WO1999022014A1 - Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique - Google Patents

Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique Download PDF

Info

Publication number
WO1999022014A1
WO1999022014A1 PCT/JP1998/004776 JP9804776W WO9922014A1 WO 1999022014 A1 WO1999022014 A1 WO 1999022014A1 JP 9804776 W JP9804776 W JP 9804776W WO 9922014 A1 WO9922014 A1 WO 9922014A1
Authority
WO
WIPO (PCT)
Prior art keywords
glycidic acid
alkyl group
acid ester
lower alkyl
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1998/004776
Other languages
English (en)
Inventor
Takeji Shibatani
Ryuzo Yoshioka
Hiroaki Matsumae
Akiko Idei
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Tanabe Pharma Corp
Original Assignee
Tanabe Seiyaku Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tanabe Seiyaku Co Ltd filed Critical Tanabe Seiyaku Co Ltd
Priority to KR1020007004486A priority Critical patent/KR20010031453A/ko
Priority to AU96458/98A priority patent/AU9645898A/en
Priority to EP98950335A priority patent/EP1029071A1/fr
Priority to IL13514998A priority patent/IL135149A0/xx
Publication of WO1999022014A1 publication Critical patent/WO1999022014A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D281/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D281/02—Seven-membered rings
    • C07D281/04—Seven-membered rings having the hetero atoms in positions 1 and 4
    • C07D281/08—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
    • C07D281/10—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/02—Oxygen as only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures

Definitions

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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Analytical Chemistry (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
  • Epoxy Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Nouveau procédé servant à préparer un ester d'acide (2R,3S)-3-(4-alkoxyphényle inférieur)glycidique et procédé servant à préparer un composé de (2S,3S)-1,5-benzothiazépine utile en tant que médicament au moyen dudit ester. La préparation de cet ester consiste à effectuer la réaction d'un ester racémique d'acide trans-3-(4-alkoxyphényle inférieur)glycidique avec un composé d'amine en présence d'une enzyme provenant d'un micro-organisme appartenant au genre Serratia et pouvant créer des groupes amido asymétriques sur l'ester d'acide (2S,3R)-3-(4-alkoxyphényle inférieur)glycidique et, par conséquent, des groupes amido stéréosélectifs sur l'isomère de (2R,3S), puis à séparer et à recueillir un ester restant d'acide (2R,3S)-3-(4-alkoxyphényle inférieur)glycidique depuis le mélange réactionnel. La préparation du composé de (2S,3S)-1,5-benzothiazépine consiste à effectuer la réaction de l'ester obtenu d'acide (2R,3S)-3-(4-alkoxyphényle inférieur)glycidique avec un composé de 2-aminophénol, à hydrolyser le composé obtenu, si nécessaire, puis à le soumettre à une cyclisation intramoléculaire et à une O-alkanoylation et, si on le souhaite, à une N-alkylation.
PCT/JP1998/004776 1997-10-27 1998-10-22 Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique Ceased WO1999022014A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
KR1020007004486A KR20010031453A (ko) 1997-10-27 1998-10-22 (2ｒ,3ｓ)-3-(4-저급 알콕시페닐)글리시드산 에스테르의제조방법
AU96458/98A AU9645898A (en) 1997-10-27 1998-10-22 Process for preparing (2r,3s)-3-(4-lower alkoxyphenyl)glycidic acid esters
EP98950335A EP1029071A1 (fr) 1997-10-27 1998-10-22 Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique
IL13514998A IL135149A0 (en) 1997-10-27 1998-10-22 Process for preparing (2r, 3s)-3-(4-alkoxyphenyl) glycidic acid esters

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/294685 1997-10-27
JP29468597 1997-10-27

Publications (1)

Publication Number Publication Date
WO1999022014A1 true WO1999022014A1 (fr) 1999-05-06

Family

ID=17810991

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1998/004776 Ceased WO1999022014A1 (fr) 1997-10-27 1998-10-22 Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique

Country Status (7)

Country Link
EP (1) EP1029071A1 (fr)
JP (1) JP3252900B2 (fr)
KR (1) KR20010031453A (fr)
CN (1) CN1273608A (fr)
AU (1) AU9645898A (fr)
IL (1) IL135149A0 (fr)
WO (1) WO1999022014A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100379756B1 (ko) * 2000-10-02 2003-04-11 한국과학기술연구원 이성질체 분할방법

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100400669C (zh) * 2003-03-12 2008-07-09 科学和工业研究委员会 用于制备旋光上经富集的苯基缩水甘油酸酯的立体选择性化学酶方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0446771A2 (fr) * 1990-03-13 1991-09-18 Tanabe Seiyaku Co., Ltd. Estérase de Serratia et procédé de préparation
JPH0678790A (ja) * 1992-09-03 1994-03-22 Tanabe Seiyaku Co Ltd 光学活性３−（４−メトキシフェニル）グリシッド酸エステル類化合物の製法
JPH08259552A (ja) * 1995-03-23 1996-10-08 Tanabe Seiyaku Co Ltd 光学活性フェニルグリシッド酸エステル類の製法
EP0795609A2 (fr) * 1996-03-15 1997-09-17 Tanabe Seiyaku Co., Ltd. Procédé de préparation de composés trans-3-phénylglycidamidiques optiquement actifs
JPH1028596A (ja) * 1996-04-08 1998-02-03 Tanabe Seiyaku Co Ltd 不斉アミド化による（２ｓ，３ｒ）型３−（非置換フェニルまたは低級アルキル−フェニル）グリシッドアミド類化合物の製法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0446771A2 (fr) * 1990-03-13 1991-09-18 Tanabe Seiyaku Co., Ltd. Estérase de Serratia et procédé de préparation
JPH0678790A (ja) * 1992-09-03 1994-03-22 Tanabe Seiyaku Co Ltd 光学活性３−（４−メトキシフェニル）グリシッド酸エステル類化合物の製法
JPH08259552A (ja) * 1995-03-23 1996-10-08 Tanabe Seiyaku Co Ltd 光学活性フェニルグリシッド酸エステル類の製法
EP0795609A2 (fr) * 1996-03-15 1997-09-17 Tanabe Seiyaku Co., Ltd. Procédé de préparation de composés trans-3-phénylglycidamidiques optiquement actifs
JPH1028596A (ja) * 1996-04-08 1998-02-03 Tanabe Seiyaku Co Ltd 不斉アミド化による（２ｓ，３ｒ）型３−（非置換フェニルまたは低級アルキル−フェニル）グリシッドアミド類化合物の製法

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
APPL. BIOCHEM. BIOTECHNOL. (1996), 59(3), 319-328 *
CHEMICAL ABSTRACTS, vol. 121, no. 9, 29 August 1994, Columbus, Ohio, US; abstract no. 106699, SHIBATANI, TAKEJI ET AL: "Manufacture of optically active glycidic acid esters with esterase and preparation of diltiazem from the glycidic acid esters" XP002089880 *
CHEMICAL ABSTRACTS, vol. 124, no. 13, 25 March 1996, Columbus, Ohio, US; abstract no. 173468, FURUI, MASAKATSU ET AL: "Development of membrane bioreactor for industrial production of optically active 3-phenylglycidic acid ester" XP002089882 *
CHEMICAL ABSTRACTS, vol. 125, no. 7, 12 August 1996, Columbus, Ohio, US; abstract no. 84748, FURUTANI, TOSHIYUKI ET AL: "Production of (2R,3S)-3-(4- methoxyphenyl ) glycidic acid methyl ester using an emulsion bioreactor containing lipase from Serratia marcescens" XP002089881 *
CHEMICAL ABSTRACTS, vol. 126, no. 5, 3 February 1997, Columbus, Ohio, US; abstract no. 59845, FURUI, MASAKATSU ET AL: "Optical resolution of phenylglycidates using transesterification enzymes" XP002089883 *
CHEMICAL ABSTRACTS, vol. 128, no. 15, 13 April 1998, Columbus, Ohio, US; abstract no. 179451, MATSUMAE, HIROAKI ET AL: "Glycidamide enzymic manufacture and 1,5-benzothiazepine derivatives" XP002089879 *
MAKU (1996), 21(1), 41-8 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100379756B1 (ko) * 2000-10-02 2003-04-11 한국과학기술연구원 이성질체 분할방법

Also Published As

Publication number Publication date
CN1273608A (zh) 2000-11-15
KR20010031453A (ko) 2001-04-16
IL135149A0 (en) 2001-05-20
AU9645898A (en) 1999-05-17
JP3252900B2 (ja) 2002-02-04
JPH11192098A (ja) 1999-07-21
EP1029071A1 (fr) 2000-08-23

Similar Documents

Publication Publication Date Title
HUT67410A (en) Method for producing optically active alcanols
US6872823B1 (en) Process for producing benzoxazine derivative and production intermediate thereof
JPH07121231B2 (ja) 立体異性体的に純粋なフエニルグリシド酸エステルの製造方法および（２ｓ，３ｓ）‐２‐（４′‐メトキシフエニル）‐３‐アセトキシ‐５‐〔２‐（ジメチルアミノ）エチル〕‐２，３‐ジヒドロ‐１，５‐ベンゾチアゼピン‐４（５ｈ）‐オンの製造方法
US20030216596A1 (en) Process for the purification of pravastatin
EP1029071A1 (fr) Procede servant a preparer des esters d'acide (2r,3s)-3-(4-alkoxyphenyle inferieur)glycidique
US5945533A (en) Process for preparing optically active benzothiazepine compound and intermediate therefor
CA2161849A1 (fr) Production de composes optiquement actifs
Matsumae et al. Microbial asymmetric reduction of (RS)-2-(4-methoxyphenyl)-1, 5-benzothiazepin-3, 4 (2H, 5H)-dione, the key intermediate in the synthesis of diltiazem hydrochloride
EP1273665B1 (fr) Obtention d'alcools beta-amino optiquement actifs
NZ521087A (en) Method for the enzymatic resolution of the racemates of aminomethy-aryl-cyclohexanol derivatives
US6197953B1 (en) Process for preparing optically active trans-3-substituted glycidic acid ester
US5883264A (en) Process for preparing optically active trans-3-phenylglycidamide compounds
EP0528607B1 (fr) Procédé de préparation d'esters de l'acide 3-phényl-glycidiques optiquements actifs
JP2622251B2 (ja) 光学活性３−（４−メトキシフェニル）グリシッド酸エステル類化合物の製法
US5841001A (en) Process for the preparation of optically active 2-halo-1-(substituted phenyl) ethanol
JPH1028596A (ja) 不斉アミド化による（２ｓ，３ｒ）型３−（非置換フェニルまたは低級アルキル−フェニル）グリシッドアミド類化合物の製法
HK1015375A (en) Process for preparing optically active trans-3-substituted glycidic acid ester
JPWO1999007875A1 (ja) 不斉アミド化による（２ｒ，３ｓ）型３−（置換または非置換フェニル）グリシッドアミド類化合物の製法
JPH08277A (ja) 酵素反応による光学活性ベンゾチアゼピン類化合物の製法
MXPA98001569A (en) Procedure to prepare ester of glycic acid trans-3-substituted optically act
JP3349086B2 (ja) 光学活性トランス−３−置換グリシッド酸エステルの製造方法
Noshida et al. Preparation of (2S, 3S)-2, 3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-1, 5-benzothiazepin-4 (5H)-one by microbial conversion
JPH09299099A (ja) 光学活性トランス−３−フェニルグリシッドアミド類化合物の製法
CA2230299A1 (fr) Procede pour preparer un ester glycidique trans-3-substitue optiquement actif
MXPA97001992A (en) Procedure for preparing compounds of trans-3-phenylglicidamide optically acti

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 135149

Country of ref document: IL

Ref document number: 98809815.6

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CU CZ EE GD GE HR HU ID IL IS KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 09537236

Country of ref document: US

WWE Wipo information: entry into national phase

Ref document number: 1998950335

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 1020007004486

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1998950335

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1998950335

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1020007004486

Country of ref document: KR

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1020007004486

Country of ref document: KR