WO1999007875A1 - Procede permettant de preparer des composes de (2r,3s)-3-(phenyle substitue ou non substitue)-glycidamide par amidation asymetrique - Google Patents

Procede permettant de preparer des composes de (2r,3s)-3-(phenyle substitue ou non substitue)-glycidamide par amidation asymetrique Download PDF

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WO1999007875A1
WO1999007875A1 PCT/JP1998/003453 JP9803453W WO9907875A1 WO 1999007875 A1 WO1999007875 A1 WO 1999007875A1 JP 9803453 W JP9803453 W JP 9803453W WO 9907875 A1 WO9907875 A1 WO 9907875A1
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Prior art keywords
substituted
group
ring
hydrogen atom
lower alkyl
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PCT/JP1998/003453
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English (en)
Japanese (ja)
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Ikuko Tsujioka
Hiroaki Matsumae
Takuo Nishida
Takeji Shibatani
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Tanabe Seiyaku Co., Ltd.
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Priority to AU84630/98A priority Critical patent/AU8463098A/en
Publication of WO1999007875A1 publication Critical patent/WO1999007875A1/fr

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    • 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
    • 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
    • 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
    • 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

  • the present invention provides a method for producing (2R, 3S) type 3- (substituted or unsubstituted phenyl) glycidamides by asymmetric amidation and (2S, 3S) type 1, 5 using the same. —Related to the production of benzothiazepine derivatives.
  • a racemic trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compound and an ammonia or amine compound are combined with a (2R, 3S) -type 3- (substituted or unsubstituted fuunyl) glycidic acid
  • the (2R, 3S) type isomer is converted to the (2R, 3S) type isomer by reacting the ester compound in the presence of an enzyme capable of asymmetrically amidating the (2R, 3S) type isomer.
  • Japanese Examined Patent Application Publication No. 8-8879 discloses that a microbial enzyme acts on racemic trans-3- (4-methylphenyl) glycidic acid methyl ester to asymmetrically hydrolyze the (2R, 3S) isomer.
  • a method for obtaining the (2S, 3R) isomer is disclosed.
  • (2R, 3S) type 3 (Substituted or unsubstituted phenol) glycidamides
  • (2S, 3S) type 1,5— A method for producing a benzothiazepine derivative is provided.
  • the present inventors reacted the (2R, 3S) type 3- (substituted or unsubstituted phenyl) glycidamide compound with a 2-aminothiophenol derivative and then closed the product intramolecularly with a ring. It has been found that the reaction can lead to a desired (2S, 3S) type 1,5-benzothiazepine derivative.
  • certain enzymes are capable of asymmetrically amidating the (2R, 3S) -type isomer of trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compounds.
  • the compound was found to have power, and a racemic trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compound was reacted with ammonia or an amine compound to form an asymmetric amid in the presence of a powerful enzyme. It was found that the desired (2R, 3S) -type 3- (substituted or unsubstituted fuunyl) glycidamide compounds can be efficiently produced by separating and collecting the amides formed from the amides. Was completed.
  • the present invention provides a compound represented by the general formula [I]:
  • ring A represents a substituted or unsubstituted benzene ring, and R represents an ester residue
  • R 1 represents a hydrogen atom or a lower alkyl group
  • ring A is a substituted or unsubstituted benzene ring.
  • the lower alkyl group is an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group and a butyl group
  • the lower alkoxy group is a group such as a methoxy group, an ethoxy group, a propoxy group and a butoxy group
  • the c is an alkoxy group having from 1 to 4 carbon atoms and the like, a fluorine atom as the halogen atom, chlorine atom, bromine atom and iodine atom can be mentioned.
  • ring A is preferably a 4-lower alkoxyphenyl group, particularly preferably a 4-methoxyphenyl group.
  • any of the conventional ester residues can be used, and specific examples thereof include a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, and a substituted or unsubstituted aryl group.
  • the alkyl group include an alkyl group having 1 to 10 carbon atoms such as a methyl group, an ethyl group, a propyl group, a butyl group, a hexyl group, an octyl group and a decyl group, and a cycloalkyl group such as a cyclopropyl group and a cyclobutyl group.
  • cycloalkyl groups having 3 to 7 carbon atoms, such as cyclopentyl group and cyclohexyl group.
  • examples of the aryl group include a phenyl group and a naphthyl group.
  • examples of the substituent of the alkyl group or the cycloalkyl group include a substituted or unsubstituted fuunyl group, a halogen atom, and a lower alkoxy group.
  • examples of the substituent of the aryl group include a lower alkyl group, a halogen atom, and a lower alkoxy group. Etc. can be given.
  • R is preferably a lower alkyl group, especially a methyl group.
  • racemic trans-3- (substituted or unsubstituted phenyl) glycidides include not only those containing equal amounts of the (2R, 3S) isomer and the (2S, 3R) isomer, but also those containing both of these optical isomers. Debris and misalignment can also be used as raw materials in the method of the present invention.
  • R 1 is a hydrogen atom or a lower alkyl group
  • examples of the lower alkyl group include an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group and a butyl group.
  • the enzymes that can be used in the present invention include the ability to preferentially amidate the (2R, 3S) form of racemic trans-3- (substituted or unsubstituted fuunyl) glycidic acid ester compound [I]
  • Any enzyme having any of animal origin, plant origin, or microbial origin may be used.
  • an enzyme produced by a microorganism such as a bacterium, a yeast, or a power plant can be suitably used.
  • Such enzyme sources include, for example, microorganisms belonging to the family Pseudomonas and Enterobacteriaceae: Specific examples of microorganisms of the family Pseudomonas include Pseudomonas putida I AM1177 (Pseud omo nasputida). Pseudomonasputida CCTB 344; FERM BP-6410), and other specific examples of Enterobacteriaceae microorganisms. Intestinal bacteria E_123 E strain isolated from soil (Enterobacter sp. E-123 E [Enterobacters p.
  • E-123 E; F ERM B P-640 8]), E- 133 D strain Microorganisms which are considered to belong to the genus Enterobacter, such as Enterobacter sp. E-133D [Enterobacters p. E-133D: FERM BP-6409]) can be mentioned. These microorganisms are wild strains and mutant strains. And those derived from these microorganisms by biotechnological techniques such as genetic recombination and cell fusion.
  • the enzymes produced by these microorganisms are usually separated and purified from cultures of microorganisms and used in the method of the present invention. Instead of using the isolated enzymes, cultures of microorganisms or processed products thereof may be used.
  • any medium may be used as long as the microorganism can grow and proliferate.
  • glucose, sucrose, molasses, sugars such as molasses, organic acids such as fumaric acid and its salts, alcohols such as glycerol, or alcohols such as glycerol are 0.4 to 15% as a carbon source.
  • Inorganic ammonium salts such as sodium nitrate, ammonium sulfate, ammonium chloride or urea, or peptone, meat extract, corn steep liquor, yeast extract, casein hydrolyzate, etc. in the range of 0.3 to 6.0%.
  • a medium can be suitably used.
  • an appropriate amount of inorganic salts such as phosphates, magnesium salts, potassium salts, and calcium salts, and metal ions such as manganese, zinc, and iron may be present in the medium.
  • an amino acid such as proline or histidine, or biotin or thiamine, if necessary.
  • a surfactant such as vegetable oil and caraline may be added. These media are preferably adjusted to a pH of 5 to 7.5.
  • the culture can be carried out by a conventional method after inoculating the microorganism into the above-mentioned medium, and can be carried out by any method such as shaking culture, aeration and stirring culture, stationary culture, and continuous culture.
  • Culture conditions may be appropriately selected depending on the type of culture medium and culture method. It is desirable to adjust the pH at the start of feeding to 5 to 7.5, and to culture at room temperature to heating, for example, at 20 to 40 ° C.
  • (2R, 3S) form of racemic trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compound [I] can be used as the culture of the microorganism used in the present invention or a processed product thereof. Any substance that has the ability to preferentially amidate may be used.
  • the processed product of such a culture include live cells, washed cells, culture solution, culture supernatant, disrupted cells, cell extracts, or partially purified or purified enzymes obtained therefrom. Examples include those from which water has been distilled off by freeze-drying or acetone drying. When performing lyophilization, adjust the pH of the processed product to 6-8, and
  • the suspension is suspended in an aqueous solution containing a stabilizer such as 0% glycerol and dried.
  • a stabilizer such as 0% glycerol
  • the viable cells and the culture supernatant can be obtained from a culture solution obtained by culturing the microorganism as described above by centrifugation, filtration, or the like.
  • the washed cells can be obtained by washing the viable cells with physiological saline or the like.
  • the crushed cells can be obtained by using various physicochemical methods such as ultrasonic cells, French press, osmotic pressure, freeze-thaw, freeze-thaw, alumina lysis, bacteriolytic enzymes, surfactants or organic solvents. Obtained by processing.
  • the bacterial cell extract can be obtained, for example, by removing solids from the disrupted bacterial cells by filtration or centrifugation.
  • the partially purified enzyme or the purified enzyme can be obtained, for example, from disrupted cells or culture supernatant by an ordinary method such as ammonium sulfate fractionation, ion exchange chromatography, or gel filtration chromatography.
  • Enzymes used in the present invention include, for example, polyacrylamide, sulfur-containing polysaccharide gel (carrageenan gel, etc.), alginate gel, agar gel, photocrosslinkable resin, It can also be used by immobilizing it on a known carrier such as polyethylene glycol or celite. '
  • a racemic trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compound [I] can be added to a (2R, 3S) -type 3- (substituted or unsubstituted phenyl) in an appropriate organic solvent.
  • the ammonia or amine compound represented by the general formula [II] is reacted in the presence of an enzyme capable of asymmetrically converting a glycidic acid ester compound to give the (2 R, 3 S) isomer. After amidation, the resulting amide form is separated and collected from the reaction solution to obtain the desired (2R, 3S) type 3- (substituted or unsubstituted fuunyl) glycidamide compound [III ] Is obtained.
  • the concentration of the racemic trans-3- (substituted or unsubstituted phenyl) glycidic acid ester compound [I], which is one of the substrates in the method of the present invention, is generally 0.1% to 80%, particularly 0.1 to 40%. % Is preferable, and the other substrate
  • the concentration of the compound [II] in the reaction mixture is preferably 0.1% to 8%, particularly preferably 0.2 to 1.0%. What is necessary is just to add.
  • the reaction suitably proceeds at room temperature or under heating, preferably at 10 to 50 ° C, particularly preferably at 20 to 40 ° C.
  • a small amount of water may be added to the enzyme, and when a treated product obtained by freeze-drying a culture of a microorganism is used as the enzyme, the amount of 0.05 to 0.5 to the treated product is used. Preferably, 40% of water is added.
  • the organic solvent a solvent capable of dissolving trans-3- (substituted or unsubstituted fuunyl) glycidic acid ester compound [I] can be used.
  • an aromatic hydrocarbon solvent which may be halogenated for example, benzene, tonolene, xylene, cyclobenzene, dichlorobenzene
  • an aliphatic hydrocarbon solvent which may be halogenated for example, hexane) , Cyclohexane, heptane, isooctane, carbon tetrachloride, dichloromethane, trichloroethane, dichloroethane), ketone solvents (eg, methyl isobutyl ketone, acetone, methyl ethyl ketone), ester solvents (eg, ethyl acetate) , Butyl acetate), ether solvents (eg, t-butyl methyl ether, diisopropyl ether, getyl ether, 1,4-dioxane, tetrahydrofuran), nitrile solvents (eg, acetate
  • Isolation of (2R, 3S) type 3- (substituted or unsubstituted phenyl) glycidamide compounds [III] from the reaction solution obtained by the effort can be easily carried out according to a conventional method. it can. For example, after completion of the reaction, the enzyme is removed by filtration, and the filtrate is subjected to distillation under reduced pressure. The residue obtained is separated and purified by chromatography to obtain (2R, 3S) type 3- (substituted or unsubstituted). (Phenyl) glycidamides [III] can be obtained.
  • (2R, 3S) -type 3- (substituted or unsubstituted phenyl) glycidamide compounds [III] mixed with (2S, 3R) -enantiomer is obtained by enzymatic reaction
  • Form 3— (Substituted or unsubstituted phenyl) glycamide compounds [III] can be selectively extracted and the solvent can be distilled off to improve the optical purity of the target compound.
  • Such solvents include ester solvents (eg, ethyl acetate, methyl acetate, etc.), alcohol solvents (eg, methanol, ethanol, isopropanol, t-butynol alcohol), ether solvents (eg, ethyl ether, 1, 4-dioxane), aliphatic hydrocarbon solvents (eg, dichloromethane), which may be halogenated, aromatic hydrocarbon solvents (eg, toluene), which may be halogenated, ketone solvents (eg, Examples include acetone) and non-proton polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide).
  • ester solvents eg, ethyl acetate, methyl acetate, etc.
  • alcohol solvents eg, methanol, ethanol, isopropanol, t-butynol alcohol
  • ether solvents eg, ethy
  • ring B represents a substituted or unsubstituted benzene ring
  • R 2 represents a hydrogen atom or a substituted lower alkyl group
  • ring B in the general formula [IV] include a benzene ring which may be substituted with a halogen atom or a lower-alkyl group.
  • R 5 represents a hydrogen atom, a chlorine atom or a benzyl group
  • ring B is an unsubstituted benzene ring are particularly preferred.
  • R 2 in the general formula [IV] include a hydrogen atom, a di-lower alkylamino lower alkyl group, and a substituted piperazinyl lower alkyl group.
  • the substituent of the piperazinyl lower alkyl group is lower alkyl.
  • Examples include a substituted fuzyl group such as a coxifuunyl group.
  • a compound in which R 2 is a hydrogen atom capable of raising a hydrogen atom, a 2- (dimethylamino) ethyl group, a 3- [4- (2-methoxyphenyl) -11-piperazinyl] propyl group Is particularly preferred.
  • the solvent examples include aromatic hydrocarbon solvents which may be halogenated (for example, benzene, toluene, xylene, mesitylene, benzene, dichlorobenzene, and trichlorobenzene), and alcohol solvents (for example, Methanol, ethanol, propanol), among which xylene, benzene, dichlorobenzene, and methanol are preferred.
  • aromatic hydrocarbon solvents which may be halogenated (for example, benzene, toluene, xylene, mesitylene, benzene, dichlorobenzene, and trichlorobenzene)
  • alcohol solvents for example, Methanol, ethanol, propanol
  • xylene, benzene, dichlorobenzene, and methanol are preferred.
  • the iron catalyst examples include inorganic or organic salts or complexes containing divalent or trivalent iron ions. Specific examples of such an iron catalyst include ferric n
  • Subsequent intramolecular ring closure is achieved by reacting in a suitable organic solvent in the presence or absence of an acid or base at 0-250 ° C, especially at 80-200 ° C. You.
  • the solvent is not limited as long as it does not interfere with the reaction, and may be, for example, an aromatic hydrocarbon solvent which may be halogenated (for example, benzene, to / leene, xylene, mesitylene, Benzene, dichlorobenzene, trichlorobenzene, and optionally halogenated aliphatic hydrocarbon solvents (eg, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, n- hexane) , N-heptane, cyclohexane), non-protonic polar solvents (eg, N, N-dimethylformamide, dimethylsulfoxide), ketone solvents (eg, acetone, methylethylketone), ester Solvent (eg, ethyl acetate), ether solvent (eg, 1,4-dioxane) Sun, tetrahydrofuran),
  • solvents may be used alone, but if necessary, two or more kinds thereof may be mixed at an appropriate ratio and used in a single-phase or two-phase form.
  • alcohol solvents aromatic hydrocarbon solvents, and ether solvents are preferable, and toluene, xylene, chloroform benzene, and dichlorobenzene are particularly preferable.
  • any inorganic or organic acid can be used as the brensted acid; mineral acids (eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, perchloric acid), lower alkanoic acids (E.g., formic acid, acetic acid, propionic acid, butyric acid), hydroxy-substituted lower alkanoic acids (e.g., citric acid), halogeno lower alkanoic acids (e.g., trifluoroacetic acid), lower alkanesulfonic acids (e.g., methanesulfonic acid), Allylsulfonic acid (eg, p-toluenesulfonic acid, benzenesulfonic acid), oxalic acid, and the like can be used.
  • mineral acids eg, hydrochloric acid, sulfuric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, perchloric acid
  • Lewis acid titanium tetrachloride, aluminum chloride, boron trifluoride, tin chloride, and the like can be used.
  • mineral acid lower alkanesulfonic acid or aryl sulfonic acid is preferable.
  • any inorganic or organic base can be used as the base.
  • examples of such a base include alkali metal hydrogen carbonate, alkali metal carbonate, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal hydride, and the like.
  • Inorganic bases such as alkali metal amides, alkali metal alkoxides, alkali metals, and alkaline earth metals; 1,8-diazabicyclo [5.4.0] , Diisopropylethylamine, triethylamine, pyri
  • R 1 and R 2 are hydrogen atoms, and that ring A is a 4-methoxyphenyl group and ring B is an unsubstituted benzene ring.
  • R 3 represents a substituted lower alkyl group
  • R 4 represents a lower alkanoyl group
  • ring A and ring B have the same meanings as described above.
  • R 2 is a hydrogen atom
  • R 3 is a 2- (dimethylamino) ethyl group or 3- (4- (2-methoxyphenyl) -11-piperazinyl) propyl group
  • R 4 is acetyl
  • a ring B is an unsubstituted benzene ring
  • R 2 is a hydrogen atom
  • R 3 is a 2- (dimethylamino) ethyl group
  • R 4 is an acyl group. Particularly preferred is a tyl group.
  • the O-alkanoylation in the above method can be easily carried out, for example, according to the method described in JP-A-58-99471, JP-A-5-43564, JP-A-5-201865 or JP-A-2-289558. You can do it.
  • examples of the lower alkyl group include a linear or branched alkyl group having 1 to 4 carbon atoms.
  • examples of the lower alkoxy group include a linear or branched alkoxy group having 1 to 4 carbon atoms.
  • FIG. 1 is a diagram showing the change over time of MPGM using Pseudomonas putida CCTB 344.
  • PA indole-rubyruvic acid
  • SIM Sul fide Ido 1 e Moti 1 ity
  • TSI Triple Sugar Iron
  • nitrate reduction was performed using a nitrate broth medium.
  • the arginine dihydrolase, oretin and lysine decarboxylase reactions were performed according to the method described in Meraichi.
  • the citrate utilization test was prepared using Simmons sodium citrate medium (Eiken Chemical), and the urease test was prepared using UREA A GAR BASE (OXO ID).
  • the malonate utilization test was performed using a malonate medium (Eiken Chemical), the dalconic acid oxidation test was performed using a self-prepared product, the DNase production test was performed using DNase medium (Eiken Chemical), and acid from various carbohydrates was used.
  • the productivity was examined using a glycolysis semi-fluid medium (Eiken Chemical) as a basal medium. Unless otherwise stated, the procedure was carried out by a conventional method, and other basal medium was carried out at 37 C using Tributsoy agar medium (Eiken Chemical).
  • E-123E strain and the E-133D strain are shown in Tables 2-3. Both the E-123E strain and the E-133D strain are Gram-negative rods of facultative anaerobic bacteria that grow aerobically and anaerobically. Survival temperature is in the range of 15 to 45 ° C And grew best at around 37 ° C.
  • E-123E strain and E-133D strain could not be finally identified, they are presumed to be a species of the genus Enterobacter based on the above test results.
  • the E-123E strain was named Enterobacter sp. E-123E, and this strain was established on July 6, 1999, in Tsukuba East, Ibaraki, Japan 1 Deposited under the Budapest Treaty as Accession No. 6408 (FERM BP-6408) at the Institute of Biotechnology and Industrial Technology of the Industrial Technology Institute on the 1st to 3rd floors.
  • the E-133D strain was named Enterobacter sp. E-133D (E. 133D), and the strain was named Higashi 1-chome, Tsukuba City, Ibaraki, Japan on July 6, 1999. Accession No. 6409 (FERM B) under the Budapest Treaty with the Institute of Biotechnology and Industrial Technology, P-6409).
  • the cells were inoculated into a medium (pH 7) containing 1 ° / o iron sulfate ⁇ 7 hydrate and 0.03% caralin 102, and cultured at 30 ° C. for 24 hours.
  • Pseudomonasputida CCTB 344 (Pseudomonasputida CCTB 344; Accession No. FE RM BP under the Budapest Treaty on July 6, 1999 at the same Institute of Biotechnology and Industrial Technology) — Deposited as 6 410) treats Pseudomonasputida IAM 1 17 7 with NTG (N — methy 1 — N'—nitro— N— nitrosoguanidine) This is a highly active mutant strain obtained by the above method.
  • Example 1 4 g of freeze-dried cells of Pseudomonas putida CCTB 344 prepared in the same manner as in (1) were added with 400/1 of water while dispersing 400/1 of water.
  • the bacterial cell thus obtained, 40 ml of ammonia in a solution of t-butinoleanorecol 16 m 1, (2 RS, 3 SR) -MPGM 3.2 g (1 5.38 mm o 1), and t Add 144 ml of butyl methyl ether to an eggplant-shaped flask,
  • the reaction was carried out at 30 ° C with stirring for 48 hours.
  • the reaction solution was filtered, and the filtered cells were further washed with acetone. After combining the filtrate and the washings, the solvent was distilled off to obtain a mixture of MPGA and MPGM.
  • This mixture was subjected to flash gel column chromatography [filler: silica gel (pre-treated with 1% triethylamine); solvent: ethyl acetate] to give (2R, 3S) — MPGA was isolated.
  • ru ⁇ 3 10 hours after the start of the reaction, further contains 1 g of Pseudomonas putida CC ⁇ 344 lyophilized cells (added while dispersing 100 ⁇ l of water) and 10 mm ⁇ 1 of ammonia t 4 ml of a monobutyl alcohol solution was added to the reaction solution.
  • Table 5 shows the yield of MPGA after 28 hours of reaction and the optical purity of (2R, 3S) -MPGA.
  • the yield is a value based on the number of moles of (2RS, 3SR) -MPGM supplied, and the quantification was performed by HPLC as in Example 1- (2).
  • the yield of MPGA in run 1 was 23%, and the optical purity of (2R, 3S) -MPGA was 87% ee, while the yield of MPGA in run 2 was Rate is 34%, (2 R, 3 S) — optical purity for MPGA is 84% ee, yield of ⁇ 2 is 4 2% in 1 "l 3, (2 R, 3 S)- MP G
  • the optical purity of A was 70% ee, indicating an increase in reactivity compared to run 1.
  • Soil isolate strain Enterobacter sp. E-123E Enterobactersp. E-123E; FERMBP-640
  • enterobacter sp. E-133D Entobacterobacter p. E-1) 3 3D; FE RM BP-6409
  • a medium consisting of water salt, 0.05% calcium chloride, dihydrate, 0.01% iron sulfate, and 7 hydrate, respectively.
  • the process of the present invention provides a process for the preparation of racemic trans-3- (substituted or unsubstituted phenyl)
  • the desired optically active (2R, 3S) type 3- (substituted or unsubstituted phenyl) glycidamide compound can be obtained from the ricid acid ester compound in a single step, and the optically active (2R, 3S) type (S) type 3— (substituted or unsubstituted phenyl) glycidamides are advantageously used as a process for producing such compounds, and pharmaceutically useful optically active (2S, 3 ⁇ ) type 1, Since a 5-benzothiazepine derivative can be easily obtained, it is useful as an industrial production method for the 1,5-benzothiazepine derivative.

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Abstract

L'invention concerne un procédé qui permet de préparer des composés de (2R,3S)-3-(phényle substitué ou non substitué)-glycidamide, caractérisé en ce que l'on fait réagir un composé d'ester trans-3-(phényle substitué ou non substitué)-glycidique racémique avec de l'ammoniaque ou un composé aminé en présence d'une enzyme capable d'amider de manière asymétrique les composés d'ester glycidique, de façon à amider l'isomère (2R,3S), puis on sépare et on récupère le composé amidé (2R,3S) obtenu à partir de la solution de réaction. L'invention concerne également un procédé qui permet de préparer des dérivés de la (2R,3S)-1,5-benzodiazépine, utiles comme produits pharmaceutiques, en faisant réagir le composé de (2R,3S)-glycidamide préparé ci-dessus avec un dérivé du 2-aminothiophénol, puis en soumettant le produit obtenu à une cyclisation.
PCT/JP1998/003453 1997-08-07 1998-08-04 Procede permettant de preparer des composes de (2r,3s)-3-(phenyle substitue ou non substitue)-glycidamide par amidation asymetrique WO1999007875A1 (fr)

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AU84630/98A AU8463098A (en) 1997-08-07 1998-08-04 Process for preparing (2r,3s)-3-(substituted or unsubstituted phenyl)glycidamidecompounds by asymmetric amidation

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JP21293697 1997-08-07
JP9/212936 1997-08-07

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WO1999007875A1 true WO1999007875A1 (fr) 1999-02-18

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PCT/JP1998/003453 WO1999007875A1 (fr) 1997-08-07 1998-08-04 Procede permettant de preparer des composes de (2r,3s)-3-(phenyle substitue ou non substitue)-glycidamide par amidation asymetrique

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WO (1) WO1999007875A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6013776A (ja) * 1983-07-05 1985-01-24 Sawai Seiyaku Kk 光学活性３−（ｐ−アルコキシフエニル）グリシツド酸誘導体の製造法
WO1995007359A1 (fr) * 1993-09-10 1995-03-16 Technische Universiteit Delft Procede de conversion catalysee par voie enzymatique de composes organiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6013776A (ja) * 1983-07-05 1985-01-24 Sawai Seiyaku Kk 光学活性３−（ｐ−アルコキシフエニル）グリシツド酸誘導体の製造法
WO1995007359A1 (fr) * 1993-09-10 1995-03-16 Technische Universiteit Delft Procede de conversion catalysee par voie enzymatique de composes organiques

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