms can be used either as wild strains or mutant strains and those which are derived from these microorganisms in accordance with the biotechnological manner such as gene recombination and cell fusion. Examples of the means for cultivating the microorganisms include any medium in which the aforementioned microorganisms can grow. For example, a medium containing 0.4 to 152 carbon sources (eg, saccharide such as glucose, sucrose or molasses, organic acid such as fumaric acid or citric acid, or alcohol such as glycerol) can be preferably used. , and from 0.3% to 2.0X of nitrogen sources (eg, inorganic ammonium salt such as ammonium sulfate or ammonium chloride, urea, peptone, meat extract, corn steep liquor, yeast extract or hydrolyzed caffeine). Furthermore, if necessary, an appropriate amount of an inorganic salt such as phosphate, magnesium salt, potassium salt or calcium salt and a metal ion such as manganese or zinc may also be present in the medium. When a synthetic medium is used, if necessary, it is effective to add for example an amino acid such as proline or histidine, biotin or thiamine, etc. In addition, if necessary, from 0.1 to 2.0X of vegetable oil, a racemic trans-3-phenylglycinamide compound I and a surfactant can also be added as an enzyme-inducing substance or a foaming agent to increase the activity of the enzyme The medium is preferably used with adjustment at pH 5 to 7. The culture after inoculation of the microorganism in the aforementioned medium can be carried out in a conventional manner such as a shaking culture, a stirred culture with aeration, a stationary culture and a continuous culture. As long as the aforementioned microorganisms can grow to produce amidase, the culture conditions are not limited and can be appropriately selected depending on the type of the medium or the culture method. In general, it is desired to adjust the pH value of an initial culture to 5 to 7, and to carry out the cultivation at room temperature or under heat, for example, at a temperature of 20 ° C to 40 ° C. The treated culture or culture of microorganisms used in the present invention can be any that can hydrolyze preferably one of a (2R, 3S) and? (2S, 3R) isomer of racemic trans-3-phenylglycinamide compounds (I). Examples of the culture include culture broth and viable cells, and the treated culture includes washed cells, dried cells, culture supernatant, ground cells, self-digested cell product, cell extract of the aforementioned microorganism or purified or partially purified enzyme obtained therefrom. according to a conventional method. Viable cells or culture supernatant can be obtained by centrifugation or filtration of the culture broth which is prepared by culturing the microorganism as mentioned above. The washed cells are obtained by washing the viable cells with saline. The dried cells are obtained by subjecting viable cells or washed cells to lyophilization or drying with acetone. Lae milled cells are obtained by treating viable cells or cells washed with various physical-chemical methods, for example, ultrasonic treatment, French braiding, osmotic shock, freeze-thawing, milled with alumina, treatment with lytic enzyme, a surfactant or an organic solvent, and so on. Cell extracts are obtained, for example, by removing solid materials from ground cells by filtration, centrifugation, etc. The partially purified enzyme or the purified enzyme is obtained, for example, by fractionating ground or overcultured cells by a conventional method e.g., fractionation with ammonium sulfate, ion exchange chromatography or gel filtration chromatography, etc. .), and purifying them using a co-index of the ability to hydrolyze preferably one of an (2R, 3S) isomer and an (2S, 3R) isomer of compound (I). The above culture (viable cells, etc.) or the treated culture of the present invention can be used without any additional treatment, but it can also be immobilized by known methods such as the methods using polyacrylamide, a polysaccharide gel containing sulfur ( eg, carrageenan gel), an alginic acid gel or an agar gel, etc., before use. In addition, an enzyme obtained by purification of the microbial cell extract can be employed by combination of known methods as well. The preferential hydrolysis reaction of the trans-3-phenyl-glycidamide compound (I) by the aforementioned microorganisms is illustrated by the following scheme. where ring A and R * are the same as defined above. That is, by using a microorganism which has the ability to preferably hydrolyze a (2R, 3S) -3-phenylglycinamide compound of racemic trans-3-phenylglycidamide compounds (I), an optically active compound (2S, 3R) is obtained (IA). On the other hand, using a microorganism that has the ability to preferentially hydrolyse a (2S, 3R) -3-phenylglycinamide compound of trans-3-phenylglycidni compounds to racemic (I), a compound (2R, 3S) is obtained. ) optically active (IB). In accordance with the procedure of the present invention, the hydrolysis of the racemic trans-3-phenylglycinamide compounds (I) can be carried out by allowing the culture or the treated culture of the microorganism to come in contact with the trans-3 compounds. racemic phenylglycinamide (I) and incubating the mixture. The concentration of the substrate: composed of racemic trans-3-phenylglycidamide (I) can generally be from 0.1 to 80X by weight, preferably from 0.1 to 20% by weight, and the reaction can be carried out at room temperature or under heating, preferably at a temperature of 10 to 50 ° C, most preferably at a temperature of 20 to 40 ° C. During the reaction, it is preferable to adjust the pH value of the reaction mixture to 5 to 9, most preferably 6 to 8. As the reaction mixture, an aqueous solvent such as water, a mixture of water-dimethylformamide can be used , but from the standpoint of substrate stabilization, the reaction can be carried out in a two-phase solvent system of an aqueous solvent (eg, water, etc.) and an organic solvent. The organic solvent includes, for example, aromatic hydrocarbons (eg, toluene, xylene, chlorobenzene, etc.), halogenated or non-halogenated aliphatic hydrocarbons (eg, isooctane, carbon tetrachloride, dichloromethane, trichloromethane, etc.), esters of acetic acid (eg, ethyl acetate, butyl acetate, etc.), ketones (eg, methyl isobutyl ketone, acetone, etc.), ethers (eg, t-butylmethyl ether, diisopropyl ether, etc.), alcohols (eg, alcohol methyl, ethyl alcohol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, t-butyl alcohol, etc.). Among these solvents, toluene, methyl isobutyl ketone, methanol, ethanol and carbon tetrachloride are preferable. When the reaction is carried out in the presence of a surfactant, the reaction is promoted so that the reaction time is shortened, and the yield of desired optically active trans-3-phenylglycidamide compounds is increased. The surfactant can be cetylpyridinium bromide, cetyltrimilamonium bromide, polyethylene glycol, polyoxyethylene octylphenyl ether, etc., and the amount of the surfactant is preferably in the range of about 0.0001 to about 0.1% by weight based on the reaction mixture. .

The optically active trans-3-phenylglycinamide compound obtained by the above hydrolysis can be easily isolated from the reaction mixture by a conventional method. For example, when the hydrolysis is carried out in an aqueous solvent system such as water-dimethyl formamide, one of the active trans-3-phenylglycinamide compound is hydrolyzed and then decarboxylated to become the aldehyde compound, which can be subsequently changed into a water-soluble adduct by adding sodium acid sulfite thereto. On the other hand, the non-hydrolyzed optically active antipode is hardly soluble in water and therefore the optically active trans-3-phenylglycinamide compound ee can isolate as crystals of the reaction mixture after hydrolysis by extracting it with an organic solvent such ethyl acetate and concentrating under reduced pressure. When the hydrolysis is carried out in a two-fae solvent system of a water-organic solvent, one of the optically active trans-3-phenylglycinamide compound is hydrolyzed and migrates to the aqueous layer while the antipode compound optically The non-hydrolyzed active remains in the organic solvent and therefore the desired optically active compound can be isolated from the reaction mixture after hydrolysis by collecting the organic layer and concentrating under reduced pressure. The optically active trans-3-phenylglycinamide compound (IB) or (IA) thus obtained can be converted to the derivative of (2S, 3S) -l, 5-benzo-tiaze? Ina of the formula (III): wherein ring B is a substituted or unsubstituted benzene ring, R 2 is a hydrogen atom or a lower dialkylamino-lower alkyl group and ring A is the same as defined above, or the derivative of (2R, 3R) -2,5-benzothiazepine corresponding to formula IV: wherein ring A, ring B and R2 are the same as defined above, respectively, by reacting it with a 2-aminothiophenol derivative of the formula (II). wherein ring B and 2 are the rnismoe defined above, followed by subjecting the product to intramolecular cyclization reaction. The reaction of the compound (25, 3R) -3-phenylglycididene (Ifl) or the compound (2R, 3S) -3-phenylglycinamide (IB) with the 2-aminothiophenol derivative (II) can be carried out in the presence or absence of an appropriate iron catalyst (eg, iron sulfate, etc.) in an organic solvent (eg, xylene, etc.) The subsequent intramolecular cyclization reaction can be carried out in the presence or absence of an acid (eg , metaneulonic acid, etc.) in an organic solvent (eg, xylene, etc.) at a temperature of 0 to 250 ° C. Ring B of the 2-aminothiophenol derivative (II) used in the above reaction is a benzene ring which may optionally have a substituent selected from the lower alkyl group and a halogen atom. The lower dialkyl-lower alkyl group for R 2 is, for example, a dimethylaminomethyl group, a 2- (dimethylamino) ethyl group, etc. The starting material of racemic trans-3-phenylglycinamide (I) can be prepared for example , by the methods described in USP 4959359, etc. That is, the racemic trans-3-phenylglycinamide compound (I) is prepared by reacting a glycidic acid ester compound of the formula (VID: wherein the ring A is the same as defined above, with a compound of formula VIII: H2NRi (VIII) wherein R1 is the moiety defined above, in an appropriate solvent (eg, methanol, tetrahydrofuran, dimethylformamide, toluene, xylene, etc.), at a temperature of 0 to 100 ° C. In the claims and the specification, the lower alkyl group means an alkyl group of Ci-Ce and the lower alkoxy group means an alkoxy group of Ci-C.

EFFECTS OF THE INVENTION In accordance with the process of the present invention, an optically active trans-3-phenylglycinamide compound can be obtained as a high-purity crystal of the corresponding racemic trans-3-phenylglycinamide compounds in a single step. Therefore, the process of the present invention can be an industrially advantageous process for preparing the optically active trans-3-phenylglycide ida compounds. Further, in accordance with the present invention, an optically active 1,5-benzothiazepine derivative, which is useful as a medicament, can be easily prepared using the optically active trans-3-phenylglycidime compounds. Therefore, the process of the present invention is also useful for preparing optically active 1,5-benzothiazepine derivatives in an industrial scale.

EXAMPLES The present invention is illustrated by the following examples and reference examples, but should not be considered as limited thereto.

EXAMPLE 1 An a idasa producing medium (3 rnl) (components: 2% monosodium fumarate, 1% yeast extract, - 0.2% ammonium chloride, 0.2% dipotassium phosphate, 0.2% magnesium sulfate, heptahydrate 0.003% iron sulphate heptahydrate, 0.1% sodium chloride, 0.1% 6-caprolactam, pH 7.0) is loaded in a test tube (13 mm 0 x 120 mm) and sterilized at 120 ° C during 10 minutes. In the medium a platinum loop of various microorganisms is inoculated as listed in Table 1, and the culture (shaking culture) is carried out at 30 ° C for 24 hours (for bacteria), or for two days (for yeasts) with agitation at 300 rpm. To the culture broth (2.9 ml) thus obtained is added pH regulator Trie-HCl at 1.0 M (pH 7.0, 0.3 ml) and a solution (0.075 ml) of racemic trans-3- (4-methylphenyl) glycidamide (from here hereinafter referred to as racemic trans-MPGA (40 mg / ml) in dimethylformamide (DMF) (the total amount of racemic trans-MPGA; 3 mg), and the mixture is subjected to hydrolysis with agitation at 300 rpm at 30 ° C for 24 hours. The remaining amount (mg) of optically active MPGA in each reaction solution is determined in the following manner. Ethyl acetate (3 ml) is added to the reaction solution to extract MPGA. The lime acetate layer (100 ul) is collected and added in a mixture (2.9 ml) of n-hexane and isopropanol (15: 1). Eeta mueetra is analyzed by high performance liquid chromatography (HPLC) of CHIRALCEL OB-H (4.6 m 0 x 250 mm, manufactured by Daicel Chemical Induetries, Ltd.) and the remaining quantities of (2R, 3S) -MPGA and ( 2S, 3R) -MPGA in the reaction eeolution determined. HPLC is carried out as an eluent of a mixture of n-hexane: isopropanol (15: 1) at a flow rate of 1 ml / min at 40 ° C. The results are shown in Table 1. In Table 1, "preforms" means the amount of optically active MPGA in the reaction solution where the same procedures were carried out without a microorganism culture broth.

TABLE 1 Microorganisms The remaining amount of MPGA optically active (mg) isomer (2S, 3R) isomer (2R, 3S) Preform 1.28 1.28 Bacteria Comamonas acidovarans ATCC 11299a 0.87 < 0.01 Achromobacter to uatilie OUT 8003 0.35 1.23 Rhodococcus sp. ATCC 15592 0.03 1.17 Arthrobacter paraffineus ATCC 21219 0.23 1.28 Flavobacterium rigense NO. 35 0.84 1.28 (FERM BP-5289) Yeast Candida maltose IAM 12247 0.17 1.91 Candida maltose JCM 1504 0.83 1.15 Candida parapsilosis IFO 0708 0.14 0.92 Candida rugosa IFO 0591 0.18 1.04 Candida tropicalis IFO 1401 0.37 0.95 Rhodoeporidium toruloides IFO 0559 0.57 0.89 Rhodotorula gulutinie OUT 6152 0.23 0.09 Rhodotorula rubra OUT 6158 0.51 0.90 Yarrowia lipolytica IFO 0717 0.82 1.03 Yarroiia lipolytica IFO 1209 0.77 0.95 EXAMPLE 2 Using the same amidase-producing medium (pH 6.0) as used in Example 1 except that 3% glucose is used in place of 2% monoeodium fumarate, the microorganisms are cultured as listed in Table 2. Incubation is carried out for three days (for molds) or for two days (for yeast). To the culture broth thus obtained (3.0 ml) is added pH buffer Tris-HCl at 1.0 M (pH 7.0, 0.3 ml) and a solution (0.075 ml) of racemic trans-MPGA (40 mg / ml) in DMF, and the mixture is subjected to hydrolysis at 3 ° C for 24 hours with agitation at 300 rpm. The remaining amount (mg) of optically active MPGA in each reaction solution is determined in the same manner as in example 1. The results are shown in Table 2.

TABLE 2 Microorganism The remaining amount of optically active MPGA (mg) isomer (2S, 3R) isomer (2R, 3S) Preform 1.28 1.28 Molds Aspergillus oryzae IFO 5719 0.48 1.01 Aspergillue flavus IFO 5839 0.30 0.81 Mucor racemoeus, IFO 6745 1.28 0.64 Mucor hiemalie OUT 1047 1.32 0.18 Mucor janeeenii OUT 1050 1.48 1.12 Mucor circinelloidee IFO 6746 1.31 1.00 Mucor hie alis IFO 6753 1.38 0.85 Penicillium notatum IFO 4640 0.32 0.86 Aureobasidi? M pullulans IFO 6405 0.59 1.22 Yeast Cryptococcus laurentii OUT 6027 1.08 1.33 (FERM P-14400) EXAMPLE 3 Comamonas acidovarans ATCC 11299a is grown using 500 ml of volume shake flasks (20 flasks) with the amide-producing half mole (100 ml) used in example 1 is charged, at 30 ° C with shaking at 140 rpm for 24 hours. To the culture broth phosphate pH regulator is added to M (pH 7.10 ml) and a solution of racemic trans-MPGA (100 mg) in DMF (1 ml), and the reaction mixture is incubated at 30 ° C. with stirring at 140 rpm (total amount of eubstrate: 2 g / 20 flasks). After reacting for 1.5 hours, all the reaction mixtures are combined and acetone (6 liters, three times the volume of the reaction mixture) is added thereto. The mixture is stirred for 10 minutes to give cells etched with acetone. The obtained cells are removed by filtration using celite. The filtrate is concentrated under reduced pressure to remove the acetone, and the aqueous layer containing (2S, 3R) -MPGA is extracted with ethyl acetate (1.5 liters). The ethyl acetate layer is washed successively with sodium sulfite solution (pH 6.4, 600 ml), a saturated aqueous solution of sodium chloride (500 ml), an aqueous solution of sodium bicarbonate (pH 7-9), and a saturated aqueous solution of sodium chloride (500 ml x 3). The ethyl acetate layer is dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting solid is dissolved in toluene (200 ml) at 90 ° C. The solution is allowed to stand at room temperature for 1 hour, and then allowed to stand at 4 ° C for more than 2 hours. The precipitated (2S, 3R) -MPGA crystals are collected by filtration. Recrystallization field: First crystals 647 mg Seconds crystals 99.7 rng Third crystals 15.1 mg Total 761.8 mg Insulation yield (%) of the optically active compound: 76%. The results of the mechanical analysis: IR (KBr) vmax: 3402.2 cm-1, 3200 cm-i, 1640 cpri NMR (DMSO): 2.30 (s, 3H), 3.47 (d, 1H, J = 1.9Hz), 3.97 (d, 1H, J = 1.9HZ), 7.15-7.33 (4H), 7.42 and 7.57 (sx2, 1HX2) MS (m / z): 177 (M +) Optical purity: 100% ee (Analysis by CLAR ueando CHIRALCEL OB-H p.f. 176.5-177.5 ° C Optical rotation: C «] D26 = + 15B ° (c = 0.50, methanol) EXAMPLE 4 In the same manner as in Example 3, Comamonas acidovorans ATCC 11299a is grown with agitation in the a idase producing medium for 24 hours. To the culture broth phosphate pH regulator is added to the M (pH 7.10 ml) and a solution (1 ml) of trans-MPGP. racemic (100 g) in DMF, and the mixture is incubated with shaking at 140 rmp at 30 ° C. Every 2 ml of the reaction solution is collected at constant intervals, and the MPGA in the mixture is extracted with the same volume of ethyl acetate. The remaining amount of optically active MPGA in each sample is determined by HPLC analysis using CHIRALCEL 0B-H. The reaction is carried out in two eiste ae of reaction, ie Lot 0 and Lot B, and the change with time of the remaining amount of (2S, 3R) -MPGA and (2R, 3S) -MPGA in each batch. is shown in Tables 3 and 4. In Table 3 and 4, the hydrolysis ratio (%) of the racemic trans-MPGA and the optical purity of 2S, 3R) -MPGA are also indicated. The hydrolysis relationship (O (%) ee is calculated according to the following equation.

Ao + Bo: The amount of racemic MPGA added as an euet ato. A: The recurring amount of (2S, 3R) -MPGA B: The remaining amount of (2R, 3S) -MPGA TABLE 3 The results in lot A TABLE 4 The results in lot B EXAMPLE 5 Hydrolysis of racemic tra-3- (4-methoxyphenyl) glycidamide (racemic trans-MeOPGA): To an amidase product medium (components: 2% monosodium fumarate, 1% yeast extract, 0.2% ammonium chloride; 0.2% dipotassium phosphate, 0.02% magnesium sulfate heptahydrate: 0.003% iron sulphate heptahydrate, 0.1% sodium chloride, 0.1% 6-caprolactam, pH 7) is inoculated with Comamonas acidovarons ATCC 11299a, and the mixture incubate at 30 ° C with shaking at 300 rpm for 42 hours. To the culture broth (2.2 ml) are added pH buffer Tris-HCl at 0.4 M (pH 7.8 or 9, each 0.75 ml) and a solution (0.05 ml) containing racemic trans-MeOPGA (3 mg) in DMF , and the mixture is incubated at 30 ° C with shaking at 300 rpm for 25 minutes. The MeOPGA in the reaction solution is extracted with ethyl acetate (3 ml), and analyzed by HPLC using DHIRALCEL OD. The remaining ratio of (2S, 3R) -MeOPGA and (2R, 3S) -MeOPGA is shown in Table 5.

TABLE 5 Remaining retention (%) of optically active MeOPGA at several PH values Conditions for CLAR analysis: Column: CHIRALCEL OD Flow rate: 1.0 ml / min. Temperature: 40 ° C Detection: 235 nm Solvent: n-hexan: isopropanol = 20: 1 EXAMPLE 6 Microorganism producing (2S, 3R) -3- (4-methyl phenyl) glycidamide ((2S, 3R) -MPGA): To a 500 ml shake flask containing an amidase-producing medium (100 ml / matras, components : 2% monosodium fumarate, 1% yeast extract, 0.2% ammonium chloride, 0.2% dipotassium phosphate, 0.02% magnesium sulphate heptahydrate, 0.003% iron sulphate heptahydrate, 0.1% chloride sodium, 0.1% 6-caprolactam, pH 7) was inoculated with Comamonas acidovarans IFO 13582, and the mixture was incubated at 30 ° C with shaking at 140 rpm for 24 hours. To the culture broth is added phosphate pH regulator at 1 M (pH 7.10 ml) and a solution (1 ml) containing racemic trane-MPGA (100 mg) in DMF, and the mixture is incubated at 30 ° C. with stirring at 140 rpm for 6 hours. The MPGA in the reaction solution (2 ml) is extracted with ethyl acetate (2 ml), and analyzed by CLAR and CHIRALCEL OB-H. The remaining ratio of (2S, 3R) -MPGA and (2R, 3S) -MPGA is shown in Table 6.

TABLE 6 Conditions for CLAR analysis: Column: CHIRALCEL OB-H Flow rate: 1.0 ml / min. Temperature: 40 ° C Detection: 235 nm Solvent: n-hexan: isopropanol = 15: 1 Reference example 1 (1) A mixture of (2R, 3S) -3- (4-methoxyphenyl) glycidamide (1.93) and xylene (15 ml) is refluxed under nitrogen atmosphere. To the reaction solution is added a solution of 2-aminothiophenol (1.38 g) and iron sulphate heptahydrate (0.28 mg) in methane (0.2 ml) immediately after reflux begins. After the reaction at the same temperature for 5 minutes, the reaction solution is cooled to room temperature. The reaction solution is subjected to HPLC analysis to confirm the production of (3- (2-amonophenylthio) -2hi roxy -3- (4-methoxy phenyl) propionate a (2.69 g) (treo / erythro = 91/9) The reaction solution is concentrated under reduced pressure to remove the solvent, and the residue obtained is heated by heating in ethanol (3 ml) and water (3 ml) The solution is gradually cooled with stirring at 0 ° C for crystallization. The precipitated crystals are collected by filtration.The collected crystals are washed with ethanol on 50% ice, and are added at 50 ° C to give (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3-. (4-methoxyphenyl) propioamide (0.84 g) p-.f. 110-112 ° C [aJD26 = + 506o (c = 1.0, methanol) Conditions for HPLC analysis: Column: UATERS PURESIL 5u C18 120 fl (4.6 x 150 m) manufactured by Uaters, Inc. Solvent: Acetonitrile: 10 mM diacid potassium propylate (pH 3) = 30: 70. Flow rate: 1.0 ml / min UV detection: 254 nm Temperature: 40 ° C ( 2) One m The mixture of (2S, 3S) -3- (2-aminophenylthio) -2-hydroxy-3- (4-methoxy phenyl) propioamide (1.59 g) xylene and methanesulphonic acid (8 ml) is refluxed for 11 hours. The reaction is allowed to cool to room temperature with stirring. The precipitated crystals are collected by filtration, washed with cold methanol and dried at 50 ° C to give (2S, 3S) -3,2-dihydro-3-hydroxy-2- (4-methoxyphenyl) -1- benzothiazepin-4 (5H) -one (1.41 g). p.f. 203-205 ° CC «] D26 = + 114.3 ° (c = 0.5, dimethylformamide) 1 H-NMR (DMSO-dß, 6): 3.76 (3H, e), 4.30 (lH, dd), 4.74 (lH, d) , 5.05 (1H, d), 6.87-7.62 (9H,), 10.32 (lH, e). Optical purity by CLAR >; 99.9 e.e. %. Conditions for CLAR analysis: Column; CHIRALCEL OD (4.6 x 150 rnm), manufactured by Daicel Chemical Industries, Ltd Solvent: n-hexane: ethanol = 85: 15 Flow rate: 0.5 ml / min. UV detection: 254 nm Temperature: 35 ° C Reference example 2 (1) (2S, 3R) -3- (4-methylphenyl) glycidamide and 2-amino-5-methylthiophenol are treated in the same manner as in reference example 1- (1) to give (2R, 3R) - 3- (2-amino-5-methylphenylthio) -2-hydroxy-3- (4-methylphenyl) -propionamide. p.f. 145-146 ° C Ca] D25; -410 ° (c = 1, methanol) (2) (2R, 3R) -3- (2-amino-5-methylphenylthio) -2-hydroxy-3- (4-methyl) phenyl) -α-pyrionamide are treated in the same manner as in reference example 1- (1) to give (2R, 3R) -2,3-dihydro-3-hydroxy-2- (4-methyl phenyl) -8 -met i 1-1, 5-benzotacepin-4 (5H) -one. p.f. 212-214 ° C Ca] D 2 S; -219.2 ° (c = 1, dimethyl formate) 1 H-NMR (DMSO-dβ, d): 2.29 (3H, s), 4.29 (lH, dd), 4.67 (lH, d ), 5.03 (1H, d), 7.02-7.42 (7H, m), 10.20 (lH, e).

Claims (10)

NOVELTY OF THE INVENTION CLAIMS

1. - A process for preparing an optically active trane-3-phenylglycinamide compound, comprising subjecting a racemic trans-3-phenylglycinamide compound of the formula (I) wherein ring A is a substituted or unsubstituted benzene ring, and * is a hydrogen atom or a lower alkyl group, for optical resolution.

2. A process for preparing an optically active trane-3-phenylglycinamide compound according to claim 1, further characterized in that the optical resolution is carried out by contacting the racemic trans-3-phenylglycinamide compound (I) with a culture or a treated culture of a microorganism having the ability to preferentially hydrolyse one of a (2S, 3R) or an oomer (2R, 3S) of said racemic compound (I) to hydrolyze one of these isomers, and isolate and collecting the non-hydrolyzed optically active antipode from the reaction mixture.

3. - A method according to claim 2, further characterized the microorganism is a member selected from bacteria belonging to genus Comamonas, the genus Achromobacter, the genus Rhodococcus, the genus Arthrobacter, the genus Rhodobacter, or the genus Flavobacterium, yeasts belonging the genus Candida, the genus Rhodosporidiu, the genus Criptococcus, the genus Rhodotorula, or the genus Yarrowia, and molds that belong to the genus Mucor, the genus Aepergillus, the genus Penicillium, or the genus Aureobasidi? m.

4. A method according to claim 3, further characterized in that the microorganism is a member selected from acidovorane Comamonas, ñchromobacter aquatilis, Thodococcus ep. , Arthrobacter paraffineue, Rhodobacter sphaeroides, Flavobacterium rigense; maltose Candida, Candida parapsilosie, Candida rugoea, Candida tropicalie, Rhodosporidi? m toruloidee, Thodotorula gulutinie, Rhodotorula rubra, lipolytica Yarrowia, Cryptococcue laurentii, Aepergillue oryzae, Aspergillue flavus, Mucor racemosus, Mucor hiemalis, Mucor janssenii, Mucor circinelloidee, Penicillium notatum, Aureobasidium pull? Lane.

5. A method according to any of claims 2, 3 and 4, further characterized in that the microorganism has the ability to preferentially hydrolyse an (2R, 3S) isomer of the trans-3-phenylglycinamide compound (I).

6. - A method according to any of claims 2, 3 and 4, further characterized in that the microorganism has the ability to preferentially hydrolyse an (2S, 3R) isomer of the trans-3-phenylglycinamide compound (I).

7. A compliance method 5, further characterized in that the (2R, 3S) isomer of the trans-3-phenylglycididene compound (I) is (2R, 3S) -3- (4-methylphenyl) -glycidamide.

8. A method of compliance 6, further characterized in that the (2S, 3R) isomer of the trans-3-phenylglycidamide compound (I) is (2S, 3R) -3- (4-methylphenyl) -glycidide.

9. A process with any of claims 1 and 2, further characterized in that ring A of the trans-3-phenylglycinamide compound (I) is a benzene ring that can be optionally substituted by a group selected from a lower alkyl group , a lower alkoxy group and a halogen atom.

10. A process for preparing a (2S, 3S) -l, 5-enzotiazepine derivative of the formula (III): wherein ring A is a substituted or unsubstituted benzene ring, ring B is a substituted or unsubstituted benzene ring, and R2 is a hydrogen atom or a lower dialkylamino-lower alkyl group, or a derivative of (2R , 3R) -l, 5-benzothiazepine of the formula (IV): wherein ring A, ring B and R2 are the same as defined above, which comprises reacting the optically active trans-3-phenylglycinamide compound obtained in claim 1 or 2 with a 2-aminothiophenol derivative of the formula II): wherein ring A, ring B and R2 are the same as defined above, followed by subjecting the product to intramolecular cyclization reaction.