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WO1998043967A1 - PROCEDE DE PRODUCTION DE DERIVES D'ACIDE 2-(BENZO[b]THIOPHEN-5-YL)-2-HYDROXYACETIQUE, DE LEURS COMPOSES OPTIQUEMENT ACTIFS OU DE SELS DES DEUX - Google Patents

PROCEDE DE PRODUCTION DE DERIVES D'ACIDE 2-(BENZO[b]THIOPHEN-5-YL)-2-HYDROXYACETIQUE, DE LEURS COMPOSES OPTIQUEMENT ACTIFS OU DE SELS DES DEUX Download PDF

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Publication number
WO1998043967A1
WO1998043967A1 PCT/JP1998/001436 JP9801436W WO9843967A1 WO 1998043967 A1 WO1998043967 A1 WO 1998043967A1 JP 9801436 W JP9801436 W JP 9801436W WO 9843967 A1 WO9843967 A1 WO 9843967A1
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Prior art keywords
salt
general formula
optically active
hydrogen atom
compound
Prior art date
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PCT/JP1998/001436
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English (en)
Japanese (ja)
Inventor
Hirohiko Yamamoto
Tetsuo Yamafuji
Kenji Yonezawa
Akihito Saitoh
Tamotsu Takamatsu
Hironori Kotsubo
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Toyama Chemical Co Ltd
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Toyama Chemical Co Ltd
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Priority to JP54144798A priority Critical patent/JP4245668B2/ja
Priority to AU65197/98A priority patent/AU6519798A/en
Publication of WO1998043967A1 publication Critical patent/WO1998043967A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/18—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by addition of thiols to unsaturated compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups

Definitions

  • the present invention provides a compound of the general formula [1] useful as a brain function improving agent:
  • 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.
  • JP-A-3-23230 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.
  • JP-A-3-23230 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.
  • JP-A-3-23230 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.
  • JP-A-3-23230 As a method for producing the compound of
  • 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.
  • 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.
  • 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
  • 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.
  • 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-trihalo
  • 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 —Adam
  • 2 Metalethoxyethoxymethyl, 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.
  • 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.”
  • 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.
  • a salt with an alkali metal such as lithium, sodium and potassium. Salts
  • salts with alkaline earth metals such as barium and calcium
  • 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].
  • 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.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • methylene chloride and Hydrogenated hydrocarbons such as chloroforms
  • ethers such as tetrahydrofuran and dioxane
  • Bases used in this reaction include, for example, triethylamine, diisopropylamine, diisopropylethylamine, dicyclohexylamine, 1,8-diazavicine Raw [5.4.0] 7-ene (DBU).
  • DBU 1,8-diazavicine Raw [5.4.0] 7-ene
  • 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.
  • 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.
  • 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 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.
  • Alcohols such as methanol, ethanol and isopropanol.
  • Teryls Teryls
  • nitriles such as acetonitrile
  • amides such as N, N-dimethylformamide
  • sulfoxides such as dimethylsulfoxide, and water.
  • solvents may be used as a mixture.
  • 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.
  • 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.
  • 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.
  • 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;
  • 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; ⁇ , ⁇ -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.
  • 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.
  • a halogenating agent in the presence or absence of a (4.1) base
  • 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.
  • halogenated aryl examples 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.
  • 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
  • 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 compound of the general formula [8] or its optically active substance 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.
  • Aroma 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.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • methylene chloride and chlorene such as methylform
  • 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.
  • the compound of the general formula [3] or a salt thereof can be produced, for example, by the following reaction.
  • 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.
  • R 5 is a leaving group; R 6 is a carboxyl protecting group; R 2 has the same meaning as described above.
  • R 5 the same as R 4 And a leaving group of
  • the compound of the general formula [4a] 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.
  • 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
  • the isomers for example, optical isomers, geometric isomers and tautomers
  • the isomers can be used, and hydrates, solvates and all crystal forms can be used.
  • 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.
  • 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.
  • Examples of the compound of the general formula [6] include the following compounds. ⁇ 2-(4-carboxymethylthiol ethyl)-1-2-ethyl acetate
  • More preferred compounds include the following compounds.
  • Examples of the compound of the general formula [8] or an optically active compound thereof include the following compounds.
  • preferred compounds include the following.
  • preferred compounds include the following compounds ⁇ • 1 — (benzo [b] thiophen-1-5-yl) -1 2 — [2 — ( ⁇ , ⁇ — [Mino) ethoxy] ethanol
  • 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.
  • 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.
  • 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.
  • S (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.
  • (+)-2 _ (4 — carboxymethyl thiol 12 — fluoro (Phenyl) 1-2-36.3 g of ethyl acetate (95.3% yield) is obtained.
  • 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.
  • 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 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.
  • (+)-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 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un nouveau procédé de production de dérivés d'acide 2-(benzo[b]thiophen-5-yl)-2-hydroxyacétique utilisés comme intermédiaires de composés de la formule générale [1] ou de leurs composés optiquement actifs, s'utilisant comme produits d'amélioration de la fonction cérébrale.
PCT/JP1998/001436 1997-03-31 1998-03-30 PROCEDE DE PRODUCTION DE DERIVES D'ACIDE 2-(BENZO[b]THIOPHEN-5-YL)-2-HYDROXYACETIQUE, DE LEURS COMPOSES OPTIQUEMENT ACTIFS OU DE SELS DES DEUX Ceased WO1998043967A1 (fr)

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JP54144798A JP4245668B2 (ja) 1997-03-31 1998-03-30 ２−（ベンゾ〔ｂ〕チオフェン−５−イル）−２−ヒドロキシ酢酸誘導体もしくはその光学活性体またはそれらの塩の製造法
AU65197/98A AU6519798A (en) 1997-03-31 1998-03-30 Process for producing 2-(benzo{b}thiophen-5-yl)-2-hydroxyacetic acid derivatives, optically active compounds thereof, or salts of both

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006104088A1 (fr) * 2005-03-28 2006-10-05 Toyama Chemical Co., Ltd. Procede de production du 1-(3-(2-(1-benzothiophen-5-yl)- ethoxy)propyl)azetidin-3-ol ou de ses sels
RU2397169C2 (ru) * 2005-03-28 2010-08-20 Тояма Кемикал Ко., Лтд. Способ получения 1-(3-(2-(1-бензотиофен-5-ил)этокси) пропил)азетидин-3-ола или его солей

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH069615A (ja) * 1992-04-13 1994-01-18 Toyama Chem Co Ltd ベンゾ［ｂチオフェン−５−イル誘導体もしくはその光 学活性体またはそれらの塩並びにそれらの製造法
JPH08113580A (ja) * 1994-10-17 1996-05-07 Sagami Chem Res Center フルオロアルキル基を有するアミノアルコール誘導体の製造方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH069615A (ja) * 1992-04-13 1994-01-18 Toyama Chem Co Ltd ベンゾ［ｂチオフェン−５−イル誘導体もしくはその光 学活性体またはそれらの塩並びにそれらの製造法
JPH08113580A (ja) * 1994-10-17 1996-05-07 Sagami Chem Res Center フルオロアルキル基を有するアミノアルコール誘導体の製造方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006104088A1 (fr) * 2005-03-28 2006-10-05 Toyama Chemical Co., Ltd. Procede de production du 1-(3-(2-(1-benzothiophen-5-yl)- ethoxy)propyl)azetidin-3-ol ou de ses sels
RU2397169C2 (ru) * 2005-03-28 2010-08-20 Тояма Кемикал Ко., Лтд. Способ получения 1-(3-(2-(1-бензотиофен-5-ил)этокси) пропил)азетидин-3-ола или его солей
EP2248809A1 (fr) 2005-03-28 2010-11-10 Toyama Chemical Co., Ltd. Alkyl-3-[2-(benzo[b]thiophèn-5-yl)-éthoxy]-propanoates en tant qu'intermediaires dans la production de dérivés d'azétidin-3-ol
US7951963B2 (en) 2005-03-28 2011-05-31 Toyama Chemical Co., Ltd. Process for production of 1-(3-(2-(1-benzothiophen-5-yl)-ethoxy)propyl)azetidin-3-ol or salts thereof
EP2348022A1 (fr) 2005-03-28 2011-07-27 Toyama Chemical Co., Ltd. Procédé de fabrication de l'azétidin-3-ol 1-(3-(2-(1-benzothiophén-5-yl)-éthoxy)propyl) et de leurs sels

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JP4245668B2 (ja) 2009-03-25

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