JP2006328058A - New method for producing 2-(1-benzothiophen-5-yl)ethanol and its intermediate - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing 2-(1-benzothiophen-5-yl)ethanol, being safe to human bodies, having slight environmental load and enabling mass production by using an inexpensive raw material. <P>SOLUTION: The production method using an acetal derivative represented by general formula [1] [wherein R<SP>1</SP>is a hydrogen atom or a hydroxyl-protecting group; R<SP>2</SP>and R<SP>3</SP>are each an alkyl group which may be same or different and may be substituted or R<SP>2</SP>and R<SP>3</SP>together form an alkylene or alkenylene group which may be substituted] as a production intermediate is useful as a method for safely and readily producing 2-(1-benzothiophen-5-yl)ethanol which is important as a synthetic intermediate for medicines. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a novel production method of 2- (1-benzothiophen-5-yl) ethanol, which is important as a pharmaceutical production intermediate, a novel acetal derivative which is a production intermediate thereof, and a production method thereof.

2- (1-Benzothiophen-5-yl) ethanol is an important compound as a pharmaceutical intermediate. For example, 1- (3- (2- (1- (benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol maleate, which is being developed as a therapeutic agent for neurodegenerative diseases, is 2- (1- It is produced from benzothiophen-5-yl) ethanol (Patent Documents 1 and 2).
As a method for producing 2- (1-benzothiophen-5-yl) ethanol, for example, 5-methyl-1-benzothiophene is brominated with N-bromosuccinimide and subjected to reaction with a cyanide compound (1 -Benzothiophen-5-yl) A method of making acetonitrile, followed by hydrolysis and then reduction is known (Non-Patent Documents 1, 2, and 3). Further, a method is known in which magnesium is allowed to act on 5-bromo-1-benzothiophene to give a Grignard reagent, and then subjected to a reaction with ethylene oxide (Patent Document 3). Furthermore, it is known that 5- (1-benzothiophene) carbaldehyde is subjected to methoxymethylene ylide and Wittig reaction, then hydrolyzed to (1-benzothiophen-5-yl) acetaldehyde, and then reduced. (Patent Document 4).
However, these production methods use (1) an intermediate is irritating, (2) uses a highly toxic reagent (cyanide compound), (3) uses a carcinogenic reagent (ethylene oxide), ( 4) The use of highly ignitable reagents (butyllithium, Grignard reagent), (5) complicated reaction operation, etc., are not satisfactory as an industrial production method.

International Publication No. 00/76957 Pamphlet International Publication No. 03/035647 Pamphlet EP0129478 WO99 / 31056 pamphlet Journal of Medicinal Chemistry (J. Med. Chem.), 1991, Volume 34, p. 65-73 Journal of Medicinal Chemistry (J. Med. Chem.), 1997, Vol. 40, p. 1049-1062 Nihon Chemical Journal, 1967, Vol. 88, p. 445-447

  There is a strong demand for a process for producing 2- (1-benzothiophen-5-yl) ethanol that is safe for the human body, has a low environmental impact, and can be mass-produced using inexpensive raw materials.

「式中、Ｒ^１は、水素原子またはヒドロキシル保護基を；Ｒ^２およびＲ^３は、同一または異なって置換されていてもよいアルキル基、または、一緒になって置換されていてもよいアルキレンもしくはアルケニレン基を示す。」で表されるアセタール誘導体が、２−（１−ベンゾチオフェン−５−イル）エタノールの製造において重要な製造中間体であること、ならびに一般式［２］

「式中、Ｘは、ハロゲン原子または置換されていてもよいアルカンスルホニルオキシもしくはアリールスルホニルオキシ基を；Ｒ¹は、前記と同様の意味を有する。」で表されるハロフェネチルアルコール誘導体を、パラジウム触媒の存在下、一般式［３］

「式中、Ｒ^２およびＲ^３は、前記と同様の意味を有する。」で表されるチオール誘導体またはその塩とのカップリング反応に付すことにより、一般式［１］のアセタール誘導体が製造できること、および一般式［１］のアセタール誘導体を、酸の存在下、分子内閉環反応し、必要に応じ脱保護反応に付すことにより、２−（１−ベンゾチオフェン−５−イル）エタノールが簡便に製造できることを見出し、本発明を完成させた。 Under such circumstances, the present inventors conducted extensive studies, and as a result, the following general formula [1]

“Wherein R ¹ represents a hydrogen atom or a hydroxyl protecting group; R ² and R ³ represent an alkyl group which may be the same or different, or an alkylene which may be substituted together or The acetal derivative represented by “denotes an alkenylene group” is an important production intermediate in the production of 2- (1-benzothiophen-5-yl) ethanol, and the general formula [2]

A halophenethyl alcohol derivative represented by “wherein X is a halogen atom or an optionally substituted alkanesulfonyloxy or arylsulfonyloxy group; R ¹ has the same meaning as described above” In the presence of a catalyst, the general formula [3]

The acetal derivative of the general formula [1] can be produced by subjecting it to a coupling reaction with a thiol derivative represented by “wherein R ² and R ³ have the same meaning as described above” or a salt thereof. And the acetal derivative of the general formula [1] is subjected to an intramolecular ring-closing reaction in the presence of an acid, and subjected to a deprotection reaction as necessary, whereby 2- (1-benzothiophen-5-yl) ethanol can be conveniently obtained. The present invention has been completed by finding that it can be produced.

  By using the novel acetal derivative represented by the general formula [1] of the present invention as a production intermediate, 2- (1-benzothiophen-5-yl) ethanol useful as a pharmaceutical intermediate can be more easily obtained. And the outstanding effect that it can manufacture industrially is show | played. In addition, the production method of the present invention (1) does not use an irritant intermediate, (2) does not use a highly toxic reagent (cyanide compound), and (3) uses a carcinogenic reagent (ethylene oxide). (4) not using highly ignitable reagents (butyllithium, Grignard reagent), (5) having a simple reaction operation, and the like. That is, the production method of the present invention is safe for the human body, has little environmental impact, and is useful as an industrial production method for 2- (1-benzothiophen-5-yl) ethanol.

Hereinafter, the present invention will be described in detail.
In the present specification, unless otherwise specified, a halogen atom is a fluorine atom, a chlorine atom, a bromine atom and an iodine atom; an alkyl group is, for example, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, Linear or branched C _1-12 alkyl groups such as isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl and octyl; alkylene groups include, for example, ethylene, propylene, butylene and 2-methyl A linear or branched C _2-6 alkylene group such as propylene; a cycloalkyl group refers to, for example, a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; For example, methoxy, ethoxy, propoxy, i Propoxy, butoxy, isobutoxy, sec- butoxy, tert- butoxy, straight or branched _{C 1-6} alkyl group such as pentyloxy and isopentyloxy; Alkenyl groups include, for example, vinyl, propenyl A straight chain or branched C _2-12 alkenyl group such as butenyl, pentenyl, hexenyl, heptenyl and octenyl; an alkenylene group is, for example, a straight chain such as vinylene, propenylene, 1-butenylene and 2-butenylene. A chain or branched C _2-6 alkenylene group; an aryl group such as phenyl, naphthyl, indanyl and indenyl; an aralkyl group such as benzyl, diphenylmethyl, trityl and Al _{C 1-6} alkyl, such as phenethyl Group; The alkanesulfonyloxy group, for example, a C _1-6 alkanesulfonyloxy group such as methanesulfonyloxy and ethanesulfonyloxy; an arylsulfonyl group, e.g., benzenesulfonyloxy and toluenesulfonyloxy group such as oxy An alkanesulfonyl group is, for example, a C _1-6 alkanesulfonyl group such as methanesulfonyl, trichloromethanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl and propanesulfonyl; an arylsulfonyl group is, for example, benzenesulfonyl, toluenesulfonyl And alkylamino group means methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino Mono- or di-C _1-6 alkylamino groups such as diethylamino, diisopropylamino and dibutylamino; acyl groups include, for example, C _2-12 alkanoyl groups such as formyl group, acetyl, isovaleyl, propionyl and pivaloyl, benzyl An aralkylcarbonyl group such as carbonyl and an aroyl group such as benzoyl and naphthoyl;

The alkyloxycarbonyl group is, for example, linear or branched such as methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl and tert-pentyloxycarbonyl. A branched C _1-12 alkyloxycarbonyl group; an aralkyloxycarbonyl group is, for example, an al C _1-6 alkyloxycarbonyl group such as benzyloxycarbonyl and phenethyloxycarbonyl groups; a heterocyclic oxycarbonyl group Is, for example, groups such as 2-furfuryloxycarbonyl and 8-quinolyloxycarbonyl; oxygen-containing heterocyclic groups are, for example, 2-tetrahydropyranyl and 2-tetrahydro The sulfur-containing heterocyclic group, for example, a group such as tetrahydrothiopyranyl; based on such Ranil The alkoxyalkyl group, for example, C _1-6 alkyloxy C such as methoxymethyl and 1-ethoxyethyl _{A 1-6} alkyl group; an aralkyloxyalkyl group, for example, an ar C _1-6 alkyloxy C _1-6 alkyl group such as benzyloxymethyl and phenethyloxymethyl; a substituted silyl group, for example, trimethylsilyl , Groups such as triethylsilyl, tributylsilyl, tribenzylsilyl and triphenylsilyl.

  Hydroxyl protecting groups include all groups that can be used as protecting groups for conventional hydroxyl groups. W. Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, INC., 1999, 3rd edition , P. Examples include groups described in 17-245. Specifically, for example, optionally substituted acyl, alkyloxycarbonyl, aralkyloxycarbonyl, heterocyclic oxycarbonyl, alkyl, alkenyl, aralkyl, oxygen-containing heterocyclic, sulfur-containing heterocyclic, alkoxyalkyl , Aralkyloxyalkyl, substituted silyl groups and the like.

Acyl, alkyloxycarbonyl, aralkyloxycarbonyl, heterocyclic oxycarbonyl, alkyl, alkenyl, aralkyl, oxygen-containing heterocyclic, sulfur-containing heterocyclic, alkoxyalkyl, aralkyloxyalkyl and the hydroxyl protecting group for R ¹ Substituted silyl groups are halogen atoms, nitro groups, alkyl groups, cycloalkyl groups, alkenyl groups, aryl groups, aralkyl groups, alkoxy groups, substituted silyl groups, cyano groups, acyl groups, alkanesulfonyl groups, arylsulfonyl groups, and alkyl groups. It may be substituted with one or more groups selected from amino groups. For example, when the hydroxyl protecting group of R ¹ is an acyl group, it may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group, an alkenyl group, an aryl group and an alkoxy group.
The alkyl, alkylene or alkenylene group of R ² and R ³ may be substituted with one or more groups selected from halogen atoms, alkyl groups, alkenyl groups, cycloalkyl groups, aralkyl groups, aryl groups and alkoxy groups. .
The alkanesulfonyloxy group of X may be substituted with one or more halogen atoms.
The arylsulfonyloxy group of X may be substituted with one or more groups selected from a halogen atom, a nitro group, an alkyl group, and an alkoxy group.

In the compound of the present invention represented by the general formula [1], preferable compounds include the following compounds.
A compound in which R ¹ is a hydrogen atom or an optionally substituted acyl group is preferable, a compound in which R ¹ is an optionally substituted acyl group is more preferable, and a compound in which R ¹ is an optionally substituted benzoyl group More preferred is a compound which is a benzoyl group.
A compound in which R ² and R ³ are alkyl groups which may be the same or differently substituted, or alkylene groups which may be substituted together is preferable, and may be the same or differently substituted The compound which is a good alkyl group is more preferable, and the compound which is the same or different and is a methyl group or an ethyl group is further more preferable.

  In the present invention, as a preferable production method, the following methods may be mentioned.

「式中、Ｒ^１、Ｒ^２およびＲ^３は、前記と同様の意味を有する。」で表されるアセタール誘導体の製造における、一般式［２］

「式中、Ｒ^１およびＸは、前記と同様の意味を有する。」で表されるハロフェネチルアルコール誘導体を、パラジウム触媒の存在下、一般式［３］

「式中、Ｒ^２およびＲ^３は、前記と同様の意味を有する。」で表されるチオール誘導体またはその塩とのカップリング反応に付す方法において、一般式［２］の化合物のＲ^１が、水素原子または置換されていてもよいアシル基、Ｘが、塩素原子、臭素原子、ヨウ素原子または置換されていてもよいアルカンスルホニルオキシ基；一般式［３］の化合物またはその塩のＲ^２およびＲ^３が、同一または異なって置換されていてもよいアルキル基、または、一緒になって置換されていてもよいアルキレン基である化合物を用いる方法が、好ましい。一般式［２］の化合物のＲ^１が、置換されていてもよいアシル基、Ｘが、臭素原子、ヨウ素原子または置換されていてもよいアルカンスルホニルオキシ基；一般式［３］の化合物またはその塩のＲ^２およびＲ^３が、同一または異なって置換されていてもよいアルキル基である化合物を用いる方法が、より好ましい。一般式［２］の化合物のＲ^１が、置換されていてもよいベンゾイル基、Ｘが、ヨウ素原子またはトリフルオロメタンスルホニルオキシ基；一般式［３］の化合物またはその塩のＲ^２およびＲ^３が、同一または異なってメチル基またはエチル基である化合物を用いる方法が、さらに好ましい。一般式［２］の化合物のＲ^１が、ベンゾイル基、Ｘが、ヨウ素原子またはトリフルオロメタンスルホニルオキシ基；一般式［３］の化合物またはその塩のＲ^２およびＲ^３が、同一または異なってメチル基またはエチル基である化合物を用いる方法が、よりさらに好ましい。 General formula [1]

In the production of an acetal derivative represented by “wherein R ¹ , R ² and R ³ have the same meaning as described above”, the general formula [2]

The halophenethyl alcohol derivative represented by “wherein R ¹ and X have the same meanings as described above” is represented by the general formula [3] in the presence of a palladium catalyst.

In the method in which R ² and R ³ have the same meanings as described above, in the method of subjecting to a coupling reaction with a thiol derivative or a salt thereof, R ¹ of the compound of the general formula [2] is , A hydrogen atom or an optionally substituted acyl group, X represents a chlorine atom, a bromine atom, an iodine atom or an optionally substituted alkanesulfonyloxy group; R ² of the compound of the general formula [3] or a salt thereof and A method using a compound in which R ³ is an alkyl group which may be the same or different, or an alkylene group which may be substituted together is preferable. R ¹ of the compound of the general formula [2] is an optionally substituted acyl group, X is a bromine atom, an iodine atom or an optionally substituted alkanesulfonyloxy group; the compound of the general formula [3] or its A method using a compound in which R ² and R ^{3 of the} salt are the same or different and optionally substituted alkyl groups is more preferable. R ¹ of the compound of the general formula [2] is an optionally substituted benzoyl group, X is an iodine atom or a trifluoromethanesulfonyloxy group; R ² and R ³ of the compound of the general formula [3] or a salt thereof are Further preferred is a method using a compound which is the same or different and is a methyl group or an ethyl group. R ¹ of the compound of the general formula [2] is a benzoyl group, X is an iodine atom or a trifluoromethanesulfonyloxy group; R ² and R ³ of the compound of the general formula [3] or a salt thereof are the same or different and are methyl A method using a compound which is a group or an ethyl group is still more preferable.

「式中、Ｒ^１、Ｒ^２およびＲ^３は、前記と同様の意味を有する。」で表されるアセタール誘導体を、酸の存在下、分子内閉環反応に付し、必要に応じ脱保護反応に付す方法において、一般式［１］の化合物のＲ^１が、水素原子または置換されていてもよいアシル基、Ｒ^２およびＲ^３が、同一または異なって置換されていてもよいアルキル基、または、一緒になって置換されていてもよいアルキレン基である化合物を用いる方法が、好ましい。Ｒ^１が、置換されていてもよいアシル基、Ｒ^２およびＲ^３が、同一または異なって置換されていてもよいアルキル基である化合物を用いる方法が、より好ましい。Ｒ^１が、置換されていてもよいベンゾイル基、Ｒ^２およびＲ^３が、同一または異なってメチル基またはエチル基である化合物を用いる方法が、さらに好ましい。Ｒ^１が、ベンゾイル基、Ｒ^２およびＲ^３が、同一または異なってメチル基またはエチル基である化合物を用いる方法が、よりさらに好ましい。 General formula [1] in the production of 2- (1-benzothiophen-5-yl) ethanol

The acetal derivative represented by “wherein R ¹ , R ² and R ³ have the same meaning as described above” is subjected to an intramolecular cyclization reaction in the presence of an acid, and a deprotection reaction is performed as necessary. Wherein R ¹ of the compound of the general formula [1] is a hydrogen atom or an optionally substituted acyl group, R ² and R ³ are the same or differently substituted alkyl groups, or A method using a compound which is an alkylene group which may be substituted together is preferable. More preferred is a method using a compound in which R ¹ is an optionally substituted acyl group, and R ² and R ³ are the same or different alkyl groups that may be substituted. More preferred is a method using a compound in which R ¹ is an optionally substituted benzoyl group, and R ² and R ³ are the same or different and are a methyl group or an ethyl group. A method using a compound in which R ¹ is a benzoyl group and R ² and R ³ are the same or different and each is a methyl group or an ethyl group is even more preferable.

  Next, the manufacturing method of this invention is demonstrated.

  A method for producing the acetal derivative of the general formula [1] from the compound of the general formula [2] will be described.

「式中、Ｒ¹、Ｒ^２、Ｒ^３およびＸは、前記と同様の意味を有する。」 [Production Method 1]

“Wherein R ¹ , R ² , R ³ and X have the same meaning as described above.”

As the compound of the general formula [2], for example, 2- (4-bromophenyl) ethanol is commercially available. 2- (4-bromophenyl) ethyl acetate, 2- (4-iodophenyl) ethanol, 2- (4-iodophenyl) ethyl acetate and 4- (2- (acetoxy) ethyl) phenyl = trifluoromethane Sulfonate is known.
Examples of the compound of the general formula [3] or a salt thereof include 2-mercaptoacetaldehyde = dimethylacetal (Japanese Patent Laid-Open No. 63-233970), 2-mercaptoacetaldehyde = diethylacetal (Japanese Patent Laid-Open No. 08-119967) and 2 -Mercaptomethyl-1,3-dioxolane (DE 3927992) is known.

  Coupling reaction of a compound of general formula [2] with a compound of general formula [3] or a salt thereof in the presence of a palladium catalyst, in the presence or absence of a base, in the presence or absence of a ligand To give a compound of the general formula [1].

  The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, aromatic hydrocarbons such as benzene, toluene and xylene; aliphatic hydrocarbons such as hexane and cyclohexane Halogenated hydrocarbons such as methylene chloride, dichloroethane, chlorobenzene and dichlorobenzene; ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and bis (2-methoxyethyl) ether; N, N-dimethylformamide, N Amides such as N, dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; esters such as ethyl acetate; ketones such as acetone; and nitriles such as acetonitrile; These may be used as a mixture. Preferred solvents include aromatic hydrocarbons and amides, with toluene and 1-methyl-2-pyrrolidone being more preferred. Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-20 times amount (v / w) with respect to the compound of General formula [2], More preferably, it is 1-10 times amount (v / w). .

  Examples of the palladium catalyst used in this reaction include palladium metal such as palladium-carbon and palladium black; inorganic palladium salt such as palladium chloride; organic palladium salt such as palladium acetate; tetrakis (triphenylphosphine) palladium (0). , Organopalladium complexes such as bis (triphenylphosphine) palladium (II) chloride, 1,1′-bis (diphenylphosphino) ferrocenepalladium (II) chloride and tris (dibenzylideneacetone) dipalladium (0); Examples thereof include polymer-fixed organic palladium complexes such as supported bis (acetate) triphenylphosphine palladium (II) and polymer-supported di (acetate) dicyclohexylphosphine palladium (II). Preferred palladium catalysts include inorganic palladium salts, organic palladium salts, organic palladium complexes, and the like, with palladium chloride, palladium acetate, and tris (dibenzylideneacetone) dipalladium (0) being more preferred. The usage-amount of a palladium catalyst should just be 0.0001 times mole or more with respect to the compound of General formula [2], Preferably, it is 0.001-0.02 times mole.

  Examples of the base optionally used in this reaction include trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, diethylamine, dicyclohexylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5. 4.0] organic bases such as undec-7-ene (DBU) and pyridine; metal alkoxides such as sodium = methoxide, sodium = ethoxide, potassium = tert-butoxide and sodium = tert-butoxide; and sodium hydroxide, water Examples thereof include inorganic bases such as potassium oxide, sodium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium hydride and potassium hydride. Preferred bases include organic bases such as triethylamine and N, N-diisopropylethylamine, with triethylamine being more preferred. The usage-amount of a base should just be 1 time mole or more with respect to the compound of General formula [2], Preferably, it is 1-3 times mole.

  The ligands optionally used in this reaction include, for example, trialkylphosphines such as trimethylphosphine and tri (tert-butyl) phosphine; tricycloalkylphosphines such as tricyclohexylphosphine; triphenylphosphine and tritolyl Triaryl phosphines such as phosphine; trialkyl phosphites such as trimethyl phosphite, triethyl phosphite and tributyl phosphite; tricycloalkyl phosphites such as tricyclohexyl phosphite; Imidazolium salts such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride; acetylacetone and octafluoroacetyl Diketones such as seton; amines such as trimethylamine, triethylamine, tripropylamine and triisopropylamine; 1,1′-bis (diphenylphosphino) ferrocene; and 2,2′-bis (diphenylphosphino) -1, 1'-binaphthyl etc. are mentioned. Preferred ligands include 1,1'-bis (diphenylphosphino) ferrocene and 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl. The usage-amount of a ligand should just be 0.0001 times mole or more with respect to the compound of General formula [2], Preferably, it is 0.001-0.02 times mole.

The amount of the compound of the general formula [3] or a salt thereof used in this reaction may be 1 mol or more, preferably 1 to 2 mol, relative to the compound of the general formula [2].
This reaction may be carried out at 0 to 200 ° C., preferably 50 to 120 ° C. for 1 minute to 24 hours. Moreover, it is preferable to carry out in inert gas stream, and nitrogen, argon, etc. are mentioned as an inert gas.
In the above production method, the compound of the general formula [3] can also be used as a salt. Examples of the salt include salts with alkali metals such as sodium, potassium and cesium; alkaline earth such as calcium and magnesium. Salts with other metals; ammonium salts; and trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, diethylamine, dicyclohexylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0]. And salts with nitrogen-containing organic bases such as undec-7-ene (DBU) and pyridine.

  The compound of the general formula [1] obtained in this manner can be combined with other general formulas as necessary by appropriately combining known methods such as hydroxyl group acylation reaction and carboxyl group hydrolysis reaction. It can derive to the compound of [1]. In addition, the compound of the general formula [1] may be used as it is in the next reaction without isolation.

  A method for producing 2- (1-benzothiophen-5-yl) ethanol represented by the formula [4a] from the compound of the general formula [1] will be described.

「式中、Ｒ^１、Ｒ^２およびＲ^３は、前記と同様の意味を有する。」 [Production Method 2]

“Wherein R ¹ , R ² and R ³ have the same meaning as described above.”

(2-1)
A compound of the general formula [4] can be produced by subjecting the compound of the general formula [1] to an intramolecular ring closure reaction in the presence of an acid.
The solvent used in this reaction is not particularly limited as long as it does not adversely influence the reaction. For example, aliphatic hydrocarbons such as hexane, cyclohexane and heptane; aromatics such as benzene, toluene, xylene and mesitylene Group hydrocarbons; and halogenated hydrocarbons such as dichloroethane, chlorobenzene, and dichlorobenzene, and the like. These may be used as a mixture. Preferable solvents include aromatic hydrocarbons and halogenated hydrocarbons, and toluene and chlorobenzene are more preferable. Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-20 times amount (v / w) with respect to the compound of General formula [1], More preferably, it is 1-10 times amount (v / w). .

Examples of the acid used in this reaction include phosphoric acids such as orthophosphoric acid, metaphosphoric acid, polyphosphoric acid and diphosphorus pentoxide; and Lewis acids such as boron trifluoride diethyl complex, zinc chloride and tin chloride. . Preferred acids include phosphoric acids, and orthophosphoric acid and diphosphorus pentoxide are more preferred. Although the usage-amount of an acid is not specifically limited, What is necessary is just 1 time mole or more with respect to the compound of General formula [1], Preferably, it is 1-10 times mole.
This reaction is preferably performed by adding water, and the amount of water added is not particularly limited, but is 0.2 to 1 times the amount of the compound of the general formula [1] (w / w) It is preferable to add.
This reaction may be carried out in the range of 0 ° C. to the reflux temperature of the reaction system, and is preferably carried out under reflux for 30 minutes to 24 hours. Moreover, it is more preferable to react while distilling off the alcohol and water produced by the reaction by azeotropic distillation.

Alternatively, the compound of the general formula [1] may be deprotected by a method known per se to isolate the aldehyde form of the general formula [5]. The compound of general formula [5] can be produced by subjecting the obtained compound of general formula [5] to an intramolecular ring closure reaction in the presence of an acid under the conditions described above.
The compound of the general formula [4] thus obtained may be used as it is in the next reaction without isolation.

(2-2)
The compound of the general formula [4] can be derived into 2- (1-benzothiophen-5-yl) ethanol represented by the formula [4a] by subjecting it to a deprotection reaction as necessary.
The deprotection reaction of the hydroxyl protecting group of R ¹ is described, for example, in W.W. W. Greene et al., Protective Groups in Organic Synthesis, John Wiley & Sons, INC., 1999, 3rd edition , P. What is necessary is just to carry out by the method as described in 17-245 etc. or the method according to it.

For example, when R ¹ is an optionally substituted acyl group, the compound of the general formula [4] is subjected to a hydrolysis reaction in the presence of a base to give 2- ( 1-benzothiophen-5-yl) ethanol can be derived.

  The solvent used in this reaction is not particularly limited as long as it does not affect the reaction. For example, ethers such as dioxane, tetrahydrofuran, 1,2-dimethoxyethane and bis (2-methoxyethyl) ether Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and 1-methyl-2-pyrrolidone; sulfoxides such as dimethyl sulfoxide; ketones such as acetone and 2-butanone; methanol, ethanol, propanol, Examples include alcohols such as 2-propanol and butanol; nitriles such as acetonitrile; and water. These may be used as a mixture. Preferable solvents include alcohols, and 2-propanol is more preferable. Although the usage-amount of a solvent is not specifically limited, Preferably it is 1-20 times amount (v / w) with respect to the compound of General formula [4], More preferably, it is 1-10 times amount (v / w). .

  Examples of the base used in this reaction include triethylamine, N, N-diisopropylethylamine, N-methylpiperidine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU). ) And organic bases such as pyridine; metal alkoxides such as sodium = methoxide, sodium = ethoxide, potassium = tert-butoxide and sodium = tert-butoxide; and sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and And inorganic bases such as barium carbonate. Preferable bases include inorganic bases, and sodium hydroxide and potassium hydroxide are more preferable. The usage-amount of a base should just be 1 time mole or more with respect to the compound of General formula [4], Preferably, it is 1-2 times mole.

The amount of water used in this reaction may be 1 mol or more, and is preferably 0.5 to 2 times (w / w) in order to have a function as a solvent.
This reaction may be carried out at 0 to 200 ° C., preferably 0 to 100 ° C. for 1 minute to 24 hours.

The compounds of general formulas [1], [4] and [5] and 2- (1-benzothiophen-5-yl) ethanol represented by formula [4a] obtained by the production method described above are: It can be isolated and purified by usual methods such as extraction, crystallization, distillation and column chromatography.
In the compounds represented by the general formulas [1], [2], [3], [4] and [5] or salts thereof in the production method described above, isomers (for example, optical isomers, geometric isomers and All tautomeric isomers can be used, and metal salts, hydrates, solvates and all crystalline forms can be used.

Next, the present invention will be described with reference examples and examples, but the present invention is not limited thereto.
The mixing ratio in the eluent is a volume ratio. Unless otherwise specified, the carrier in silica gel column chromatography is Fuji Silysia Chemical Ltd., B.I. W. Silica gel, BW-127ZH or PSQ100B.
In each example, each abbreviation has the following meaning.
Bz: benzoyl, Et: ethyl, Me: methyl, Tf: trifluoromethanesulfonyl

４−ヨードフェネチルアルコール6.19gをトルエン20mLに溶解し、トリエチルアミン2.77gおよび塩化ベンゾイル3.85gを加え、室温で1時間攪拌した。反応液に水20mLを加えた後、攪拌した。有機層を分取し、水20mLおよび飽和食塩水20mLで順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物に、トルエン5mLおよびシクロヘキサン20mLを加えて冷却後、析出物をろ取し、白色固体の４−ヨードフェネチル＝ベンゾアート6.58gを得た。
¹H-NMR(CDCl₃)δ値：3.02(2H,t,J=6.8Hz),4.50(2H,t,J=6.8Hz),7.00-7.10(2H,m),7.40-7.50(2H,m),7.50-7.60(1H,m),7.60-7.70(2H,m),7.95-8.05(2H,m) Reference example 1

4-iodophenethyl alcohol (6.19 g) was dissolved in toluene (20 mL), triethylamine (2.77 g) and benzoyl chloride (3.85 g) were added, and the mixture was stirred at room temperature for 1 hour. 20 mL of water was added to the reaction solution, followed by stirring. The organic layer was separated, washed successively with 20 mL of water and 20 mL of saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. To the obtained residue, 5 mL of toluene and 20 mL of cyclohexane were added and cooled, and then the precipitate was collected by filtration to obtain 6.58 g of 4-iodophenethyl = benzoate as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.02 (2H, t, J = 6.8 Hz), 4.50 (2H, t, J = 6.8 Hz), 7.00-7.10 (2H, m), 7.40-7.50 (2H, m), 7.50-7.60 (1H, m), 7.60-7.70 (2H, m), 7.95-8.05 (2H, m)

メチル＝（４−ヒドロキシフェニル）アセタート10.0gをトルエン50mLに懸濁し、トリエチルアミン7.31gを加えた後、氷冷下、トリフルオロメタンスルホン酸無水物18.7gを滴下し、同温度で0.5時間撹拌した。反応液を氷水100mLに加えた。有機層を分取し、水および飽和食塩水で順次洗浄後、活性炭処理し、無水硫酸マグネシウムで乾燥した。減圧下で溶媒を留去し、褐色油状の４−（（メトキシカルボニル）メチル）フェニル＝トリフルオロメタンスルホナート17.8gを得た。
¹H-NMR(CDCl₃)δ値：3.66(2H,s),3.72(3H,s),7.20-7.30(2H,m),7.35-7.40(2H,m). Reference example 2

After suspending 10.0 g of methyl = (4-hydroxyphenyl) acetate in 50 mL of toluene and adding 7.31 g of triethylamine, 18.7 g of trifluoromethanesulfonic anhydride was added dropwise under ice cooling, followed by stirring at the same temperature for 0.5 hour. The reaction solution was added to 100 mL of ice water. The organic layer was separated, washed successively with water and saturated brine, treated with activated carbon, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 17.8 g of 4-((methoxycarbonyl) methyl) phenyl = trifluoromethanesulfonate as a brown oil.
¹ H-NMR (CDCl ₃ ) δ value: 3.66 (2H, s), 3.72 (3H, s), 7.20-7.30 (2H, m), 7.35-7.40 (2H, m).

塩化リチウム3.03gをジグライム62mLに懸濁し、水素化ホウ素ナトリウム2.70gを加えた後、室温で0.5時間撹拌した。反応液に氷冷下、４−（（メトキシカルボニル）メチル）フェニル＝トリフルオロメタンスルホナート17.8gのジグライム27mL溶液を滴下し、室温で1.5時間撹拌後、塩化リチウム0.76gおよび水素化ホウ素ナトリウム0.68gを加え、室温で2時間撹拌した。反応液を冷却後、アセトン18mL、6mol/L塩酸9mL、水90mLおよびトルエン90mLを加えた後、不溶物をろ去した。有機層を分取し、3回水洗後、飽和食塩水で洗浄した。無水硫酸マグネシウムで乾燥後、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝３：１）で精製し、淡黄色油状の４−（２−ヒドロキシエチル）フェニル＝トリフルオロメタンスルホナート15.8gを得た。
¹H-NMR(CDCl₃)δ値：1.49(1H,t,J=5.6Hz),2.90(2H,t,J=6.5Hz),3.80-3.95(2H,m),7.15-7.25(2H,m),7.30-7.35(2H,m). Reference example 3

Lithium chloride (3.03 g) was suspended in diglyme (62 mL), sodium borohydride (2.70 g) was added, and the mixture was stirred at room temperature for 0.5 hr. To the reaction solution was added dropwise a solution of 4-((methoxycarbonyl) methyl) phenyl = trifluoromethanesulfonate 17.8 g in 27 mL of diglyme under ice-cooling, stirred at room temperature for 1.5 hours, then 0.76 g of lithium chloride and 0.68 g of sodium borohydride. And stirred at room temperature for 2 hours. After cooling the reaction solution, 18 mL of acetone, 9 mL of 6 mol / L hydrochloric acid, 90 mL of water and 90 mL of toluene were added, and the insoluble material was removed by filtration. The organic layer was separated, washed 3 times with water, and then with saturated brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to obtain 15.8 g of 4- (2-hydroxyethyl) phenyl = trifluoromethanesulfonate as a pale yellow oil. .
¹ H-NMR (CDCl ₃ ) δ value: 1.49 (1H, t, J = 5.6 Hz), 2.90 (2H, t, J = 6.5 Hz), 3.80-3.95 (2H, m), 7.15-7.25 (2H, m), 7.30-7.35 (2H, m).

４−（２−ヒドロキシエチル）フェニル＝トリフルオロメタンスルホナート15.8gをトルエン79mLに溶解し、トリエチルアミン6.49gを加えた後、氷冷下、塩化ベンゾイル8.19gを滴下し、室温で0.5時間撹拌した。反応液に水79mLを加えた。有機層を分取し、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物に２−プロパノールを加えて冷却後、析出物をろ取し、白色固体の４−（２−（ベンゾイルオキシ）エチル）フェニル＝トリフルオロメタンスルホナート14.6gを得た。
¹H-NMR(CDCl₃)δ値：3.12(2H,t,J=6.8Hz),4.54(2H,t,J=6.8Hz),7.20-7.30(2H,m),7.30-7.40(2H,m),7.40-7.50(2H,m),7.50-7.60(1H,m),7.95-8.05(2H,m). Reference example 4

15.8 g of 4- (2-hydroxyethyl) phenyl = trifluoromethanesulfonate was dissolved in 79 mL of toluene, 6.49 g of triethylamine was added, 8.19 g of benzoyl chloride was added dropwise under ice cooling, and the mixture was stirred at room temperature for 0.5 hour. 79 mL of water was added to the reaction solution. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. 2-Propanol was added to the obtained residue and cooled, and then the precipitate was collected by filtration to obtain 14.6 g of 4- (2- (benzoyloxy) ethyl) phenyl = trifluoromethanesulfonate as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 3.12 (2H, t, J = 6.8 Hz), 4.54 (2H, t, J = 6.8 Hz), 7.20-7.30 (2H, m), 7.30-7.40 (2H, m), 7.40-7.50 (2H, m), 7.50-7.60 (1H, m), 7.95-8.05 (2H, m).

窒素雰囲気下、２−（４−ヨードフェニル）エチル＝ベンゾアート0.50gを１−メチル−２−ピロリドン5mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.26g、トリエチルアミン0.35g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.03gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.06gを加え、55℃で3時間撹拌した。反応液を冷却後、水および酢酸エチルを加えた。有機層を分取し、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝１５：１）で精製し、黄色油状の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート0.45gを得た。
¹H-NMR(CDCl₃)δ値：1.18(6H,t,J=7.1Hz),3.04(2H,t,J=6.9Hz),3.11(2H,d,J=5.6Hz),3.45-3.70(4H,m),4.51(2H,t,J=6.9Hz),4.63(1H,t,J=5.6Hz),7.15-7.25(2H,m),7.30-7.40(2H,m),7.40-7.50(2H,m),7.50-7.60(1H,m),7.95-8.05(2H,m) Example 1

Under a nitrogen atmosphere, 0.50 g of 2- (4-iodophenyl) ethyl = benzoate is dissolved in 5 mL of 1-methyl-2-pyrrolidone, 0.26 g of 2-mercaptoacetaldehyde = diethylacetal, 0.35 g of triethylamine, tris (dibenzylideneacetone) ) 0.03 g of dipalladium (0) and 0.06 g of 1,1′-bis (diphenylphosphino) ferrocene were added and stirred at 55 ° C. for 3 hours. After cooling the reaction solution, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 15: 1) to give 0.45 g of 4-((2,2-diethoxyethyl) thio) phenethyl = benzoate as a yellow oil. Got.
¹ H-NMR (CDCl ₃ ) δ value: 1.18 (6H, t, J = 7.1 Hz), 3.04 (2H, t, J = 6.9 Hz), 3.11 (2H, d, J = 5.6 Hz), 3.45-3.70 (4H, m), 4.51 (2H, t, J = 6.9Hz), 4.63 (1H, t, J = 5.6Hz), 7.15-7.25 (2H, m), 7.30-7.40 (2H, m), 7.40- 7.50 (2H, m), 7.50-7.60 (1H, m), 7.95-8.05 (2H, m)

アルゴン雰囲気下、４−ヨードフェネチル＝ベンゾアート1.00gを１−メチル−２−ピロリドン5mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.51g、トリエチルアミン0.69g、酢酸パラジウム0.03gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.08gを加え、80〜90℃で0.5時間撹拌した。反応液を冷却し、氷水および酢酸エチル混液に滴下した。有機層を分取し、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝５：１）で精製し、淡黄色油状の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート1.05gを得た。
CDCl₃中における¹H-NMRは、実施例１の値と一致した。 Example 2

Under an argon atmosphere, 1.00 g of 4-iodophenethyl benzoate is dissolved in 5 mL of 1-methyl-2-pyrrolidone, 0.51 g of 2-mercaptoacetaldehyde = diethylacetal, 0.69 g of triethylamine, 0.03 g of palladium acetate and 1,1′- Bis (diphenylphosphino) ferrocene 0.08g was added, and it stirred at 80-90 degreeC for 0.5 hour. The reaction solution was cooled and added dropwise to a mixture of ice water and ethyl acetate. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 5: 1) to give 4-((2,2-diethoxyethyl) thio) phenethyl = benzoate 1.05 as a pale yellow oil. g was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 1.

窒素雰囲気下、２−（４−ヨードフェニル）エチル＝ベンゾアート1.00gをトルエン5mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.47g、トリエチルアミン0.32g、酢酸パラジウム0.01gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.03gを加え、90〜100℃で2時間撹拌した。反応液を冷却後、水を加え、6mol/L塩酸でpH1に調整した。有機層を分取し、水を加え、5mol/L水酸化ナトリウム水溶液でpH12に調整した。有機層を分取し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝１０：１）で精製し、淡黄色油状の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート1.05gを得た。
CDCl₃中における¹H-NMRは、実施例１の値と一致した。 Example 3

Under a nitrogen atmosphere, 1.00 g of 2- (4-iodophenyl) ethyl = benzoate is dissolved in 5 mL of toluene, 0.47 g of 2-mercaptoacetaldehyde = diethylacetal, 0.32 g of triethylamine, 0.01 g of palladium acetate and 1,1′-bis (Diphenylphosphino) ferrocene 0.03g was added, and it stirred at 90-100 degreeC for 2 hours. The reaction mixture was cooled, water was added, and the pH was adjusted to 1 with 6 mol / L hydrochloric acid. The organic layer was separated, water was added, and the pH was adjusted to 12 with a 5 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1) to give 4-((2,2-diethoxyethyl) thio) phenethyl = benzoate 1.05 as a pale yellow oil. g was obtained.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 1.

窒素雰囲気下、２−（４−ヨードフェニル）エチル＝ベンゾアート2.00gをトルエン10mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.94g、トリエチルアミン1.38g、塩化パラジウム0.01gおよび２，２’−ビス（ジフェニルホスフィノ）−１，１’−ビナフチル0.04gを加え、5時間加熱還流した。反応後の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアートの生成率は、HPLCで分析した結果、57％であった。 Example 4

Under nitrogen atmosphere, 2.00 g of 2- (4-iodophenyl) ethyl = benzoate is dissolved in 10 mL of toluene, 0.94 g of 2-mercaptoacetaldehyde = diethylacetal, 1.38 g of triethylamine, 0.01 g of palladium chloride and 2,2′-bis. (Diphenylphosphino) -1,1′-binaphthyl (0.04 g) was added, and the mixture was heated to reflux for 5 hours. The production rate of 4-((2,2-diethoxyethyl) thio) phenethyl benzoate after the reaction was 57% as a result of analysis by HPLC.

窒素雰囲気下、２−（４−ブロモフェニル）エチル＝ベンゾアート1.00gをトルエン5mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.54g、トリエチルアミン0.80g、酢酸パラジウム0.01gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.04gを加え、8時間加熱還流した。反応後の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアートの生成率は、HPLCで分析した結果、35％であった。 Example 5

Under nitrogen atmosphere, 1.00 g of 2- (4-bromophenyl) ethyl = benzoate is dissolved in 5 mL of toluene, 0.54 g of 2-mercaptoacetaldehyde = diethylacetal, 0.80 g of triethylamine, 0.01 g of palladium acetate and 1,1′-bis (Diphenylphosphino) ferrocene 0.04 g was added, and the mixture was heated to reflux for 8 hours. The production rate of 4-((2,2-diethoxyethyl) thio) phenethyl benzoate after the reaction was 35% as a result of analysis by HPLC.

アルゴン雰囲気下、４−（２−（ベンゾイルオキシ）エチル）フェニル＝トリフルオロメタンスルホナート0.50gを１−メチル−２−ピロリドン5mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール0.24g、トリエチルアミン0.33g、トリス（ジベンジリデンアセトン）ジパラジウム（０）0.02gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.04gを加え、80℃で2時間撹拌した。反応液を冷却後、水および酢酸エチルを加えた。有機層を分取し、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝１０：１）で精製し、無色油状の４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート0.42gを得た。
CDCl₃中における¹H-NMRは、実施例１の値と一致した。 Example 6

In an argon atmosphere, 0.50 g of 4- (2- (benzoyloxy) ethyl) phenyl = trifluoromethanesulfonate was dissolved in 5 mL of 1-methyl-2-pyrrolidone, 0.24 g of 2-mercaptoacetaldehyde = diethylacetal, 0.33 g of triethylamine, 0.02 g of tris (dibenzylideneacetone) dipalladium (0) and 0.04 g of 1,1′-bis (diphenylphosphino) ferrocene were added, and the mixture was stirred at 80 ° C. for 2 hours. After cooling the reaction solution, water and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1), and colorless oily 4-((2,2-diethoxyethyl) thio) phenethyl = benzoate 0.42 g Got.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 1.

４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート1.05gをトルエン10mLに溶解し、85％リン酸0.3mLを加え、加熱還流下、2.5時間共沸脱水した。反応液を冷却し、水、セライトおよび活性炭を加えて撹拌した後、不溶物をろ去した。有機層を分取し、飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：トルエン＝１：１）で精製し、淡黄色固体の２−（１−ベンゾチオフェン−５−イル）エチル＝ベンゾアート0.67gを得た。
¹H-NMR(CDCl₃)δ値：3.20(2H,t,J=7.0Hz),4.59(2H,t,J=7.0Hz),7.25-7.35(2H,m),7.40-7.45(3H,m),7.50-7.60(1H,m),7.74(1H,s),7.83(1H,d,J=8.3Hz),8.00-8.05(2H,m) Example 7

4-((2,2-diethoxyethyl) thio) phenethyl = benzoate (1.05 g) was dissolved in toluene (10 mL), 85% phosphoric acid (0.3 mL) was added, and the mixture was subjected to azeotropic dehydration under heating and reflux for 2.5 hours. The reaction solution was cooled, water, celite and activated carbon were added and stirred, and then insolubles were removed by filtration. The organic layer was separated, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane: toluene = 1: 1) to obtain 0.67 g of 2- (1-benzothiophen-5-yl) ethyl = benzoate as a pale yellow solid. It was.
¹ H-NMR (CDCl ₃ ) δ value: 3.20 (2H, t, J = 7.0 Hz), 4.59 (2H, t, J = 7.0 Hz), 7.25-7.35 (2H, m), 7.40-7.45 (3H, m), 7.50-7.60 (1H, m), 7.74 (1H, s), 7.83 (1H, d, J = 8.3Hz), 8.00-8.05 (2H, m)

４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアート1.5gをクロロベンゼン15mLに溶解し、五酸化二リン0.57gおよび水0.5mLを加え、加熱還流下、7時間共沸脱水した。反応液を冷却し、不溶物をろ去し、水およびトルエンを加えて撹拌した。有機層を分取し、水および飽和食塩水で順次洗浄後、無水硫酸マグネシウムで乾燥し、減圧下で溶媒を留去した。得られた残留物をシリカゲルカラムクロマトグラフィー（溶離液；ヘキサン：酢酸エチル＝３０：１）で精製し、白色固体の２−（１−ベンゾチオフェン−５−イル）エチル＝ベンゾアート0.84gを得た。
CDCl₃中における¹H-NMRは、実施例７の値と一致した。 Example 8

4-((2,2-diethoxyethyl) thio) phenethyl = benzoate (1.5 g) was dissolved in chlorobenzene (15 mL), diphosphorus pentoxide (0.57 g) and water (0.5 mL) were added, and azeotropic dehydration was carried out for 7 hours while heating under reflux. . The reaction solution was cooled, insolubles were removed by filtration, water and toluene were added, and the mixture was stirred. The organic layer was separated, washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 30: 1) to obtain 0.84 g of 2- (1-benzothiophen-5-yl) ethyl = benzoate as a white solid. It was.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 7.

窒素雰囲気下、４−ヨードフェネチル＝ベンゾアート100.0gをトルエン500mLに溶解し、２−メルカプトアセトアルデヒド＝ジエチルアセタール44.8g、トリエチルアミン34.5g、酢酸パラジウム0.06gおよび１，１’−ビス（ジフェニルホスフィノ）フェロセン0.16gを加え、85〜95℃で7時間撹拌した。反応液を冷却後、水200mLを加え、6mol/L塩酸でpH2に調整した。有機層を分取し、水200mLを加え、2mol/L水酸化ナトリウム水溶液でpH12に調整した。有機層を分取し、水洗し、４−（（２，２−ジエトキシエチル）チオ）フェネチル＝ベンゾアートを含むトルエン溶液529gを得た。このトルエン溶液291gにシリカゲル5.5gを加え、0.5時間撹拌後、不溶物をろ去し、ろ滓をトルエン165mLで洗浄した。ろ液と洗液を合わせ、トルエン110mL、85％リン酸16.5mLおよび水27.5mLを加え、加熱還流下、1時間共沸脱水した。水27.5mLを加え、加熱還流下、8時間共沸脱水した。反応液を冷却後、水165mL、セライト5.5gおよび活性炭5.5gを加えて撹拌した後、不溶物をろ去し、ろ滓をトルエン55mLで洗浄した。ろ液と洗液を合わせ、有機層を分取し、水洗後、減圧下で溶媒を留去した。得られた残留物にシクロヘキサンを加えて冷却後、析出物をろ取し、黄色固体の２−（１−ベンゾチオフェン−５−イル）エチル＝ベンゾアート34.5gを得た。
CDCl₃中における¹H-NMRは、実施例７の値と一致した。 Example 9

Under nitrogen atmosphere, 4-iodophenethyl = benzoate 100.0 g was dissolved in toluene 500 mL, 2-mercaptoacetaldehyde = diethyl acetal 44.8 g, triethylamine 34.5 g, palladium acetate 0.06 g and 1,1′-bis (diphenylphosphino) Ferrocene 0.16g was added and it stirred at 85-95 degreeC for 7 hours. After cooling the reaction solution, 200 mL of water was added, and the pH was adjusted to 2 with 6 mol / L hydrochloric acid. The organic layer was separated, 200 mL of water was added, and the pH was adjusted to 12 with a 2 mol / L aqueous sodium hydroxide solution. The organic layer was separated and washed with water to obtain 529 g of a toluene solution containing 4-((2,2-diethoxyethyl) thio) phenethyl = benzoate. To 291 g of this toluene solution was added 5.5 g of silica gel, and after stirring for 0.5 hour, the insoluble material was removed by filtration, and the filter cake was washed with 165 mL of toluene. The filtrate and the washing solution were combined, 110 mL of toluene, 16.5 mL of 85% phosphoric acid and 27.5 mL of water were added, and azeotropic dehydration was performed for 1 hour under heating and reflux. 27.5 mL of water was added, and azeotropic dehydration was performed for 8 hours while heating under reflux. After cooling the reaction solution, 165 mL of water, 5.5 g of celite and 5.5 g of activated carbon were added and stirred, insoluble matter was removed by filtration, and the filter cake was washed with 55 mL of toluene. The filtrate and the washing solution were combined, the organic layer was separated, washed with water, and then the solvent was distilled off under reduced pressure. After adding cyclohexane to the obtained residue and cooling, the precipitate was collected by filtration to obtain 34.5 g of 2- (1-benzothiophen-5-yl) ethyl = benzoate as a yellow solid.
¹ H-NMR in CDCl ₃ was consistent with the value of Example 7.

２−（１−ベンゾチオフェン−５−イル）エチル＝ベンゾアート46.0gを２−プロパノール70mL、水70mLおよび水酸化ナトリウム9.77g混液に加え、50〜60℃で3時間攪拌した。反応液を冷却後、トルエン140mLおよび水140mLを加えた。有機層を分取し、水洗後、活性炭処理し、減圧下で溶媒を留去した。得られた残留物にシクロヘキサンを加え、析出物をろ取し、白色固体の２−（１−ベンゾチオフェン−５−イル）エタノール26.9gを得た。
¹H-NMR(CDCl₃)δ値：1.40-1.55(1H,m),2.98(2H,t,J=6.5Hz),3.90(2H,t,J=6.5Hz),7.21(1H,dd,J=1.5,8.3Hz),7.29(1H,dd,J=0.7,5.4Hz),7.43(1H,d,J=5.4Hz),7.65-7.70(1H,m),7.82(1H,d,J=8.3Hz) Example 10

4- (1-benzothiophen-5-yl) ethyl = benzoate (46.0 g) was added to a mixture of 2-propanol (70 mL), water (70 mL) and sodium hydroxide (9.77 g), and the mixture was stirred at 50 to 60 ° C. for 3 hours. After cooling the reaction solution, 140 mL of toluene and 140 mL of water were added. The organic layer was separated, washed with water, treated with activated carbon, and the solvent was distilled off under reduced pressure. Cyclohexane was added to the obtained residue, and the precipitate was collected by filtration to obtain 26.9 g of 2- (1-benzothiophen-5-yl) ethanol as a white solid.
¹ H-NMR (CDCl ₃ ) δ value: 1.40-1.55 (1H, m), 2.98 (2H, t, J = 6.5 Hz), 3.90 (2H, t, J = 6.5 Hz), 7.21 (1H, dd, J = 1.5,8.3Hz), 7.29 (1H, dd, J = 0.7,5.4Hz), 7.43 (1H, d, J = 5.4Hz), 7.65-7.70 (1H, m), 7.82 (1H, d, J = 8.3Hz)

Claims (7)

General formula

“Wherein R ¹ represents a hydrogen atom or a hydroxyl protecting group; R ² and R ³ represent an alkyl group which may be the same or different, or an alkylene which may be substituted together or An acetal derivative represented by “denotes an alkenylene group.” R ¹ is a hydrogen atom or an optionally substituted acyl group; R ² and R ³ are the same or different alkyl groups that may be substituted, or alkylene groups that may be substituted together The acetal derivative according to claim 1, wherein The acetal derivative according to claim 1 or 2, wherein R ¹ is an optionally substituted acyl group; R ² and R ³ are the same or different alkyl groups that may be substituted. The acetal derivative according to claim ¹ , wherein R ¹ is an optionally substituted benzoyl group; R ² and R ³ are the same or different and are a methyl group or an ethyl group. General formula

A halophenethyl alcohol derivative represented by “wherein X represents a halogen atom or an optionally substituted alkanesulfonyloxy or arylsulfonyloxy group; R ¹ represents a hydrogen atom or a hydroxyl protecting group”, In the presence of a palladium catalyst, the general formula

In the formula, R ² and R ³ represent an alkyl group which may be the same or differently substituted, or an alkylene or alkenylene group which may be substituted together. Or subjected to a coupling reaction with a salt thereof,

In the formula, R ¹ , R ² and R ³ have the same meanings as described above, and then an intramolecular ring-closing reaction in the presence of an acid is performed, and deprotection is performed as necessary. A method for producing 2- (1-benzothiophen-5-yl) ethanol, which is subjected to a reaction. General formula

A halophenethyl alcohol derivative represented by “wherein X represents a halogen atom or an optionally substituted alkanesulfonyloxy or arylsulfonyloxy group; R ¹ represents a hydrogen atom or a hydroxyl protecting group”, In the presence of a palladium catalyst, the general formula

In the formula, R ² and R ³ represent an alkyl group which may be the same or differently substituted, or an alkylene or alkenylene group which may be substituted together. Or a general formula characterized by being subjected to a coupling reaction with a salt thereof

The manufacturing method of the acetal derivative represented by "In formula, R < ¹ >, R < ² > and R < ³ > have the same meaning as the above." General formula

“Wherein R ¹ represents a hydrogen atom or a hydroxyl protecting group; R ² and R ³ represent an alkyl group which may be the same or different, or an alkylene which may be substituted together or 2- (1-benzothiophen-5-yl, characterized in that an acetal derivative represented by an alkenylene group is subjected to an intramolecular ring-closing reaction in the presence of an acid and subjected to a deprotection reaction as necessary. ) Ethanol production method.