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    • 专利摘要:
    The present invention has the ability to asymmetrically amidify racemic trans-3- (4-lower alkoxyphenyl) glyacid esters with (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid esters. Acting on an amine compound in the presence of an enzyme derived from a genus of Serratia to stereoselectively amidate the (2S, 3R) isomers, and retain the remaining (2R, 3S) -3- (4-lower alkoxyphenyl) glysides. Novel process for separating (2R, 3S) -3- (4-lower alkoxyphenyl) glycolic acid esters and separating the acid esters from the reaction mixture and resulting (2R, 3S) -3- (4-lower) By alkoxyphenyl) -glycidic acid esters acting on the 2-aminophenol compound and hydrolyzing the resulting compound, optionally followed by intramolecular ring closure and o-alkanoylation and optionally N-alkylation , Novel of the (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid esters described above One method of preparation provides a method for preparing a (2S, 3S) -1,5-benzothiazepine compound useful as a medicament.
    公开号:KR20010031453A
    申请号:KR1020007004486
    申请日:1998-10-22
    公开日:2001-04-16
    发明作者:시바타니다케지；요시오카류조；마쓰마에히로아키；이데이아키코
    申请人:찌바따 이찌로, 다나까 도시오；다나베 세이야꾸 가부시키가이샤；
    IPC主号:
    专利说明:

    Process for preparing (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid esters
    Field of invention
    The present invention provides a process for the preparation of (2R, 3S) -3- (4-lower alkoxyphenyl) -glycidic acid esters by asymmetrical amidation of racemic trans-3- (4-lower alkoxyphenyl) glycolic acid esters and It relates to a method for preparing a (2S, 3S) -1,5-benzothiazepine derivative using the same.
    Background technology
    (2S, 3S) -1,5-benzothiazepine derivatives widely used as calcium channel blockers for the treatment of angina or essential hypertension, such as diltiazem hydrochloride. , 3S) -2- (4-methoxyphenyl) -3-acetoxy-5- [2- (dimethylamino) ethyl] -2,3-dihydro-1,5-benzothiazepine-4 (5H) -One hydrochloride) and the like are known to be usefully prepared by using a (2R, 3S) -3-phenylglycolic acid ester compound (see Japanese Patent Laid-Open No. 13776/1985 and Japanese Laid-Open Patent Publication). 145174/1986 and US Pat. No. 4,885,375.
    In addition, (2S, 3R) -3- (4-methoxyphenyl) glycolic acid methyl ester is racemic trans-3-of lipase SP523 (trade name, available from Novo Nordisk, Denmark). It is known to asymmetric amidation by action on (4-methoxyphenyl) glycidic acid methyl ester (WO 95/07359), but the enzyme activity and enzyme selectivity in this process are not sufficient. not.
    The present inventors have studied hardly amidation of racemic trans-3- (4-lower alkoxyphenyl) glycidic acid esters with fast reaction rates and excellent stereoselectivity.
    According to the study of the present inventors, racemic trans-3- (4-lower alkoxyphenyl) glycidic acid esters are combined with ammonia or lower alkyl amines in the presence of enzymes produced by microorganisms belonging to the genus Serratia genus. It has been found that asymmetric amidation by the reaction and the remaining esters can be separated and collected from the reaction mixture and the (2R, 3S) -3- (4-lower alkoxyphenyl) glycidic acid esters can be prepared in a short time with good efficiency The present invention was completed.
    Summary of the Invention
    The present invention
    (a) amide asymmetrically to the racemic trans-3- (4-lower alkoxyphenyl) glyacid ester compound of formula (I) and to the (2S, 3R) -3- (4-lower alkoxyphenyl) glyacid ester compound Stereoselectively amidation of (2S, 3R) isomers by acting on an amine compound of formula (II) in the presence of an enzyme derived from a microorganism belonging to the genus Serratia,
    (b) separating and collecting the remaining (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid ester compound from the reaction mixture (2R, 3S) -3- (4) A lower alkoxyphenyl) glycid acid ester compound is provided.
    In Formula I above,
    R 1 is a lower alkyl group,
    R is an ester moiety.
    In Formula II above,
    R 2 is a hydrogen atom or a lower alkyl group.
    In Formula III,
    R 1 and R are as defined above.
    Description of the Preferred Embodiments
    Embodiments of the present invention are described below.
    In the process of the invention, the lower alkyl group R 1 of formula (I) preferably comprises alkyl groups having 1 to 4 carbon atoms (eg methyl group, ethyl group, propyl group, n-butyl group, etc.), more preferably Preferably a methyl group. The ester moiety R may comprise an alkyl group which may have a substituent. Substituents of an alkyl group may include an alkoxy group having 1 to 4 carbon atoms, a hydrogen atom, and the like. Alkyl group R may comprise an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group, propyl group, isopropyl group, butyl group, pentyl group, hexyl group, etc.). R is preferably a lower alkyl group (eg methyl group, ethyl group, etc.), particularly preferably methyl group.
    Lower alkyl groups R 2 of formula (II) preferably comprise alkyl groups having 1 to 4 carbon atoms (eg methyl groups, ethyl groups, propyl groups, n-butyl groups, etc.), more preferably methyl groups . The amine compound of formula (II) is preferably a compound in which R 2 is a hydrogen atom.
    In the present invention, as the starting material, racemic trans-3- (4-lower alkoxyphenyl) glycidic acid ester compound of formula (I) as well as a compound containing the same amount of (2R, 3S) isomer and (2S, 3R) isomer But compounds containing both optically active isomers in any ratio can be used.
    As an enzyme that can be used in the process of the present invention, an enzyme derived from a microorganism belonging to the genus Serratia, which has the ability to asymmetrically amidate (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid ester compound Mention may be made, for example, of lipases, esterases and the like produced by Serratia marcescens et al. Microorganisms belonging to the genus Serratia may be wild strains or mutant strains and may further be strains derived from such microorganisms according to biotechnological methods (eg, gene recombination and cell fusion).
    Such enzymes can generally be isolated and purified from the culture broth of the microorganism from which the enzyme is produced.
    Enzymes derived from the microorganism belonging to the genus Ceratia used in the present invention are commonly known methods such as polyacrylamide method, sulfur-containing polysaccharide gel method (e.g. carrageenan gel method), Alginate gel method, agar gel method, photocross-linkable resin method, polyethylene glycol method, Celite (trade name, Celite Corporation, USA) ), Etc., to fix it before use.
    Asymmetric amidation according to the invention is represented by Scheme 1.
    In Scheme 1 above,
    R, R 1 and R 2 are as defined above.
    That is, asymmetrically amidation of the racemic trans-3- (4-lower alkoxyphenyl) glyacid ester compound of formula (I) with the (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid ester compound In the presence of an enzyme derived from a microorganism belonging to the genus Serratia, which acts on an amine compound of formula (II) in a suitable solvent to stereoselectively amidate the (2S, 3R) isomer and retain (2R, 3S)- By separating and collecting the 3- (4-lower alkoxyphenyl) glyacid ester compound from the reaction mixture, a preferred (2R, 3S) -3- (4-lower alkoxyphenyl) glycolic acid ester compound can be obtained.
    The concentration of the racemic trans-3- (4-lower alkoxyphenyl) glyacid ester compound of formula I in one of the substrates of the process of the invention is generally about 0.1 to 80% (w / w) and And particularly preferably 1 to 20% (w / w). In addition, the amine compound of formula (II), which is another substrate, is preferably in an amount of 0.5 to 3.0 mol, especially 0.6 to 2.0 mol per mol of the racemic trans-3- (4-lower alkoxyphenyl) glyacid ester compound of formula (I). use. In addition, the concentration of the amine compound of the formula (II) in the reaction mixture is generally about 0.1 to 5% (w / w), particularly preferably 0.2 to 2% (w / w). If the amount of the amine compound of formula II in the reaction mixture is reduced, it can be added continuously or continuously. The reaction proceeds suitably at room temperature or while heating, preferably at 10 to 50 ° C, particularly preferably at 20 to 40 ° C.
    As solvents, aromatic hydrocarbon solvents that can be halogenated (e.g. benzene, toluene, xylene, chlorobenzene, etc.), aliphatic hydrocarbon solvents that can be halogenated (e.g. hexane, cyclohexane, heptane, isooctane, dichloroethane, trichloroethane , Carbon tetrachloride, etc.), ester solvents (e.g. ethyl acetate, butyl acetate, etc.), ketone solvents (e.g. methyl isobutyl ketone, etc.), ether solvents (e.g. tertiary butyl methyl ether, isopropyl ether, 1,4- Dioxane, tetrahydrofuran and the like), nitrile solvents such as acetonitrile and the like, and alcohol solvents such as isopropanol, tert-butanol, and the like. Among these solvents, preference is given to using aromatic hydrocarbon solvents, ether solvents and ester solvents, particularly preferably toluene, tertiary butyl methyl ether, ethyl acetate and butyl acetate. In the process of the present invention, it is preferred to carry out the reaction in an organic solvent which does not contain enough water to prevent hydrolysis of the racemic trans-3- (4-lower alkoxyphenyl) glycolic acid ester compound of formula (I). Do.
    Separation and collection of the (2R, 3S) -3- (4-lower alkoxyphenyl) glycolic acid ester compound of the formula (III) thus obtained from the reaction mixture can be easily carried out in a conventional manner. For example, after completion of the enzyme reaction, the enzyme is filtered off and the filtrate is concentrated under reduced pressure. The residue is then dissolved in an aromatic hydrocarbon solvent such as toluene and the precipitate is filtered off to remove the (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid amide compound. The solvent is then removed from the filtrate, alcohol solvent (e.g. methanol) is added to the residue to crystallize the resulting material, and the crystals are filtered to give (2R, 3S) -3- (4-lower alkoxyphenyl) glycol of formula III. Obtain a seed acid ester compound.
    The (2R, 3S) -3- (4-lower alkoxyphenyl) -glycidic acid ester compound of formula III thus obtained is reacted with the 2-aminothiophenol compound of formula IV and, optionally, the ester portion of the product After hydrolysis, the resultant compound was closed intramolecularly to obtain the (2S, 3S) -1,5-benzothiazepine compound of the formula (V).
    In Formula IV above,
    R 3 is a hydrogen atom or a di lower alkylamino lower alkyl group,
    Ring A is a benzene ring which may be substituted.
    In Formula V above,
    R 1 is a lower alkyl group,
    Rings A and R 3 are as defined above.
    The reaction of the (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid ester compound of formula III with the 2-aminothiophenol compound of formula IV is carried out in a suitable organic solvent in the presence or absence of an iron catalyst Can be.
    As solvents, aromatic hydrocarbon solvents which can be halogenated (eg benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene or trichlorobenzene) and alcohol solvents (eg methanol, ethanol or propanol), particularly preferably methanol Mention may be made of xylene, chlorobenzene and dichlorobenzene.
    As iron catalysts, mention may be made of inorganic or organic salts or complexes having divalent or trivalent iron ions. Specific examples of such iron catalysts are iron nitrate, iron hydroxide (III) oxide [FeO (OH)], iron chloride, ferric chloride, iron sulfate, ferrous iodide, iron sulfide, iron 4-cyclohexylbutyrate, iron oxide, iron bromide, ferrous fluoride, Iron fluoride and the like, and in particular, it is preferable to use iron chloride, iron sulfate, iron nitrate and the like.
    The reaction is suitably carried out at 60 to 200 ° C, in particular at 100 to 150 ° C.
    The hydrolysis of the ester portion of the product is carried out according to commonly known hydrolysis methods of esters, for example, bases such as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkaline earth metal hydroxides such as calcium hydroxide, and the like. Or by hydrolysis of the product with an acid such as inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid.
    Subsequent intramolecular ring closure can be carried out in a suitable solvent at 0-250 ° C., in particular 80-200 ° C., with or without acid or base.
    As the solvent, any solvent can be used as long as it does not interfere with the reaction. Such solvents can be halogenated aromatic hydrocarbon solvents (e.g. benzene, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, trichlorobenzene or naphthalene), aliphatic hydrocarbon solvents that can be halogenated (e.g. methylene chloride, carbon tetrachloride, Dichloroethane or cyclohexane), aprotic polar solvents such as N, N-dimethylformamide or dimethylsulfoxide, ketone solvents such as acetone or methyl ethyl ketone, ester solvents such as ethyl acetate or butyl acetate ), Ether solvents such as dioxane or tetrahydrofuran, nitrile solvents such as acetonitrile and alcohol solvents such as methanol, ethanol or propanol. These solvents may optionally be used in the form of a single phase or a dual phase in appropriate proportions in two or more kinds of mixtures. Among these solvents, alcohol solvents, halogenated aromatic hydrocarbon solvents and ether solvents are preferred, and chlorobenzene, dichlorobenzene, toluene, xylene and mesitylene are particularly preferred. Intramolecular ring closure is preferably carried out in the absence of water to prevent hydrolysis.
    As the acid, Bronsted acid or Lewis acid can be used. As Bronsted acid, organic or inorganic acids can be used, inorganic acids (e.g. hydrochloric acid, sulfuric acid, phosphoric acid, phosphonic acid, hydrofluoric acid, hydrobromic acid or perchloric acid), lower alkanoic acids (e.g. formic acid, acetic acid, propionic acid or butyric acid) Hydroxy group-substituted lower alkanoic acid (e.g. citric acid), halogeno lower alkanoic acid (e.g. trifluoroacetic acid), lower alkanesulfonic acid (e.g. methanesulfonic acid or ethanesulfonic acid), arylsulfonic acid (e.g. : p-toluenesulfonic acid or benzenesulfonic acid), oxalic acid and the like can be mentioned. As the Lewis acid, titanium tetrachloride, aluminum chloride, boron trifluoride, tin chloride and the like can be used. Among these acids, inorganic acids, lower alkanoic acids or arylsulfonic acids are preferred, and methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, hydrochloric acid and hydrobromic acid are particularly preferred.
    As the base, an inorganic base or an organic base can be used. Such bases include alkali metal hydrogen carbonates (e.g. sodium bicarbonate or potassium hydrogen carbonate), alkali metal carbonates (e.g. sodium carbonate or potassium carbonate), alkali metal hydroxides (e.g. sodium or potassium hydroxide), alkali metal amides (e.g. : Sodium amidide, lithium amidated or potassium amidated), alkali metal alkoxide (e.g. sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide), alkali metal (e.g. metal lithium, sodium metal, potassium metal) ), Alkaline earth metals such as calcium, organic bases such as 1,8-diazabicyclo [5.4.0] undec-7-ene, diisopropylamine, triethylamine or pyridine, and the like. have.
    The reaction between the (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid acid ester compound of formula III and the 2-aminothiophenol compound of formula IV and the intramolecular ring closure are a one-pot reaction. ). That is, the reaction of the (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid acid ester compound of formula III with the 2-aminothiophenol compound of formula IV, followed by addition of an acid or a base directly to the reaction mixture Perform my ringback.
    In the above-mentioned process, it is preferred if R is a lower alkyl group (eg methyl group or ethyl group) and ring A is an unsubstituted benzene ring or a halogen substituted benzene ring, R and R 1 are methyl groups, It is especially preferable when R <3> is a hydrogen atom and ring A is an unsubstituted benzene ring.
    The (2S, 3S) -1,5-benzothiazepine compound thus derived is o-alkanoylated and when R 3 is a hydrogen atom, N-alkylated to di-lower alkylamino-lower alkyl in a conventional manner. A group is introduced and optionally, the product is converted to a pharmaceutically acceptable salt to obtain a (2S, 3S) -1,5-benzothiazepine compound of formula VI or a pharmaceutically acceptable salt thereof.
    In Formula VI above,
    R 4 is a di-lower alkylamino-lower alkyl group,
    R 5 is a lower alkanoyl group,
    R 1 and ring A are as defined above.
    O-alkanoylation mentioned above is described, for example, in Japanese Patent Publication No. 16749/1971, Japanese Patent Publication No. 13994/1988, and Japanese Patent Publication No. 28594/1990 and Japanese Laid-Open Patent Publication. 99471/1983] and the like can be carried out easily.
    In addition, introduction of di-lower alkylamino-lower alkyl groups by N-alkylation when R 3 is a hydrogen atom is described, for example, in Japanese Patent No. 116749/1971 and Japanese Patent No. 13942. 1988 and JP 28594/1990, JP 99471/1983, JP 118377/1986, JP 78673/1990, JP 228117 / 1994 and Japanese Unexamined Patent Publication No. 269026/1996, etc., can be easily performed.
    In the above-mentioned conversion method, it is preferable that R 1 is a methyl group, R 3 is a hydrogen atom, R 4 is a dimethylaminoethyl group, R 5 is an acetyl group, and ring A is an unsubstituted benzene ring.
    Incidentally, the lower alkyl group herein may include a straight or branched alkyl group having 1 to 4 carbon atoms, and the lower alkanoyl group may include a straight or branched chain alkanoyl group having 2 to 5 carbon atoms.
    Industrial availability
    In the process of the present invention, the (2S, 3R) isomer of racemic trans-3- (4-lower alkoxyphenyl) glyacid ester is selected from (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid. By using an enzyme derived from a microorganism belonging to the genus Cerratia, which has the ability to asymmetrically asterize esters, it is significantly faster and has better stereoselectivity than the method described in WO 95/07359. It can be amidated and the (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid ester can be separated and collected with good efficiency.
    The (2R, 3S) -3- (4-lower alkoxyphenyl) glycolic acid esters thus obtained are useful for the preparation of (2S, 3S) -1,5-benzothiazepine compounds such as diltiazem hydrochloride. Do. Thus, when using the process of the present invention, (2S, 3S) -1,5-benzothiazepine compounds can be prepared from racemic trans-3- (4-lower alkoxyphenyl) glycidic acid esters with good efficiency. have.
    Example
    Example 1
    Toluene (86 mL), racemic trans-3- (4-methoxyphenyl) glycolic acid methyl ester (hereinafter abbreviated as ″ racemic ester ″) in a 200 mL branch flask, 5 g of ammonia Grade butanol solution (2.65 mol / l, 14 ml) and Serratia marcesense Sr 41 [Reference: Fermentation Research Institute Agency, International Depository, 1-3, Higashi 1-chome, Tsukuba-shi, Ibarakiken, Japan, dated February 20, 1984] a lipase derived from the International Accession No. FERM BP-487 to the Industrial Institute of Bioscience and Human-Technology (NIBH), hereafter abbreviated ″ lipase SM ″. Charge 1 g). After the flask was sealed, the mixture was reacted at 30 ° C. under 300 rpm for 4.5 hours.
    Lipase SM used in the above reaction was cultured according to the method described in Reference Example of JP-78790 / 1994 and sterilized by MF film [EMP-313, trade name, available from Asahi Kasei]. And lyophilized to prepare. In addition, the olive oil decomposition activity described in the reference example of Unexamined-Japanese-Patent No. 4 is 4.95x10 <5> unit / g (it is the same hereafter). Ammonia gas was bubbled into tert-butanol for 4 hours under ice-cooling to prepare a tert-butanol solution of ammonia (2.65 mole / l), and a potentiometer automatic titrator (available from Kyoto Denshi Kogyo) was prepared. To measure the ammonia concentration.
    The reaction mixture is analyzed according to the equipment and conditions for high performance liquid chromatography (HPLC) described below, and the analysis results are quantified by comparing the analysis results with the analysis results of pure products. As a result, 50.4% of the racemic ester substrate (the molar number of the substrate is made up to 100%, is the same thereafter) is decomposed and (2R, 3S) -3- (4-methoxyphenyl) glycidyl methyl ester (Hereinafter referred to as "(2R, 3S) ester") and 49.4% and (2S, 3R) -3- (4-methoxyphenyl) glyacid amide (hereinafter referred to as "(2S, 3R) amide" 49.6% was found to be contained in the reaction mixture.
    Column: CHIRALCEL OB-H, available from Daicel Chemical Industries, Ltd.
    Mobile phase: n-hexane: isopropanol = 9: 1
    Flow rate: 1.0 ml / min
    Temperature: 40 ℃
    Detection: 235nm
    The enzyme is filtered from the reaction mixture thus obtained, the filtered material is washed with acetone, the filtrate and wash water are combined, and the solvent is removed under reduced pressure. Toluene (26 mL) is added to the residue to dissolve it, the solution is filtered through a glass filter, and the filtered material is washed with toluene. The filtrate and wash water are combined, toluene is removed from the mixture, and then methanol (10 ml) is added thereto to crystallize the amber product obtained. The crystals are filtered through a glass filter and washed twice with methanol (5 mL) to give (2R, 3S) ester (2.07 g, yield: 41%) as crystals. The filtrate and wash water are combined, ice-cooled, and the precipitated crystals are collected by filtration and (2R, 3S) ester (0.15 g, yield: 3%) is obtained as crystals. Total yield isolated: 44%. When the two crystals were analyzed in the same manner as mentioned above, the optical purity was found to be 99.9% or more.
    Example 2
    In a test tube (6 test tubes) each 1.5 cm in diameter and 12.3 cm in length, toluene (1.72 ml), racemic ester (100 mg), tertiary butanol solution of ammonia (2.65 mole / L, 0.28 ml) and lipase SM ( 20 mg) are filled and each test tube is sealed with a screw cap, and then the mixture is reacted at 30 ° C. at 300 rpm.
    At 0, 15, 30, 1, 2 or 5 hours from the beginning of the reaction, the test tubes are taken one by one and N, N-dimethylformamide is added to the test tubes to stop the enzyme reaction. When the resulting material is sampled from each reaction mixture and titrated by HPLC in the same manner as mentioned above, 49.3% of the racemic ester of the substrate is decomposed 2 hours after the start of the reaction, and the (2R, 3S) ester 49.9 %, (2S, 3R) -3- (4-methoxyphenyl) glycolic acid methyl ester 0.8% (hereinafter referred to as ″ (2S, 3R) ester ″) and 46.7% of (2S, 3R) amide It was found to be contained in the mixture.
    When E value which shows the stereoselectivity of an enzyme is calculated by Formula (1) based on the above result, E value computed from composition ratio is 3457 after 2 hours from the beginning of reaction.
    In Equation 1 above,
    1-C is the amount of trans-3- (4-methoxyphenyl) glycidic acid methyl ester (containing the optical isomers, hereinafter referred to as the amount of the residual ester) (as in Example 1, the amount of racemic ester Ee is the optical purity of the (2R, 3S) ester in the remaining ester (calculated on the basis of 100% optical purity as in Example 1).
    The change in the amount of each compound in the reaction mixture over time is described in Table 1.
    Elapsed time (hours)% Of residual esterAmount of (2R, 3S) Ester (%)Amount of (2S, 3R) Ester (%)Amount of (2S, 3R) Amide (%) 0100.050.050.00.0 1/473.850.023.823.9 1/261.850.011.837.3 One53.850.03.843.2 250.749.90.846.7 549.649.60.049.4
    Example 3
    In a test tube 1.5 cm in diameter and 12.3 cm in length, toluene (1.72 ml), racemic ester (100 mg), tertiary butanol solution of ammonia (2.65 mole / L, 0.28 ml), 1,3-dimethoxybenzene (internal) Standard, 5 μL) and Lipase SM (50 mg) are charged, the test tube is sealed with a screw cap, and the mixture is allowed to react at 40 ° C. at 300 rpm for 15 minutes. N, N-dimethylformamide is added to the test tube to stop the enzymatic reaction and the resulting material is titrated by HPLC in the same manner as mentioned above by the sampling portion of the reaction mixture. As a result, 49.4% of the racemic ester used as the substrate is decomposed and 48.2% of the (2R, 3S) ester is contained in the reaction mixture, while only 2.3% of the (2S, 3R) ester is contained in the reaction mixture.
    Example 4
    In a test tube 1.5 cm in diameter and 12.3 cm long, toluene (1.72 ml), racemic ester (100 mg), tertiary butanol solution of ammonia (3.0 mole / L, 0.28 ml), 1,3-dimethoxybenzene (internal) Standard, 5 μL) and Lipase SM (10 mg) are charged, the test tube is sealed with a screw cap, and the mixture is reacted at 30 ° C. under 300 rpm for 4 hours. N, N-dimethylformamide is added to the test tube to stop the enzymatic reaction and the resulting material is titrated by HPLC in the same manner as mentioned above by the sampling portion of the reaction mixture. The amounts of (2R, 3S) esters and (2S, 3R) esters contained in the reaction mixture are listed in Table 2.
    Organic solventAmount of (2R, 3S) Ester (%)Amount of (2S, 3R) Ester (%) Ethyl acetate48.90.6 n-butyl acetate49.60.6 Tert-butyl methyl ether47.80.2
    权利要求:
    Claims (9)
    [1" claim-type="Currently amended] (a) Asymmetrically amidating the racemic trans-3- (4-lower alkoxyphenyl) glycolic acid ester of formula (I) with (2S, 3R) -3- (4-lower alkoxyphenyl) glycolic acid ester Stereoselectively amidation of (2S, 3R) isomers by acting on an amine compound of formula (II) in the presence of an enzyme derived from a microorganism belonging to the Serratia genus
    (b) separating and collecting the remaining (2R, 3S) -3- (4-lower alkoxyphenyl) glyacid ester from the reaction mixture, (2R, 3S) -3- (4- Process for the preparation of lower alkoxyphenyl) glycidic acid esters.
    Formula I

    In Formula I above,
    R 1 is a lower alkyl group,
    R is an ester moiety.
    Formula II

    In Formula II above,
    R 2 is a hydrogen atom or a lower alkyl group.
    Formula III

    In Formula III above,
    R 1 and R are as defined above.
    [2" claim-type="Currently amended] The method of claim 1 wherein R is a lower alkyl group.
    [3" claim-type="Currently amended] The method of claim 1, wherein R 2 is a hydrogen atom.
    [4" claim-type="Currently amended] The method of claim 1, wherein R 1 and R are both methyl groups.
    [5" claim-type="Currently amended] The method of claim 1, wherein the enzyme is a lipase or esterase.
    [6" claim-type="Currently amended] The method of claim 1, wherein the microorganism belonging to the genus Serratia is Serratia marcescens.
    [7" claim-type="Currently amended] The (2R, 3S) -3- (4-lower alkoxyphenyl) -glycolic acid ester obtained by the process according to claim 1 is reacted with a 2-aminothiophenol compound of the formula (IV) and, optionally, an ester of the product A method for preparing a (2S, 3S) -1,5-benzothiazepine compound of Formula (V), comprising hydrolyzing a portion thereof and then closing the resulting compound intramolecularly.
    Formula IV

    In Formula IV above,
    R 3 is a hydrogen atom or a di-lower alkylamino-lower alkyl group,
    Ring A is a benzene ring which may be substituted.
    Formula V

    In Formula V above,
    R 1 is a lower alkyl group,
    Rings A and R 3 are as defined above.
    [8" claim-type="Currently amended] The (2S, 3S) -1,5-benzothiazepine compound of formula V obtained by the process according to claim 7 is o-alkanoylated and when R 3 is a hydrogen atom, N-alkylated to di-lower alkyl (2S, 3S) -1,5-benzothiazepine compound or medicament of formula (VI), comprising introducing an amino-lower alkyl group and then optionally converting the resulting compound into a pharmaceutically acceptable salt A method for preparing a salt thereof, which is acceptable.
    Formula V

    In Formula V above,
    R 3 is a hydrogen atom or a di-lower alkylamino-lower alkyl group,
    Ring A is a benzene ring which may be substituted.
    R 1 is a lower alkyl group.
    Formula VI

    In Formula VI above,
    R 4 is a di-lower alkylamino-lower alkyl group,
    R 5 is a lower alkanoyl group,
    Rings A and R 1 are as defined above.
    [9" claim-type="Currently amended] The method of claim 8, wherein ring A is an unsubstituted benzene ring, R 1 is a methyl group, R 4 is a dimethylaminoethyl group and R 5 is an acetyl group.
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    同族专利:
    公开号 | 公开日
    JPH11192098A|1999-07-21|
    JP3252900B2|2002-02-04|
    CN1273608A|2000-11-15|
    IL135149D0|2001-05-20|
    AU9645898A|1999-05-17|
    WO1999022014A1|1999-05-06|
    EP1029071A1|2000-08-23|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1997-10-27|Priority to JP97-294685
    1997-10-27|Priority to JP29468597
    1998-10-22|Application filed by 찌바따 이찌로, 다나까 도시오, 다나베 세이야꾸 가부시키가이샤
    1998-10-22|Priority to PCT/JP1998/004776
    2001-04-16|Publication of KR20010031453A
    优先权:
    申请号 | 申请日 | 专利标题
    JP97-294685|1997-10-27|
    JP29468597|1997-10-27|
    PCT/JP1998/004776|WO1999022014A1|1997-10-27|1998-10-22|Process for preparing -3-glycidic acid esters|
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