WO1999052891A1 - Procede de fabrication d'un compose hydroxylactone - Google Patents

Procede de fabrication d'un compose hydroxylactone Download PDF

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WO1999052891A1
WO1999052891A1 PCT/JP1999/001615 JP9901615W WO9952891A1 WO 1999052891 A1 WO1999052891 A1 WO 1999052891A1 JP 9901615 W JP9901615 W JP 9901615W WO 9952891 A1 WO9952891 A1 WO 9952891A1
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group
compound
formula
salt
ring
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PCT/JP1999/001615
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English (en)
Japanese (ja)
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Masahiko Seki
Tooru Kuroda
Takeshi Yamanaka
Ritsuo Imashiro
Takeji Shibatani
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Tanabe Seiyaku Co., Ltd.
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Priority to AU29600/99A priority Critical patent/AU2960099A/en
Publication of WO1999052891A1 publication Critical patent/WO1999052891A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00

Definitions

  • the present invention relates to a method for producing a ketone compound used as a catalyst in the production of an optically active phenylglycidic acid derivative and a hydroxylactone compound which is a precursor thereof. More specifically, an asymmetric ketone compound used as a catalyst in the production of an optically active phenyldaricidic acid derivative, which is an intermediate for producing a 1,5-benzothiazepine derivative useful as a medicament, and a precursor, i.e.
  • the present invention relates to a method for producing a droxylactone compound.
  • Certain 1,5-benzothiazepine derivatives are useful compounds for cardiovascular diseases such as angina pectoris, myocardial infarction and arrhythmia, hypertension, coronary infarction and cerebral infarction It is known that, in particular, diltiazem hydrochloride [Chemical name: (2S, 3S)
  • 1,5-benzothiazepine derivatives can be produced by various methods. One of them is to use an optically active phenyldaricic acid derivative, which is reacted with o-amino thiophenol and then subjected to a ring closure reaction.
  • a method has been proposed in which an optically active 1,5-benzothiazepine derivative is obtained by the addition of a derivative thereof (Japanese Patent Laid-Open No. 60-137776).
  • Various methods have been proposed as a method for producing the optically active phenylglycidic acid derivative of the starting compound used in this method.
  • asymmetric ketone compounds are known to be used for catalytic asymmetric epoxidation of olefins (J. Am. Chem. Soc., Vol. 118, 491-492 and 11311-11312, 1996), It is produced by reacting asymmetric 1,1-binaphthyl-2,2,1-dicarboxylic acid with dihydroxyacetone in an organic solvent (see j. Am. Chem. Soc.
  • the above-mentioned known method for producing an asymmetric ketone compound requires a large amount of an organic solvent, and is not suitable as an industrial production method.
  • the present inventors have conducted various studies to find a method for efficiently producing a series of asymmetric ketone compounds considered to be useful for such catalytic asymmetric epoxidation, and as a result, using an epoxy derivative of a biaryl compound, By subjecting the compound to an internal ring-closure reaction, a hydroxylactone compound as a precursor was obtained in high yield, and it was found that oxidation of this compound could lead to a desired asymmetric ketone compound. I got it.
  • the present invention provides a compound of the general formula (I)
  • ring Ar is a monocyclic to tricyclic aromatic ring which may have a substituent
  • Alk is a single bond or may have a substituent
  • an alkylene group and Q is a carbonyl.
  • X represents an oxygen atom or a sulfur atom
  • R 1 represents a hydrogen atom or a lower alkyl group.
  • the present invention also provides a compound represented by the general formula (VI): oxidizing the hydroxylactone compound (II) or a salt thereof.
  • reaction formula 11 the epoxy compound represented by the general formula (I) or the salt thereof is subjected to intramolecular ring closure to lead to the hydroxylatatatone compound represented by the general formula (II) or a salt thereof.
  • the epoxy compound (I) or a salt thereof is converted to a hydroxylactone compound by the above method.
  • reaction leading to (II) or a salt thereof is easily carried out by the following methods (a) and (b).
  • the hydroxylactone compound (II) or a salt thereof is obtained by reacting the epoxy compound (I) or a salt thereof with an ammonium salt in a suitable solvent in the presence of a base.
  • Solvents used include alcoholic solvents (methanol, ethanol, isopropyl alcohol / t-butyl alcohol / t-butyl alcohol), ether solvents (jetinole-no-tenol, disopropinole-no-tenol, t-butynol-methinole) Ethanol, tetrahydrofuran, 1,4-dioxane), aliphatic hydrocarbon solvents that may be halogenated (hexane, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), Aromatic hydrocarbon solvents that may be hydrogenated (benzene, toluene, xylene, benzene, dichlorobenzene), ester solvent
  • the amount of the solvent to be used is generally in the range of 2 to 50 g, preferably 10 to 30 g, per 1 g of compound (I).
  • Bases include alkali metal hydrides (lithium hydride, sodium hydride, lithium hydride), alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide). ), Alkaline earth metal hydroxides (calcium hydroxide, barium hydroxide), alkylamines (triethylamine, N, N-diisopropyl-N-ethylethylamine) and the like, preferably lithium hydroxide and sodium hydroxide. It is.
  • ammonium salt to be reacted examples include a quaternary ammonium salt [quaternary ammonium hydroxide / phosphate (tetra-n-butyl ammonium hydroxide sulfate), and a quaternary ammonium halide (tetra-n-butyl).
  • Ammonia a phosphonium salt [quaternary phosphonium borate (methyltrimethoxyphosphate tetrafluoroborate)] and the like, and preferably tetra-n-butylammonium oxide and tetra-n-butylammonium. It is hydrohydrogen sulfate.
  • the amount of use is from 10 mg to 20 O mg, preferably from 20 mg to 5 O mg, based on 1 g of compound (I).
  • the above reaction is carried out under cooling to heating, and is usually carried out at a temperature of 5 to 150 ° C, preferably 80 to 120 ° C.
  • a hydroxylatatatone compound (II) or a salt thereof treatments of the epoxy compound (I) or a salt thereof with a transition metal complex catalyst in a suitable solvent in the presence of a base leads to a hydroxylatatatone compound (II) or a salt thereof.
  • the solvent to be used include ether solvents (getyl ether, diisopropionate ethere, butynolemethinoleatenole, tetrahydrofuran, 1,4-dioxane), aliphatic hydrocarbon solvents which may be halogenated ( Hexane, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbon solvents which may be halogenated (benzene, toluene, xylene, cyclobenzene, dichlorobenzene) , Ester solvents (methyl acetate, ethyl acetate), nitrile solvents (aceton
  • the amount of the compound to be used is 2 to 50 g, preferably to compound (I) )
  • a base a plate group [alkylamine (triethylamine, N, N-diisopropyl-1-N-ethylamine); aromatic amine (pyridine, lutidine, 41N, N-dimethylaminopyridine), Arylamine (aniline, N, N-Jetylaniline), Bridged amine (1,4-diazabicyclo [2,2,2] octane, 1,8-diazabicyclo [5,4,0] pandeca7-ene)] And N, N-diisopropyl-1-N-ethylamine.
  • This reaction is carried out under cooling to heating, usually from 0 to 100 ° C, preferably from 10 to 30 ° C. Performed in the range of C.
  • the transition metal complex catalyst used in the above method (b) includes any chiral catalyst used for the epoxidation reaction of ethylene and the like.
  • any chiral catalyst used for the epoxidation reaction of ethylene includes any chiral catalyst used for the epoxidation reaction of ethylene and the like.
  • JP-A-59-219272, JP-A-6-219272 The compounds described in JP-A-49051, JP-A-5-507645, JP-T-6-5099981, and International Publication No. 96-28402 pamphlet can be used.
  • transition metal complex catalyst examples include a complex represented by the following formula (VII) or a complex in which a halogen ion or a fatty acid ion is further coordinated to this complex.
  • ⁇ I a hydrogen atom, an alkyl or aryl group
  • R 2 'to R 5 ' and R 2 "to R 5 " are a hydrogen atom, an alkyl or aryl group
  • R al ′ to R a4 ′ are a hydrogen atom, an alkyl group or an aryl group), or (iii) a bond represented by the following formula:
  • M is a transition metal or Means aluminum
  • a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms preferably a straight-chain or branched-chain alkyl group having 1 to 4 carbon atoms, more preferably Is a branched-chain alkyl group having 1 to 4 carbon atoms, most preferably t-butyl
  • the aryl group is an aromatic hydrocarbon group having 6 to 10 carbon atoms, preferably an aromatic hydrocarbon group having 6 to 8 carbon atoms.
  • a hydrocarbon group more preferably a phenyl group
  • the alkylene group is a straight-chain or branched-chain alkylene group having 1 to 6 carbon atoms, preferably a straight-chain or branched-chain alkylene group having 3 to 5 carbon atoms; More preferably, it is a straight-chain alkylene group having 3 to 5 carbon atoms, most preferably a tetramethylene group.
  • the transition metal of M include cobalt, titanium, vanadium, and chromium, with cobalt and titanium being most preferred, and cobalt being most preferred.
  • a preferred complex used in the present invention is a compound represented by the formula (VII) wherein R a ′ and R a ′′ are bonded to each other.
  • R al 'to R a4 ' are a hydrogen atom, an alkyl group, or an aryl group) or bonded to each other to form a compound represented by the formula:
  • R bl ′ and R b2 ′ are a hydrogen atom, an alkyl group or an aryl group, and Alk ′ is the same as above
  • Another preferred complex used in the present invention is a compound represented by the formula (VII), wherein R 1 ′ and R 1 ′′ are a hydrogen atom, and R 2 ′ to R 5 ′ and R 2 ′′ to R 5 ′′ are a hydrogen atom or an alkyl group. ,
  • R a1 ′ to R a4 ′ are each a hydrogen atom, and R b 1 ′ and R b 2 ′ are hydrogen atoms.
  • R 1 ′ and R 1 ′′ are a hydrogen atom
  • R 3 ′, R 5 ′, R 3 ′′ and R 5 ′′ are each a hydrogen atom or Alkyl group
  • R 2 ′, R 4 ′, R 2 ′′ and R 4 ′′ are each a hydrogen atom
  • R a ′ and R a are bonded to each other and are unsubstituted o-phenylene group or It is a compound that forms an unsubstituted 1,2-cyclohexylene group.
  • Preferred complexes (VII) for use in the present invention are those wherein the transition metal M is cobalt, titanium, nonadium or chromium, more preferably M is cobalt, especially divalent cobalt.
  • the complex (VII) used in the present invention includes those in which haguchigenion or fatty acidion is coordinated to the transition metal M site, and those in which these ions are not coordinated are also preferably used.
  • transition metal complex catalyst used in the present invention include complexes represented by the following formulas (VIII) and (IX).
  • the ton compounds can also be converted to R-type hydroxylactone compounds (II-a) or S-type hydroxylactone compounds ( ⁇ -b), respectively. Be guided.
  • ring Ar is an optionally substituted 1 to 3 cyclic aromatic ring, has a configuration in which the part shown by a bold line is in front, and Alk is a single bond
  • solvent used in the above reaction examples include aromatic hydrocarbon solvents that may be halogenated (benzene, toluene, xylene, cyclobenzene, dichlorobenzene), and among them, toluene is preferable.
  • the oxidizing agent examples include a metal oxidizing agent [manganese dioxide, potassium dichromate, pyridinum chromate chromate, ruthenium oxide, ruthenium chloride sodium periodate, tetrapropylammonium pearltenate-N-methylmorpholine Oxide] and non-metallic acid oxidizing agent [Dic oxalic acid dimethyl sulfoxide, 1,1,1-tris (acetyl oxy) -1,1,1-dihydro-1,2, benzodoxol _ 3 (1H) —one], of which manganese dioxide is preferred.
  • the above reaction is usually carried out at 10 to 200 ° C., preferably 20 to: I 10. Performed at C.
  • ring Ar is an optionally substituted 1 to 3 cyclic aromatic ring, has a configuration in which the part shown by a bold line is in front, and Alk is a single bond
  • the epoxy compound (I) or a salt thereof, which is a starting compound in the method of the present invention, can be produced by the two routes using the biaryl compound (III) as shown in the following reaction formula 13. Reaction formula 1 3
  • an acid anhydride is produced from a biaryl compound ( ⁇ ) by a conventional method.
  • the compound (Pro-III) is reacted with the compound (V-a) in a suitable solvent in the presence or absence of a base by reacting the compound represented by or a salt thereof to introduce a protecting group.
  • the desired epoxy compound (I) is obtained by reacting and removing the protecting group.
  • a dehydrating agent is allowed to act on compound (III) in an appropriate solvent.
  • the dehydrating agents used in this method include ⁇ , ⁇ '-dicyclohexylcarbodiimide (DCC), DCC and 1-hydroxybenzotriazolone, azodiphenol diesterol olevonate (diethyl azodicarboxylate). ), Acid anhydrides (acetic anhydride, propionic anhydride), etc., of which anhydrous acetic acid is preferred.
  • Solvents include acid anhydrides (acetic anhydride, propionic anhydride), ether solvents (getyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, 1,4-dioxane), and halogenated solvents.
  • aliphatic hydrocarbon solvents hexane, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride
  • aromatic hydrocarbon solvents benzene, ⁇ Ene, xylene, benzene, dichlorobenzene
  • ester solvents methyl acetate, ethyl acetate
  • nitrile solvents acetonitrile
  • ketone solvents acetone, 2-butanone, methyl isobutyl ketone
  • Amide solvents dimethylformamide, dimethylacetamide
  • acetic anhydride is particularly Preferred.
  • An alternative method for producing the acid anhydride is to react the biaryl compound (III) with a reactive derivative of a fatty acid, phosphoric acid or sulfonic acid or a halogenating agent in a suitable solvent in the presence of a deoxidizing agent.
  • the reactive derivatives of fatty acids, phosphoric acids or sulfonic acids used in this method include acid halides (p-toluenesulfochloride, benzenesulfonic acid chloride, methanesulfonic acid chloride, acetylc-mouth chloride, formic acid) And diphenylphosphoric acid chloride), among which diphenylphosphoric acid chloride is particularly preferred.
  • halogenating agent examples include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, phosphorus trioxide and the like. Of these, thioyl chloride and oxalyl chloride are particularly preferred.
  • the deoxidizing agent examples include alkali metal hydroxides (sodium hydroxide and potassium hydroxide), alkaline earth metal hydroxides (calcium hydroxide and barium hydroxide), and organic radicals such as alkylamine (triethylamine, N, N-diisopropyl-N-ethylamine); Aroma Aromatic amines (pyridine, lutidine, 4- ⁇ , ⁇ -dimethylaminopyridine), arylamines (aniline, ⁇ , ⁇ ⁇ -getylaniline), bridged amines (1,4-diazabicyclo [2,2,2] octane, 1 , 8-Diazabicyclo [5,4,0] indene 7-ene)], of which triethylamine is particularly preferred.
  • alkali metal hydroxides sodium hydroxide and potassium hydroxide
  • alkaline earth metal hydroxides calcium hydroxide and barium hydroxide
  • organic radicals such as alkylamine (
  • solvent to be used examples include ether solvents (getyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane), and aliphatic hydrocarbon solvents (optionally).
  • Xane dimethylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride
  • aromatic hydrocarbon solvents which may be halogenated (benzene, toluene, xylene, cyclobenzene, cyclobenzene), Ester solvents (methyl acetate, ethyl acetate), nitrile solvents (acetonitrile), ketone solvents (acetone, 2-butanone, methyl isobutyl ketone), amide solvents (dimethylformamide, dimethylacetamide) And the like, of which methylene chloride is particularly preferred.
  • the acid anhydride produced by any of the above methods includes, for example, the following formula ( ⁇ ):
  • an acid anhydride may be formed between molecules as shown in the above. Any of the acid anhydrides is used in the following steps and is similarly used, but the acid anhydride is used in the molecule of the formula ( ⁇ '). Are preferred.
  • the protecting group is introduced by reacting the above acid anhydride with compound (IV) or a salt thereof in a suitable solvent in the presence of a deoxidizing agent.
  • a compound which is useful for protecting one Q—X— ⁇ group that is, a carboxylic acid or a sulfonic acid, and in which the protecting group can be removed by a method other than hydrolysis, may be mentioned.
  • the substituent include an alkyl group such as a methyl group and an ethyl group; an alkoxy group such as a methoxy group; a nitro group; an aryl group such as a phenyl group and a naphthyl group; an aralkyl group such as a trityl group.
  • Preferred compound (IV) is benzyl alcohol.
  • Salt of the compound (IV) Examples include: alkali metal salts (lithium salt, sodium salt, potassium salt), alkaline earth metal salts (calcium salt, norium salt), organic amine salts [alkylamine salts (triethylammonium salt, N, N —Disopropyl-1-N-ethylammonium salt), aromatic amine salts (pyridinium salt, lutidinium salt, 4-N, N-dimethylaminopyridinium salt)], of which lithium salt and sodium salt are preferred.
  • the compound (IV) or a salt thereof is used in an amount of 1 to 10 mol, preferably 1.5 to 3.0 mol, per 1 mol of the compound ( ⁇ ) before forming an acid anhydride.
  • Examples of the deoxidizing agent used in the above reaction include organic amines [alkylamines (triethylamine, N, N-diisopropyl-1-N-ethylamine); aromatic amines (pyridines, 4-N, N-dimethylaminopyridine); Arylamine (anilin, ⁇ , ⁇ -ethylylaniline)], among which triethylamine, 4-—, ⁇ -dimethylaminopyridine, and mixtures thereof are preferable.
  • Examples of the solvent include halogenated aliphatic hydrocarbon solvents (methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), and optionally halogenated aromatic hydrocarbons.
  • Hydrogen solvents (benzene, toluene, xylene, black benzene, dichlorobenzene), ether solvents (getyl ether, diisopropyl ether, t-butylmethyl ether, tetrahydrofuran, 1,4-dioxane), amides Solvents (dimethylformamide, dimethylacetamide) and sulfoxide solvents (dimethylsulfoxide). Of these, methylene chloride and tetrahydrofuran are preferable.
  • the reaction is usually carried out at 5 to 150 ° C, preferably at 20 to 30 ° C. Performed at a temperature of C.
  • the compound (Prot-111) protected by the above method is reacted with an epoxy compound (V-a) to lead to an epoxy compound (Prot-I).
  • This reaction can be carried out according to a known method. For example, J. Org. Chem. Vol. 26, 2681-2688 (1961), Ind. Eng. Chem. Prod. Res. Dev. Vol. 23, 452 -454 (1984) and so on.
  • the protected epoxy compound (Prot-III) is reacted with an epoxy compound (Va) in a suitable solvent in the presence or absence of a base to thereby protect the protected epoxy compound (Prot-II).
  • a suitable solvent in the presence or absence of a base to thereby protect the protected epoxy compound (Prot-II).
  • the solvent to be used include aliphatic hydrocarbon solvents which may be halogenated (methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), and aromatic hydrocarbons which may be halogenated.
  • Solvents (benzene, toluene, xylene, black benzene, dichlorobenzene), ether solvents (getyl ether, diisopropyl ether, t-butylmethylinoether, tetrahydrofuran, 1,4-dioxane), amide solvents (Dimethylformamide, dimethylacetamide), sulfoxide-based solvents (dimethylsulfoxide), and the like, with toluene being particularly preferred.
  • alkali metal hydrides lithium hydride, sodium hydride, potassium hydride
  • alkali metal hydroxides lithium hydroxide, sodium hydroxide, lithium hydroxide
  • alkaline earth metal hydroxide Calcium hydroxide, barium hydroxide
  • alkylamines triethylamine, N, N-diisopropyl-N-ethylethylamine
  • a quaternary ammonium salt [quaternary ammonium hydroxide salt (tetra-n-butyl / ammonium hydroxide salt sulfate), a quaternary ammonium halide (tetra-n-butylammonium salt) ), And phosphonium salts [quaternary phosphonium borate (methinoletrimethoxyphosphate tetraf / leoloborolate)] and the like, among which tetra n-butylammonium hydrogen sulfate, Tetra n-butyl ammonium hydroxide is preferred.
  • the above reaction is usually carried out at a temperature of from 10 to 200 ° C, preferably from 80 to 150 ° C.
  • a conventional leaving group can be used, and examples thereof include a halogen atom such as a chlorine atom, a bromine atom and an iodine atom; and toluenesulfonyloxy.
  • a sulfonyloxy group such as a methanesulfonyloxy group; and an acyloxy group such as an acetoxy group and a ptyryloxy group.
  • the compound (V-a) is used in an amount of about 1.0 to 1.5 mol per 1 mol of the compound (Prot-III).
  • Protected epoxy compound (Prot-I) obtained by the above method The desired epoxy compound (I) can be obtained by removing the protecting group.
  • the protecting group can be removed by a conventional method according to the type of the protecting group.
  • the method includes catalytic hydrogenation (for example, hydrogenation using palladium-carbon) in an appropriate solvent, or treatment with formic acid or ammonium formate.
  • Solvents used include alcohol solvents (methanol, ethanol, isopropyl alcohol, t-butyl alcohol), and ether solvents (getyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran,
  • 1,4-dioxane 1,4-dioxane
  • aromatic hydrocarbon solvents benzene, tonolene, xylene
  • methanol and ethanol are preferred.
  • the reaction temperature varies depending on the type of the protecting group removing means, but is usually in the range of 10 to 100 ° C, preferably 20 to 30 ° C.
  • the desired epoxy compound (I) can be obtained by introducing the biaryl aldehyde compound (III) to the acid anhydride in the same manner as described above, and then directly reacting the resulting compound with the epoxy compound (V-b).
  • the reaction between the acid anhydride and the compound (Vb) is performed in a suitable solvent in the presence of a deoxidizing agent.
  • the amount of the compound (Vb) to be used in this reaction is in the range of 1 to 10 mol, preferably 1.0 to 1.5 mol, per 1 mol of the compound (II) before being converted into the acid anhydride.
  • the deoxidizing agents used include alkali metal hydrides (lithium hydride, sodium hydride, potassium hydride), alkali metal hydroxides (lithium hydroxide, sodium hydroxide, potassium hydroxide), organic amines [ Alkylamines (triethylamine, N, N-diisopropyl-1-N-ethylamine); aromatic amines (pyridine, 4- ⁇ , ⁇ -dimethylaminopyridine), arylamines (aniline, ⁇ , ⁇ ⁇ -ethylenilamine), etc. Among them, triethylamine, 4- ⁇ , ⁇ -dimethylaminopyridine, or a mixture thereof is preferable.
  • the solvent examples include an aliphatic hydrocarbon solvent which may be halogenated (methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), a non-halogenated aromatic hydrocarbon which may be halogenated.
  • aliphatic hydrocarbon solvent which may be halogenated (methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), a non-halogenated aromatic hydrocarbon which may be halogenated.
  • Hydrogen solvents (benzene, toluene / xylene, xylene, benzene, dichlorobenzene), ether solvents (getyl ether, diisopropyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane) ), Amide solvents (dimethylformamide, dimethylacetamide), sulfoxide solvents (dimethylsulfoxide) And methylene chloride and tetrahydrofuran are preferred. This reaction is usually carried out at a temperature of 5 to 150 ° C, preferably 20 to 30 ° C.
  • the compound (III) is an asymmetric compound, that is, if an R-type compound or an S-type compound is used, the corresponding asymmetric compound is obtained. Through the compound, it is led to an R-type epoxy compound (I-a) or an S-type epoxy compound (I-b).
  • ring Ar is a 1 to 3 cyclic aromatic ring which may have a substituent, has a configuration in which a portion shown by a bold line is in front, and Alk is a single ring.
  • the optionally substituted 1 to 3 cyclic aromatic ring of the ring Ar includes, for example, a benzene ring, a naphthalene ring, a naphthoquinone ring, Examples include anthracene ring, anthraquinone ring, and phenanthrene ring.
  • the substitution position of Alk that bonds the aromatic ring is not particularly limited as long as it causes molecular asymmetry, but it is preferable that Alk is bonded to the ortho position of the bond between two rings Ar. .
  • Examples of the substituent on the aromatic ring include a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-toluenesulfonyl group, a trifluoromethyl group, and a cyano group.
  • An electron-withdrawing group such as a group, a methoxycarbonyl group, a methylsulfoxide group or a sulfolamide group; a lower alkyl group having 1 to 4 carbon atoms represented by a methyl group, an ethyl group, a propyl group and a butyl group; Lower alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy and butoxy groups, cyclopropyl, cyclobutyl, cyclopentyl And electron-donating groups such as a cycloalkyl group having 3 to 7 carbon atoms typified by a group and a cyclohexyl group, and an aralkyl group having 7 to 10 carbon atoms typified by a benzyl group and a phenethyl group.
  • an electron-withdrawing group is preferable, and a halogen atom is particularly preferable.
  • Examples of preferred rings Ar include the following partial structures:
  • R e and R b each represent a hydrogen atom or a substituent, and R e and R d represent groups satisfying the following conditions:
  • R d are each a hydrogen atom or a substituent, or /, Is
  • RR j , R k, and R m each represent a hydrogen atom or a substituent
  • Examples of the substituent in R a to R m include a halogen atom represented by a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, a nitro group, a methylsulfonyl group, a p-toluenesulfonyl group, a trifluoromethyl group, Electron-withdrawing groups such as cyano, methoxycarbonyl, methylsulfoxide, and sulfonylamide; lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, and butyl; Group, ethoxy group, propoxy group and butoxy group represented by lower alkoxy group having 1 to 4 carbon atoms, cyclopropyl group, cyclobutyl group, cyclopentyl group and cyclohexyl group having 3 to 7 carbon atoms Electron donation of C7-C10 aralkyl
  • a lk represents a single bond or a linear or branched lower alkylene group having 1 to 5 carbon atoms which may have a substituent.
  • the lower alkylene group include, for example, a linear or branched group represented by a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a methylmethylene group, a methylethylene group and a methyltrimethylene group.
  • a lower alkylene group having 1 to 4 carbon atoms having a branched chain is exemplified.
  • substituents examples include a sulfiel group, a sulfonyl group, a hydroxy group, a nitro group, a nitrile group, an alkyl group, an aryl group, an aralkyl group, an alkoxy group, an aryloxy group, an aralkyloxy group, and a quaternary amino group.
  • ring Ar is, for example, a benzene ring, a naphthalene ring, Or when the configuration of an anthracene ring compound is represented, the R-type and S-type configurations are represented by the following partial structures:
  • the starting compound (III) used in the method of the present invention is described in Journal of, The Chemistry, Society (J. Chem. Soc.) 1242-1251 (1955) and 1579-1. 1 582 (1949), Chemical 'and' Pharmaceutical 'Bulletin (Chem. Pharm. Bull.) 37 (8) Vol. 2207-2208 (1 989), Journal' Ob 'American' Chemical ' Society (J. Am. Chem. Soc) 111 4 9309- 931 7 (1992), Journal of America (Chemical) Society (J. Am. Chem.
  • Soc 118 1849 49- It can be produced according to the method described in “Supplementary Material” on page 492 (1996), and its optical resolution can be determined by using optically active amines (eg, quinidine, cinchonidine, amino acids, amino acid esters) , Kyun, Brusin, amino alcohol) etc.
  • optically active amines eg, quinidine, cinchonidine, amino acids, amino acid esters
  • Kyun Brusin, amino alcohol
  • catalysts that generate reactive species include acetone, methyl ethyl ketone, isobutyl methyl ketone, and lower fatty acids (acetic acid and propionic acid).
  • Cobalt acetate (11), cobalt bromide (II), cobalt chloride (11), manganese acetate (11), manganese bromide (11), manganese chloride (II), etc. can also be used.
  • the oxidation reaction can be carried out in an oxygen gas atmosphere of 1 to 30 atm. However, oxygen gas may be allowed to act on the reaction solution by publishing. The reaction can easily proceed at 20-200 ° C, especially at 90-150 ° C.
  • the carboxyl group of the resulting compound (XI) can be esterified by a conventional esterification reaction. If necessary, the carboxyl group of the compound (XI) can be esterified with a nitrogenating agent, a mixed acid ester, or the like. And then react with an alcohol (methanol, ethanol).
  • a dehydrating agent sulfuric acid, P-toluene Sulfonic acid
  • a deoxidizing agent triethylamine, pyridine, N, N-dimethylaniline.
  • Alcohol-based solvents methanol, ethanol
  • Alcohol, which is a reactant can also serve as a solvent.
  • the reaction is preferably carried out at 0 to 150 ° C, especially at 50 to 90 ° C.
  • Subsequent coupling can be carried out by the usual method of the Ullmann reaction [Merck Index (12th ed.) 0NR—92 383]. It can be carried out by stirring at 1170 ° C.
  • Ester hydrolysis of the product is carried out according to the usual method, using an acid (hydrochloric acid, sulfuric acid) or a base (alkali metal hydroxide, alkaline earth metal hydroxide) in water or an aqueous solvent (water-ethanol, water-tetrahydrofuran). By doing so, it can be implemented.
  • the corresponding starting compounds were (A) any one of Examples 1- (1) to (3) or Examples 6 to 10, and (B) any one of Examples 1- (4) or Examples 2-4.
  • the compounds described in Table 2 are obtained by treating according to the procedure described in Example 5 with force. Table 2
  • the compound 12 (46.69 g, yield: 82.5%) is obtained by air drying at 50 ° C. COOCH 3
  • HPLC HPLC was measured under the following conditions, and no contamination with isomers was observed.
  • reaction mixture is poured into half-saturated saline and extracted with ether.
  • organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate.
  • an asymmetric ketone compound which is used as a catalyst in the production of an optically active furglycidic acid derivative which is an intermediate for producing a 1,5-benzothiazepine derivative useful as a medicament, and a precursor which is a precursor thereof. Since the droxylactone compound can be obtained in a high yield without using a large amount of an organic solvent, the method of the present invention is useful as an industrial production method of the compound.

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Abstract

Procédé industriel de fabrication d'un composé cétone pour l'utilisation comme catalyseur dans la production d'un dérivé d'acide phénylglycidique optiquement actif et pour la production d'un composé hydroxylactone utilisé comme précurseur du composé cétone, caractérisé en ce qu'on soumet un composé époxy (I) ou un sel de celui-ci à une cyclisation intramoléculaire en vue d'obtenir le composé hydroxylactone (II) ou un sel de celui-ci, et en ce qu'on oxyde ce composé (II) de manière à obtenir le composé cétone correspondant. (Dans les formules (I) et (II), Ar désigne un noyau aromatique monocyclique à tricyclique, éventuellement substitué; Alk désigne une liaison simple ou un alkylène éventuellement substitué; Q représente CO ou SO2; X représente O ou S; et R1 désigne un H ou un alkyle inférieur).
PCT/JP1999/001615 1998-04-08 1999-03-30 Procede de fabrication d'un compose hydroxylactone WO1999052891A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29600/99A AU2960099A (en) 1998-04-08 1999-03-30 Process for producing hydroxylactone compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9577198 1998-04-08
JP10/95771 1998-04-08

Publications (1)

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WO1999052891A1 true WO1999052891A1 (fr) 1999-10-21

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AU (1) AU2960099A (fr)
WO (1) WO1999052891A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056762A2 (fr) * 1997-06-11 1998-12-17 Tanabe Seiyaku Co., Ltd. Procede de preparation de composes de phenyloxyrane actifs sur le plan optique

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998056762A2 (fr) * 1997-06-11 1998-12-17 Tanabe Seiyaku Co., Ltd. Procede de preparation de composes de phenyloxyrane actifs sur le plan optique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DAN YANG, ET AL.: "HIGHLY ENANTIOSELECTIVE EPOXIDATION OF TRANS-STILBENES CATALYZED BY CHIRAL KETONES", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 118, no. 45, 1 January 1996 (1996-01-01), US, pages 11311/11312, XP002921245, ISSN: 0002-7863, DOI: 10.1021/ja9626805 *

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