WO1999052891A1

WO1999052891A1 - Process for producing hydroxylactone compound

Info

Publication number: WO1999052891A1
Application number: PCT/JP1999/001615
Authority: WO
Inventors: Masahiko Seki; Tooru Kuroda; Takeshi Yamanaka; Ritsuo Imashiro; Takeji Shibatani
Original assignee: Tanabe Seiyaku Co., Ltd.
Priority date: 1998-04-08
Filing date: 1999-03-30
Publication date: 1999-10-21
Also published as: AU2960099A

Abstract

A process for industrially producing a ketone compound for use as a catalyst in the production of an optically active phenylglycidic acid derivative and for producing a hydroxylactone compound as a precursor for the ketone compound, which comprises subjecting an epoxy compound (I) or a salt thereof to intramolecular ring closure to produce the hydroxylactone compound (II) or a salt thereof and oxidizing this compound (II) to obtain the corresponding ketone compound. (In the formulae, ring Ar is an optionally substituted mono- to tricyclic aromatic ring; Alk is a single bond or optionally substituted alkylene; Q is CO or SO2; X is O or S; and R1 is H or lower alkyl).

Description

Description Manufacturing method for hydroxylactone compounds Technical field

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.

Background art

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)

—3—acetoxy-5— [2- (dimethylamino) ethyl] -1-2- (4-methoxyphenyl) 1-1,5-benzothiazepine-14 (5H) -one hydrochloride] is a drug for angina pectoris, It is widely used to treat essential hypertension.

Such 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. Japanese Patent Application Laid-Open No. 4-501130, Japanese Patent Application Laid-Open No. No. 2,280,955, Japanese Patent Application Laid-Open No. 60-137776, International Publication No. 95/07359, pamphlet, etc.), all of which are used as raw materials for racemic trans-glycidic acid. Since the derivative is used, the yield of the target optically active substance is very low, less than 50% of that of the racemic form.

As an improved process for producing this optically active phenyldaricidic acid derivative, The following formula is used for the cinnamate derivative:

A method for deriving an optically active phenyldaric acid derivative by reacting with an asymmetric ketone compound and an oxidizing agent represented by the following formula (WO98 / 56672) has been proposed.

The above-mentioned 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.

Disclosure of the invention

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.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention provides a compound of the general formula (I)

(Wherein, 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. Group or a sulfonyl group, X represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a lower alkyl group.)

The intramolecular ring closure of the epoxy compound or a salt thereof represented by the formula (II):

(Wherein, the rings Ar, Alk, Q, X and R ¹ have the same meanings as described above)

And a method for producing the hydroxylactone compound or a salt thereof represented by the formula:

The present invention also provides a compound represented by the general formula (VI): oxidizing the hydroxylactone compound (II) or a salt thereof.

(Wherein, rings Ar, Alk, Q, X and R ¹ are the same as described above)

In this case, by using an asymmetric compound as the hydroxylactone compound (II), a corresponding asymmetric ketone compound can be obtained.

As shown in the following 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. . Reaction formula-

(I) (Π)

(Wherein the rings Ar, Alk, Q, X and R ¹ are as defined above).

The epoxy compound (I) or a salt thereof is converted to a hydroxylactone compound by the above method.

The reaction leading to (II) or a salt thereof is easily carried out by the following methods (a) and (b).

Method (a):

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 solvents (methyl acetate, ethyl acetate), nitrile solvents (acetonitrile), Ketone solvents (acetone, 2-butanone, methyl isobutyl ketone), amide solvents (dimension Ruhorumuamido, dimethyl Asetoamido), and the like, preferably, ethanol, tetrahydrofuran, 4 one Jiokisan. 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.

Examples of the ammonium salt to be reacted 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. Method (b):

Treatment 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. Examples of 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 (acetonitrile), ketone solvents (acetone, 2-butanone, methyl isobutyl ketone), amide solvents (dimethylformamide, dimethylacetamide), Alcohol solvents (methanol, ethanol, isopropyl alcohol) Alcohol, t-butyl alcohol) and the like, preferably, tetrahydrofuran, methylene chloride, and benzene having a chloro opening. The amount of the compound to be used is 2 to 50 g, preferably to compound (I) ) For lg, it is 10 to 30 g. As 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. For example, 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.

Specific examples of the transition metal complex catalyst 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.

[In the formula, ^ Is 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 ^a 'and R ^e "are (i) a hydrogen atom, Alkyl or aryl groups, or (ii) linked to each other to form

(Wherein, 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:

(Where, ^ is a hydrogen atom, an alkyl group or an aryl group, Alk 'is an alkylene group optionally substituted with an alkyl group or an aryl group), M is a transition metal or Means aluminum].

As the alkyl group for the substituent in the complex (VII), 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, and 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, and 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. Examples of 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.

(Wherein, 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:

(Where R ^bl ′ and R ^b2 ′ are a hydrogen atom, an alkyl group or an aryl group, and Alk ′ is the same as above) Is a compound of

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.

Further preferred other complexes used in the present invention are, in the above formula (VII), 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.

Preferred specific examples of the transition metal complex catalyst used in the present invention include complexes represented by the following formulas (VIII) and (IX).

In any of the above methods, hydroxylactone obtained by using the R-type epoxy compound (I-a) or the S-type epoxy compound (I-b) as the starting epoxy compound (I). As shown in the following Reaction Formula 11 'and Reaction Formula 11 に, the ton compounds can also be converted to R-type hydroxylactone compounds (II-a) or S-type hydroxylactone compounds (Π-b), respectively. Be guided.

Reaction formula 1 '

(I-a) (II-a)

(In the formula, 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 An alkylene group which may have a hand or a substituent, Q is a carbonyl group or a sulfonyl group, X is an oxygen atom or a sulfur atom, and R ¹ is a hydrogen atom or a lower alkyl group).

Reaction formula 1 "

(I-b) (Π-b)

(Wherein, ring Ar and its bold line, Alk, Q, X and R ¹ are the same as above). By treating the hydroxylactone compound (Π) or its salt obtained by the above method with an oxidizing agent in an appropriate solvent, a corresponding ketone compound is obtained as shown in the following reaction formula 12. Can be Reaction Formula 1 2

(Π) (VI)

(Wherein the rings Ar, Alk, Q, X and R ¹ are as defined above).

Examples of the solvent used in the above reaction include aromatic hydrocarbon solvents that may be halogenated (benzene, toluene, xylene, cyclobenzene, dichlorobenzene), and among them, toluene is preferable. Examples of the oxidizing agent 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.

In the above method, the ketone compound obtained by using an R-type hydroxylactone compound (Π-a) as the hydroxylactone compound (Π) or an S-type hydroxylactone compound (Il-b) is used. Is also led to the R-type ketone compound (VI-a) or the S-type ketone compound (VI-b) as shown in the following reaction formulas 12 'and 12', respectively. Reaction formula 1 2 '

(II-a) (VI-a)

Reaction Formula 1 "

(II-b) (VI-b)

(Wherein, ring Ar and its bold line, Alk, Q, X and R ¹ are the same as above). 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

(Prot-I)

(Prot-III)

(Wherein, rings Ar, Alk, Q, X and R ¹ are the same as above, Prot represents a protecting group, and L represents a removable group).

That is, an acid anhydride is produced from the biaryl compound (III), and the compound (IV) or a salt thereof is reacted therewith to introduce a protecting group, and then reacted with the epoxy compound (V-a). Route (a) for deprotecting group treatment, and biaryl compound

After producing the acid anhydride from (III), it can be produced by a route (b) in which an epoxy compound (V-b) is directly reacted. These production methods will be described in more detail below.

Lou h (a):

First, an acid anhydride is produced from a biaryl compound (ΙΠ) by a conventional method.

(IV):

Prot-X-H (IV)

(Where X and Prot are the same as above)

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.

In order to prepare the corresponding acid anhydride from the biaryl aldehyde compound (ΙΠ), there is a method in which a dehydrating agent is allowed to act on compound (III) in an appropriate solvent. The dehydrating agents used in this method include Ν, Ν'-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. In addition, aliphatic hydrocarbon solvents (hexane, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), and 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) and the like, but 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. Is the way. 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. Examples of the halogenating agent include thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus pentoxide, phosphorus trioxide and the like. Of these, thioyl chloride and oxalyl chloride are particularly preferred. Examples of the deoxidizing agent 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-Ν, Ν-dimethylaminopyridine), arylamines (aniline, Ν, ジェ -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. Examples of the solvent to be used 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 (ΠΓ):

(Wherein, rings Ar, Alk, Q and X are the same as above)

When an acid anhydride is formed in the molecule represented by

(Wherein, rings Ar, Alk, Q and X are the same as above)

In some cases, 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 (ΙΠ '). 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.

As the compound (IV), a compound which is useful for protecting one Q—X—Η 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. . For example, substituted or unsubstituted benzyl alcohol, or substituted or unsubstituted aryl alcohol. Examples of 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. You. 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 (Ι) 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, Ν, Ν-ethylylaniline)], among which triethylamine, 4-—, Ν-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.

For example, 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). — I) is obtained. Examples of 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. As bases, 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) and the like, with sodium hydride being preferred. As the base, 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.

As the leaving group (L) in the compound (V-a), 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), aromatic hydrocarbon solvents (benzene, tonolene, xylene) and the like, among which 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.

Route (b):

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- 、, Ν-dimethylaminopyridine), arylamines (aniline, Ν, ジェ -ethylenilamine), etc. Among them, triethylamine, 4-Ν, Ν-dimethylaminopyridine, or a mixture thereof is preferable. Examples of the solvent 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. 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. In the above method for obtaining the starting epoxy compound (I) from the conjugated product (Ι), if 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).

Reaction formula 1 3 '

(Prot-I-a)

(Prot-m-a)

(In the formula, 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. An alkylene group which may have a bond or a substituent, Q is a carbonyl group or a sulfol group, X is an oxygen atom or a sulfur atom, R ¹ is a hydrogen atom or a lower alkyl group, P rot is a protecting group, L represents a group capable of leaving). Reaction formula 1 3

(Prot-I-b)

(Prot-III-b) (wherein, ring Ar and its bold line, Alk, Q, X, R Prot and L are the same as above).

In the compounds (I), (Π) and (ΙΠ) of the present invention, 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. Among these groups, an electron-withdrawing group is preferable, and a halogen atom is particularly preferable.

Examples of preferred rings Ar include the following partial structures:

Is the expression

[Wherein, 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:

(a) R. And R ^d are each a hydrogen atom or a substituent, or /, Is

(b) R ^c and R ^d are bonded together to form:

(Where, R ^e , R! ^ ぉょぴ! ^ Represents one of the following:

(Two adjacent groups are bonded to each other to form an optionally substituted benzene ring together with two carbon atoms between them, and the other two groups are a hydrogen atom or a substituent.

(β) each is a hydrogen atom or a substituent) The force forming the group represented by or

(c) 1 ^ and R ^d combine with each other to form the formula:

(Wherein, 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 groups such as cycloalkyl, benzyl and phenethyl groups It is possible to increase the group. Among these groups, an electron-withdrawing group is preferable, and a halogen atom is particularly preferable.

In the compounds (1), (Π), (III) and (VI), 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. Specific examples of 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. Examples of the substituent 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.

In the compound of the present invention, 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:

Where, when the ring Ar is a benzene ring,

(Where the bold line has the configuration of the structure appearing in the foreground), and when the ring Ar is a naphthalene ring, the following formula:

R type S type

(In the formula, the part shown by a bold line has the same meaning as above.)

And when ring Ar is an anthracene ring, the following formula

R type s type

(In the formula, the part shown by a bold line has the same meaning as above.)

Indicated by

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. The force can be carried out by the fractional crystallization method used.

(Wherein, ring Ar has the same meaning as described above)

The compound represented by the general formula:

(In the formula, Hal represents a bromine atom or an iodine atom, and ring Ar has the same meaning as described above.)

Is oxidized by oxygen gas in the presence of a catalyst that generates reactive species such as an acyl radical and a transition metal catalyst, to produce a compound represented by the following general formula:

(Wherein Hal and ring Ar have the same meaning as described above)

Can be produced by esterifying a carboxyl group of the product, coupling the product in the presence of a copper catalyst, and subjecting the product to ester hydrolysis.

Examples of catalysts that generate reactive species such as acyl radicals 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).

When reacting compound (XI) directly with alcohol, a dehydrating agent (sulfuric acid, P-toluene Sulfonic acid), while in the case of using a reactive derivative, it can be performed in the presence of a deoxidizing agent (triethylamine, pyridine, N, N-dimethylaniline). . Alcohol-based solvents (methanol, ethanol) can be used as a solvent for these reactions. 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.

Example

Hereinafter, the method of the present invention will be described more specifically with reference to examples.

Example 1

1 2

17 Oml of acetic anhydride is added to compound 1 (17 g), and the mixture is heated under reflux for 15 hours. After evaporating the reaction solution under reduced pressure, 10 Oml of toluene is added and the mixture is concentrated under reduced pressure. To the residue is added 100 ml of toluene, and the mixture is again concentrated under reduced pressure. 4 Oml of benzyl alcohol is added, and the mixture is refluxed for 3 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent; η-hexane: ethyl acetate = 4: 1 → 1: 1), and crystallized with n-hexane to give the compound. 2 (9.6 g) are obtained. Yield: 44.7. / ₀

m.p .: 161-162 ° C

SI MS (m / z): 433 (M +) NMR (CDC 13, δ): 4.79-4.92 (m, 2 H), 6.70—7.24 (m, 9 H), 7.44-7.52 (m, 2 H), 7.81- 8.15 (m, 5H), 8.15-8.20 (m, 1H)

(2)

twenty three

Compound 2 (432 mg) was dissolved in 0.5 ml of toluene, 38.4 mg of sodium hydride was added at 25 ° C under a nitrogen stream, and the mixture was stirred at 25 ° C for 30 minutes, and tetra-n-hexylammo-prompromide Add 22 mg and 185 mg of epichlorohydrin and heat to reflux for 2 hours. After cooling, the reaction solution is purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 4: 1) to obtain Compound 3 (356.7 mg). Yield: 73.0%

m.p .: 138-1 39 ° C

EI | MS (m / z): 488 (M ⁺ )

NMR (CDC 13, δ): 2.18-2.27 (m, 1 H), 2.47-2.66 (m, 2 H), 3.75-3.84 (m, 1 H), 3.93-4.02 (m , 1 H), 4.82-4.92 (m, 2H), 6.84-- 6.89 (m, 2H), 7.08-- 7.27 (m, 8H), 7.46--7.54 (m, 2H), 7.87 -8. 25 (m, 5 H)

(3)

3 4

Compound 3 (140.4 mg) was dissolved in a mixture of 10 ml of methanol and 2 ml of tetrahydrofuran, and 5 Omg of 10% palladium-carbon (containing 50% water) was added. Blow at 25 ° C for 1 hour. The reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The concentrated residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 4: 1 → chloroform: methanol = 30: 1), and then crystallized by ethyl acetate-n-hexane. Compound 4 (92.6 mg) is obtained. Yield: 80.9% mp: 158—159. C

E I | MS (m / z): 398 (M +)

_{NMR (CDC 1 3, 6)} :.. 2. 19-2.28 (m, l H), 2.47-2 54 (m, 1 H), 2.60-2 70 (m, 1 H), 3. 75- 3 88 (m, 1H), 3.95—4.05 (m, 1H), 6.99—7.03 (m, 2H), 7.17—7.27 (m, 3H), 7.48—7.55 ( m, 2 H), 7.90-8.02 (m, 3 H), 8, 1 1-8.20 (m, 2 H) (4)

4 5

398 mg of compound 4 (racemic), 16 mg of tetra-n-butylammonium hydrogen sulphate, 3 mg of sodium hydroxide and 8 ml of ethanol are heated to reflux for 24 hours. After evaporating the reaction solution under reduced pressure, the concentrated residue was purified by silica gel column chromatography (solvent; toluene: ethyl acetate = 4: 1 → n-hexane: ethyl acetate = 2: 1) to give compound 5 ( 133.2 mg). Yield: 33.4%

Example 2

4 ₅

Dissolve 10 Omg of compound 4 (racemic) and 35 mg of Ν, Ν-diisopropylethylamine in 2 ml of tetrahydrofuran, add compound 7 (7.5 mg) at room temperature under oxygen atmosphere, and stir at the same temperature for 142 hours I do. To the reaction solution is added 1 Oml of saturated saline, and the mixture is extracted with 2 Oml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2: 1) to give Compound 5. (10 Omg) as a light brown powder. Yield: 100%

Physical properties were the same as those of the compound obtained in Example 1 (4).

Example 3

Four

Compound 4 (racemic) 10 Omg and N, N-diisopropylethylamine 35 was dissolved in 2 ml of tetrahydrofuran, compound 8 (4.7 mg) was added at room temperature under an oxygen atmosphere, and the mixture was stirred at the same temperature for 190 hours. To the reaction solution is added 1 Oml of saturated saline, and the mixture is extracted with 2 Oml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; n-hexane: ethyl acetate = 2: 1) to give Compound 5. (8 Omg) are obtained as colorless crystals. Yield: 80%

Example 4

4 5

Compound 4 (racemic) A solution of 10 Omg (0.25 mmol) and 35 mg (0.275 mmol) of N, N-diisopropylethylamine in 2 ml of tetrahydrofuran (degassed by blowing nitrogen) was added with Compound 7 (at room temperature) under an argon atmosphere at room temperature. (5 mg, 0.01 25 mmol) and stirred at the same temperature for 135 hours. To the reaction solution is added 1 Oml of saturated saline, and the mixture is extracted with 2 Oml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (solvent; hexane: ethyl acetate = 2: 1) to give Compound 5 (93 mg). , 93%) as a colorless powder.

Physical properties were the same as those of the compound obtained in Example 1 (4). Example 5

5 6

Compound 5 (racemic) 5 Omg (0. 1 25 mmol), MnO _z 418mg, and a mixture of toluene lml stirred for 1 7 hours at 50-60 ° C. The insolubles are removed by filtration, and the filtrate is concentrated under reduced pressure. After adding diisopropyl ether to the precipitated crystals, the crystals are collected by filtration, washed with n-hexane, and dried under reduced pressure to obtain 25 mg (50.3%) of compound 6.

m. ρ .:> 280 ° C

IR (KB r): 1754 cm- ¹

Example 6

14

(1) Compound 1 (342 mg, 1 mmol) was suspended in 5 ml of methylene chloride, triethylamine (223 mg, 2.2 mmol) was added at room temperature, and the mixture was cooled with ice, and oxalyl chloride (140 mg, (1 mmol) was added dropwise over 1 hour, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction mixture, the resulting residue was suspended in 5 ml of methylene chloride, cooled with ice, and added with glycidol (101 mg, 1.3 mmol), triethylamine (0.17 ml, 1.2 mmol) and 4-dimethylamino. After adding pyridine (12 mg, 0.1 mmol), the mixture is stirred at room temperature for 1 hour. The reaction mixture is diluted with 50 ml of ethyl acetate, washed with a 10 / o aqueous solution of citric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solution is subjected to silica gel column chromatography (solvent; Oral form: ethyl acetate = 50: 1 → chloroform: methanol 30: 1) to give compound 4 (320 mg, 80%) as a colorless powder.

(2) Compound 4 (319 mg, 80%) is obtained in the same manner as in the above (1), except that thionyl chloride (143 mg, 1.2 mmol) is used instead of oxalyl chloride.

(3) Compound 1 (342 mg, 1 mmol) is suspended in 5 ml of methylene chloride, and triethylamine (223 mg, 2.2 mmol) is added at room temperature. The mixture is cooled with ice, a solution of diphenyl phosphorochloride (296 mg, 1.1 mmol) diluted with 1 ml of methylene chloride is added dropwise over 1 hour, and the mixture is stirred at room temperature for 1 day. The reaction solution was then cooled on ice, and glycidol (101 mg, 1.3 mmol), triethylamine (0.17 ml, 1.2 mmol) and 4-dimethylaminopyridine (12 mg, 0.1 mmol) were added. Then, stir at room temperature for 1 hour. The reaction solution is diluted with 5 Oml of ethyl acetate, washed with a 10% aqueous solution of citric acid, water and saturated saline, and dried over anhydrous magnesium sulfate. The mixture was concentrated, and the obtained residue was purified by silica gel column chromatography (solvent: chloroform: ethyl acetate = 50: 1 → chloroform: methanol = 30: 1) to obtain Compound 4 (308 mg, 77%).

Example 7-9

In the method described in Example 6 above, the conditions for the acid anhydride formation reaction were variously changed as shown in Table 1, and the reaction with glycidol was performed using 1.3 mimol of triethylamine and the dose of glycidol was adjusted as shown in Table 1. Compound 4 is obtained by carrying out in the same manner except for changing as shown in.

The results are shown in Table 1. table 1

Example 10

14

2. Oml of acetic chloride is added to compound 1 (342 mg), and the mixture is heated under reflux. The reaction mixture is concentrated under reduced pressure, 2 ml of THF is added to the residue, and the mixture is again concentrated under reduced pressure. This residue was dissolved in 2 ml of methylene chloride, and glycidol (0.1 ml, 1.5 mmol), triethylamine (0.1 ml, 1.5 mmol), 4-dimethylaminopyridine (12 mg, 0 1 mmol), and react at room temperature for 3 hours. Dilute the reaction solution with 50 ml of ethyl sulphate, wash with a 10% aqueous solution of citric acid, water and saturated saline, and dry over anhydrous magnesium sulfate. The residue obtained by concentrating the solution is Purification by force gel force chromatography (solvent; chloroform: ethyl acetate = 50: 1 → clonal form: methanol = ₃₀ : 1) to obtain compound 4 (247 mg, 62%).

Example 1 1

(R) -l (R) -4

(R) Compound 1 (optical purity 99.5% ee; 3.00 g, 8.76 mmol) was dissolved in 44 ml of methylene chloride, and triethylamine (2.44 ml, 17.5 mmol) was added at room temperature. Add. After cooling this mixture on ice, at the same temperature, a solution of oxalyl chloride (1.1 lg, 8.76 mmol) in 8.8 ml of methylene chloride is added dropwise over 1 hour. The mixture was stirred at room temperature for 1 hour, cooled on ice again, and at the same temperature, triethylamine (1.47 ml, 10.5 mmol), glycidol (0.69 ml, 9.88 mmol) and N, N-dimethylaminopyridine (107 mg) , 0.876 mmol). The mixture is stirred at room temperature for 1 hour. After the reaction mixture is washed with 10% citric acid, the aqueous layer is extracted with chloroform, and the chloroform layer is washed with water and brine, dried and concentrated. The residue was purified by silica gel chromatography (solvent; chloroform: ethyl acetate = 50: 1 → chloroform: methanol = 30: 1) to give the (R) -type compound 4 (2.52 g, yield: 72%) as a colorless foam.

E 1 MS (m / Z): 398 (M +)

NMR (CDC 13, δ): 2.21-2.30 (m, 1H), 2.50-2.56 (m, 1H), 2.63—2.73 (m, 1H), 3.77—3.89 (m, 1H ), 3.99— 4.07

(m, l H), 7.02 (d, J = 8.7 Hz, 2H), 7.19-7.32 (m, 2H), 7.4 8-7.56 (m, 2H), 7.92-8.03 (m, 4H ), 8.1 1 -8. 19 (m, 2H) [a] ²⁴ _D = + 36.7 ° (C = 1.00, black-hole form) Example 1 2

(R)-(R) -6

By applying the method described in Example 1- (4) or Example 3 and the method described in Example 5 to (R) -type compound 4, (R) -type compound 6 is obtained.

Physicochemical properties of this product, the journal. Supplement of O Bed 'American' Chemical 'Vegetables Variety one _(Journal of American Chemical Society) Λ first 1 8 Certificates, 4 9 1-49 2 pages (1 9 1996) It was the same as that described in the “Supplementary Material”.

Example 13: 16

9 10

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

Example 17

The (R) -9 (R) -10 corresponding starting compound was added to either (A) Example 11, (B) Example 1- (4) or Example 3, and (C) Example 5. The compound shown in Table 3 is obtained by treating according to the procedure. Table 3

Reference example

11 12

(1) Compound 11 (50 g, 226 mmol), cobalt acetate (II) tetrahydrate (12 g

A mixture of 48 mmol), methyl ethyl ketone (6.2 ml, 69 mmol) and acetic acid (400 ml) is stirred at 90 ° C. for 10 hours while blowing oxygen. After cooling the reaction mixture to room temperature, it is poured over 50 Og of ice. After stirring the mixture for 1 hour, the precipitated crystals are collected by filtration and washed with water. The obtained crude crystals are dissolved in ethyl acetate (600 ml), treated with activated carbon and dried, and the insoluble matter is removed by filtration. The filtrate is concentrated under reduced pressure, η-hexane is added to the residue, and the mixture is stirred at 10 ° C or less for 1 hour. The precipitated crystals are collected by filtration, washed with n-xane,

The compound 12 (46.69 g, yield: 82.5%) is obtained by air drying at 50 ° C. COOCH ₃

COOCH

CH ₃ OH COOCH3

H, S0 ₄

1

(2-1) The compound obtained in (1) above is heated and refluxed with concentrated sulfuric acid in methanol to form a methyl ester, and then heated to 270 to 280 ° C for 20 minutes in the presence of a copper catalyst. . After cooling the reaction mixture, the mixture is extracted with toluene, and the extract is cooled to precipitate crystals. Compound 14 is obtained by filtering the precipitated crystals and recrystallizing from ethanol. This compound is hydrolyzed using sodium hydroxide and recrystallized from ethanol to obtain Compound 1.

The physicochemical properties of this product were consistent with those described in the Journal of the Chemical Society, Journal of Chemical Society, pages 1242-1251 (1955).

(2-2) In a 1 L eggplant-shaped flask, put the compound obtained in the above (1) (105.3 _g , 419 mmol) and methanol (35 Oml), and add thionyl chloride (36. 7 ml, 503 mmol) is added dropwise over about 10 minutes. After the completion of dropping, heat and reflux for 3 hours.

The residue obtained by distilling off the solvent was dissolved in toluene (30 Oml), and this was added to water. (30 Oml), saturated aqueous sodium bicarbonate (30 Oml) and saturated saline (30 Oral), then magnesium sulfate (1 Og) and activated carbon (25 g) were added, followed by filtration. The filtrate is concentrated under reduced pressure to obtain Compound 13 (10.634 g, yield 96%) as brown crystals. Compound 13 can be obtained by treating compound 13 in the same manner as in the above (2-1).

Reference example 2

15 17 Compound 15 (2.4 Og) is dissolved in 120 ml of ethanol, and the mixture is refluxed under heating. Further, compound 16 (3.13 g) is added little by little, and the mixture is heated under reflux for 15 minutes. Then, the mixture was allowed to cool to room temperature, allowed to stand, and the precipitated quinidine salt of bianthraquinonecarboxylic acid was collected by filtration, washed with ethanol, and added with 114 ml of a 1% aqueous sodium hydroxide solution. Heat at 60 ° C for 30 minutes. After heating, the mixture is left to cool to room temperature, adjusted to pH 2 by adding 3.5% hydrochloric acid, and stirred for 30 minutes.

Next, ethyl acetate is added to the reaction mixture for extraction, followed by drying and distilling off the solvent. The obtained extract is dissolved in methanol and recrystallized. The solvent is distilled off until about 17 ml of the solvent remains, and the obtained crystals are collected by filtration.

Next, the obtained crystals are dried under reduced pressure at 60 to 70 ° C. for 16 hours to obtain Compound 17 (89 Omg).

The physical properties of this product are as follows.

Decomposition point (dp): 1 96.8-2 20.6 [H] _D ²⁵ : — 2 ²⁵ ° (C = 0.8 MeOH)

^{_{IR (nujol) v ma x (}} cm- 1): 34 90, 1 7 2 1, 1 6 70, 1 5 84

LC-MS (E S l) m / z: 50 1 (M-H)

! HNMR (DMS O— d ₆ , a) 7.80-7.95 (m, 6H), 8.2 1—8.26 (m, 2H), 8.33 (d, J = 8H z ₍ 2H), 8.4 1 (d, J = 8Hz, 2H), 13.0 (brs, 2H)

Next, HPLC was measured under the following conditions, and no contamination with isomers was observed.

L i C h ro CART 2 50 -4 C h i r a D e c 5 m

Me OH: 1/4 5M phosphate buffer (pH 6.5) (50/5 0)

Reference example 3

18 19 Compound 1 8 (1 9 2mg, 1. 0 mmol), 1, 2-dimethyl Tokishetan 1 5 ml After dissolving at room temperature, added to 4 X 1 0- ⁴ M Echirenjiamin tetraacetate Ninatoriumu salt solution 1 0 ml Then, (R) -type compound 6 (40 mg, 0.1 mmol) is added, and the mixture is cooled to 0 ° C by an external bath. Thereafter, a mixture of 6.14 g (10 mmol) of oxone and 2.6 g (31 mmol) of sodium bicarbonate is added in six portions every hour. After completion of the addition, the mixture is further stirred for 2 hours, and the obtained reaction mixture is poured into half-saturated saline and extracted with ether. The organic layer is washed with saturated saline and then dried over anhydrous magnesium sulfate.

After drying, anhydrous magnesium sulfate is filtered off, and the solvent is distilled off from the filtrate. To the obtained residue, 9 ml of a mixture of ethyl acetate and n-hexane (1: 8 by volume) is added, and the mixture is stirred at room temperature for 1 hour. The precipitated white powder is collected by filtration and dried under reduced pressure to recover the (R) -type compound 6 (32 mg) (recovery rate: 80% by weight).

On the other hand, the obtained filtrate (HP LC yield: 91%) was purified by flash chromatography on silica gel (mobile phase: ethyl acetate: n-hexane = 1: 8 (volume ratio)) to give the compound. This gives 19 (135 mg, isolation yield: 65%). The optical purity of this product determined by HP LC was 81% e.e.

Reference Examples 4 to 7

18 19 Compound 18 and the compound of Table 4 obtained in Examples 17 to 20 were treated according to Reference Example 3 to give Compound 19.

Table 4

Industrial applicability

According to the method of the present invention, 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.

Claims

The scope of the claims

1. General formula (I):

(Wherein, ring Ar is a 1 to 3 cyclic aromatic ring which may have a substituent, Alk is a single bond or may have a substituent, an alkylene group, and Q is carbonyl. Group or a sulfonyl group, X represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a lower alkyl group.)

Wherein the epoxy compound or a salt thereof represented by the general formula (II):

In a method for producing a human Dorokishiraku tons or a salt thereof shown _c

2. i) General formula (III):

(Wherein, ring Ar is an optionally substituted 1 to 3 cyclic aromatic ring, Alk is a single bond Or an alkylene group which may have a substituent, Q represents a carbonyl group or a sulfonyl group, and X represents an oxygen atom or a sulfur atom.)

To produce a corresponding acid anhydride from a biaryl compound represented by

(ii)-(a) The acid anhydride has the general formula (IV):

Prot-X-H (IV)

(Wherein, Prot represents a protecting group, and X has the same meaning as described above)

After introducing a protecting group by reacting the compound represented by the formula (I) or a salt thereof, the compound represented by the general formula (V-a):

(Wherein L represents a leaving group, R ¹ represents a hydrogen atom or a lower alkyl group), and then the protecting group is removed or

(ii) — (b) The acid anhydride is represented by the general formula (V-b): (V-b)

(Wherein, R ¹ and X have the same meanings as described above)

With the compound shown in

General formula (I):

To produce an epoxy compound represented by

(iii) Next, the compound or a salt thereof is intramolecularly closed.

General formula (II) characterized by the following:

A method for producing a hydroxylactone compound or a salt thereof represented by the formula:

3. The method according to claim 1, wherein the intramolecular ring closure of the epoxy compound (I) is performed in the presence of a transition metal complex catalyst.

4. The transition metal catalyst has the general formula (VII):

[Wherein, R ¹ ′ and a hydrogen atom, an alkyl group or an aryl group, R ² ′ to R ⁵ ′ and R ² ″ to R ⁵ ″ are a hydrogen atom, an alkyl group or an aryl group, R ^a ′ and R ^a ″ Is (i) a force that is a hydrogen atom, an alkyl group or an aryl group, or (ii)

(Wherein, R ^al 'to R ^a4 ' are a hydrogen atom, an alkyl group or an aryl group), or aii) bonded to each other to form a group represented by the formula:

(Wherein, R ^bl 'and R ^b2 ' represent a hydrogen atom, an alkyl group or an aryl group, and Alk 'may be substituted with an alkyl group or an aryl group, or an alkylene group) Group, M represents a transition metal or aluminum]

4. The method according to claim 3, which is a compound represented by the formula:

5. The transition metal catalyst has the formula (VIII):

Or formula (IX):

5. The method according to claim 4, wherein the method is:

6. The method according to claim 1, wherein the intramolecular ring closure of the epoxy compound (I) is carried out in the presence of an ammonium salt.

7. The method according to claim 6, wherein the ammonium salt is tetra-n-butylammonium hydrogen sulfate.

8. The method according to claim 1 or 2, wherein in the intramolecular ring closure of the epoxy compound (I), a solvent is used in an amount of 2 to 5 Og per lg of the compound (I).

9. In the compounds represented by the general formulas (1), (II) and (III),

Is the expression

[Wherein, R ^a and R ^b each represent a hydrogen atom or a substituent, and FT and R ^d represent groups satisfying the following conditions:

(a) R ^e and R ^d are each a hydrogen atom or a substituent, or

(b) Rc and R ^d are bonded to each other wherein:

(Where, R ^e , R! ^ ぉ ^ び ^ び ^^, which means one of the following:

(α two adjacent groups are bonded to each other to form an optionally substituted benzene ring together with two carbon atoms between them, and the other two groups are a hydrogen atom or a substituent, or

(β) each is a hydrogen atom or a substituent)

Forming a group represented by or

(c) R ^c and R ^d are linked together to form:

(Wherein, RRR ^k and R ^m each represent a hydrogen atom or a substituent)], wherein Alk, Q, X and R ¹ are the same as defined in claim 1 The method according to any one of claims 1 to 8.

1 0. — In formulas (1), (Π) and (ΠΙ), Alk is a single bond and Q is 10. The method according to claim 9, wherein X is an oxygen atom, and R ¹ is a hydrogen atom.

1 1. In the general formulas (1), (Π) and (ΠΙ), the partial structure of the following formula:

Is the formula:

10. The method according to claim 10, which is a partial structure represented by the formula:

12. In claim 1, the starting epoxy compound (I) is represented by the general formula (I)

(In the formula, 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 An alkylene group which may have a hand or a substituent, Q is a carbonyl group or a sulfonyl group, X is an oxygen atom or a sulfur atom, and R ¹ is a hydrogen atom or a lower alkyl group. Or a salt thereof using the general formula (II-a):

(Wherein, ring Ar and its thick line portion, Alk, Q, X and R ¹ have the same meanings as described above. Have)

The method according to Claim, for producing an R-type hydroxylactone compound represented by or a salt thereof.

13. In claim 2, the starting biaryl aldehyde compound (ΙΠ) is represented by the general formula (III-a):

(In the formula, 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 An alkylene group which may have a hand or a substituent, Q represents a carbonyl group or a sulfonyl group, and X represents an oxygen atom or a sulfur atom)

Using an R-type starting biaryl compound or a salt thereof represented by the general formula (II-a)

(Wherein, R ¹ represents a hydrogen atom or a lower alkyl group; ring Ar and its thick line portion; Alk, Q and X are the same as above)

3. The method according to claim 2, wherein the R-type hydroxylactone compound represented by or a salt thereof is produced.

14. In claim 1, the starting epoxy compound (I) is represented by the general formula (I_b):

(Wherein, 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, Alk is a single bond An alkylene group which may have a hand or a substituent, Q is a carbonyl group or a sulfonyl group, X is an oxygen atom or a sulfur atom, and R ¹ is a hydrogen atom or a lower alkyl group. Or a salt thereof using the general formula (II-b):

(Wherein, ring Ar and its bold line portion, Alk, Q, X and R ¹ are the same as described above) or a salt thereof.

15. In claim 2, the starting biaryl compound (ΠΙ) is represented by the general formula (III-b):

(In the formula, 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 An alkylene group which may have a hand or a substituent, Q is a carbonyl group or a sulfonyl group, and X is an acid Represents an elementary atom or a sulfur atom)

Using an S-type biaryl compound represented by the formula or a salt thereof, the general formula (Π-b)

(In the formula, R ¹ represents a hydrogen atom or a lower alkyl group, and ring Ar and its thick line portion, Alk, Q and X are the same as above.)

3. The method according to claim 2, for producing an S-type hydroxylactone compound represented by or a salt thereof.

1 6. In Claims 1 2 or 13, the partial structure of the following formula:

Is the expression

The method according to claim 12 or 13, wherein the method is a partial structure represented by:

17. In Claims 14 or 15, the partial structure of the following formula:

Is the expression

16. The method according to claim 14 or 15, which is a partial structure represented by:

18. Oxidizing the hydroxylactone compound (II) or a salt thereof obtained in any one of claims 1-11, and formula (VI):

(Wherein, ring Ar is an optionally substituted 1 to 3 ring aromatic ring, Alk is a single bond or an optionally substituted alkylene group, and Q is carbonyl Group or sulfonyl group, X represents an oxygen atom or a sulfur atom, and R ¹ represents a hydrogen atom or a lower alkyl group.)

And a method for producing a ketone compound or a salt thereof.

1 9. Oxidizing the R-type hydroxylactone compound (Π-a) or a salt thereof obtained in Claims 12 or 13 to obtain a compound of the general formula (VI_a):

(In the formula, 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 An alkylene group which may have a hand or a substituent, Q is a carbonyl group or a sulfonyl group, X is an oxygen atom or a sulfur atom, and R ¹ is a hydrogen atom or a lower alkyl group) A method for producing an R-type ketone compound or a salt thereof represented by the formula:

20. Oxidizing the S-type hydroxylactone compound (II-b) or a salt thereof obtained in claims 14 or 15 to obtain a compound of the general formula (VI_b):

(Wherein, the ring Ar may have a substituent:! To a tricyclic aromatic ring, having a configuration in which a portion shown by a bold line is in front, and Alk is a single ring. An alkylene group which may have a bond or a substituent, Q is a carboel group or a sulfonyl group, X is an oxygen atom or a sulfur atom, and R ¹ is a hydrogen atom or a lower alkyl group. A method for producing a compound or a salt thereof.

21. In Claim 19, the partial structure of the following formula:

Is the formula:

20. The method according to claim 19, which is a partial structure represented by

22. In Claim 20, the partial structure of the following formula:

Is the expression

21. The method according to claim 20, which is a partial structure represented by: