WO1998043967A1

WO1998043967A1 - PROCESS FOR PRODUCING 2-(BENZO[b]THIOPHEN-5-YL)-2-HYDROXYACETIC ACID DERIVATIVES, OPTICALLY ACTIVE COMPOUNDS THEREOF, OR SALTS OF BOTH

Info

Publication number: WO1998043967A1
Application number: PCT/JP1998/001436
Authority: WO
Inventors: Hirohiko Yamamoto; Tetsuo Yamafuji; Kenji Yonezawa; Akihito Saitoh; Tamotsu Takamatsu; Hironori Kotsubo
Original assignee: Toyama Chemical Co., Ltd.
Priority date: 1997-03-31
Filing date: 1998-03-30
Publication date: 1998-10-08
Also published as: JP4245668B2; AU6519798A

Abstract

A new process for producing 2-(benzo[b]thiophen-5-yl)-2-hydroxyacetic acid derivatives used as intermediates for compounds of general formula [1] or optically active compounds thereof, useful as a cerebral function ameliorant.

Description

Specification

21- (Benzo [b] thiophen-15-yl) 1-2-Hydroacetic acid derivative or its optically active form or a method for producing a salt thereof

Technical field

The present invention provides a compound of the general formula [1] useful as a brain function improving agent:

Wherein R is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R ³ is a hydrogen atom or a hydroxyl protecting group; R ⁰ and R ⁶ are the same or Different and each represents a lower alkyl group. ”2— (Venzo [b] thiophene 1— which is useful as an intermediate in producing a compound represented by the formula The present invention relates to a method for producing a 2-hydroxyacetic acid derivative or an optically active form thereof or a salt thereof, and a series of useful intermediates.

As a method for producing the compound of the general formula [1] or an optically active compound thereof, JP-A-3-23230, JP-A-4-95070, JP-A-6-91615 and The method described in W096 / JP / 1 2771 is known. In particular,

— The method described in No. 9615 is an excellent method for industrial production of the compound of the general formula [1] wherein R ² is a hydrogen atom or an optically active compound thereof, but the method is Since it is a preferential crystallization method, it is highly dependent on the physical properties of the compound, and it is difficult to apply to a compound in which R ² is a halogen atom, a lower alkyl group or a lower alkoxy group.

In order to produce a compound of the general formula [1] or an optically active compound thereof, wherein R is a halogen atom, a lower alkyl group or a lower alkoxy group, a dangerous ^Grignard reaction, an expensive asymmetric reducing agent, etc. Had to be used. An object of the present invention is to provide an intermediate for producing a compound of the general formula [1] or an optically active compound thereof on an industrial scale, ie, 2- (benzo [b] thiophenyl-5-yl) It is an object of the present invention to provide a novel method for producing a 2-hydroxyacetic acid derivative or an optically active form thereof or a salt thereof.

Disclosure of the invention

Under such circumstances, an intermediate for producing the compound of the general formula [1] or an optically active compound thereof, particularly, 2- (benzo [b] thiophen-15-yl) 1-2-hydroxyacetic acid There has been a demand for the development of a method for industrially producing a derivative or its optically active substance or a salt thereof.

In order to solve the above-mentioned problems, the present inventors have conducted intensive studies and as a result, using a compound having a simple chemical structure and easily available as a starting material, the following general formula [2]

Wherein R ¹ is a hydrogen atom or a hydroxyl group; R ² is a hydrogen atom, a nitrogen atom, a lower alkyl group or a lower alkoxy group; R ³ is a hydrogen atom or a hydroxyl-protected group; Respectively. "

21- (benzo [b] thiophene 15-yl) 1-2-hydroxyacetic acid derivative or its optically active compound or a salt thereof is industrially inexpensive and They have found that they can be obtained in high yield, and have completed the present invention.

Hereinafter, the present invention will be described in detail.

In this specification, unless stated otherwise, a halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom; a lower alkyl group means methyl, ethyl, propyl, a Linear or branched C_.alkyl groups such as isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups; lower alkoxy groups include methoxy, ethoxy, propoxy, Linear or branched C 1 such as isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy and hexyloxy groups _s means an alkoxy group or the like.

6

The carboxyl protecting group includes all groups that can be used as a normal carboxyl protecting group, for example, methyl, ethyl, propyl, isopropyl, 1, 1 — Lower alkyl groups such as dimethylpropyl, butyl and tert-butyl; aryl groups such as phenyl and naphthyl; benzyl, diphenylmethyl, trityl, p-nitrobenzyl, Al-lower alkyl groups such as p-methoxybenzene) and bis (P-methoxyphenyl) methyl; acetylmethyl, benzoylmethyl, P-nitrobenzene Acyl-lower alkyl groups such as zolemethyl, p.butene mobenzylmethyl and P-methansulfonylbenzylmethyl; 2—tetrahydroviranyl and And 2 — including tetrahydrofuranyl A heteroheterocyclic group; 2,2,2-trihaloethyl lower alkyl group such as tricycloethyl; 2— (trimethylsilyl) ethyl lower alkylsilyl lower alkyl group such as ethyl; Lower alkyl groups such as cetoxymethyl, propionyl xymethyl and pinoloyloxymethyl; phthalimidmethyl and succinimide methyl Any nitrogen-containing heterocyclic mono-lower alkyl group; cycloalkyl group such as cyclohexyl; methoxymethyl, methoxethyl methoxymethyl and 2 — (trimethylsilyl) ) Lower alkoxy, such as ethoxymethyl, lower alkyl, such as benzyloxymethyl, lower alkoxy, and lower alkyl groups; lower alkyl, such as methylthiomethyl and 2-methylthioethyl. Quirchio-quaternary alkyl group; arylthio-lower alkyl groups such as phenylthiomethyl; 1,1-dimethyl-12-propenyl, 3-methyl-3-butenyl Lower alkenyl groups such as triaryl, trimethylsilyl, triethylsilyl, trisopyl pilsyl, getylisop pilsyl, tert-butyldimethylsilyl, tert-butyldiif Substituted silyl groups such as enylsilyl, diphenylmethylsilyl, and tert-butylmethoxyphenylsilyl.

Hydroxyl protecting groups include all groups that can be used as ordinary protecting groups for hydroxy groups, for example, benzyloxycarbonyl, 4 12-Troben ziroxycarbonyl; 4-, 1-Bromobenzyl xycarbonyl, 4-Methoxybenziloxycarbonyl, 3.4—Dimethoxybenziloxycarbonyl, Methoxycarbonyl , Ethoxycarbonyl, tert-butoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isobutyl oxycarbonyl, isobutyloxycarbonyl, diphenyl methoxycarbonyl, 2,2, 2—Tricycloethoxycarbonyl, 2,2,2—Tribromoethoxycarbonyl, 2— (trimethylsilyl) ethoxycarbonyl, 2— (phenylsulfonyl) Ethoxycarbonyl, 2 — (triphenylphosphonio) ethoxycarbonyl2 — Furfuryl, 1 —Adamanti Roxycarbonyl, vinyloxycarbonyl, aryloxycarbonyl, S—benzylthiocarbonyl, 4-ethoxy-11-naphthyloxycarbonyl, 8—quinoloxycarbonyl, acetyl, formyl, croyl Acetyl groups such as polyacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, pinoyl and benzoyl; methyl, tert-butyl , 2, 2, 2-Trialkyl mouth and 2-Trialkyl lower alkyl groups such as silyl acetyl; lower alkenyl groups such as aryl; benzyl, P-methoxybenzil Al-lower alkyl groups such as jyl, 3,4-dimethoxybenzyl, diphenylmethyl and trityl; tetra Oxygen- and sulfur-containing heterocyclic groups such as hydrofuryl, tetrahydrobiranil and tetrahydropyranyl; methoxymethyl, methylthiomethyl, benzyloxy Methyl,

2—Methoxyethoxyethoxymethyl, 2,2,2—Trichloro mouth ethoxymethyl, 2— (Trimethylsilyl) ethoxymethyl, 1-ethoxyethyl and 1-Methyl-1-Methoxyl and other lower alkyloxy and lower alkylthio lower alkyl groups; methansulfonyl and lower alkyl groups such as p.toluenesulfonyl Triruthyl sulphonyl group; trimethylsilyl, triethylsilyl, triisopropyl, pilsilyl, ethyl isopropyl propylsilyl, tert-butyldimethylsilyl, rt-butyldiphenylsilyl , Diphenylmethylsilyl and tert-butylmethoxyphenyl Examples include substituted silyl groups such as silyl.

Next, the production method of the present invention and the compound of the present invention will be described.

[Five]

"Wherein, R ^1a has the same carboxyl protecting group as R ¹ ; R ⁴ has a leaving group; and RRR ³ and X have the same meanings as described above.” Examples of the leaving group include a lower alkylsulfonyloxy group such as a halogen atom, methylsulfonyloxy, ethylsulfonyloxy and isopropylsulfonyloxy; and phenylsulfonyloxy, toluene. Examples include aryl sulfonyloxy groups such as sulfonyloxy and naphthylsulfonyloxy.

The compound of the general formula [2] or an optically active form thereof may be in the form of a salt, for example, a salt with an alkali metal such as lithium, sodium and potassium. Salts; salts with alkaline earth metals such as barium and calcium; propylamine, butylamine, isobutylamine, hexylamine, benzylamine, phenylamine Enethylamine, getylamine, diisopropylamine, dicyclohexylamine, triethylamine, methylpiperidine, methylbiperazine, aniline and pyridine And salts with organic amines.

Compounds of general formulas [3], [4], [6], [7], [8] and 2-mercaptoacetic acid can also be used as salts. Examples of the salt include salts similar to the salts of the compound of the general formula [2].

(1) Method for producing compound of general formula [6] or a salt thereof

1.1) The compound of the general formula [6] or a salt thereof is reacted with 2-mercaptoacetic acid or a salt thereof in the presence of a base to give a compound of the general formula [6]. Alternatively, it can produce a salt thereof.

The solvent used may be any solvent that does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride and Hydrogenated hydrocarbons such as chloroforms; ethers such as tetrahydrofuran and dioxane; methanol, ethanol, and isoprono; Alcohols and the like; nitriles such as acetonitrile; ketones such as acetone; esters such as ethyl acetate; N, N-dimethylformamide and the like Amides; sulfoxides such as dimethyl sulfoxide; and water. These solvents may be used in combination. Bases used in this reaction include, for example, triethylamine, diisopropylamine, diisopropylethylamine, dicyclohexylamine, 1,8-diazavicine Raw [5.4.0] 7-ene (DBU). Pyridine, tert-butoxylium, sodium carbonate, potassium carbonate, sodium hydroxide, potassium oxide and hydrogen Machines such as sodium chloride or inorganic bases.

The amount of the base and 2-mercaptoacetic acid or a salt thereof to be used is at least equimolar, preferably 1 to 5 mol, relative to the compound of the general formula [3] or a salt thereof.

This reaction is usually carried out at 10 to 150 ° (: preferably 0 to 100 ° C for 10 minutes to 24 hours.

The obtained compound of the general formula [6] or a salt thereof may be used for the next reaction without isolation.

1.2) A compound of the general formula [6] or a salt thereof is produced by reacting a compound of the general formula [4] or a salt thereof with a compound of the general formula [5] in the presence of lewis acid. It can be.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction. Examples of such solvents include, for example, nodogenated hydrocarbons such as methylene chloride and chloroform, and dibenzene. Nitrogen compounds; carbon disulfide; and the like, and these solvents may be used as a mixture.

Lewis acids used in this reaction include, for example, aluminum chloride, aluminum bromide, boron trifluoride, titanium tetrachloride, iron chloride, tin chloride, mercuric chloride and Sulfuric acid and the like.

The amount of the use of Lewis acid and the compound of the general formula [5] is 1 to 5 mol with respect to the compound of the general formula [4] or a salt thereof.

This reaction is usually carried out at a temperature of 10 to 100 ° (:, preferably, 0 to 50 ° C for 5 minutes to 24 hours.

The obtained compound of the general formula [6] or a salt thereof may be used for the next reaction without isolation. (2) —a method for producing the compound of general formula [7] or a salt thereof

Subjecting the compound of the general formula [6] or a salt thereof to a usual ketone reduction reaction using a reducing agent such as a metal and a metal salt, a metal hydride, a metal hydride complex compound or a borane. As a result, 5 of the compound of the general formula [7] or a salt thereof can be produced. Specifically, it should be manufactured according to the method described in the 4th Edition Experimental Chemistry Course, Vol. 26, edited by Kuchimoto Chemical Society, pp. 159-25, 1 (1992) (Maruzen). Can be.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include alcohols such as methanol, ethanol and isopropanol. Classes: Tetra-dani Drofuran, Dioxane, 1,2—Dimethoxyethane and Diethylene glycol glycol methyl ether

—Teryls; nitriles such as acetonitrile; amides such as N, N-dimethylformamide; sulfoxides such as dimethylsulfoxide, and water. These solvents may be used as a mixture.

15 Examples of the reducing agent used in this reaction include alkali metals such as lithium, sodium, and potassium; alkaline earth metals such as magnesium and calcium; Metals such as zinc, aluminum, chromium, titanium, iron, summary rum, selenium, and hydrododium sodium, and their salts, and diisobutyl aluminum hydride Metal hydrides such as aluminum, trialkyl hydride, mini- dium, tin hydride compounds, and hydrosilane; sodium borohydride, lithium borohydride, and potassium borohydride Metal hydride complex compounds such as hydrogenated aluminum complex compounds such as hydrogenated aluminum complex compounds; aluminum hydride lithium metal; borane, alkylborane and the like.

25 The amount of the reducing agent used in this reaction varies depending on the type of the reducing agent, and is required to be 0.25 mol or more. For example, in the case of a borohydride complex compound, the compound of the general formula [6] or its compound It is at least 0.25 mol, preferably 0.25 to 2 mol, based on the salt.

This reaction is usually performed at —20 to 100 ° C, preferably at 0 to 50 ° C for 10 minutes to 24:00. It may be carried out for a while.

(3) Process for producing optically active compound of general formula [7] or a salt thereof

Asymmetric hydrogenation reaction of a compound of the general formula [6] or a salt thereof with an optically active catalyst such as an optically active phosphine-coordinating dimeric complex and a BINA-ruthenium complex; Reaction; lithium aluminum hydride. Power of optically active metal hydride compound obtained by modifying metal hydride such as sodium borohydride and borane with optically active protonic compound. Asymmetric reduction; Meerwein-Ponndorf-Verley (MPV) type asymmetric reduction; Asymmetric reduction using enzymes, microbes such as baker's yeast, etc. By subjecting the ketone to an asymmetric reduction reaction, followed by optical resolution with an optically active amine, an optically active compound of the general formula [7] or a salt thereof can be produced. , Bulletin Chemical-Sosai Te I, O blanking-changer Bruno,. (Bull. Chem. So Jpn.), Vol. 64, pp. 175-182 (1991); 4th Ed. Experimental Chemistry, Vol. 26, edited by The Chemical Society of Japan, pp. 23-68 (1 It can be manufactured according to the method described in (992) (Maruzen).

Optically active amines include, for example, 2-amino-1,2-diphenylethanol, 2-amino-1-phenyl-1,3-pronondiol, Arginine, lysine, phenylalanine, brucine, cinchonidine, cinchonine, dihydrabiethylamine, "1-methyl_4-12-trobenzylamine, 1 — ( Examples include optically active substances such as 1-naphthyl) ethylamine, hydroquinidine, quinidine, quinine, strykinin, 11- (p-tolyl) ethylamine and 1-phenylethylamine. Can be

The amount of the optically active metal hydride used in the asymmetric reduction of the carbonyl compound by the optically active metal hydride modified from the metal hydride with the optically active protonic compound is ^: Different power depending on the type of? It is 0.001 to 10 times, preferably 0.01 to 3 times, the moles of the compound of the general formula [6] or a salt thereof.

The solvent used in this reaction does not adversely affect the reaction. Any alcohol, for example, alcohols such as methanol, ethanol and isopronool; tetrahydrofuran, diethanolamine 1,2,3-Dimethoxhetane and ethers such as diethyl glycol dimethyl ether; ditolyls such as acetonitril; Ν, Ν -Amides such as dimethylformamide; sulfoxides such as dimethylsulfoxide; water; and the like, when one or more of these solvents are used. May be used.

The reaction is usually carried out at a temperature of from 120 to 100 t, preferably from 0 to 50 ° C for 10 minutes to 24 hours.

(4) A method for producing a compound of the general formula [8] or an optically active form thereof or a salt thereof

A compound of the general formula [7] or an optically active form thereof or a salt thereof is reacted with a halogenating agent in the presence or absence of a (4.1) base to form a compound of the general formula [7] or a salt thereof. Is converted to an acid halide of the optically active isomer or a salt thereof, followed by reaction with Lewis acid to effect ring closure, and further subject to (4.2) reduction reaction, whereby the compound of the general formula [8] is obtained. Alternatively, an optically active substance or a salt thereof can be produced.

The solvent used in the reaction of (4.1) may be any solvent that does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride and chloroform. Examples thereof include di-total compounds such as trobenzene; and carbon disulfide. These solvents may be used as a mixture.

As the base used in the reaction of (4.1), for example, triethylamine, diisopropylethylamine, 1,8-diazabicyclo- [5.4.0] ゥ dex 7 And organic or inorganic bases such as benzene (DBU), pyridine, tert-butoxylium, potassium sodium carbonate and sodium hydride. '

Examples of the halogenated aryl used in the reaction of (4.1) include, for example, oxychlorinated linole, oxybromide, linoleum trichloride, linoleum pentachloride, thionyl chloride and Oxalyl chloride and the like. The amount of the halogenating agent and the base to be used (if necessary) is determined by the general formula

The compound of [7] or its optically active substance or a salt thereof is each equimolar or more, preferably 1 to 3 moles, respectively.

Luisic acid used in the reaction of (4.1) includes, for example, aluminum bromide, aluminum bromide, boron trifluoride, titanium tetrachloride, iron chloride, Examples include tin chloride, mercury chloride and sulfuric acid.

The amount of Lewis acid is at least equimolar, preferably 2 to 5 moles, per mole of the compound of the general formula [7] or the optically active compound or a salt thereof:

The reaction of (4.1) may be carried out usually at 120 to 100 ° C, preferably 0 to 50 ° C, for 10 minutes to 24 hours.

The solvent used in the reaction of (4.2) may be any solvent that does not adversely affect the reaction, and examples thereof include halogenated carbonization such as methylene chloride and chloroform. Hydrogens; methanol, ethanol and isobrono. Alcohols such as ethanol; ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxetane and diethyl glycol dimethyl ether; acetonitrile Amides such as N, N-dimethylformamide; sulphoxides such as dimethylsulfoxide; and water. These solvents are mixed. May be used.

Examples of the reducing agent used in this reaction include alkaline metals such as lithium, sodium and potassium; 7-alkali earth metals such as magnesium and calcium; zinc; , Aluminum, chromium, titanium, iron, samarium, selenium, hydrosulfite, sodium and the like, and metal salts thereof; diisobutylaluminum hydride, hydrogen Metal hydrides such as trialkylaluminum, tin hydride, and hydroxysilane; sodium borohydride, lithium borohydride, and potassium borohydride Hydrogen hydride complex compounds such as aluminum hydride aluminum metal hydride complex compounds such as aluminum lithium hydride; and borane and alkylborane.

The amount of reducing agent used in this reaction depends on the type of reducing agent However, for example, in the case of a borohydride complex compound, it is 0.25 mol or more, preferably 0.25 to 2 mol, based on the compound of the general formula [7] or the optically active substance or a salt thereof. .

This reaction is carried out usually at a temperature of 20 to 100 ° C, preferably 0 to 50 ° C for 10 minutes to 24 hours.

The obtained compound of the general formula [8] or an optically active form thereof or a salt thereof can be used for the next reaction without isolation.

(5) —a method for producing a compound of the general formula [2] or an optically active form thereof or a salt thereof

By subjecting the compound of the general formula [8] or its optically active substance or a salt thereof to a dehydration reaction in an acid catalyst, the compound of the general formula [2] or its optical activity The body or salts thereof can be produced.

The solvent used in this reaction may be any solvent that does not adversely affect the reaction, and examples thereof include aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride and chlorene. Halogenated hydrocarbons such as methylformaldehyde; ethers such as tetrahydrofuran and dioxane; alcohols such as methanol, ethanol and isopronole Classes; nitriles such as acetonitrile; ketones such as acetone; esters such as ethyl acetate; N, N-amides such as N-dimethylformamide; Sulfoxides such as dimethyl sulfoxide; and water. These solvents may be used alone or in combination of two or more.

Acid catalysts used in this reaction include, for example, hydrochloric acid, sulfuric acid, methansulphonic acid, trifluoromethansulphonic acid, p-toluenesulphonic acid and dichloromethane. Protonic acids such as acetic acid; and Lewis acids such as aluminum chloride, boron trifluoride and boron trichloride.

The amount of the acid catalyst to be used is 0.01 to 1-fold the molar amount of the compound of the general formula [8] or the optically active substance or a salt thereof.

This reaction is usually carried out at 0 to 150 ° C, preferably 20 to 100 ° C, for 5 minutes to 24 hours. Then, the general formula [3] and [4] the compound or preparation of a salt thereof '; removed by Nitsu have been explained _c

The compound of the general formula [3] or a salt thereof can be produced, for example, by the following reaction.

X

"Wherein, R ¹ R ^la , R ² , R ⁴ and X have the same meaning as described above.”

This reaction may be carried out in the same manner as described in the above production method (1.2).

The compound of the general formula [4] or a salt thereof can be produced, for example, by the following reaction.

"Wherein, R ⁵ is a leaving group; R ⁶ is a carboxyl protecting group; R ² has the same meaning as described above." As the leaving group for R ⁵ , the same as R ⁴ And a leaving group of

By reacting the compound of the general formula [11] or a salt thereof with the compound of the general formula [11] in the presence of a base, the compound of the general formula [4a] can be produced. . Examples of the salt of the compound of the general formula [10] include the same salts as those of the compound of the general formula [2]. This reaction may be carried out in the same manner as described in the production method (1.1). Then, a compound of general formula [4 a], and with the deprotection reaction I by the known method, Ru can and this for preparing a compound or salt thereof of the general formula [4] _r

When the isomers (for example, optical isomers, geometric isomers and tautomers) are present in the compounds of the general formulas [3] to [11] in the above-mentioned production method, all of these isomers Can be used, and hydrates, solvates and all crystal forms can be used.

In addition, the hydroxyl group or carbonyl group in the compounds of the general formulas [3] to [11] is protected by a commonly used hydroxyl or carbonyl group. In addition, after the reaction, if necessary, these protecting groups can be eliminated by a method known per se.

Examples of the compound of general formula [2] or an optically active compound thereof which can be produced by the production method of the present invention include the following compounds.

• 2— (Benzo [b] thiophen-5-yl) -1 2—Ethyl hydroxyacetate

• (+) — 2— (Benzo [b] thiophen-5-yl) 1-2—Ethyl hydroxyacetate

• (—) 1 2 — (Benzo [b] thiophene 5—yl) 1 2—Ethyl hydroxyacetate

• 2- (4-fluorobenzo [b] thiophen-5-yl) -1-ethyl 2-hydroxyacetate

• 2— (6-Fluorobenzo [b] thiophene-1-yl) -1—2-Ethyl hydroxyacetate · (+) — 2— (6—Fluorobenzo [b] thiophene-1—5-yl) 1 2 — Ethyl hydroxyacetate

· (—) — 2 _ (6 —Fluorobenzo [b] thiophen-5-yl) -1 2 —Ethyl hydroxy drone

2- (7-Fluorobenzo [b] thiophene-1-yl) -1-2-hydroxyethyl acetate 2- (4-chlorobenzo [b] thiophene-5-yl) -1-2-hydroxyacetic acid 2-ethyl (2-bromobenzo [b] thiophen-5-yl) -1-hydroxyethyl acetate 2- (4-methylbenzo [b] thiophen-15-yl) 1-2-ethyl ethyl acetate 2- ( 6-Methylbenzo [b] thiophen-1-yl) -1-ethyl 2-hydroxyacetate 2- (6-Methylbenzo [b] thiophen-5-yl) -1-ethyl 2-hydroxyacetate In addition, preferred compounds include the following compounds:

2 — (Benzo [b] thiophene 1-5 —yl) 1 2 —Ethyl hydroxyacetate

• (I) I 2 — (Benzo [b] thiophen 15 — yl) I 2 — Ethyl hydroxyacetate

· 2- (6-fluorobenzo [b] thiophene-1-yl) -1-hydroxyacetate

• (+) — 2 — (6 — Fluorobenzo [b] thiophene 1 — yl)-2 — Ethyl hydroxyacetate

Examples of the compound of the general formula [6] include the following compounds. · 2-(4-carboxymethylthiol ethyl)-1-2-ethyl acetate

• 2- (4-Carboxymethylthio-1-fluorophenyl) -12-Ethyl oxoacetate

• 2- (4-carboxymethylthio-3-fluorophenyl) -1-oxo

• 2- (4-Carboxymethylthio-12-chlorophenyl) -1-oxo-oxoethyl. 2- (4-Carboxymethylthio-12-bromophenyl) -1-ethyl oxoate

'2- (4-carboxymethylthio-l-methylphenyl) -l-oxo-oxoethyl -2- (4-carboxymethylthio-l-methoxyethoxy) -l-oxo-ethyl acetate More preferred compounds Examples thereof include the following compounds.

2 — (4 — carboxymethylthiol ethyl) 1 2 — ethyl oxoacetate

• 2_ (4-carboxymethylthio-12-fluorophenyl) -1-oxoethyl ester The compound of the general formula [7] or an optically active compound thereof includes, for example, the following compounds.

• 2— (4—carboxymethylthiophenyl) -1-2—ethyl hydroxyacetate

• (+) — 2 — (4 carboxymethylthiophene) 1 2 — ethyl acetate

• (1) 1 2 — (4 — carboxime thiol ethyl) 1 2 — Hydroxyethyl acetate

-2 _ (4-carboxymethylthio 1-2-fluorophenyl) 1-2-ethyl acetate • (+) — 21- (4-carboxymethylthio1-2-fluorophenyl) -1-2-hydroxyethyl acetate

• (-)-2-1 (4-Carboxymethylthio-1-2-fluorofurininyl) 1-2-Ethyl hydroxyacetate

· 2-(4-carboxymethylthio-3- 3 -fluorophenyl)-1-2-ethylethyl acetate

• 2 — (4 — carboxymethylthio 1-2-chloro mouth) 1 2 — Ethyl hydroxyacetate

• 2— (4-Carboxymethylthio-2-2-bromophenyl) 1-2—Ethyl Hydroxyacetate

• 2 — (4 — carboxymethylthio — 2 — methylphenyl) 1 2 — ethyl acetate

• 2 — (4 — carboxymethylthio 1-2-methoxyphenyl) 1-2-ethyl acetate

More preferred compounds include the following compounds.

• 2— (4—carboxymethylthiophenyl) -1-2—ethyl hydroxyacetate

• (1) 1 2 — (4 — carboxymethyl thiophene) 1 2 — ethyl acetate

· 2-(4-carboxymethylthio 1-2-fluorophenyl) 1-2-ethylethyl hydroxyacetate

• (+) — 2— (4—Carboximetylthio 1—2—Fluorophenyl) 1—2—Ethyl hydroxyacetate

Examples of the compound of the general formula [8] or an optically active compound thereof include the following compounds.

• 2— (2,3—dihydroxy 3—hydroxybenzo [b] thiophene'5—yl) -1 2—ethyl acetate

• (+) — 2— (2,3—dihydroxy 3—hydroxybenzo [b] thiophene—5—yl) 1-2—ethyl ethyl acetate 8/01 36

• (I) I 2 — (2.3-Dihydroxy 3 — Hydroxybenzo [b] Chih phen 1-5 — yl) I 2 — Ethyl hydroxyacetate

-2 — (2, 3 — Jidraw 4 — Fluoro 3 — Hydroxybenzo [b] thiophene 1 — 5-) 1 2 — Ethyl hydroxyacetate

• 2 — (2, 3 — dihydroxy 6 — fluoro 3 — hydroxybenzo [b] thiophene 15 — yl) 1 2 — ethyl acetate

• (+) — 2— (2,3—Dihydroxy 6—Fluoro 3—Hydroxybenzo [b] thiophen 15—yl) 1-2—Ethyl hydroxyacetate

• (—)-1 2 — (2,3—Dihydroxy 6—Fluoro 3—Hydroxybenzo [b] thiophen 1—5—yl) 1 2—Ethyl hydroxyacetate

• 2 — (2, 3 — dihydroxy 7 — fluoro 3 — hydroxybenzo [b] thiophene 1 — yl) 1 2 — ethyl ethyl hydroxyacetate

• 2 — (4 — chloro 2,3 —dihydroxy 3 —hydroxybenzo [b] thiophen 1 —yl) 2 —ethyl ethyl acetate

• 2— (6—Bromo-2,3—Dihydroxy-1-3—Hydroxybenzo [b] thiophen-1-5—yl) 1-2—Ethyl hydroxyacetate

• 2 — (2, 3 — dihydro 3 — hydroxy 4 -methylbenzene [b] thiophen 1-5-yl) 1 2 — ethylethyl hydroxyacetate

'2 — (2,3 dihydric draw 3 —hydroxy 6 methyl benzo [b] thiof: -n 1-5—yl) 1 2 —ethyl ethyl hydroxyacetate

Further, preferred compounds include the following.

• 2_ (2,3—dihydroxy 3—hydroxybenzo [b] thiophen-5-yl) -1 2—ethyl acetate

• (—) 1 2 — (2, 3 — dihydro 3 — hydroxy benzo [b] thiophene — 5 — yl) 1 2 — ethyl ethyl acetate

'2 — (2,3—dihydroxy 6 _fluoro-3 —hydroxybenzo [b] thiophen-5-yl) -1 2 —ethyl ethyl acetate

• (+) — 2— (2,3—dihydroxy-6—fluoro3—hydroxybenzo [b] thiophen-5—yl) 1-2—ethylethyl hydroxyacetate Examples of the compound of the general formula [1] or the optically active form thereof produced from the compound of the general formula [2] or the optically active form thereof or a salt thereof according to the present invention include: The compound of.

• 1— (Benzo [b] thiophene 1—5—yl) 1 2— [2— (N, N—dimethylamino) ethoxy] ethanol

• 1- (Benzo [b] thiophen-5-yl) 1-1- [21- (N, N-Jetylamino) ethoxy] ethanol

-(+) — 1 — (Benzo [b] thiophene 1—5) -1—2— [2— (Ν, Ν—Jethylamino) ethoxy] ethanol

· (1) 1 1 — (Benzo [b] thiophene 1_5 yl) 1 2-[2 — (Ν, Ν—Jethylamino) ethoxy] ethanol

1 1- (Benzo [b] thiophene 1-5-yl) -2— [2— (Ν, ブロ -dibromopyramino) ethoxy] ethanol

1— (4-Fluorobenzo [b] thiophene-1—5-yl) -1-2- [2- (N, N-Jetylamino) ethoxy] ethanol

-1 — (6 — Fluorobenzo [b] thiophene 1 — 5 — yl) 1 2 — [2 — (N, N — getylamino) ethoxy] ethanol

· (+) — 1 — (6 — Fluorobenzo [b] thiophene 1 — 5 — yl) 1 2 — [21 (N, N — Jetlylamino) ethoxy] ethanol

'(ー) _ 1 — (6 —Fluorobenzo [b] thiophen 1-5 —yl) -1 2 — [2 _ (N, N—Jetlamino) ethoxy] ethanol

• 1 1 (7 — Fluorobenzo [b] thiophene 1 — 5 — yl) 1 2 — [2 — (N, N—Jetilamino) ethoxy] ethanol

• 1 _ (4 1-mouth benzo [b] thiophene 1-5-yl) -1 2 _ [2— (N, N-Jetylamino) ethoxy] ethanol

1 — (6 —Promobenzo [b] thiophene 1 — yl) _ 2 — [2- (Ν, Ν-Jetylamino) ethoxy] ethanol

• 1-1 (4-1-methylbenzo [b] thiophene 1-5-yl)-1-2-[2-(Ν, Ν-getylamino) ethoxy] ethanol • 1- (4-methoxybenzo [b] thiophen-1-5-yl) -1 2— [2— (N, N-Jetylamino) ethoxy] ethanol

Further, preferred compounds include the following compounds ^ • 1 — (benzo [b] thiophen-1-5-yl) -1 2 — [2 — (Ν, Ν— [Mino) ethoxy] ethanol

• (—) 1 1 1 (benzo [b] thiophene 1—5—yl) 1 2 1 [2— (Ν, Ν—Jethylamino) ethoxy] ethanol

• 1 1 (6 — Fluo benzo [b] thiophene 1 — 5 — yl) 1 2 — [2 — (N—N—Jetylamino) ethoxy] ethanol

-(+)-1 — (6 — fluo benzo [b] thiophene 1 — lyre) 1 2 — [2 — (Ν, Ν— getylamino) ethoxy] ethanol Le

BEST MODE FOR CARRYING OUT THE INVENTION

Next, the present invention will be described with reference to Reference Examples, Examples and Production Examples, but the present invention is not limited to these. In addition, the numerical value in IR shows absorption (cm-); the numerical value in NMR shows three values. Further, symbols used in Examples 7, 9, 10 and Production Examples have the following meanings.

d „― DMSO: Heavy dimethyl sulfoxide

Reference example

In 150 ml of m-difluorobenzene and 350.5 g of anhydrous aluminum chloride are suspended in 900 ml of methylene chloride, and under cooling with water, 215.4 g of ethyl chloroglyoxylate is added dropwise over 1 hour. After stirring at 15 ° C for 30 minutes, the reaction mixture is introduced into 2000 ml of ice water, and the organic layer is separated. The separated organic layer is sequentially washed with 1 N hydrochloric acid, water, a 5% (W / V) aqueous solution of sodium hydrogen carbonate and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is distilled under reduced pressure to obtain 249 g of 2- (2,4-difluorophenyl) -12-oxoacetic acid ethyl.

Boiling point: 131-135 ° CZ 18mmHg IR (two); 1741.1694,1615

_{NMR (CDC1 3); 1.40 (} 3H, t, J = 7.2Hz), 4.44 (2H.q, J = 7.2Hz) .6.60-7.40 (. 2H m), 7.70-8.30 (lH, m)

Example 1

2 — (2, 4 — Difluorophenyl)-1 2 — 25-Og ethyl oxoacetate and 147.2 g of 2-mercapto sodium acetate are suspended in 502 ml of dimethyl sulfoxide, and triethylamine is added. the emissions 179.8ml to _c is found to added dropwise over 30 minutes at 55 ° C, after stirring for 2 hours at 60 ° C, while handling water 754Ml and acetic Echiru 754Ml, adjusted to pH2.0 with concentrated hydrochloric acid. After separating the organic layer, the aqueous layer is extracted with 251 ml of ethyl acetate. The extract is combined with the previously separated organic layer, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The magnesium sulfate is removed by filtration, 233.7 ml of dicyclohexylamine is added dropwise to the filtrate, and the mixture is stirred at room temperature for 2 hours. After stirring under ice-cooling for 1 hour, the precipitated crystals are collected by filtration, and the pale yellow 2-((4-carboxymethylthio-1-2-fluorophenyl) -12-oxoacetic acid) is obtained. 372 g (yield: 67.8%) of hexylamine salt in the mouth of Lezic is obtained.

IR (KBr); 1752, 1677,1635, 1601

Actually

2 — (4 — carboxymethylthio-1-2-fluorophenyl)-1-2-ethyl oxoacetate 355 g of dicyclohexylamine salt are suspended in 1420 ml of water and 710 ml of ethyl acetate, and concentrated hydrochloric acid at room temperature. 75.9 ml is added dropwise. After stirring at room temperature for 1 hour, add 710 ml of toluene, filter off insolubles, and separate the organic layer. Add 710 ml of water to the separated organic layer, adjust the pH to 4.0 with sodium hydrogen carbonate, and separate the organic layer. Then, 1410 ml of water and 76.5 g of sodium hydrogen carbonate are added to the separated organic layer, and the mixture is stirred at room temperature for 1 hour, and the aqueous layer is separated. After washing the separated aqueous layer with toluene, 75.9 ml of concentrated hydrochloric acid is added dropwise over 1 hour. After stirring at room temperature for 1 hour, the mixture is cooled to 5 ° C, and the precipitated crystals are collected by filtration to give 189 g of 2- (4-carboxymethylthio1-2-fluorophenyl) _2-oxoacetate (yield ⁸ f. 0%). IR (KBr); 1738.1690,1604

_{NMR (CDC1 3); 1.38 (} 3H.t, J = 7.2Hz), 3.79 (2H, s) .4.42 (2H.qJ = 7.2Hz), 6.50 (lH, bs), 6.90-7.60 (3H, m)

Example 3

Dissolve 2-(2,4-difluorophenyl)-1-2-oxoethyl acetate (1 Og) in 20 ml of dimethyl sulfoxide and add 13.46 ml of diisopropylamine at room temperature. Then, add 3.57 ml of 2-mercaptoacetic acid, stir at 50 ° C for 2 hours, and further stir at 60 ° C for 30 minutes. After cooling to 5 ° C, add 20 ml of ethyl acetate, 20 ml of toluene and 40 ml of water to the reaction mixture, adjust the pH to 1.8 with concentrated hydrochloric acid, and separate the organic layer. Further, the aqueous layer is extracted with a mixed solvent of 10 ml of ethyl acetate and 10 ml of toluene. Combine the extract with the previously separated organic layer and wash sequentially with water, 1.9% (W / V) sodium acetate aqueous solution and water.c Dry the organic layer with anhydrous magnesium sulfate, and then depressurize. The solvent is distilled off below. Add 26 ml of toluene to the obtained residue, heat to 50 ° C, and add seed crystals. Cool to 0 ° C and collect the precipitated crystals by filtration to obtain 9.43 g (yield: 70.5%) of 2- (4-carboxymethylthio-12-fluorophenyl) -12-oxoethyl acetate o

Example 4

2 — (4 — Carboxymethyl thiol 2 — Fluorophenyl)-1-oxoethyl acetate 50 g and D-(-) tartaric acid 39.3 g are dissolved in diethyl glycol methyl ether 750 ml, and this solution is dissolved. To the solution was added 6.0 g of sodium borohydride under water cooling, and the mixture was stirred at the same temperature for 1 hour. Then, 150 ml of water, 150 ml of ethyl acetate and 150 ml of 25% (W / V) saline are sequentially added, and the mixture is stirred at room temperature for 30 minutes, and the organic layer is separated. The aqueous layer is extracted with 125 ml of ethyl acetate, and the extract is combined with the previously separated organic layer and washed with 25% saline. After the organic layer is dried over anhydrous magnesium sulfate, 22.8 ml of (S)-(-)-111-phenylethylamine is added dropwise, and the mixture is stirred at room temperature for 1 hour. After stirring under ice-cooling for 2 hours, the precipitated crystals were collected by filtration to obtain (+)-2- (4-carboxymethylthio1-2-fluorophenyl) -12-ethylethyl acetate '( S) — (—) one 1 — Polyphenylamine salt · 47.6 g of crude crystals of monohydrate are obtained Recrystallized with aqueous acetate [aceton: water = 95: 5 (V / V)] Then you get 43.5g (yield 58.3%)

[a] _D , + 61.0 ^C (25. C, C = 0.95, methanol)

IR (KBr); 3422,3128,1738

Example 5

(+) — 2— (4-Carboxymethylthio-12-Fluorophenyl) -1-2-hydroxyethyl acetate (S) — (—) 1-1—Phenylethylamine salt-1 Water 56.5 g of the hydrate was suspended in 283 ml of water and 283 ml of ethyl acetate, adjusted to pH HI.0 with 6N hydrochloric acid, and the organic layer was separated. The separated organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, n-hexane was added to the obtained residue, and the crystals were collected by filtration to give (+)-2 _ (4 — carboxymethyl thiol 12 — fluoro (Phenyl) 1-2-36.3 g of ethyl acetate (95.3% yield) is obtained.

[a] _D , + 90.1 ° (25 ° C, C = 1.082, CHC)

IR (KBr); 3422,1737,1705

_{NMR (CDC1 3); 1.22 (} 3H, t, J = 7.3Hz), 3.67 (2H, s), 4.21 (2H, q, J = 7.3Hz), 5.35 (lH, s), 6.52 (lH, s) , 6.90-7.60 (3H, m)

Example 6

Dissolve 20 g of (+) — 2— (4—carboxymethylthio-12-fluorophenyl) -1-hydroxyacetate in 300 ml of methylene chloride, and add 5.57 ml of thionyl chloride under reflux for 40 minutes. And further stirred under reflux for 1 hour and 20 minutes. Cool to 5 ° C, add 21.3 g of anhydrous aluminum chloride, and stir at 25 ° C for 1 hour. The reaction mixture is cooled to -25 ° C, 160 ml of 1N hydrochloric acid is added dropwise over 15 minutes, and the organic layer is separated. The aqueous layer was extracted with 20 ml of methylene chloride, and the extract was combined with the previously separated organic layer, washed successively with 1N hydrochloric acid, 5% aqueous sodium hydrogen carbonate and saturated saline, and then extracted with methanol. 40 ml of water. To this solution, add 0.92 g of sodium borohydride under ice cooling, stir at 5 ° C for 30 minutes, add 100 ml of water, and stir for 10 minutes. Add 20g of salt, After adjusting the pH to 5.5 with 6N hydrochloric acid, separate the organic layer and extract the aqueous layer twice with 20 ml of methylene chloride. The extract was combined with the previously separated organic layer, added with activity, and stirred for 15 minutes.The activated carbon was removed by filtration, and 300 ml of the filtrate was distilled off at normal pressure. Always evaporate the solvent until 103 ° C. Cool the residual solution to 70 ° C, add 20 mg of seed crystals, and when cooled to 40 ° C, add 80 ml of toluene. After cooling to 5 ° C and stirring at the same temperature for 1 hour, the precipitated crystals are collected by filtration to give a colorless (+) — 2— (2,3—dihydroxy-1 6—fluoro—3—hydroxybenz 12.58 g (yield 66.6%) of zo [b] thiophene 15-yl) 1-2-hydroxyethyl acetate are obtained.

IR (KBr); 3315, 1744,1727

_{NMR (CDC1 3); (.} 3H, t, J = 7. lHz). 1.23, 2.30-2.85 (lH, m), 3.20-3.40 (lH, m), 3 50-3.90 (2H, m), 4.00 -4.40 (2H, m), 6.94 (lH, d, J = 9.8Hz), 7.20-7.50 (lH, m)

(+) — 2— (2,3—dihydro 6—fluoro-3—hydroxybenzo [b] thiophen-5—yl) 1-2—ethyl ethyl acetate 51 · 24 g ethanol And add 1.07 g of p.toluenesulfonate, and stir at 57.5 ° C for 30 minutes. Cool to 35 ° C, add activated carbon, stir at the same temperature for 20 minutes, and filter off the activated carbon. 153.7 ml of water is added dropwise to the filtrate over 20 minutes under ice cooling, and the mixture is stirred at the same temperature for 30 minutes. Then, 307.4 ml of water was added dropwise for 1 hour, and the mixture was stirred at the same temperature for 1 hour. The precipitated crystals were collected by filtration to obtain colorless (+) — 2— (6—fluorobenzo [b] thiophene. One 5-yl) one 2-hydroxyethyl acetate 44.05 g (yield 92.1%) was obtained.

_{[a] D, + 90.7 °} (25 ° C, C = 0.96, CHC1 3)

IR (KBr); 3374,1733

_{NMR (d 6 -DMSO); 1.13} (3H, t, J = 7.1 Hz), 4.12 (2H, q, J = 7.1 Hz), 5.41 (1H, s), 6.

22 (lH, bs), 7.49 (lH, d, J = 5.4Hz), 7.74 (lH, d, J = 5.4Hz), 7.90 (lH, d, J = 6.4Hz),

7.99 (lH, d, J = 2.9Hz)

Example 8 Dissolve 5.0 g of thiophenoxyacetic acid in 50 ml of methylene chloride and add 4.46 g of ethyl chloroglyoxylate. To this solution, under ice-cooling, add 8.72 g of anhydrous aluminum chloride over 40 minutes, stir at the same temperature for 1 hour, and further stir at room temperature for 1 hour. Then, the reaction mixture is introduced into a mixture of 150 ml of ice water and 15 ml of concentrated hydrochloric acid, stirred for 15 minutes, and the organic layer is separated. The separated organic layer is sequentially washed with 1N hydrochloric acid, water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 20 ml of n-hexane and 20 ml of toluene were added to the obtained residue, and the crystals were collected by filtration to give 2- (4-carboxymethylthiophenyl) -12-oxoacetic acid 5.30 g (66.5% yield).

IR (KBr); 1728,1713,1672

_{NMR (CDC1 3); 1.41 (} 3H, t, J = 7. lHz), 3.80 (2H, s), 4.44 (2H, q, J = 7.1Hz), 7.40 (2 H, d, J = 8.5Hz) , 7.95 (2H, d, J = 8.5Hz), 10.20 (lH, s)

Example 9

2 — (4 — carboxymethylthiophene) 1 2 — 3.5 g of oxoacetic acid in ml of water: '; Add sodium hydrogen carbonate (1.32 g) and stir at room temperature for 30 minutes. Add 0.123 _g of sodium borohydride to this solution under ice cooling over 15 minutes and stir at the same temperature for 30 minutes. Then, under ice-cooling, add 50 ml of ethyl acetate to the mixture, adjust the pH to 2.0 with 2N hydrochloric acid, and separate the organic layer. The separated organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, 20 ml of toluene was added to the obtained residue, and the crystals were collected by filtration to obtain 3.00 g of 2- (4-carboxymethylthiophenyl) 1-2-ethyl acetate. Rate 85 · 1%).

IR (KBr); 3473,1727

NMR (d ₆ -DMSO); 1.13 (3H, t, J = 7.1 Hz), 3.80 (2H, s), 4.07 (2H, q, J = 7.1 Hz), 5.08 (lH, s), 5.0- 6.50 (lH, bs), 7.33 (4H, s), 12.00- 13.20 (1H, bs)

Example 10

2 — (4-Carboxymethylthiothioenyl) 2.00 g of ethyl 2-hydroxyacetate is suspended in 20 ml of methylene chloride, and 0.57 ml of thionyl chloride is added. Stir under reflux for 1 h 30 min.Cool to 0 ° C, add 2.17 g of anhydrous aluminum chloride, stir at room temperature for 1 h, then add 50 ml of ice water and 10 ml of methanol It is introduced into a mixed solvent. The organic layer is separated, and the aqueous layer is further extracted with 10 ml of methylene chloride. The extract is combined with the previously separated organic layer, and washed successively with monobasic acid and a 5% aqueous sodium hydrogen carbonate solution. Then, 20 ml of methanol was added to the organic layer, and hydrogenated sodium hydride O.llg was added under water cooling, and the mixture was stirred at the same temperature for 15 minutes, and 20 ml of water was added to separate the organic layer. Take. Extract the aqueous layer with 20 ml of methylene chloride, combine the extract with the previously separated organic layer, wash with water, and dry the organic layer with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (silica gel; BW-127ZH manufactured by Fuji Silicon Chemical, eluent; n-hexane). Purification with ethyl acetate = 3: 1 to 2: 1) yields 2- (2,3—dihydro-3-3—hydroxybenzo [b] thiophen-5-yl) 1-2—ethyloxyacetate 0.83 g (44.1% yield).

IR (KBr); 3392,1734,1200

NMR (d ₆ -DMSO); 1.14 (3H, t, J = 7.1 Hz), 3.12 (1 H, dd, J = 6.8 Hz, J = 11.7 Hz), 3.53 (lH, dd, J = 6.8 Hz, J = l 1.7Hz), 3.90-4.30 (2H, m), 5.08 (lH, d, J = 5.lHz), 5.28 (lH, q, J = 6.8Hz), 5.77 (lH, d, J = 6.1Hz), 5.99 (lH, d, J = 5.lHz), 7.05-7.50 (3H, m)

Example 1 1

2 _ (2,3—dihydroxy-1 3—hydroxybenzo [b] thiophen-5-yl) 1 2—hydroxyethyl acetate was treated in the same manner as in Example 7 to give 2— (benzo [ b] Thiophene-1-5-yl) 1-2- Obtain ethyl acetate. IR (KBr); 3448,1727,1192,1082

_{NMR (CDCl 3); 1.20 (} 3H, t, J = 7.1Hz), 3.62 (1 H, d, J = 5.9Hz), 3.90~ 4 · 60 (2H, m), 5. 27 (lH, d, J = 5.6Hz), 7.20-7.60 (3H, m), 7.70-8.10 (2H, m)

Manufacturing example

(1) (+) — 2— (6—Fluorobenzo [b] thiophene-15-yl) -1 2—Dissolve 15 g of ethyl acetylacetate in 75 ml of methylene chloride. —Jihid B) Add 2.94 g of H-pyran and 1.48 g of P-toluenesulfonate'pyridinium salt, and stir at 25 ° C for 3 hours. The reaction mixture is washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. If the solvent is distilled off under reduced pressure, a colorless oily (+) — 2- (6—fluorobenzo [b] thiophen-15-yl) 1-2— (tetrahydrobiraniloxy) ) Obtain ethyl acetate.

(2) (+) — 2— (6—Fluorobenzo [b] thiophen-5_yl) -1-2- (Tetrahydroviranyloxy) Ethyl acetate dissolved in 60 ml of ethanol Add 3.79 g of sodium borohydride and stir at 25 ° C for 6 hours c Then, add 17.32 g of acetate dropwise under ice cooling to decompose excess sodium borohydride. After that, add 75 ml of toluene and 75 ml of water, and separate the organic layer. The separated organic layer is washed with water, and dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel chromatography to give a colorless oily (+)-2- (6—fluorobenzo [b] thiophene-1. 5-yl) 1 2-(Tetrahydroviraniloxy) to obtain 16.08 g of ethanol.

IR (unit); 3426, 2943, 2868, 1454, 1132, 1034

(3) (+)-2 — (6 — Fluorobenzo [b] thiophene 1 — 5 — yl) 1 2 — (Tetrahydroviranyloxy) 5.83 g of ethanol 5.83 ml of toluene Dissolve in a mixture of 25 ml of 50% aqueous sodium hydroxide solution and 4.40 g of 2-((N, N-Jethylamino) ethyl chloride'hydrochloride and tetrahydrogen sulfate- Add 668 mg of n-butylammonium and reflux for 1.5 hours. After cooling the reaction mixture to 20 ° C, 25 ml of toluene and 25 ml of water are added, and the organic layer is separated. The aqueous layer was extracted with 15 ml of toluene, the extract was combined with the previously separated organic layer, washed with 20 ml of water, 25 ml of water was added, and the pH was adjusted to pH 0.5 with 6N hydrochloric acid. Stir for minutes. Separate the aqueous layer, extract the organic layer with 5 ml of water, combine the extract with the previously separated aqueous layer, add 25 ml of ethyl acetate, and adjust the pH to 10.2 with sodium carbonate. The organic layer is separated, washed successively with water and saturated saline, and dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure and the resulting residue 100 ml of ethyl acetate and 2.5 ml of ethanol were added to the mixture and dissolved, and 7.48 ml of hydrogen chloride in ethyl acetate (3.95N) was added.The mixture was stirred at 25 ° C for 1 hour, and cooled to 5 ° C. If the precipitated crystals are collected by filtration, a colorless (+) — 1— (6—fluorobenzo [b] thiophen-1-5—yl) -1 2— [2— (Ν, Ν—Jetilamino) d 6.20 g (90.5% yield) of the hydrochloride of [toxic] ethanol are obtained.

[a] _D , + 40.9 ° (25. C, C = 1.05, methanol)

IR (KBr); 3196, 1449, 1143,903

_{NMR (d 6 -DMSO); 1.17} (6H, tJ = 7.32Hz), 2.90-4.00 (10H, m) .5.00-5.20 (. LH bs), 5.80-6.00 (lH, bs), 7.47 (lH, d , J = 5.37Hz), 7.73 (lH, d, J = 5.37Hz), 7.87 (lH, d, J = 10.74Hz), 8.05 (lH, d, J = 6.83Hz), 10.50-10.90 (lH, bs)

(4) In (3), p-toluenesulfonate is used in place of hydrogen chloride. +)-1 — (6 —Fluorobenzo [b] thiophen-1-5 —yl) 1 2 — [2 P-toluenesulfonate of _ (N, N-Jetylamino) ethoxy] ethanol is obtained.

[Q] _d , + 30.4 ° (25 ° C, C = 1, methanol)

IR (KBr); 3294,2890,1449,1228, 1144,902

_{NMR (d 6 -DMSO); 1.12} (6H, t, J = 7.57Hz), 2.28 (3H, s), 2.90-4.10 (1 OH, m), 5.0O-5.2O (lH, bs), 5.60- 5.80 (1 H, bs), 7000-8.30 (8 H, m), 8.90-9.20 (1 H, bs) Industrial applicability

The 2- (benzo [b] thiophen-5-yl) -12-hydroxyacetic acid derivative or its optically active form or salt thereof of the general formula [2] is represented by the general formula [1] Is useful as an intermediate for producing the compound of formula (I), and the method for producing the intermediate according to the present invention is useful as a method for industrially obtaining the compound of general formula [1] or an optically active compound thereof. It is.

The production method and the intermediate of the present invention are useful for industrially producing a compound of the general formula [1] or an optically active compound thereof, which is useful as a brain function improving agent.

Claims

Claims. General formula

In the formula, R represents a hydrogen atom or a propyloxyl protecting group; R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; and X represents a halogen atom. 2- (phenyl) -2-oxoacetic acid derivative or a salt thereof is reacted with 2-mercaptoacetic acid or a salt thereof in the presence of a base, or a compound of the general formula

In the formula, R ² has the same meaning as described above. The thiophenoxyacetic acid derivative or a salt thereof represented by the general formula

〇

R ⁴ ", CO〇R ^1a

"Wherein, R ^{1 a} is a mosquito carboxyl protecting group;. R ⁴ is showing a leaving group" is reacted with the compound represented by the general formula

Wherein, in the formula, R ¹ and R have the same meanings as described above. 2-(4-Carboxymethylthiophenyl) -12-oxoacetic acid derivative or a salt thereof is obtained. , Subject to the reduction reaction, general formula

"Wherein, R ³ represents a hydrogen atom or a human Dorokishiru protecting group, R ^{1 a} and R are as defined above." 2 represented by - (4 - Ca Le Bokishi main Chiruchio Fuweniru) Single 2—Hydroxyacetic acid derivative or its optically active compound or a salt thereof is obtained, and then subjected to a ring closure reaction and a reduction reaction to obtain a compound represented by the general formula

In the formula, R ¹ R ² and R ³ have the same meaning as described above. 2 — (2, 3 — dihydroxy 3 — hydroxybenzo [b] thiophene 1 — 5-yl ) — 2 — A general formula characterized by obtaining a hydroxyacetic acid derivative or an optically active form thereof or a salt thereof, and then subjecting to a dehydration reaction.

In the formula, R ¹ R ² and R ³ have the same meanings as described above. 2 — (benzo [b] thiophen-15-yl) 1-2—hydroxyacetic acid derivative Or a method for producing the optically active substance or a salt thereof.

2. The 2- (benzo [b] thiophen-5-yl) -12-hydroxyacetic acid derivative or the optically active form thereof according to claim 1, wherein the ^RL force is a hydrogen atom or a halogen atom. Or a method of producing those salts.

. twenty two ,

4 -Difluorophenyl) lower alkyl ester of 2-oxoacetic acid. General formula

Wherein, in the formula, R ¹ represents a hydrogen atom or a carboxyl protecting group; R ² represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group, respectively. — (4-Carboxymethylthiophenyl) —2-oxoacetic acid derivative or salt thereof.

. 5 R ² force, 2 according to claim 4, wherein a hydrogen atom or halogen atom - (4 - Ca carboxyl main Chiruchio full et two le) one 2 - Okiso acid derived compound or a salt thereof.

6. General formula

Wherein R ¹ is a hydrogen atom or a carboxyl protecting group; R ² is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;

R ³ represents a hydrogen atom or a hydroxyl protecting group, respectively. 2- (4-carboxymethylthiophenyl) 1-2-hydroxyacetic acid derivative or an optically active form thereof, or a salt thereof.

. 7 R ² force I, was or hydrogen atoms according to claim 6, wherein a halogen atom 2 - (4 - mosquito Rubokishirume Chiruchiofu enyl) one 2 - arsenide Dorokishi acid derivatives also rather its optically active substance thereof or Salt.

8. —General formula ''

"Wherein R ¹ is a hydrogen atom or a carbonyl group; R ² is a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group;

R ³ represents a hydrogen atom or a hydroxyl protecting group, respectively. 2— (2,3—dihydroxy_3—hydroxybenzo [b] thiophene—5—yl) 1-2—hydroxyacetic acid derivative or its optically active or Their salt.

. R ² force? And a hydrogen atom or a halogen atom, and the 2— (2,3—dihydroxy-13-hydroxybenzo [b] thiophen-15-yl) 1-2—hydroxyacetic acid derivative according to claim 8 is also preferable. Or its optically active substance or a salt thereof.