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WO2001040498A1 - Procede de production de derives optiquement actifs du cyclohexene et de leurs intermediaires - Google Patents

Procede de production de derives optiquement actifs du cyclohexene et de leurs intermediaires Download PDF

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Publication number
WO2001040498A1
WO2001040498A1 PCT/JP2000/008362 JP0008362W WO0140498A1 WO 2001040498 A1 WO2001040498 A1 WO 2001040498A1 JP 0008362 W JP0008362 W JP 0008362W WO 0140498 A1 WO0140498 A1 WO 0140498A1
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Prior art keywords
formula
group
substituent
salt
represented
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English (en)
Japanese (ja)
Inventor
Norikazu Tamura
Tomoyuki Kitazaki
Toru Yamno
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Takeda Pharmaceutical Co Ltd
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Takeda Chemical Industries Ltd
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Priority to AU15530/01A priority Critical patent/AU1553001A/en
Publication of WO2001040498A1 publication Critical patent/WO2001040498A1/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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/001—Amines; Imines
    • 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
    • C12P11/00—Preparation of sulfur-containing organic compounds
    • 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
    • C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers

Definitions

  • the present invention relates to a method for producing an optically active cyclohexene derivative and a synthetic intermediate thereof. More specifically, a method for producing an optically active isocyanate hexene derivative having a therapeutic and preventive action for heart disease, autoimmune disease, inflammatory disease, central nervous disease, infectious disease, sepsis, and cebutic shock. And useful synthetic intermediates used therein. Background art
  • a cyclohexene derivative having a therapeutic and preventive action for heart disease, autoimmune disease, inflammatory disease, central nervous disease, infectious disease, sepsis, septic shock, etc., is disclosed in WO99-42624. ing.
  • Cyclohexene derivatives having therapeutic and preventive effects on heart disease, autoimmune disease, inflammatory disease, central nervous disease, infectious disease, sepsis, cebutic shock, etc. described in WO 99-462 Is an optically active drug containing an asymmetric center.
  • optically active pharmaceuticals often have different biological activities, pharmacokinetics, pharmacodynamics, toxicity, etc. among the optical isomers. In the production, it is necessary to separate both optical isomers or to synthesize them separately. Therefore, a method for producing the optical isomer is eagerly desired.
  • W099-462242 discloses a method for separating both enantiomers by high performance liquid chromatography (HPLC) using an optically active compound as a stationary phase, but it is suitable for mass synthesis. An economically advantageous and environmentally friendly manufacturing method has not yet been established. Disclosure of the invention
  • the present inventors have developed a formula showing an excellent treatment and prevention effect for the above-mentioned diseases.
  • ring A represents a benzene ring which may have a substituent
  • R 2 represents a hydrocarbon group which may have a substituent
  • * represents the position of an asymmetric center.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1
  • ring A is a benzene ring which may have a substituent
  • Alk is a methylene group which may have a substituent
  • R is R 1 or OR 1 (R 1 is a substituent Represents a hydrocarbon group which may be possessed), and- ⁇ represents a racemic form.
  • ring A represents a benzene ring which may have a substituent, and represents a racemic form.
  • a 1 k is a methylene group which may have a substituent
  • R is R 1 or OR
  • R 1 represents a hydrocarbon group which may have a substituent
  • X represents a leaving group.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent)
  • the ring is an optionally substituted benzene ring
  • * indicates the position of the asymmetric center.
  • R 2 represents a hydrocarbon group which may have a substituent.
  • ring A represents a benzene ring which may have a substituent
  • - ⁇ represents a racemic body.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent); Represents a leaving group.
  • R 2 represents a hydrocarbon group which may have a substituent. Wherein the compound represented by the formula or a salt thereof is reacted.
  • ring A is a benzene ring which may have a substituent
  • Alk has a substituent.
  • ring A is a benzene ring which may have a substituent
  • Alk is a methylene group which may have a substituent
  • R is R 1 or OR 1 (R 1 is a substituent Represents a hydrocarbon group which may be possessed), and * represents the position of the asymmetric center.
  • R is (: 6 alkyl, C 3 7 Process according to any one of the cycloalkyl group or a [1] is an alkoxy group claim, second (5) sections,
  • hydrolase is a lipase derived from Pseudomonas sp. Or Alcaligenes sp.
  • the group represented by A is a formula
  • R is (: Bok 6 alkyl group, C 3 7 first [1] is a cycloalkyl group or Ji Bok 6 alkoxy group claim to process according to any one of the [5] term, (15) Expression
  • R is (: the I 6 alkyl group, a (3) section or a [4]
  • the process according R 2 is Echiru group
  • ring A is a benzene ring which may have a substituent
  • Alk is a methylene group which may have a substituent
  • R is R 1 or OR 1 (R 1 is a substituent Represents a hydrocarbon group which may be possessed), and 1 represents a racemic form.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent)
  • the ring is an optionally substituted benzene ring, and * indicates the position of the asymmetric center.
  • R is (: I 6 alkyl group, C 3 - 7 cycloalkyl group or Ci_ first [1 7] is a 6 alkoxy claim or the [1 8] The compound according to claim, [20] Formula
  • the group represented by A is a formula
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1
  • R 1 represents a hydrocarbon group which may have a substituent
  • a ring represents a benzene ring which may have a substituent
  • * represents a position of an asymmetric center.
  • R 2 represents a hydrocarbon group which may have a substituent
  • ring A represents a benzene ring which may have a substituent
  • * represents the position of an asymmetric center.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent)
  • R 1 represents a hydrocarbon group which may have a substituent
  • the ring and * are as defined above.
  • the use of the optically active compound represented by these, or its salt is provided. Further, the present invention provides
  • ring A indicates a benzene ring which may have a substituent, and ring A indicates a racemic body.
  • ring A indicates a racemic body.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent); Represents a leaving group.
  • a 1 k represents a methylene group which may have a substituent
  • R represents R 1 or OR 1 (R 1 represents a hydrocarbon group which may have a substituent)
  • the ring represents a benzene ring which may have a substituent, and represents a racemic form.
  • R 2 represents a hydrocarbon group which may have a substituent. Wherein the compound represented by the formula or a salt thereof is reacted. (IV)
  • the hydrocarbon group represented by R 1 and R 2 is a group obtained by removing one hydrogen atom from a hydrocarbon compound, and is, for example, a linear or cyclic hydrocarbon group (eg, alkyl, cycloalkyl). Alkyl, aryl, aralkyl, etc.). Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a lower (eg, (: ⁇ 6 )) aliphatic hydrocarbon group is particularly preferable.
  • a linear or cyclic hydrocarbon group eg, alkyl, cycloalkyl. Alkyl, aryl, aralkyl, etc.
  • a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable, and a lower (eg, (: ⁇ 6 )) aliphatic hydrocarbon group is particularly preferable.
  • the hydrocarbon groups represented by R 1 and R 2 include, for example, a) an alkyl group (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, hexyl, etc.), b) C 26 alkenyl (eg, vinyl, aryl, etc.),
  • C 3 _ 7 cycloalkyl e.g., cyclopropyl, cyclobutyl, Shikuropen chill, cyclohexylene hexyl, etc.
  • the C 3 _ 7 cycloalkyl may be fused with one benzene ring
  • Li Ichiru e.g., phenyl, Bok naphthyl, 2-naphthyl, 2-Indeni Le, 2-anthryl
  • phenyl preferably phenyl
  • aralkyl e.g., benzyl, phenyl, diphenylmethyl, triphenylmethyl, trinaphthylmethyl, 2-naphthylmethyl, 2,2-diphenyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenyl
  • Rupentyl preferably benzyl
  • Ci-e alkyl Such as are used, among others Ci-e alkyl, C 3 _ 7 cycloalkyl, C 6 14 ⁇ Li
  • - le is preferably such as C 7 _ 19 Ararukiru, especially d-6 alkyl such as methyl good preferable.
  • substituent of the hydrocarbon group represented by R 1 and R 2 include a halogen atom (eg, fluorine, chlorine, bromine, iodine, etc.), C ⁇ —3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.) ), nitro, Shiano one 6 alkyl which may optionally be halogenated, optionally halogenated (: 3 - 7 cycloalkyl, optionally halogen of (: I 6 alkoxy, hydroxy, Amino, mono - 6 Al Kiruamino (eg, Mechiruamino, etc.
  • Edjiruamino di - C i _ 6 alkylamino (e.g., Jimechiruamino, Jechiruamino, E chill methyl ⁇ amino etc.), formyl, carboxy, force Rubamoiru, C i _ 6 alkyl -Carbonyl (eg, acetyl, propionyl, etc.), alkoxy-carbonyl (eg, methoxycarbonyl, ethoxy Carboxymethyl sulfonyl, propoxy force Ruponiru, tert - such butoxycarbonyl), C 6 _ 1 0 ⁇ reel - Power Ruponiru (eg, Benzoiru, Bok naphthoyl, 2-naphthoyl), 0 6 _ Ariruokishi -.
  • C i _ 6 alkylamino e.g., Jimechiruamino, Jechiruamino, E chill methyl ⁇
  • Carbonyl e.g., off enoki aryloxycarbonyl etc.
  • C 7 - 1 6 Araruki Ruokishi - carbonyl e.g., benzyl O alkoxycarbonyl, such as Hue phenethyl Ruo propoxycarbonyl
  • 5-6-membered heterocyclic carbonyl eg, Nikochinoiru, Isonikochinoiru, 2- Tenoiru, 3-thenoyl, 2-furoyl, 3-furoyl, morpholinocarbonyl, piperidinocarbonyl, topirrolidinylcarbonyl, etc.
  • mono-alkyl 6- alkyl-rubamoyl eg, methylcarbamoyl, ethylcarbamoyl, etc.
  • di- - 0 Bok 6 Al kill - force Rubamoiru for example, dimethylcarbamoyl, Jechirukaruba Yl, etc.
  • Echiru methylcarbamoyl Echiru methylcarbamoyl
  • C 0 Ariru - Power Rubamoiru eg, phenylene Rukaruba moil, 1 - naphthylcarbamoyl, 2-naphthylcarbamoyl etc.
  • 5- to 6-membered heterocyclic force Rubamoiru e.g., 2-pyridylcarbamoyl, 3-pyridylcarbamoyl, 4-pyridylcarbamoyl, 2-Choi carbamoylmethyl, 3-Choi carbamoylmethyl, etc.
  • C WINCH 6 alkylsulfonyl e.g., methylsulfonyl, etc.
  • C 6 _ i Echirusuruhoniru
  • arylsulfonyl eg, benzenesulfonyl, tonafenylsulfonyl, 2-naphthalenesulfonyl, etc.
  • the number of these substituents is not particularly limited, but is usually 1 to 5, preferably 1 to 3, and more preferably 1 or 2.
  • substituent for the benzene ring represented by ring A those similar to the substituents which the hydrocarbon group represented by R 1 may have are used, and among them, a halogen atom (eg, Fluorine, chlorine, bromine and iodine are preferred.
  • the number of substituents is not particularly limited, but is usually 1 to 5, preferably 1 to 3, and more preferably 1 or 2. More specifically, one or two halogen atoms are preferable, and a combination of fluorine and chlorine is particularly preferable.
  • the position of the substituent is not particularly limited.
  • R 3 and R 4 are the same or different and each represent a hydrogen atom or a halogen atom.
  • the group represented by these is preferable.
  • a halogen atom is preferable.
  • R 3 is preferably a fluorine atom
  • R 4 is preferably a chlorine atom.
  • an alkyl group is used as a substituent which the methylene group represented by Alk may have, and among them, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a sec-butyl group group, tert - is C physician 6 alkyl group such as butyl group.
  • the R 1, a lower (C ⁇ - 6) aliphatic hydrocarbon group, ⁇ 3 _ 7 cycloalkyl group (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexylene hexyl, etc.) is good preferred, among others 0 ⁇ _ 6 alkyl group (e.g., methyl group, Echiru group, a propyl group, I an isopropyl group, a butyl group, etc. tert one butyl group), a hexyl group are preferable cyclohexylene.
  • a hexyl group are preferable cyclohexylene.
  • R is R 1
  • R 1 (C ⁇ 6) aliphatic hydrocarbon group in particular, C WINCH 6 alkyl group
  • C 3 - 7 is preferable, a cycloalkyl group, Naka
  • a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a cyclohexyl group and the like are preferable.
  • R 1 is preferably a lower (C ⁇ ) aliphatic hydrocarbon group (particularly, a C ⁇ —e alkyl group), and among them, a methyl group, an ethyl group, a propyl group, an isopropyl group, A butyl group and a tert-butyl group are preferred, and an isopropyl group is particularly preferred.
  • C ⁇ aliphatic hydrocarbon group
  • R is preferably R 1 , particularly preferably a lower (Ci ⁇ ) aliphatic hydrocarbon group, and particularly preferably an alkyl group such as a methyl group.
  • a lower (C ⁇ ) aliphatic hydrocarbon group is preferable, and among them, a ( 6 alkyl group) is preferable, and an ethyl group is particularly preferable.
  • the ring A is preferably a benzene ring which may be substituted with 1 to 4, preferably 1 or 2 halogen atoms (eg, fluorine, chlorine, bromine, iodine).
  • halogen atoms eg, fluorine, chlorine, bromine, iodine
  • the group represented by 7 is represented by the formula
  • Alk is preferably a methylene group:
  • R is at R 1
  • R 1 is an alkyl group (particularly, 3 alkyl group such as methyl)
  • R 2 is C ⁇ - 6 alkyl group (particularly, C ⁇ 3 alkyl group, such as Echiru ) Is preferably a combination in which A 1 k represents a methylene group.
  • the compound (IV) of the present invention has the formula
  • optically active compound (S form) represented by Although included, the compound (Va) which is an R-form is preferable.
  • hydrolase used in the production method of the present invention examples include microorganisms such as bacteria (Pseudomonas spp., Streptomyces spp., Bacillus spp., Acetobacter spp., Alcaligenes spp.), Fungi (Candida spp.,
  • a hydrolase derived from an animal cell (porcine liver cell, pig penile cell) or the like is used.
  • hydrolase a culture of a microorganism can be used as it is, but purification may be performed if necessary.
  • a hydrolase from a bacterium it can be obtained by the following operation according to a method known per se.
  • the cells are subjected to ultrasonic treatment, French press, alumina pulverization, cell enzyme treatment, etc., crushed and centrifuged to obtain a cell extract.
  • a purified esterase is obtained from the culture supernatant and the cell extract by organic solvent precipitation, ammonium sulfate fractionation, ion exchange chromatography, adsorption chromatography, gel filtration, affinity mouth chromatography, and the like.
  • Estella used in this reaction may be an unpurified product, a partially purified product, or a single purified product.
  • this esterase can be used as it is, it may be immobilized on a suitable carrier.
  • the carrier for example, polysaccharide derivatives such as cellulose, amino acid copolymers, synthetic polymers, activated carbon, porous glass, diatomaceous earth, alumina, silica gel and the like are used.
  • hydrolase examples include carboxylesterase, arylesterase, cholinesterase, lipase and the like, preferably lipase, for example, lipases derived from bacteria such as Pseudomonas sp. And Alcaligenes sp.
  • hydrolase used in the present invention commercially available products can also be used.
  • PS, PS-D, PS-C derived from Pseudomonas sp.
  • AK-20 derived from Pseudomonas sp.
  • AH manufactured by Amano Enzym Co., Ltd. (derived from Pseudomonas sp.)
  • Lipase QL, QLC, QLG derived from the genus Alcaligenes manufactured by Meito Sangyo Co., Ltd., and the like are preferably used.
  • AK-20 derived from Pseudomonas sp.
  • AH derived from Pseudomonas sp.
  • Lipase QL, QLC, QLG derived from the genus Alcaligenes manufactured by Meito Sangyo Co., Ltd., and the like are preferably used.
  • QLG derived from the genus Alcaligenes manufactured by Meito San
  • This reaction is carried out by reacting compound (II) or a salt thereof, specifically,
  • M represents a hydrogen atom or an alkali metal (eg, lithium, sodium, potassium, etc.), and the other symbols have the same meanings as described above].
  • the leaving group represented by X includes, for example, a halogen atom (eg, a chlorine atom, a bromine atom, an iodine atom, etc.) and a halogenated group — 6-alkylsulfonyloxy (eg, methane Suruhoniruokishi, ethanesulfonyl O carboxymethyl, preparative Rifuruorome evening down sulfonyl O carboxymethyl, etc.), substituents ⁇ 0 good c 6 _ 1 have a reel sulfonyl O carboxymethyl and hydroxyethyl are used.
  • a halogen atom eg, a chlorine atom, a bromine atom, an iodine atom, etc.
  • a halogenated group — 6-alkylsulfonyloxy eg, methane Suruhoniruokishi, ethanesulfonyl O carb
  • Arylsulfonyloxy includes, for example, a halogen atom, an optionally halogenated alkyl, and a halogenated alkyl. 1 to 3 C 6 alkoxy and the like.
  • Specific examples of "optionally substituted arylsulfonyloxy” include benzenesulfonyloxy, p-toluenesulfonyloxy, 1-naphthalenesulfonyloxy, 2-naphthalenesulfonyloxy and the like. Is mentioned.
  • reaction of compound (II) or a salt thereof with compound (VI) or a salt thereof can be carried out in the presence or absence of a base in a solvent that does not inhibit the reaction or in the absence of a solvent.
  • the compound (VI) or a salt thereof is preferably reacted with the compound (VI ⁇ ) or a salt thereof in an amount of about 1 to about 10 times (molar ratio), and preferably about 1 to about 5 times (molar ratio). Ratio) More preferably, the reaction is carried out.
  • the base examples include inorganic bases (eg, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, sodium hydroxide, etc.), organic bases (eg, triethylamine, pyridine, diisopropylethylamine, DBU etc.) can be used.
  • inorganic bases eg, cesium carbonate, potassium carbonate, sodium carbonate, sodium hydride, potassium hydride, sodium hydroxide, etc.
  • organic bases eg, triethylamine, pyridine, diisopropylethylamine, DBU etc.
  • a quaternary ammonium iodide such as tetrabutylammonium iodide, tetraethylammonium iodide, tetramethylammonium iodide and the like may be present in the reaction system.
  • the amount of the base to be used is preferably about 0.4 to about 5 times (molar ratio) based on the compound (II) or a salt thereof, and is preferably about 0.5 to about 5 times. About 2 times (molar ratio) is more preferable.
  • Examples of the solvent which does not inhibit the reaction used in the reaction of the compound (II) or a salt thereof with the compound (VI) or a salt thereof include sulfoxides (eg, dimethyl sulfoxide, etc.), ethers (eg, Tyl ether, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform, 1,2-dichloromethane, esters (eg, ethyl acetate, etc.), amides (eg, dimethylformamide, acetoamide, dimethyl acetoamide, 1,3-dimethyl-2-imidazolidinone , 1-methyl-2-pyrrolidone) and the like. These solvents may be used alone or in a combination of two or more at an
  • the reaction temperature is preferably from about ⁇ 20 to about 150, and more preferably from about 0 to about 120.
  • the reaction time is preferably from about 0.4 to about 50 hours, more preferably from about 0.5 to about 30 hours.
  • Compound (II) or a salt thereof, which is a starting compound can be produced by the method described in WO99-42624.
  • the racemate (I) or a salt thereof has the formula
  • each symbol is as defined above.
  • a mixture of an optically active compound represented by the formula: or a salt thereof can be isolated and purified by means known per se, for example, solvent extraction, liquid conversion, transfusion, salting out, crystallization, recrystallization, chromatography, and separated.
  • the amount of the hydrolase used is not particularly limited because it varies depending on the type and form of immobilization, but is usually about 0.001 times that of the racemic form (both in weight). ) To about 100 times, preferably from about 0.1 to about 10 times.
  • the reaction temperature is usually about 0 to about 80 ° C, preferably about 15 ° C to about 50 ° C, and more preferably about 15: to 35 ° C.
  • the reaction time is generally about 10 minutes to about 100 hours, preferably about 1 hour to about 72 hours.
  • This reaction may be performed, for example, in the presence of additives such as an enzyme stabilizer and a water substitute (eg, ethylene glycol).
  • additives such as an enzyme stabilizer and a water substitute (eg, ethylene glycol).
  • organic solvent examples include hydrocarbon solvents (eg, hexane, pentane, cyclohexane, etc.), amide solvents (eg, N, N-dimethylformamide (DMF), N, N-dimethylacetamide, N-methylpyrrolidone, etc., aromatic hydrocarbon solvents (eg, toluene, benzene, benzene, etc.), aliphatic ester solvents ( Examples: ethyl acetate, propyl acetate, butyl acetate, etc.), ether solvents (eg, diisopropyl ether, tert-butyl methyl ether, getyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxy ether, etc.) , Halogenated hydrocarbon solvents (eg, chloroform, dichloromethane, 1,2-dichloroethane,
  • the concentration of the racemate (I) or a salt thereof is about 0.1% to about 50%, preferably about 1% to about 30%.
  • methanol, ethanol, propanol, butanol, 2-chloroethanol and the like are used, and particularly preferred are methanol and ethanol.
  • the amount of water and alcohol added is not particularly limited, but is about 0.1% to about 100% by volume, preferably about 1% to about 20% by volume, based on the solvent. There is no problem if the reaction is performed under pH control by adding an additive to water to form a buffer.
  • additives include disodium hydrogen phosphate and sodium dihydrogen phosphate, tris (hydroxymethyl) aminomethane and hydrochloric acid, tris (hydroxymethyl) aminomethane and sodium hydroxide, citric acid and sodium citrate, acetic acid and acetic acid Sodium, citric acid and disodium hydrogen phosphate, glycine and sodium hydroxide, sodium carbonate and sodium hydrogen carbonate, and the like are used.
  • the amount of the hydrolase used is not particularly limited because it varies depending on the type and form of immobilization. Usually, the amount of the hydrolase is about 0.001 times that of the racemic form (I) or its salt. Weight) to 100 times, preferably 0.1 to 10 times.
  • This reaction may be carried out by any of stationary, shaking and stirring.
  • the reaction may be performed in a bioreactor.
  • R 2 has the same meaning as described above.
  • the reaction between the optically active compound (III) or a salt thereof and the compound (VII) or a salt thereof can be carried out in the presence of an acid, in a solvent that does not inhibit the reaction, or in the absence of a solvent.
  • reaction it is preferable to use an excess amount of the compound (VII) or a salt thereof relative to the optically active compound (III) or a salt thereof, and it is more preferable that the reaction is usually performed in an amount of about 10 to about 300 times (molar ratio).
  • the acid examples include an inorganic acid (eg, sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) or an organic acid (eg, toluenesulfonic acid, benzenesulfonic acid, methanesulfonic acid)
  • the amount thereof is preferably about 0.001 to about 100 times (molar ratio) based on the optically active compound (III) or a salt thereof. More preferably, the amount is 1 to about 50 times (molar ratio).
  • Solvents which do not inhibit the reaction used in the reaction of the optically active compound (III) or a salt thereof with the compound (VII) or a salt thereof include, for example, sulfoxides (eg, dimethyl sulfoxide, etc.), ethers (eg, Monoter, tetrahydrofuran, dioxane, etc.), nitriles (eg, acetonitrile, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.), halogenated hydrocarbons (eg, dichloromethane, chloroform) Form, 1,2-dichloroethane, amides (eg, dimethylformamide, acetoamide, dimethylacetamide, 1,3-dimethyl-2-imidazoline, 1-methyl-2-pyrrolidone, etc.). Used. One of these solvents may be used alone, or two or more thereof may be used by mixing at an appropriate ratio.
  • solvents may be used
  • the reaction temperature is preferably about 0 to about 150 ° C, more preferably about 10 to about 120 ° C. Good.
  • the reaction time is preferably from about 1 to about 300 hours, more preferably from about 10 to about 200 hours.
  • the compound (I) or a salt thereof and the optically active compound (III) or a salt thereof obtained in the above Reactions 1 and 2 can be obtained from the reaction mixture by a method known per se, for example, extraction, concentration, neutralization, filtration, crystallization, It can be isolated and purified by means of recrystallization, chromatography, etc., and used for the subsequent reaction.However, the reaction mixture can be directly used for the subsequent reaction without isolation and purification. it can.
  • the optically active compound (IV) or a salt thereof obtained in the above Reaction 3 can be obtained from the reaction mixture by a method known per se, for example, a method such as extraction, concentration, neutralization, filtration, crystallization, recrystallization, or chromatography. Thus, they can be isolated and purified, respectively.
  • the compound (I), ( ⁇ ), (III) or (IV) may form a salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, or a salt with an organic acid.
  • Salt, salt Salts with basic or acidic amino acids are used.
  • the salt with an inorganic base include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt; aluminum salt, ammonium salt and the like.
  • salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N'-dibenzylethylenediamine and the like are used.
  • Salts with inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.
  • Salts with organic acids include, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid Salts with acids, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc. are used.
  • a salt with a basic amino acid for example, a salt with arginine, lysine, orditin, and the like, and as a salt with an acidic amino acid, for example, a salt with aspartic acid, glutamic acid, and the like are used.
  • Compound (I), (II), (III) or (IV) may be a hydrate or an anhydrate.
  • optically active compound (III) or (IV) contains an enantiomer
  • it can be separated by a conventional separation method, for example, using an optically active acid (eg, camphorsulfonic acid, etc.) or an optically active base (eg, Diastereomer salt method to form a salt with 1-methylbenzylamine, etc.), or an optically active host molecule (eg, 1,6-bis (2-chlorophenyl)-1,6-diphenylhexane) -Optical separation is achieved by the inclusion compound method using 2,4-diyne-1,6-diol), various types of chromatography (eg, liquid chromatography using an optically active column), and fractional recrystallization. A pure compound can be obtained.
  • an optically active acid eg, camphorsulfonic acid, etc.
  • an optically active base eg, Diastereomer salt method to form a salt with 1-methylbenzylamine, etc.
  • the compound (I) or a salt thereof, and the optically active compound (III) or a salt thereof are useful as a novel synthetic intermediate for producing the optically active compound (IV) or a salt thereof. .
  • Optically active compound (IV) or its salt is low toxic and suppresses the production of nitric oxide (NO). It also produces inflammatory site such as TNF, IL-1 and IL-6. It has an inhibitory effect, and is used for heart diseases, autoimmune diseases, inflammatory diseases, central nervous system diseases, and feelings in mammals (for example, cats, cats, dogs, dogs, goats, monkeys, humans, etc.).
  • Diseases such as infectious diseases, sepsis, and sebotic shock, such as sepsis, endotoxin shock, exotoxic shock, heart failure, shock, hypotension, rheumatoid arthritis, osteoarthritis, gastritis, ulcerative colitis, peptic ulcer , Stress gastric ulcer, Crohn's disease, autoimmune disease, tissue damage and rejection after organ transplantation, ischemia / reperfusion injury, acute coronary microvascular embolism, shock vascular embolism (generic intravascular coagulation syndrome) (DIC), ischemic encephalopathy, arteriosclerosis, pernicious anemia, Fanconi anemia, sickle cell anemia, S-extractitis, nephrotic syndrome, nephritis, renal failure, Insulin-dependent diabetes mellitus, non-insulin-dependent diabetes mellitus, hepatic porphyria, alcoholism, Parkinson's disease, chronic leukemia, acute leukemia, tumor, myeloma
  • optically active compound (IV) or a salt thereof When administering the optically active compound (IV) or a salt thereof to a human, Is mixed with appropriate pharmacologically acceptable carriers, excipients, diluents, etc., for oral administration (eg, powders, granules, tablets, capsules, etc.), parenteral administration (eg, injections) Etc.), orally or parenterally as a pharmaceutical composition such as an external preparation (eg, a transnasal preparation, a transdermal preparation, etc.), a suppository (eg, a rectal suppository, a vaginal suppository, etc.) can do.
  • an external preparation eg, a transnasal preparation, a transdermal preparation, etc.
  • a suppository eg, a rectal suppository, a vaginal suppository, etc.
  • preparations can be produced, for example, by applying a method known per se which is generally used in the production of preparations.
  • the mixing ratio of the optically active compound (IV) or a salt thereof in the preparation varies depending on its form.
  • it is preferably about 10% by weight to about 95% by weight.
  • the preferred amount is about 0.001% to about 95% by weight.
  • an optically active compound (IV) or a salt thereof is a solubilizing agent (eg, ⁇ -cyclodextrin, etc.), a dispersing agent (eg, Tween 80 (Atlas Powder Co., USA) , HCO 60 (Nikko Chemicals), carboxymethylcellulose, sodium alginate, etc., preservatives (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol), tonicity agents (eg, sodium chloride, glycerin) Sorbitol, glucose, etc.) and can be made into aqueous injections in the usual manner, or vegetable oils (eg, olive oil, sesame oil, laccase oil, cottonseed oil, corn oil, soybean oil, etc.), propylene glycol, etc. Then, it may be dissolved, suspended or emulsified as appropriate to form an oily injection.
  • a solubilizing agent eg, ⁇ -cyclodext
  • Formulations for oral administration include optically active compound (IV) or a salt thereof, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, calcium carbonate, etc.), binders (eg, starch, etc.) , Gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose, etc.) or lubricants (eg, nylon, magnesium stearate, polyethylene glycol 6000, etc.) as appropriate and compression molded.
  • excipients eg, lactose, sucrose, starch, etc.
  • disintegrants eg, starch, calcium carbonate, etc.
  • binders eg, starch, etc.
  • lubricants eg, nylon, magnesium stearate, polyethylene glycol 6000, etc.
  • the coating agent examples include hydroxypropyl propylmethylcellulose, ethylcellulose, hydroxymethylcellulose, Hydroxypropylcellulose, polyoxyethylene glycol, Tween 80, Pull nick F68, Cellulose acetate phthalate, Hydroxypropyl methylcell mouth phthalate, Hydroxymethylcellulose acetate succinate, Oy Dragid (Rohm, West Germany , Methacrylic acid, acrylic acid copolymerization), coloring matter (eg, titanium oxide, red iron oxide, etc.) and the like are appropriately used.
  • Compound (IV) or a salt thereof can be used as a solid, semi-solid or liquid external preparation.
  • solid external preparations include optically active compound (IV) or a salt thereof as such, or excipients (eg, glycol, mannitol, starch, microcrystalline cellulose, etc.), thickeners (eg, natural gums) , A cellulose derivative, an acrylic acid polymer, etc.), and the like, and mixed to form a powdery composition.
  • the semi-solid external preparation is preferably produced according to a conventional method and used as an aqueous or oily gel or ointment.
  • Liquid external preparations can also be prepared by preparing them as oily or aqueous suspensions by the means used for the production of injections or the equivalent.
  • solid, semi-solid or liquid external preparations include pH adjusters (eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, paraoxybenzoic esters, chlorobutane) Or benzalkonium chloride).
  • pH adjusters eg, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide, etc.
  • preservatives eg, paraoxybenzoic esters, chlorobutane
  • benzalkonium chloride e.g, paraoxybenzoic esters, chlorobutane
  • it can be used as an ointment containing usually about 0.1 to about 10 mg of the optically active compound (IV) per gram based on petrolatum, lanolin or the like.
  • the optically active compound (IV) or a salt thereof may be an oily or aqueous solid, semi-solid or liquid suppository.
  • Oil bases for producing suppositories include, for example, glycerides of higher fatty acids (eg, cacao butter, witetbuzole (manufactured by Dynamite Nobel), etc.) and intermediate fatty acids (eg, miglyolic acid (manufactured by Dynamite Nobel) ) Or vegetable oils (eg, sesame oil, soybean oil, cottonseed oil, etc.) are used as appropriate.
  • aqueous base for example, polyethylene darcols, propylene glycol and the like are used
  • aqueous gel base for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers and the like are appropriately used.
  • the dosage of the optically active compound (IV) or a salt thereof varies depending on age, body weight, symptom, dosage form, administration method, administration period, and the like.
  • a patient with sepsis adult, body weight approximately 6 O kg
  • person In general, about 0.01 to about 1000 mgZkg per day, preferably about 0.01 to about 100 mgZkg, more preferably about 0.1 to about 10 mg / day as the optically active compound (IV) or a salt thereof.
  • OmgZkg especially about 0.1 to about 50 mgZkg, especially about 1.5 to about 3 mgZkg, is orally or parenterally administered once to several times a day.
  • a smaller dose may be sufficient in some cases, or it may be necessary to administer beyond the range.
  • the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.
  • IR infrared absorption spectrum
  • HPLC conditions are as follows.
  • UV light (225 nm)
  • Acetoxymethyl (6RS) -6- [N- (2-chloro-4-fluorophenyl) sulfamoyl] -tricyclohexene-carboxylate (1) Dissolve 10.0 g in 200 ml of acetone, and make it from Amano Enzym. 6.0 g of lipase PS-D and 20 ml of water for injection in the Japanese Pharmacopoeia were added, and the mixture was stirred at 28 ° C for 17.5 hours. Analysis of the reaction solution by high performance liquid chromatography showed a conversion of 53.8% and an enantiomeric excess of compound (3) of 100% ee.
  • the reaction solution was filtered through celite to remove the enzyme, and the filtrate was diluted with 250 ml of diisopropyl ether and 50 ml of ethyl acetate. And washed. After adding anhydrous magnesium sulfate and drying, the mixture is concentrated under reduced pressure to give acetooxymethyl (6R) -6- [N- (2-chloro-4--4-fluorophenyl) sulfamoyl] -tricyclohexene-1-carboxy.
  • the latet (3) was obtained as a colorless oil. Yield 4.82 g, enantiomeric excess 100% ee.
  • HPLC conditions are as follows.
  • Retention time about 16 minutes and 21 minutes for the compound represented by the chemical formula (la)
  • HPLC conditions are as follows.
  • HPLC conditions are as follows.
  • HPLC conditions are as follows.
  • HPLC conditions are as follows.
  • HPLC conditions are as follows.
  • an optically active cyclohexene derivative can be produced with high yield and high stereoselectivity.

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Abstract

L'invention porte sur des composés optiquement actifs de formule générale (III) (ou leurs sels) [dans la formule * représente un centre asymétrique; A est un cycle benzène facultativement substitué; Alk est méthylène facultativement substitué; et R est R?1 ou OR1 (où R1¿ est hydrocarbyle facultativement substitué)]. Ces dérivés peuvent être produits en grandes quantités avec une stéréosélectivité élevée à partir des mélanges réactifs obtenus en traitant par une hydrolase des composés de formule générale (I) [dans laquelle A, Alk, et R sont tels que ci-dessus, et les lignes en zigzag indiquent une modification racémique].
PCT/JP2000/008362 1999-11-29 2000-11-28 Procede de production de derives optiquement actifs du cyclohexene et de leurs intermediaires Ceased WO2001040498A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU15530/01A AU1553001A (en) 1999-11-29 2000-11-28 Process for the production of optically active cyclohexene derivatives and intermediates therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP33767399 1999-11-29
JP11/337673 1999-11-29

Publications (1)

Publication Number Publication Date
WO2001040498A1 true WO2001040498A1 (fr) 2001-06-07

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PCT/JP2000/008362 Ceased WO2001040498A1 (fr) 1999-11-29 2000-11-28 Procede de production de derives optiquement actifs du cyclohexene et de leurs intermediaires

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AU (1) AU1553001A (fr)
WO (1) WO2001040498A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334966A4 (fr) * 2000-10-18 2007-04-18 Takeda Pharmaceutical Procede de preparation de sulfonamides optiquement actifs et intermediaires pour leur synthese
EP1495756A4 (fr) * 2002-04-08 2009-10-28 Takeda Pharmaceutical Agent therapeutique pour la prevention d'etat septique grave
EP1935879A4 (fr) * 2005-09-14 2011-07-06 Daiichi Sankyo Co Ltd Dérivé de cycloalcène substitué

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0469375A (ja) * 1990-07-06 1992-03-04 Sankyo Co Ltd 光学活性なシクロヘキシルカルボキシラート類及びその製法
JPH1084990A (ja) * 1996-09-18 1998-04-07 T Hasegawa Co Ltd 光学活性２，４，４−トリメチル−２−シクロヘキセン−１−オール及びそのエステル類の製造方法
WO1999046242A1 (fr) * 1998-03-09 1999-09-16 Takeda Chemical Industries, Ltd. Derives de cycloalcene, leur procede de fabrication et d'utilisation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0469375A (ja) * 1990-07-06 1992-03-04 Sankyo Co Ltd 光学活性なシクロヘキシルカルボキシラート類及びその製法
JPH1084990A (ja) * 1996-09-18 1998-04-07 T Hasegawa Co Ltd 光学活性２，４，４−トリメチル−２−シクロヘキセン−１−オール及びそのエステル類の製造方法
WO1999046242A1 (fr) * 1998-03-09 1999-09-16 Takeda Chemical Industries, Ltd. Derives de cycloalcene, leur procede de fabrication et d'utilisation

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1334966A4 (fr) * 2000-10-18 2007-04-18 Takeda Pharmaceutical Procede de preparation de sulfonamides optiquement actifs et intermediaires pour leur synthese
EP1495756A4 (fr) * 2002-04-08 2009-10-28 Takeda Pharmaceutical Agent therapeutique pour la prevention d'etat septique grave
EP1935879A4 (fr) * 2005-09-14 2011-07-06 Daiichi Sankyo Co Ltd Dérivé de cycloalcène substitué
USRE43858E1 (en) 2005-09-14 2012-12-11 Daiichi Sankyo Company, Limited Substituted cycloalkene derivative

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