RU2397169C2 - Method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for preparing 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts which involves the use as a parent compound, (phenylthio)acetic acid derivative or its salts presented by general formula:

where X¹ represents halogen atom, and is applicable as a safe method of volume production of 1-(3-(2-(1-benzothiophene-5-yl)ethoxy)propyl)azetidine-3-ol or its salts effective as an agent in disorders of the central nervous system and peripheral nervous system.

EFFECT: there is provided high yield, safety for human body, low environment loads.

36 cl, 1 tbl, 33 ex

Description

FIELD OF THE INVENTION

The present invention relates to a new method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, which are useful as drugs for diseases of the central nervous system and peripheral nervous system system.

BACKGROUND OF THE INVENTION

1- (3- (2- (1-Benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts have a neuroprotective effect, an action that promotes nerve regeneration, and an axon effect and are applicable as drugs for diseases of the central nervous system and peripheral nervous system.

As methods for preparing said compound, for example, (1) a method for reacting 5- (2- (3-chloropropoxy) ethyl) -1-benzothiophene with 3-azetidinol or its salts is known, (2) a method for exposing 1- (3- (2- (1-Benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol obtained from 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, reduction reaction with a borantetrahydrofuran complex or subjecting it to a sodium borohydride reduction reaction in the presence of a tetrahydrofuran complex with a boron trifluoride complex, and so on (patent document 1).

However, method (1) has the following disadvantages: (A) low yield, (B) there is a need for complex purification methods, such as silica gel column chromatography, (C) a lot of waste is excreted as a result, and so on.

In addition, method (2) cannot satisfy the conditions of the industrial production process, because it has the following disadvantages: (A) the method uses a complex of tetrahydrofuran with borane and a complex of tetrahydrofuran with boron trifluoride and so on, which are harmful to the human body, as reagents flammable, highly toxic and unstable, (B) as a result of which caution is required in the handling and storage of these reagents and special equipment, and so on.

In addition, as a method for producing 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts used in the above method (2), for example, the following methods are known: (3) the method of exposure 2- (1-benzothiophen-5-yl) ethanol; Michael addition reaction using tert-butyl acrylate, then de-tert-butylation thereof; (4) method for subjecting 2- (1-benzothiophen-5-yl) ethanol addition reaction according to Michael using acrylonitrile, then subjecting it to hydrolysis with acid and so on (patent document 1).

However, methods (3) and (4) cannot satisfy the conditions of the industrial production method because they have the following disadvantages in method (3): (A) by-products are formed as a result of transesterification of acrylic acid, (B) special types of equipment and processing are required due to the release of a large amount of combustible isobutene gas during the de-tert-butylation reaction, in the method (4): low yield of hydrolysis with acid, and so on.

As a method for producing 2- (1-benzothiophen-5-yl) ethanol used in the above methods (3) and (4), for example, the following methods are known: (5) a method for subjecting 5-methyl-1-benzothiophene to bromination N-bromosuccinimide and interaction with cyano compounds to obtain (1-benzothiophen-5-yl) acetonitrile, then hydrolysis, then the reduction reaction (non-patent document 1, 2, 3), (6) method for interacting with 5-bromo-1- benzothiophene with magnesium to obtain the Grignard reagent, then exposing it to interaction with ethylene oxide (Patent Document 2), (7) a method for subjecting 5- (1-benzothiophene) carbaldehyde to the Wittig reaction using methoxymethylene phenyl, then hydrolyzing it to obtain (1-benzothiophen-5-yl) acetaldehyde, then subjecting it to a reduction reaction (patent document 3) and so on.

However, methods (5) - (7) cannot satisfy the conditions of the industrial production method because they have the following disadvantages: (A) intermediates are irritating, (B) a highly toxic reagent (cyano compounds) is used, (C) a carcinogenic reagent (ethylene oxide) is used ), (D) flammable reagents (butyllithium, Grignard reagent) are used, (E) the reaction processes are complex, and so on.

On the other hand, as methods for producing a benzothiophenacetic acid derivative or its salts, for example, the following methods are known: (8) a method for subjecting a hydroxyl group of benzothiophenomethanol to halogenation, then reacting it with cyano compounds to obtain benzothiophenacetonitrile, and then hydrolyzing it (non-patent document 3) , (9) a method for exposing 7-oxo-4,5,6,7-tetrahydrobenzothiophene derived from 3-bromothiophene, a Reformed reaction using ethyl bromoacetate, then exposing it to aromatization by dehydrogenation using sulfur and its hydrolysis, and so on (non-patent document 4).

However, methods (8) and (9) cannot satisfy the conditions of the industrial production method because they have the following disadvantages: (A) intermediates are irritating, (B) a highly toxic reagent (cyano compounds) is used, (C) therefore, complex species are required waste treatment, (D) there are many stages of the process, (E) low yield, (F) a high reaction temperature is required, (G) complex reaction processes are used and so on.

In addition, for example, the following methods are known as a process for preparing a 5-halo-1-benzothiophene derivative: then subjecting it to an intramolecular cyclization reaction in the presence of polyphosphoric acid and so on (non-patent document 5, patent document 4, patent document 5).

However, method (10) cannot satisfy the conditions of the industrial production process because it has the following disadvantages: (A) complex isolation methods, such as distillation or column chromatography with silica gel, are required, and so on, because the intermediates obtained are oily substances , (B) complex treatments are required during the cyclization reaction using the phosphate compound because complex by-products are formed, (C) complex methods are required, like distillation or chromatography on a silica gel column and so on, to separate 5-halogen-1-benzothiophene derivatives from the by-products formed, because their derivatives have low melting points, (D) a large amount of liquid waste is generated that contain phosphorus compounds, requiring complex processing processes, and so on.

As a method for producing 4-halogeniophenol used in the aforementioned method (10), there are known, for example, (11) a method for subjecting thioanisole to halogenation with chlorine or bromine, then exposing it to demethylation with a large excess of chlorine (patent document 6), (12) the interaction of (4-halogenophenylthio) acetic acid with sodium sulfide in the presence of sodium hydroxide (patent document 7), (13) a method for reacting monohalogenbenzene with sulfur monochloride in the presence of zinc chloride to obtain digalo geniphenylpolysulfide, then subjecting it to a reduction reaction with hydrochloric acid and zinc (patent document 8), (14) a method for reacting 1,4-dihalogenbenzene with sodium hydrosulfide in 1-methyl-2-pyrrolidone (patent document 9), and so on.

However, methods (11) - (14) cannot satisfy the conditions of the industrial production method because they have the following disadvantages: (A) low yield, (B) isomers are formed, (C) a high reaction temperature is required, (D) reagents are used that provide a large environmental burden, such as chlorine or sulfide, and so on.

Further, as a method for producing a benzothiophene derivative from a derivative of (phenylthio) acetic acid or its salts, for example, the following methods are known: (15) a method for subjecting it to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction, then subjecting it to a dehydration reaction and so on (patent document 10).

However, in this method, the structure of the obtained compound is limited.

[patent document 1]

International Publication No. 03/035647, Brochure

[patent document 2]

EP 0129478, Bulletin

[patent document 3]

International Publication No. 99/31056, Brochure

[patent document 4]

International Publication No. 02/100850 Brochure

[patent document 5]

International Publication No. 2005/012291, Brochure

[patent document 6]

JP No. H 08-143533, Bulletin

[patent document 7]

JP No. H 05-178816, Bulletin

[patent document 8]

JP No. H 05-140086, Bulletin

[patent document 9]

JP No. H 04-182463, Bulletin

[patent document 10]

International Publication No. 98 / 43,967 Brochure

[non-patent document 1]

Journal of Medicinal Chemistry (J. Med. Chem.), 1991, Vol. 34, p. 65-73

[non-patent document 2]

Journal of Medicinal Chemistry (J. Med. Chem.), 1997, Vol. 40, p. 1049-1062

[non-patent document 3]

Nippon Kagaku Zashi, 1967, Vol. 88, p. 445-447

[non-patent document 4]

Journal of Heterocyclic Chemistry (J. Heterocyclic Chem.), 1965, Vol. 2, p. 44-48

[non-patent document 5]

Journal of Medicinal Chemistry (J. Med. Chem.), 2003, Vol. 46, p. 246-2455

SUMMARY OF THE INVENTION

PROBLEM TO BE SOLVED BY THE PRESENT INVENTION

The objective of the present invention is to provide a new method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol and its salts, which ensures safety for the human body, low environmental stress and the possibility of mass production.

METHOD FOR SOLVING THE PROBLEM

In the course of intensive and consistent studies, we came to the conclusion that in the method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts from 2- (1-benzothiophene -5-yl) ethanol, the method for producing 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts is characterized in that it involves subjecting 2- (1-benzothiophen-5-yl) ethanol to an addition reaction according to Michael using acrylonitrile in the presence of a base, then exposing it to interaction with an alcohol represented by the general formula [1]:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,

in the presence of an acid to give an ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

then subjecting the ester derivative of propionic acid to a hydrolysis reaction in the presence of a base;

wherein said ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

is an important intermediate in the preparation of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts;

The method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol or its salts is characterized in that it involves the conversion of 3- (2- (1-benzothiophen-5-yl ) ethoxy) propionic acid or its salts into a reactive derivative, then reacting the reactive derivative with 3-azetidinol or its salts in the presence of a base, and then crystallizing crystals from the reaction mixture;

The method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts is characterized in that it involves the exposure of 1- (3- (2- (1-benzothiophen- 5-yl) ethoxy) propionyl) azetidin-3-ol reduction reactions with the addition of an activator in the presence of an alkali metal borohydride; and

The method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts is characterized in that it involves subjecting 2- (1-benzothiophen-5-yl) ethanol to a reaction Michael addition using acrylonitrile in the presence of a base, then exposing it to interaction with an alcohol represented by the general formula [1]:

where R ¹ has the meanings given above,

in the presence of an acid to give an ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

then subjecting the ester derivative of propionic acid to a hydrolysis reaction in the presence of a base to obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, then converting it into a reactive derivative, then reacting the reactive derivative with 3-azetidinol or its salts in the presence of a base to obtain 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol, then subjecting it to a reduction reaction with the addition of an activator in the presence of alkali borohydride of metal.

In addition, in the method for producing 2- (1-benzothiophen-5-yl) ethanol, which is the starting material, the method for producing the 5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ represents a halogen atom,

characterized in that it includes the implementation of the interaction of the derivative (phenylthio) acetic acid or its salts, represented by the general formula [3]:

where X ¹ has the meanings given above,

with a halogenating agent to obtain an acid halide represented by the general formula [4]:

where X ² represents a halogen atom, X ¹ has the meanings defined above,

then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction to obtain a dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

and subjecting the dihydrobenzothiophene derivative to a dehydration reaction in the presence of an acid catalyst;

wherein said dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

is an important intermediate in the method for producing the 5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ has the meanings defined above;

5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ has the meanings given above,

can be obtained by a simple method with high purity, crystallization and isolation of crystals of the indicated dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

then exposing the crystals to a dehydration reaction;

A method of obtaining a benzothiophene derivative or its salts represented by the general formula [9]:

where R ² and R ³ , identical or different, represent an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group,

characterized in that it includes the binding of a benzothiophene derivative represented by the general formula [7]:

where X ¹ has the meanings given above,

in the presence of a base and a palladium catalyst with a malonic acid derivative or its salts represented by the general formula [8]

where R ² and R ³ have the meanings given above;

A method of obtaining a derivative of benzothiophenacetic acid or its salts represented by the general formula [10]:

where R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group,

characterized in that it includes the implementation of the interaction of a benzothiophene derivative or its salts represented by the general formula [9]:

where R ² and R ³ have the meanings given above,

with acid or base, exposing the benzothiophene derivative or its salts to a decarboxylation reaction, if necessary;

benzothiophene derivative represented by the general formula [9]:

where R ² and R ³ have the meanings given above,

is an important intermediate in the method for producing a benzothiophenoacetic acid derivative or its salts represented by the general formula [10]:

where R ⁴ has the meanings defined above;

The method for producing 2- (1-benzothiophen-5-yl) ethanol is characterized in that it involves exposing the benzothiophenacetic acid derivative or its salts represented by the general formula [11]:

where R ⁴ has the meanings given above,

hydrolysis reaction, if necessary, then subjecting it to a reduction reaction with the addition of an activator in the presence of an alkali metal borohydride; and

The method of obtaining 2- (1-benzothiophen-5-yl) ethanol is characterized in that it involves the interaction of the derivative (phenylthio) acetic acid or its salts represented by the general formula [3]:

where X ¹ has the meanings given above,

with a halogenating agent to obtain an acid halide represented by the general formula [4]:

where X ¹ and X ² have the meanings given above,

then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction to obtain a dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

then exposing the dihydrobenzothiophene derivative to a dehydration reaction in the presence of an acid catalyst to obtain a 5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ has the meanings given above,

then the binding of the 5-halogen-1-benzothiophene derivative to the malonic acid derivative or its salts represented by the general formula [8]:

where R ² and R ³ have the meanings given above,

in the presence of a base and a palladium catalyst to obtain a benzothiophene derivative or its salts represented by the general formula [12]:

where R ² and R ³ have the meanings given above,

then the interaction of the benzothiophene derivative with an acid or base, its decarboxylation reaction, if necessary, to obtain a benzothiophenacetic acid derivative or its salts represented by the general formula [11]:

where R ⁴ has the meanings given above,

then subjecting the benzothiophenacetic acid derivative or its salts to a hydrolysis reaction, if necessary, then subjecting it to a reduction reaction with the addition of an activator in the presence of an alkali metal borohydride.

Further, the method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts is characterized in that it involves the interaction of the derivative (phenylthio) acetic acid or its salts, represented by the general formula [3]:

where X ¹ has the meanings given above,

with a halogenating agent to obtain an acid halide represented by the general formula [4]:

where X ¹ and X ² have the meanings given above,

then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction to obtain a dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

then exposing the dihydrobenzothiophene derivative to a dehydration reaction in the presence of an acid catalyst to obtain a 5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ has the meanings given above,

then the binding of the 5-halogen-1-benzothiophene derivative to the malonic acid derivative or its salts represented by the general formula [8]:

where R ² and R ³ have the meanings given above,

in the presence of a base and a palladium catalyst to obtain a benzothiophene derivative or its salts represented by the general formula [12]:

where R ² and R ³ have the meanings given above,

then the interaction of the benzothiophene derivative with an acid or base, its decarboxylation reaction, if necessary, to obtain a benzothiophenacetic acid derivative or its salts represented by the general formula [11]:

where R ⁴ have the meanings given above,

then subjecting the benzothiophenacetic acid derivative or its salts to a hydrolysis reaction, if necessary, then subjecting it to a reduction reaction with the addition of an activator in the presence of an alkali metal borohydride to obtain 2- (1-benzothiophen-5-yl) ethanol, then exposure to 2- (1- benzothiophen-5-yl) ethanol of the Michael addition reaction using acrylonitrile in the presence of a base, then exposing it to an alcohol represented by the general formula [1]:

where R ¹ has the meanings given above,

in the presence of an acid to give an ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

then subjecting the ester derivative of propionic acid to a hydrolysis reaction in the presence of a base to obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, then converting 3- (2- (1-benzothiophen-5-yl ) ethoxy) propionic acid or its salts into a reactive derivative, then reacting the obtained reactive derivative with 3-azetidinol or its salts in the presence of a base to obtain 1- (3- (2- (1-benzothiophen-5-yl) ) ethoxy) propionyl) azetidin-3-ol, and then exposure to 1- (3- (2- (1-benzoti) ofen-5-yl) ethoxy) propionyl) azetidin-3-ol reduction reactions with the addition of an activator in the presence of an alkali metal borohydride.

EFFECT OF THE INVENTION

The method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) -3-azetidinol or its salts of the present invention has the following characteristics: (1) high yield is achieved, (2) chromatography is not required on a silica gel column, (3) a small amount of waste, (4) reagents that are harmful and create stability problems, and so on, are not used, and this method is applicable in industrial production.

The method for producing 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts of the present invention has the following characteristics: (1) a small amount of by-products, (2) no flammable gases, (3) high output and so on, moreover, this method is applicable in industrial production.

The method for producing the benzothiophenoacetic acid derivative or its salts represented by the general formula [10] of the present invention has the following characteristics: (1) irritating intermediates are not used in the process, (2) highly toxic reagents (cyano compounds) are not used, (3) not complex types of waste treatment are required, (4) the number of process steps is small, (5) a high yield is ensured, (6) a high reaction temperature is not required, (7) reaction processes are simple and so on, and this method is applicable as an industry flax production method.

The method for producing 5-halo-1-benzothiophene derivatives represented by the general formula [6] of the present invention has the following characteristics: (1) a small amount of by-products, (2) purification can be carried out by a simple method, such as extraction and crystallization, ( 3) therefore, complex purification methods, such as distillation or chromatography on a column of silica gel, and so on, are not required, and this method is applicable in industrial production.

BEST MODE FOR CARRYING OUT THE INVENTION

Further, the present invention is described in more detail.

In this description, unless otherwise indicated, the term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom;

the term “alkyl group” means a straight or branched C _1-12 alkyl group, for example methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl or the like;

the term “cycloalkyl group” means a C _3-8 cycloalkyl group, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like;

the term “aralkyl group” means an apC _1-6 alkyl group, for example benzyl, diphenylmethyl, trityl, phenethyl, naphthylmethyl or the like;

the term “alkoxy group” means a straight or branched C _1-6 alkyloxy group, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy or the like;

the term “alkyloxycarbonyl group” means a straight or branched C _1-12 alkyloxycarbonyl group, for example methoxycarbonyl, ethoxycarbonyl, 1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, 2-ethylhexyloxycarbonyl, tert-butoxycarbonyl, tert-pentyloxycarbonyl or the like;

the term “cycloalkyloxycarbonyl group” means a C _3-8 cycloalkyloxycarbonyl group, for example a cyclopropoxycarbonyl, cyclobutoxycarbonyl, cyclopentyloxycarbonyl, cyclohexyloxycarbonyl or the like;

the term “aralkyloxycarbonyl group” means an apC _1-6 alkyloxycarbonyl group, for example benzyloxycarbonyl, phenethyloxycarbonyl or the like;

the terms “aryl group” mean a group, for example phenyl, naphthyl or the like;

the term “alkenyl group” means a C _2-12 alkenyl group, for example vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or the like, respectively.

The alkyl, cycloalkyl and aryl groups of R ¹ may be substituted by at least one group selected from a halogen atom, a hydroxyl group, a nitro group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group and an aryl group or the like.

The alkyloxycarbonyl, cycloalkyloxycarbonyl and aralkyloxycarbonyl groups of R ² and R ³ may be substituted with at least one group selected from a halogen atom, a hydroxyl group, a nitro group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group and an aryl group or the like.

The alkyl, cycloalkyl and aralkyl groups of R ⁴ may be substituted by at least one group selected from a halogen atom, a hydroxyl group, a nitro group, an alkyl group, a cycloalkyl group, an alkoxy group, an alkenyl group and an aryl group or the like.

In the present invention, the following preparation methods are preferred.

To obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, a production method comprising subjecting 2- (1-benzothiophen-5-yl) ethanol to the Michael addition reaction in the presence of a base using acrylonitrile , then its interaction with alcohol represented by the general formula [1]:

where R ¹ has the meanings given above,

in the presence of an acid to give an ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

and subjecting the ester derivative of propionic acid to a hydrolysis reaction in the presence of a base, a production method in which R ¹ represents a hydrogen atom or an alkyl group is preferred, a production method in which R ¹ represents a hydrogen atom, a methyl group, an ethyl group or a propyl group is more preferred, and a preparation method in which R ¹ represents a hydrogen atom or an ethyl group is even more preferred.

A production method in which the acid used is an inorganic acid is preferred, and a production method in which the acid used is sulfuric acid or hydrogen chloride is more preferred.

In the case where the acid is hydrogen chloride, a production method in which R ¹ represents a hydrogen atom is preferred.

In the case where the acid is sulfuric acid, a production method in which R ¹ represents an ethyl group is preferred.

To obtain 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts by a process comprising subjecting 1- (3- (2- (1-benzothiophen-5- il) ethoxy) propionyl) azetidin-3-ol reduction reaction with the addition of an activator in the presence of an alkali metal borohydride, a production method in which the alkali metal borohydride is sodium borohydride is preferred.

A production method in which the activator used is protic acid, such as sulfuric acid and hydrogen chloride, and so on, is preferred, and a production method in which the activator used is sulfuric acid, is more preferred.

In the case where the activator is sulfuric acid, a production method in which the volume of sulfuric acid used is 0.5-0.6 mol per mol of alkali metal borohydride, sulfuric acid is added at 0-30 ° C. from 10 minutes to 6 hours, and a subsequent reaction is carried out at 30-70 ° C, is preferred.

To obtain a dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

the production method, including the implementation of the interaction of the derivative (phenylthio) acetic acid or its salts represented by the general formula [3]:

where X ¹ has the meanings given above,

with a halogenating agent to obtain an acid halide represented by the general formula [4]:

where X ¹ and X ² have the meanings given above,

then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction, a production method in which X ¹ represents a chlorine atom, a bromine atom or an iodine atom, is preferred, a production method in which X ¹ represents a bromine atom or an iodine atom is more preferred, and a preparation method in which X ¹ is a bromine atom is even more preferred.

To obtain a 5-halogen-1-benzothiophene derivative represented by the general formula [6]:

where X ¹ has the meanings given above,

a production method comprising exposing a dihydrothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

dehydration reactions in the presence of an acid catalyst, a production method in which X ¹ is a chlorine atom, a bromine atom or an iodine atom is preferred, a production method in which X ¹ is a bromine atom or an iodine atom is more preferred, and a method for producing in which X ¹ represents a bromine atom, is even more preferred.

To isolate the dihydrobenzothiophene derivative represented by the general formula [5] by a crystallization method of crystals, it is preferable to isolate it by crystallization from an aliphatic hydrocarbon such as hexane and cyclohexane, and so on, by isolating it by crystallization from hexane and cyclohexane, it is more preferable, and isolate by crystallization its from cyclohexane is even more preferred.

To obtain a benzothiophene derivative or its salts represented by the general formula [9]:

where R ² and R ³ have the meanings given above,

A production method comprising exposing a benzothiophene derivative represented by the general formula [7]:

where X ¹ has the meanings given above,

binding reactions with a malonic acid derivative or its salts represented by the general formula [8a] in the presence of a palladium catalyst and a base:

where R ^3a represents an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group; R ² has the meanings given above,

is preferred, a production method in which R ² represents an alkyloxycarbonyl group, an aralkyloxycarbonyl group or a cyano group; R ^3a represents an alkyloxycarbonyl group or an aralkyloxycarbonyl group, is more preferable, a production method in which R ² represents a C _1-4 alkyloxycarbonyl group, an apC _1-4 alkyloxycarbonyl group or a cyano group, R ^3a represents a C _1-4 alkyloxycarbonyl group or apC _1-4 alkyloxycarbonyl group is even more preferred.

A production method in which X ¹ is a chlorine atom, a bromine atom or an iodine atom is preferred, and a production method in which X ¹ is a bromine atom or an iodine atom is more preferred.

A production method in which X ^{1 is} attached at the 4- or 5-position of the benzothiophene ring is preferred, and a production method in which X ^{1 is} attached at the 5- position of the benzothiophene ring is more preferred.

To obtain a benzothiophenoacetic acid derivative or its salts represented by the general formula [10]:

where R ⁴ has the meanings given above,

The production method, including the interaction of a benzothiophene derivative or its salts represented by the general formula [9a]:

where R ² and R ^3a have the meanings defined above,

with an acid or a base, subjecting it to a decarboxylation reaction, if necessary, is preferred, a preparation method in which R ² represents an alkyloxycarbonyl group, an aralkyloxycarbonyl group or cyano group, R ^3a represents an alkyloxycarbonyl group or an aralkyloxycarbonyl group, is more preferred, and the method a preparation in which R ² represents a C _1-4 alkyloxycarbonyl group, an apC _1-4 alkyloxycarbonyl group or a cyano group, R ^3a represents C _1-4 alkyl a xicarbonyl group or apC _1-4 alkyloxycarbonyl group is even more preferred.

A production method in which a group represented by the general formula:

where R ² and R ^3a are as defined above, attached at the 4- or 5-position of the benzothiophene ring, is preferred, and a preparation method in which said group is attached at the 5-position of the benzothiophene ring is more preferred.

A production method in which a group represented by the general formula:

wherein R ⁴ is as defined above, attached at the 4- or 5-position of the benzothiophene ring, is preferred, and a preparation method in which said group is attached at the 5-position of the benzothiophene ring is more preferred.

A production method in which R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group is preferred, a production method in which R ⁴ represents a hydrogen atom, an alkyl group or an aralkyl group is preferred, and a production method, in which R ⁴ represents a hydrogen atom, a C _1-4 alkyl group or an apC _1-4 alkyl group, is more preferred.

As preferred compounds for said ester derivative of propionic acid represented by the general formula [2]:

where R ¹ has the meanings given above,

The following compounds are used.

A compound in which R ¹ is a hydrogen atom or an alkyl group is preferred, a compound in which R ¹ is a hydrogen atom, a methyl group, an ethyl group or a propyl group is more preferred, and a compound in which R ¹ is a hydrogen atom or an ethyl group is even more preferred.

As preferred compounds for said dihydrobenzothiophene derivative represented by the general formula [5]:

where X ¹ has the meanings given above,

The following compounds are used.

A compound in which X ¹ is a chlorine atom, a bromine atom or an iodine atom is preferred, a compound in which X ¹ is a bromine atom or an iodine atom is more preferred, and a compound in which X ¹ is a bromine atom, is even more preferred.

As preferred compounds for said benzothiophene derivative or salts thereof represented by the general formula [9]:

where R ² and R ³ have the meanings given above,

The following compounds are used.

A compound in which R ² is an alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group is preferred, a compound in which R ² is an alkyloxycarbonyl group, an aralkyloxycarbonyl group or cyano group is more preferred, and a compound in which R ² is C _{A 1-4} alkyloxycarbonyl group, an apC _1-4 alkyloxycarbonyl group or cyano group, is even more preferred.

A compound in which R ³ is an alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group is preferred, a compound in which R ³ is an alkyloxycarbonyl group or an aralkyloxycarbonyl group is more preferred, and a compound in which R ³ is C _1-4 alkyloxycarbonyl a group or apC _1-4 alkyloxycarbonyl group is even more preferred.

A compound in which a group represented by the general formula:

where R ² and R ³ have the meanings given above,

attached at the 4- or 5-position of the benzothiophene ring is preferred, and a compound in which said group is attached at the 5-position of the benzothiophene ring is more preferred.

As typical compounds of the general formula [9] or their salts of the present invention, for example, the following compounds are indicated.

In the table, Et represents an ethyl group, ^t Bu represents a tert-butyl group.

TABLE 1

The following explains the methods of obtaining the present invention.

[Production Method 1]

where X ¹ and X ² have the meanings defined above.

A compound of the general formula [5] can be obtained by converting a compound of the general formula [3] or its salts into an acid halide, then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid, then subjecting it to a reduction reaction.

A compound of the general formula [5] can be easily converted to a compound of the general formula [6] by subjecting it to a dehydration reaction in the presence of an acid catalyst.

A compound of the general formula [3] or its salt, for example, can be easily obtained in good yield by reacting thiophenol with chloroacetic acid in the presence of a base to produce (phenylthio) acetic acid, then subjecting the (phenylthio) acetic acid to a halogenation reaction or reacting 4-halogeniophenol with chloroacetic acid in the presence of a base.

In addition, the salt of the compound of the general formula [3] is not particularly limited, but alkali metal salts such as sodium, potassium, cesium and the like are offered, for example;

alkaline earth metal salts such as calcium, magnesium and the like;

ammonium salts;

and salts with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

This method of obtaining is explained below in more detail.

Intramolecular cyclization reaction:

A compound of the general formula [13] can be obtained by reacting a compound of the general formula [3] or its salts with a halogenating agent to obtain an acid halide, then subjecting the obtained acid halide to an intramolecular cyclization reaction in the presence of a Lewis acid.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like are proposed;

nitro compounds such as nitromethane, nitrobenzene and the like;

and carbon disulfide and the like, wherein said solvents can be used in a mixture.

Aliphatic halogenated hydrocarbons are proposed as preferred solvents, with dichloromethane being more preferred.

The amount of solvent used is not particularly limited, but preferably it is 1-50 times the volume by weight (vol./mass.) Of the compound of the general formula [3] or its salts, and more preferably it is 3-15 times the indicated volume (vol ./mass.).

As the halogenating agent used in this reaction, for example, phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, thionyl chloride, thionyl bromide and oxalyl chloride are proposed, and thionyl chloride is preferred.

The amount of halogenating agent used varies depending on the type of halogenating agent, but, for example, in the case of thionyl chloride, it can be equal to or greater than 0.5 mol per mol of the compound of the general formula [3] or its salts, and is preferably 1-2 mol.

As the Lewis acid used in this reaction, there are, for example, aluminum chloride, aluminum bromide, boron trifluoride, titanium tetrachloride, iron chloride, tin chloride, mercury chloride, sulfuric acid and the like, and aluminum chloride is preferred.

The amount of Lewis acid used may be equal to or greater than 1 mol per mol of the compound of general formula [3] or its salts, and is preferably 1-5 mol.

The reaction temperature is not particularly limited, but it is in the range from

-20 ° C to a temperature equal to or higher than the boiling point of the solvent, and preferably is 0-70 ° C.

The reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 30 minutes to 20 hours.

The compound of the general formula [13] obtained in the manner described above can be isolated and purified, but it is preferable to proceed to the next reaction without isolation.

Recovery Reaction:

A compound of general formula [5] can be prepared by subjecting a compound of general formula [13] to a reduction reaction. This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like are proposed;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like;

nitriles such as acetonitrile and the like;

esters such as methyl acetate, ethyl acetate and the like;

nitro compounds such as nitromethane, nitrobenzene and the like;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

and water and the like, wherein said solvents can be used in a mixture.

Preferred solvents are mixed solvents of aliphatic halogenated hydrocarbons and alcohols, and a mixed solvent of dichloromethane and methanol is more preferred.

The amount of solvent used is not particularly limited, but preferably it is 1-50 times the volume by weight of the compound of the general formula [13], and more preferably it is 3-15 times the volume indicated (vol./mass.).

As the reducing agent used in this reaction, for example, an alkali metal such as lithium, sodium, potassium and the like;

alkaline earth metal such as magnesium, calcium and the like;

a metal such as zinc, aluminum, chromium, titanium, iron, samarium, selenium, sodium hydrosulfite and the like, and salts of these metals;

a metal hydride such as diisobutylaluminium hydride, trialkylaluminum hydride, a stannyl hydride compound, hydrosilane and the like;

a complex compound of a borohydride such as sodium borohydride, lithium borohydride, potassium borohydride and the like;

aluminum hydride complex compound such as lithium aluminum hydride and the like;

and borane and alkyl borane, and the like.

A complex compound of a borohydride is provided as a preferred reducing agent, and sodium borohydride is more preferred.

The amount of reducing agent used varies depending on the type of reducing agent, but, for example, in the case of a complex compound of borohydride, it may be equal to or greater than 0.25 mol per mol of the compound of the general formula [13], and more preferably it is 0.25-2 mol.

The reaction temperature is not particularly limited, but it is in the range from

-20 ° C to a temperature equal to or higher than the boiling point of the solvent, and preferably is 0-70 ° C.

The reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 30 minutes to 20 hours.

The compound of the general formula [5], obtained as described above, can be used as it is in the next reaction without isolation, but it is preferable to isolate it by crystallization of a crystal.

A crystallization method from aliphatic hydrocarbons such as hexane, cyclohexane and the like is preferred, a crystallization method from hexane or cyclohexane is more preferred, and a crystallization method from cyclohexane is even more preferred.

Dehydration Reaction:

A compound of general formula [6] can be prepared by subjecting a compound of general formula [5] to a dehydration reaction in the presence of an acid catalyst.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

esters such as methyl acetate, ethyl acetate and the like;

ketones such as acetone, 2-butanone and the like;

alcohols such as methanol, ethanol, propanol, 2-propanol, butanol and the like;

nitriles such as acetonitrile and the like;

aliphatic carboxylic acids such as acetic acid, propionic acid and the like;

and water and the like; moreover, these solvents can be used in a mixture.

Ketones are provided as preferred solvents, and acetone is more preferred.

The amount of solvent used is not particularly limited, but preferably it is 1-50 times the volume by weight of the compound of the general formula [5], and more preferably it is 1-10 times the volume indicated (vol./mass.).

As the acid catalyst used in this reaction, there are, for example, Bronsted acids such as hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, dichloroacetic acid and the like;

and Lewis acid, such as aluminum chloride, boron trifluoride, boron trichloride and the like, and p-toluenesulfonic acid is preferred.

The amount of acid catalyst used may be equal to or greater than 0.0001 mol per mol of compound of general formula [5], and is preferably 0.001-1 mol.

The reaction temperature is not particularly limited, but it is in the range from

-20 ° C to a temperature equal to or higher than the boiling point of the solvent, and preferably is 0-70 ° C.

The reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 30 minutes to 20 hours.

[Production Method 2]

where R ² , R ³ and X ¹ have the meanings defined above.

A compound of the general formula [8] or a salt thereof, for example diethyl malonate, di (tert-butyl) malonate, ethyl cyanoacetate, tert-butyl cyanoacetate, malononitrile and the like, are commercially available.

A compound of general formula [9] or a salt thereof can be prepared by subjecting a compound of general formula [7] to a coupling reaction with a compound of general formula [8] or its salts in the presence of a base and a palladium catalyst, in the presence or absence of a ligand, in the presence or absence of reducing agent.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but aliphatic hydrocarbons such as hexane, cyclohexane and the like are proposed, for example;

halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

esters such as ethyl acetate, butyl acetate and the like;

ketones such as acetone, 2-butanone and the like;

alcohols such as methanol, ethanol, propanol, butanol, 2-propanol, 2-methyl-2-propanol and the like;

and nitriles, such as acetonitrile and the like, and these solvents can be used in a mixture.

The amount of solvent used is not particularly limited, but preferably it is 1-20 times the mass of the compound of general formula [7], and more preferably it is 1-10 times the indicated volume (v / w).

As the base used in this reaction, for example, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide and the like;

an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, barium carbonate, sodium phosphate, potassium phosphate, sodium hydride and potassium hydride and the like;

an organic base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like.

The amount of base used may be equal to or greater than 1 mol per mol of compound of general formula [7], preferably 2-10 mol, and more preferably 2-4 mol.

As the palladium catalyst used in this reaction, for example, metallic palladium such as palladium on carbon, palladium black and the like;

an inorganic salt of palladium, such as palladium chloride;

an organic palladium salt such as palladium acetate;

organopalladium complex such as tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) chloride, 1,1'-bis (diphenylphosphino) ferrocene palladium (II) chloride, tris (dibenzylideneacetone) dipalladium (0) and the like ;

and an organopalladium complex on a polymer, such as bis (acetate) triphenylphosphine palladium (II) supported on a polymer, di (acetate) dicyclohexylphosphine palladium (II) supported on a polymer, and the like.

The amount of palladium catalyst used is not particularly limited, but preferably it is 0.0001-1 mol per mol of the compound of the general formula [7], and more preferably it is 0.005-0.1 mol.

As the ligand used, if required, in this reaction, for example, trialkylphosphines such as trimethylphosphine, tri (tert-butyl) phosphine and the like;

tricycloalkylphosphines such as tricyclohexylphosphine and the like;

triarylphosphines such as triphenylphosphine, tritolylphosphine and the like;

trialkyl phosphites such as trimethyl phosphite, triethyl phosphite, tributyl phosphite and the like;

tricycloalkylphosphites such as tricyclohexylphosphite and the like;

triarylphosphites such as triphenylphosphite and the like;

an imidazolium salt such as 1,3-bis (2,4,6-trimethylphenyl) imidazolium chloride and the like;

diketones such as acetylacetone, octafluoroacetylacetone and the like;

amines such as trimethylamine, triethylamine, tripropylamine, triisopropylamine and the like;

1,1'-bis (diphenylphosphino) ferrocene

and 2,2-bis (diphenylphosphino) -1,1'-binaphthyl and the like.

The amount of ligand used is not particularly limited, but preferably it is 0.0001-2 mol per mol of the compound of the general formula [7], and more preferably it is 0.005-0.2 mol.

As a reducing agent used, if required, in this reaction, there are provided, for example, a complex compound of a borohydride such as lithium borohydride, sodium borohydride, calcium borohydride, triacetoxy sodium borohydride, sodium cyanoborohydride and the like.

The amount of reducing agent used is not particularly limited, but preferably it is 0.0001-1 mol per mol of the compound of the general formula [7], and more preferably it is 0.01-0.1 mol.

The amount of the compound of the general formula [8] is 1-5 mol per mol of the compound of the general formula [7], and more preferably it is 1-2 mol.

This reaction can be carried out at 0-200 ° C, and preferably at 50-150 ° C from 1 minute to 24 hours.

The compound of the general formula [9] or its salt, obtained as described above, can be used as it is in the next reaction without isolation.

[Production Method 3]

where R ² , R ³ and R ⁴ have the meanings defined above.

A compound of the general formula [10] or its salt can be prepared by reacting a compound of the general formula [9] or its salts with an acid or base in the presence or absence of water, in the presence or absence of alcohol, subjecting it to decarboxylation, if necessary.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

esters such as ethyl acetate, butyl acetate and the like;

ketones such as acetone, 2-butanone and the like;

alcohols such as methanol, ethanol, propanol, butanol, 2-propanol, 2-methyl-2-propanol and the like;

glycols such as ethylene glycol, propylene glycol, diethylene glycol and the like;

nitriles such as acetonitrile and the like,

and water and the like, wherein said solvents can be used in a mixture.

The amount of solvent used is not particularly limited, but preferably it is equal to 1-50 times by weight of the compound of the general formula [9] or its salt, and more preferably it is equal to 1-15 times the indicated volume (v / w).

As the acid used in this reaction, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide and the like;

organic carboxylic acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid and the like,

and organic sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid and the like.

The amount of acid used may be equal to or greater than 0.001 mol per mol of the compound of the general formula [9] or its salts, and is preferably 0.01-5 mol.

In addition, the acid can be used as a solvent.

In addition, as the base used in this reaction, there are provided, for example, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide and sodium tert-butoxide and the like;

an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate and the like,

and an organic base such as triethylamine, N, N-diisopropylethylamine, pyridine and the like.

The amount of base used is 2-10 mol per mol of the compound of the general formula [9] or its salts, and is preferably 2-5 mol.

The amount of water used, if required, in this reaction is not particularly limited, but preferably it is equal to 0.5-5 times the volume by weight of the compound of the general formula [9] or its salts in order to ensure that the water functions as a solvent.

As the alcohol used, if required, in this reaction, for example, primary alcohols such as methanol, ethanol, propanol, butanol and the like,

and glycols such as ethylene glycol, propylene glycol, diethylene glycol and the like.

The amount of alcohol used is not particularly limited, but preferably it is 0.5-5 times the volume by weight of the compound of the general formula [9] or its salts in order to ensure that the alcohol functions as a solvent.

This reaction can be carried out at 0-200 ° C, and preferably at 20-150 ° C in the time interval from 1 minute to 24 hours.

The decarboxylation reaction, which can be carried out, if necessary, is carried out by heating.

As the acid used, if required, in this reaction, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride, hydrogen bromide and the like;

organic carboxylic acid such as acetic acid, trichloroacetic acid, trifluoroacetic acid and the like,

and organic sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid and the like.

The amount of acid used may be equal to or greater than 0.001 mol per mol of the compound of the general formula [9] or its salts, and is preferably 0.01-5 mol.

In addition, the acid can be used as a solvent.

This reaction can be carried out, if necessary, in a coexisting solvent.

Moreover, the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

a halogenated hydrocarbon such as dichloromethane, chloroform, dichloroethane and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

esters such as ethyl acetate, butyl acetate and the like;

ketones such as acetone, 2-butanone and the like;

alcohols such as methanol, ethanol, propanol, butanol, 2-propanol, 2-methyl-2-propanol and the like;

glycols such as ethylene glycol, propylene glycol, diethylene glycol and the like;

nitriles such as acetonitrile and the like,

and water and the like, wherein said solvents can be used in a mixture.

This reaction can be carried out at 50-200 ° C, and preferably at 50-150 ° C from 1 minute to 24 hours.

[Production Method 4]

where R ⁴ has the meanings defined above.

2- (1-Benzothiophen-5-yl) ethanol of the compound of formula [15] can be obtained by subjecting the compound of general formula [11] or its salts to a hydrolysis reaction, if necessary, and converting it to (1-benzothiophen-5-yl) acetic acid or its salts of a compound of the formula [14], then by subjecting (1-benzothiophen-5-yl) acetic acid or its salts to a reduction reaction with the addition of an activator in the presence of an alkali metal borohydride.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether are proposed , dioxane and the like, and tetrahydrofuran is preferred.

In addition, these solvents may be mixed with a solvent of halogenated hydrocarbons, such as dichloromethane, chloroform and the like,

and aromatic hydrocarbons such as benzene, toluene, xylene and the like can be used,

and aliphatic hydrocarbons such as hexane, cyclohexane, octane and the like, and mixed solvents.

The amount of solvent used is not particularly limited, but it is preferably equal to 1-20 times by weight of the compound of formula [14] or its salts, and preferably equal to 2-10 times the indicated volume (vol./mass.).

As the alkali metal borohydride used in this reaction, for example, sodium borohydride, lithium borohydride, potassium borohydride and the like are proposed, and sodium borohydride is preferred.

The amount of alkali metal borohydride used may be equal to or greater than 1 mol per mol of the compound of formula [14] or its salts, preferably 1-10 mol, and more preferably 1-2 mol.

As the activator used in this reaction, for example, protic acid, such as sulfuric acid, hydrogen chloride, trifluoroacetic acid and the like, and sulfuric acid and hydrogen chloride are preferred.

The amount of activator used varies depending on the type of activator, but, for example, in the case of sulfuric acid, it is preferably 0.5-1 mol per mol of alkali metal borohydride, and more preferably it is 0.5-0.6 mol.

In addition, the time of addition of the activator varies depending on the type of activator, but in the case of sulfuric acid, it is preferably in the range of 10 minutes to 6 hours, and more preferably it is in the range of 30 minutes to 2 hours.

In addition, the activator may be dissolved in a suitable solvent and may be added in dissolved form.

The reaction temperature is not particularly limited, but it can be in the range of -20 to 150 ° C, and preferably is 0-80 ° C.

In addition, a process with the addition of an activator at 0-30 ° C and subsequent reaction at 40-80 ° C is more preferable because the formation of by-products can be suppressed.

In addition, the reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and is preferably 1-20 hours.

In addition, the hydrolysis reaction of the compound of general formula [11] or its salts, which can be carried out if necessary, can be carried out by itself, for example, the compound of formula [14] or its salts can be obtained by subjecting them to a hydrolysis reaction in the presence of grounds.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

halogenated hydrocarbons such as dichloromethane, chloroform and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

sulfoxides such as dimethyl sulfoxide and the like;

alcohols such as methanol, ethanol, propanol, butanol, 2-propanol, tert-butanol and the like,

and water and the like, and these solvents can be used in a mixture.

Preferred solvents are a mixed solvent of aromatic hydrocarbons such as benzene, toluene and xylene, and alcohols, and a mixed solvent of alcohols and water, a mixed solvent of toluene and methanol and a mixed solvent of methanol and water are preferred.

The amount of solvent used is not particularly limited, but preferably it is 0.5-10 times the volume by weight of the compound of the general formula [11] or its salts, and more preferably it is 0.5-5 times the volume indicated (vol./mass .).

As the base used in this reaction, for example, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and the like, are provided,

and an inorganic base such as sodium hydroxide, potassium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate and the like.

An inorganic base is provided as a preferred base, and sodium hydroxide and potassium hydroxide are preferred.

The amount of the base used may be equal to or greater than 1 mol per mol of the compound of the general formula [11] or its salts, and is preferably 1-3 mol.

This reaction is preferably carried out by adding water.

The amount of added water may be equal to or greater than 1 mol per mol of the compound of the general formula [11] or its salts, preferably equal to 0.1-10 times the indicated volume (vol./mass.), And more preferably it is 0.3- 2 times the indicated volume (vol./mass.) To ensure that the water functions as a solvent.

The reaction temperature is not particularly limited, but it can be in the range from 0 ° C to a temperature equal to or higher than the boiling point of the solvent, and is preferably 10-40 ° C.

The reaction time is not particularly limited, but it can range from 10 minutes to 50 hours, and is preferably 1-24 hours.

The compound of the formula [14] or its salts, obtained as described above, can be isolated from the reaction mixture after completion of the reaction in the usual manner.

For example, after the completion of the reaction, they can be isolated by acidification with dilute hydrochloric acid, extraction with an organic solvent such as toluene, followed by removal of the solvent.

In addition, they can be isolated as salts by adding a base to the extract.

As for the salt of the compounds of formula [14], the salt is not particularly limited, but salts, for example, are provided with an alkali metal such as sodium, potassium, cesium and the like;

salts with an alkaline earth metal such as calcium, magnesium and the like;

ammonium salts

and salts with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

An alkali metal salt such as sodium and potassium is provided as a preferred salt, and a sodium salt is preferred.

[Production Method 5]

where R ¹ has the meanings defined above.

3- (2- (1-Benzothiophen-5-yl) ethoxy) propionic acid of a compound of formula [17] or its salts can be prepared by subjecting a compound of formula [15] to a Michael addition reaction using acrylonitrile in the presence of a base to give a compound of formula [ 16], then by subjecting a compound of formula [16] to an alcohol with a general formula [1] in the presence of an acid, then converting it to a compound of a general formula [2] and subjecting a compound of a general formula [2] to a hydrolysis reaction in the presence of a base.

This method of obtaining is explained below in more detail.

Michael addition reaction:

A compound of formula [16] can be prepared by subjecting a compound of formula [15] to a Michael addition reaction using acrylonitrile in the presence of a base.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

halogenated hydrocarbons such as dichloromethane, chloroform and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

sulfoxides such as dimethyl sulfoxide and the like;

and tertiary alcohols, such as tert-butanol, tert-amyl alcohol and the like, and these solvents can be used in a mixture.

Preferred solvents are a single solvent of aromatic hydrocarbons and a mixed solvent of aromatic hydrocarbons, ethers and tertiary alcohols, wherein a single solvent of aromatic hydrocarbons, a mixed solvent of aromatic hydrocarbons and ethers and a mixed solvent of aromatic hydrocarbons and tertiary alcohols are preferred, and toluene, a mixed solvent of toluene and tetrahydrofuran, a mixed solvent of Uola and tert-butanol, and a mixed solvent of toluene and tert-amyl alcohol are more preferred.

The amount of solvent used is not particularly limited, but preferably it is equal to 0.5-10 times the volume by weight of the compound of the formula [15], and more preferably it is equal to 0.5-3 times the specified volume (vol./mass.).

In addition, primary alcohols such as a small amount of methanol and ethanol and the like can be admixed as additives to these solvents;

secondary alcohols such as 2-propanol and the like;

and water and the like.

The amount of additive used is equal to or less than 0.5 times the volume by weight of the compound of the formula [15], and more preferably it is equal to or less than 0.1 times the indicated volume (v / w).

As the base used in this reaction, for example, an organic base such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), tetramethylammonium hydroxide, benzyltrimethylammonium hydroxide and the like;

a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and the like;

an inorganic base such as sodium hydroxide, potassium hydroxide, sodium hydride and the like.

An organic base and a metal alkoxide are provided as a preferred base, and benzyltrimethylammonium hydroxide and potassium tert-butoxide are more preferred.

The amount of base used may be equal to or greater than 0.0001 mol per mol of the compound of formula [15], and more preferably it is 0.01-0.1 mol.

In addition, this reaction can be carried out in the presence of a catalyst.

As a catalyst, if required, a commonly known quaternary ammonium salt is proposed, preferably tetrabutylammonium bromide, benzyltrimethylammonium chloride and benzyltrimethylammonium bromide.

The amount of catalyst used may be equal to or greater than 0.0001 mol per mol of compound of the formula [15], and more preferably it is 0.01-0.1 mol.

In the case of using a base, for example, an inorganic base such as sodium hydroxide and potassium hydroxide and the like, it is preferable to carry out this reaction in the presence of a catalyst.

The amount of acrylonitrile used in this reaction may be equal to or greater than 1 mol per mol of compound of the formula [15], and more preferably it is 1-2 mol.

The reaction temperature is not particularly limited, but it can range from 0 ° C to a temperature equal to or higher than the boiling point of the solvent, and is preferably 0-35 ° C.

The reaction time is not particularly limited, but it can range from 1 minute to 24 hours and is preferably from 30 minutes to 4 hours.

The compound of formula [16], obtained as described above, can be used as it is in the next reaction without isolation.

The esterification reaction:

A compound of general formula [2] can be prepared by subjecting a compound of formula [16] to an alcohol with general formula [1] in the presence of an acid.

As the acid used in this reaction, for example, an inorganic acid such as hydrochloric acid, sulfuric acid, hydrogen chloride, hydrogen bromide and the like,

and organic sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid and the like.

An inorganic acid is provided as a preferred acid, and sulfuric acid and hydrogen chloride are more preferred.

The amount of acid used varies depending on the amount of solvent used, but may be equal to or greater than 1 mol per mol of the compound of formula [16] and preferably it is 2-10 mol.

As the alcohol of the general formula [1] used in this reaction, straight chain alkyl alcohols such as methanol, ethanol, propanol, butanol, pentanol and the like;

branched chain alkyl alcohols such as isobutanol and the like;

substituted alkyl alcohols such as methoxyethanol, chloroethanol, cyclohexane ethanol and the like;

and aralkyl alcohols such as benzyl alcohol, phenethyl alcohol and the like.

As a preferred alcohol, straight chain alkyl alcohols are provided, and methanol, ethanol, propanol and butanol are more preferred.

The amount of alcohol used may be equal to or greater than 1 mol per mol of the compound of the formula [16], preferably equal to 0.5-10 times the indicated volume (vol./mass.), And more preferably it is equal to 0.5-5 times the specified volume (vol./mass.) to ensure that the alcohol performs the function of a solvent.

In this reaction, in the case of using an inorganic acid such as sulfuric acid and hydrogen chloride and the like, and an organic sulfonic acid such as methanesulfonic acid and the like, it is preferable to carry out the reaction by adding water.

The amount of added water may be equal to or greater than 1 mol per mol of the compound of the formula [16], preferably equal to 1-10 mol, and more preferably it is 1-6 mol.

This reaction can be carried out in the presence of a solvent.

The solvent used is, although not particularly limited, the same solvent as for the Michael addition reaction.

The reaction temperature is not particularly limited, but it can range from 0 ° C. to a temperature equal to or higher than the boiling point of the solvent, and is preferably 20-150 ° C.

The reaction time is not particularly limited, but it can range from 10 minutes to 50 hours, and is preferably from 1-24 hours.

The compound of the general formula [2], obtained as described above, can be used as it is in the next reaction without isolation.

Hydrolysis reaction:

A compound of general formula [17] or a salt thereof can be prepared by hydrolysis of a compound of formula [2] in the presence of a base.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

halogenated hydrocarbons such as dichloromethane, chloroform and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane and the like;

sulfoxides such as dimethyl sulfoxide and the like;

alcohols such as methanol, ethanol, propanol, butanol, 2-propanol, tert-butanol and the like;

and water and the like, wherein said solvents can be used in a mixture.

Preferred solvents are a mixed solvent of a solvent used in the esterification reaction and alcohols, and a mixed solvent of alcohols and water, and a mixed solvent of toluene and methanol and a mixed solvent of methanol and water are more preferred.

The amount of solvent used is not particularly limited, but preferably it is 0.5 to 10-fold by weight of the compound of the general formula [2], and more preferably it is 0.5 to 3-fold of the indicated volume (v / w).

As the base used in this reaction, for example, a metal alkoxide such as sodium methoxide, sodium ethoxide, potassium tert-butoxide, sodium tert-butoxide and the like, and an inorganic base such as sodium hydroxide, potassium hydroxide, hydroxide are provided. barium, sodium carbonate, potassium carbonate and the like.

An inorganic base is provided as a preferred base, and sodium hydroxide and potassium hydroxide are preferred.

The amount of base used may be equal to or greater than 1 mol per mol of compound of general formula [2], and more preferably it is 1-3 mol.

This reaction is preferably carried out with the addition of water.

The amount of added water may be equal to or greater than 1 mol per mol of the compound of the general formula [2], preferably equal to 0.1-10 times the indicated volume (vol./mass.), And more preferably it is equal to 0.3-2 times the specified volume (vol./mass.) to ensure that the water functions as a solvent.

The reaction temperature is not particularly limited, but it can range from 0 ° C to a temperature equal to or higher than the boiling point of the solvent, and is preferably 10-40 ° C.

The reaction time is not particularly limited, but it can range from 10 minutes to 50 hours and is preferably 1-24 hours.

The compound of the formula [17] or its salts, obtained as described above, can be isolated from the reaction mixture after completion of the reaction in the usual manner.

For example, after completion of the reaction, they can be isolated by acidification with dilute hydrochloric acid, followed by extraction with an organic solvent, such as toluene, and removal of the solvent.

In addition, they can be isolated as salts by adding a base to the extract.

As for the salt of the compound of the formula [17], the salt is not particularly limited, but salts, for example, are provided with an alkali metal such as sodium, potassium, cesium and the like;

salts with an alkaline earth metal such as calcium, magnesium and the like;

ammonium salt

and salts with a nitrogen-containing organic base such as trimethylamine, triethylamine, tributylamine, N, N-diisopropylethylamine, pyridine, N-methylpiperidine, N-methylmorpholine, diethylamine, dicyclohexylamine and the like.

An alkali metal salt such as sodium and potassium and the like is provided as a preferred salt, and a sodium salt is more preferred.

[Ways to get 6]

1- (3- (2- (1-Benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol compound of the formula [18] can be obtained by converting the compound of the formula [17] or its salts into a reactive derivative, then subjecting the reactive derivative to amidation by reaction with 3-azetidinol or its salts in the presence of a base.

This method of obtaining is explained below in more detail.

Conversion to reactive derivative:

The compound of the formula [17] or its salts can be converted into a reactive derivative by reacting it with an activator.

As the reactive derivative, for example, an acid halide, an anhydride, an activated amide and an activated ester and the like, and an acid halide are preferred.

As a method for converting a compound into a reactive derivative, there are provided, for example, conversion to an acid halide using a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride and the like;

conversion to anhydride by condensation with an acid halide such as ethyl chloroformate, isobutyl chloroformate, pivaloyl chloride and the like;

conversion to activated amide using condensation with imidazole and an activated amidation agent such as carbonyldiimidazole and the like,

and conversion to the activated ester by condensation with p-nitrophenol, 2-mercaptobenzothiazole and the like.

As a method of conversion to a reactive derivative, conversion to an acid halide using a halogenating agent is preferred, and conversion to an acid chloride using thionyl chloride is more preferred.

The amount of activator used in this conversion is different depending on the type of activator, but, for example, in the case of thionyl chloride, it may be equal to or greater than 0.5 mol per mol of the compound of the formula [17] or its salts, and is preferably 1-2 mol .

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like are offered;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

halogenated hydrocarbons such as dichloromethane, chloroform and the like;

ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like;

amides such as N, N-dimethylformamide, N, N-dimethylacetamide, 1-methyl-2-pyrrolidone and the like;

sulfoxides such as dimethyl sulfoxide and the like;

esters such as methyl acetate, ethyl acetate and the like;

ketones such as acetone, 2-butanone and the like,

and nitriles, such as acetonitrile and the like, and these solvents can be used in a mixture.

Aromatic hydrocarbons such as benzene, toluene and xylene and the like, and ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether, dioxane and the like, and toluene and 1 are preferred solvents; , 2-dimethoxyethane are preferred.

The amount of solvent used is not particularly limited, but preferably it is 1-20 times the mass of the compound of the formula [17] or its salts, and more preferably it is 1-10 times the indicated volume (v / w).

The reaction temperature is not particularly limited, but preferably it is −60 to 150 ° C., and more preferably it is −30 to 120 ° C.

The reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 30 minutes to 20 hours.

The reactive derivative of a compound of formula [17] or its salts, obtained as described above, can be isolated and purified, but it is preferable to proceed to the next reaction without isolation.

Amidation Reaction:

A compound of formula [18] can be obtained by reacting a solution of a reactive derivative of a compound of formula [17] or its salts described above with 3-azetidinol or its salts in the presence of a base.

As the base used in this reaction, for example, an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine and the like;

and an inorganic base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like.

An inorganic base is provided as a preferred base, with sodium hydroxide being more preferred.

The amount of base used may be equal to or greater than 1 mol per mol of the compound of formula [17] or its salts, and is preferably 1-10 mol.

The amount of 3-azetidinol or its salts may be equal to or greater than 1 mol per mol of the compound of the formula [17] or its salts, and is preferably 1-2 mol.

In addition, it is preferable to use 3-azetidinol or its salts in an aqueous solution.

The amount of water containing dissolved 3-azetidinol or its salts is not particularly limited, but preferably it is equal to 1-20 times the mass of the compound of the formula [17] or its salts, and preferably equal to 1-10 times the indicated volume (vol. / mass.).

The reaction temperature is not particularly limited, but preferably it is from -60 to 100 ° C, and more preferably it is from -30 to 50 ° C.

The reaction time is not particularly limited, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 30 minutes to 20 hours.

After completion of the reaction, the compound of the formula [18] obtained in the manner described above can be isolated and purified by crystallization from the reaction mixture by performing processing such as neutralizing the reaction mixture and diluting with water, if necessary, followed by heating and cooling.

[Production Method 7]

1- (3- (2- (1-Benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol compounds of the formula [19] or its salts can be obtained by subjecting the compound of the formula [18] to a reduction reaction with the addition of an activator, such as protic acid, a methylating agent and a silylating agent and the like in the presence of an alkali metal borohydride.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it does not adversely affect the reaction, is not particularly limited, but ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis (2-methoxyethyl) ether are proposed, for example. , dioxane and the like, and tetrahydrofuran is more preferred.

In addition, these solvents can be used in a mixture of halogenated hydrocarbons such as dichloromethane, chloroform and the like;

aromatic hydrocarbons such as benzene, toluene, xylene and the like;

and aliphatic hydrocarbons such as hexane, cyclohexane, octane and the like.

The amount of solvent used is preferably 1-20 times the volume by weight of the compound of the formula [18], and more preferably it is 3-10 times the indicated volume (v / w).

As the alkali metal borohydride used in this reaction, for example, sodium borohydride, lithium borohydride, potassium borohydride and the like are provided, and sodium borohydride is preferred.

The amount of alkali metal borohydride is preferably 1-10 mol per mol of the compound of the formula [18], and more preferably it is 2-3 mol.

As the activator used in this reaction, for example, protic acid such as sulfuric acid, hydrogen chloride, trifluoroacetic acid and the like, are provided,

methylating agent such as dimethyl sulfate and the like,

and a silylating agent such as trimethylsilyl chloride and the like.

As a preferred activator, protic acid such as sulfuric acid, hydrogen chloride and the like is provided, and sulfuric acid is more preferred.

The amount of activator used varies depending on the type of activator, but, for example, in the case of sulfuric acid, it is preferably 0.5-1 mol per mol of alkali metal borohydride, and more preferably it is 0.5-0.6 mol.

In addition, the time of addition of the activator varies depending on the type of activator, but in the case of sulfuric acid, it is preferably in the range of 10 minutes to 6 hours, and more preferably it is in the range of 30 minutes to 4 hours.

In addition, the activator may be dissolved in a suitable solvent and may be added in dissolved form.

In addition, in the case where the amount of alkali metal borohydride is 2.0-2.2 mol per mol of the compound of the formula [18] and the amount of sulfuric acid is 0.5-0.6 mol per mol of the alkali metal borohydride, and the time for adding sulfuric the acid dropwise is 1-4 hours, a compound of the formula [19] or its salts having high purity can be obtained by further suppressing the formation of by-products.

The reaction temperature is not particularly limited, but it can range from -20 to 150 ° C, and is preferably 0-70 ° C.

After adding the activator at 0-30 ° C, it is preferable to carry out the interaction at 30-70 ° C, and more preferred after adding the activator at 0-30 ° C is the interaction at 40-60 ° C.

The reaction time is not particularly limited, but it can range from 10 minutes to 50 hours, and is preferably 1-20 hours.

In the present invention, as a preferred preparation method, the following method is provided:

the method of obtaining the suspension of the compounds of formula [18] in ether (3-10-fold specified volume (vol./mass.)), the addition of alkali metal borohydride (2-3 mol), the addition of activator at 0-30 ° C and then the interaction at 30-70 ° C for 1-20 hours, it is preferable that the method of obtaining the suspension of the compounds of formula [18] in ether (3-10 times the specified volume (vol./mass.)), adding sodium borohydride (2-3 mol ) by adding protic acid (0.5-1 mol per mole of sodium borohydride) at 0-30 ° C and then interacting at 30 -70 ° C for 1-20 hours is more preferable, and the method of obtaining the suspension of the compounds of formula [18] in tetrahydrofuran (3-10-fold specified volume (vol./mass.)) Adding sodium borohydride (2.0-2 , 2 mol), adding sulfuric acid (0.5-0.6 mol per mol of sodium borohydride), adding sulfuric acid at 0-30 ° C for 1-4 hours, and then interacting at 40-60 ° C in a period of 1-20 hours is even more preferred.

After completion of the reaction, a compound of the formula [19] or its salts, obtained as described above, can be isolated in the usual way.

For example, after completion of the reaction, they can be isolated by adding 6.0 mol / L hydrochloric acid to decompose the excess reducing agent, cooling to room temperature, then alkalizing the reaction mixture with an aqueous sodium hydroxide solution, extracting with an organic solvent such as ethyl acetate, and then removing the solvent from extract.

In addition, they can be isolated as salts by adding acid to the extract.

As for the salt of the compound of the formula [19], the salt, if it is usually known as a salt by a basic group such as an amino group, is not particularly limited, but mineral acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, for example, are proposed. sulfuric acid and the like,

salts of an organic carboxylic acid such as formic acid, acetic acid, citric acid, oxalic acid, fumaric acid, maleic acid, succinic, malonic acid, tartaric acid, aspartic acid, trichloroacetic acid, trifluoroacetic acid and the like,

and sulfonic acid salts such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like.

A pharmacologically acceptable salt is provided as a preferred salt, and a maleic acid salt is more preferred.

If a compound of the present invention has an isomer (e.g., an optical isomer), a hydrate, a solvate, and various kinds of crystalline forms, they are all encompassed by the present invention.

In addition, if the compound used in the preparation method described above has an isomer (eg, an optical isomer), a hydrate, a solvate and various kinds of crystalline forms, all of them can be used in the preparation method of the present invention.

Examples

The invention will now be described in the following reference examples and examples. However, the present invention is not limited to these examples.

Relations in eluent mixtures are taken by volume. Unless specifically indicated, the carrier in silica gel column chromatography is B.W. silica gel, BW-127ZH or PSQ100B (product of Fuji Silysia Chemical Ltd.).

The abbreviations in the examples mean the following: Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl, ^t Bu: tert-butyl, DMSO-d ₆ : dimethyl sulfoxide-d ₆ .

Reference Example 1

To an aqueous (275 ml) suspension of 546 g of thiophenol was added dropwise an aqueous (550 ml) solution of 585 g of potassium hydroxide at a temperature not exceeding 20 ° C. Then, an aqueous (825 ml) solution of 492 g of chloroacetic acid was added dropwise to the mixture, and the mixture was stirred at 80-90 ° C. for 3 hours. After cooling the reaction mixture, the pH was adjusted to 1.5 with hydrochloric acid and 1650 ml of dichloromethane and 550 ml of water were added to the mixture. The organic layer was separated and anhydrous magnesium sulfate was added to it. Insoluble material was filtered off and 5.95 g of iron (III) chloride was added to the filtrate, after which 832 g of bromine was added dropwise at 5-10 ° C and the mixture was stirred at room temperature for 5 hours. After the reaction solution was cooled to 5 ° C, an aqueous (825 ml) solution of 187 g of sodium sulfite was added dropwise to it, and the pH was adjusted to 1.2 with hydrochloric acid. After stirring at 5-10 ° C for 1 hour, the precipitate was collected by filtration to obtain a solid. 2000 ml of toluene was added to the obtained solid, and water was removed from the mixture by heating and azeotropic distillation. The reaction mixture was cooled to 5 ° C for 2 hours. After stirring at the same temperature for 1 hour, the crystalline precipitate was collected by filtration to obtain 1108 g of (4-bromophenylthio) acetic acid as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 3.65 (2H, s), 7.25-7.35 (2H, m), 7.40-7.50 (1H, m).

Reference Example 2

To an aqueous (600 ml) solution of 88.9 g of sodium hydroxide, 200 g of 4-bromothiophenol was added and an aqueous (300 ml) solution of 105 g of chloroacetic acid was added dropwise, and the mixture was stirred at 60-70 ° C. for 1 hour. After the reaction mixture was cooled to 40 ° C, 140 ml of hydrochloric acid and 600 ml of toluene were added thereto, and the mixture was then heated to 80 ° C. The organic layer was separated and slowly cooled to 5 ° C. After stirring at the same temperature for 1 hour, the crystalline precipitate was collected by filtration to obtain 243 g of (4-bromophenylthio) acetic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of reference example 1.

Example 1-1

To a dichloromethane (750 ml) suspension of 250 g of (4-bromophenylthio) acetic acid, 2.5 ml of N, N-dimethylformamide and 132 g of thionyl chloride were added, and the mixture was then refluxed for 1 hour. After the reaction mixture was cooled to 20 ° C, a dichloromethane (1500 ml) suspension of 148 g of aluminum chloride was added dropwise thereto at 5-15 ° C, and the mixture was stirred at 15-25 ° C for 1.5 hours. Then, the resulting reaction mixture was added dropwise to a mixed solution of 1310 ml of water and 188 ml of hydrochloric acid under cooling. The organic layer was separated, 1250 ml of water was added thereto, and the pH was adjusted to 3.0 by the addition of a 5% aqueous potassium carbonate solution. The organic layer was separated and cooled to 5 ° C. 15.3 g of sodium borohydride and 500 ml of methanol were added to it, and the mixture was stirred at 10-20 ° C for 2 hours. 750 ml of water was added to the reaction solution, after which the mixture was adjusted to pH 7.0 by the addition of acetic acid and left at room temperature overnight. 200 ml of a 5% aqueous potassium hydroxide solution was added to the reaction solution, and the organic layer was separated. 25.0 g of activated carbon was added to the organic layer, and the mixture was stirred at room temperature. The insoluble material was filtered off and the solvent was distilled off from the filtrate. Cyclohexane was added to the obtained residue, and the precipitated crystals were collected by filtration to obtain 194 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol as a pale red solid.

¹ H-NMR (CDCl ₃ ) δ value: 2.18 (1H, d, J = 8.3 Hz), 3.30 (1H, dd, J = 12.0, 4.4 Hz), 3.61 (1H, dd, J = 12.0, 6.3 Hz), 5.30-5.40 (1H, m), 7.11 (1H, d, J = 8.3 Hz), 7.35 ( 1H, dd, J = 8.3, 2.0 Hz), 7.50 (1H, d, J = 2.0 Hz).

Example 1-2

To an acetone (600 ml) solution of 300 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol was added 12.4 g of p-toluenesulfonic acid monohydrate and the mixture was then refluxed for 2 hours. 15.0 g of activated carbon was added to the reaction solution, and the mixture was stirred. The insoluble material was filtered off and washed with 300 ml of acetone. The filtrate and washings were combined and 2700 ml of water was added dropwise to the mixture at 5-15 ° C. The precipitate was collected by filtration to obtain 268 g of 5-bromo-1-benzothiophene as a pale violet solid.

¹ H-NMR (CDCl ₃ ) δ value: 7.27 (1H, d, J = 5.4 Hz), 7.44 (1H, dd, J = 8.5, 1.9 Hz), 7.48 (1H, d, J = 5.4 Hz), 7.74 (1H, d, J = 8.5 Hz), 7.97 (1H, d, J = 1.9 Hz).

Example 2-1

(1) To a 1,2-dimethoxyethane (10 ml) suspension of 0.02 g of tris (dibenzylideneacetone) dipalladium (0) was added 0.11 g of a 10% (w / w) mixture of three (tert-butyl) phosphine / hexane 1.76 g of cesium carbonate, 0.50 g of 5-bromobenzothiophene and 0.45 g of diethyl malonate, and the mixture was then refluxed for 2 hours. Water and ethyl acetate were added to the reaction mixture, after which the mixture was adjusted to pH 2 by the addition of 2 mol / L hydrochloric acid. The organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1) to obtain 0.69 g of diethyl 2- (1-benzothiophen-5-yl) malonate as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 1.27 (6H, t, J = 7.1 Hz), 4.1-4.3 (4H, m), 4.73 (1H, s), 7 , 33 (1H, d, J = 5.4 Hz), 7.40 (1H, dd, J = 8.3, 2.0 Hz), 7.45 (1H, d, J = 5.4 Hz) 7.87 (1H, d, J = 8.3 Hz); 7.87 (1H, d, J = 2.0 Hz).

(2) To an ethylene glycol (1.0 ml) suspension of 0.25 g of diethyl 2- (1-benzothiophen-5-yl) malonate was added 1.0 ml of a 40% (w / w) aqueous potassium hydroxide solution and 0, 3 ml of water and the mixture was then refluxed for 2 hours. Water and toluene were added to the reaction mixture, and the aqueous layer was separated. The pH was adjusted to 2 with 6 mol / L hydrochloric acid and ethyl acetate was added to the aqueous layer. The organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was suspended in 5 ml of xylene and 0.01 g of p-toluenesulfonic acid monohydrate was added to the suspension, and the mixture was then refluxed for 30 minutes. The solvent was distilled off under reduced pressure, and toluene and cyclohexane were added to the obtained residue. The precipitate was collected by filtration to obtain 0.02 g of 2- (1-benzothiophen-5-yl) acetic acid as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ value: 3.76 (2H, s), 7.2-7.3 (1H, m), 7.29 (1H, d, J = 5.4 Hz), 7 44 (1H, d, J = 5.4 Hz), 7.73 (1H, s), 7.83 (1H, d, J = 8.1 Hz).

Example 2-2

(1) To a 1,2-dimethoxyethane (10 ml) solution of 0.11 g of 10% (w / w) tri (tert-butyl) phosphine / hexane was added 0.02 g of tris (dibenzylideneacetone) dipalladium (0), 1.76 g of cesium carbonate, 0.50 g of 5-bromobenzothiophene and 0.61 g of tert-butyl malonate and the mixture was then refluxed for 2 hours. Then, 0.02 g of tris (dibenzylideneacetone) dipalladium (0) and 0.11 g of 10% (w / w) tri (tert-butyl) phosphine / hexane were added thereto, and then refluxed for 1 hour. The resulting reaction mixture was added to a mixed solution of 30 ml of water and 20 ml of ethyl acetate, and the pH was adjusted to 3 by the addition of 6 mol / L hydrochloric acid. The organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 20: 1) to obtain 0.49 g of di (tert-butyl) 2- (1-benzothiophen-5-yl) malonate as a white solid colors.

¹ H-NMR (CDCl ₃ ) δ value: 1.47 (18H, s), 4.55 (1H, s), 7.32 (1H, d, J = 5.4 Hz), 7.39 (1H dd, J = 8.5, 1.7 Hz), 7.43 (1H, d, J = 5.4 Hz), 7.84 (1H, d, J = 1.7 Hz), 7.86 (1H, d, J = 8.5 Hz).

(2) To a toluene (2.5 ml) solution of 0.25 g of di (tert-butyl) 2- (1-benzothiophen-5-yl) malonate was added 0.01 g of p-toluenesulfonic acid monohydrate and then refluxed within 1 hour. After cooling the reaction mixture, the precipitate was collected by filtration to obtain 0.14 g of 2- (1-benzothiophen-5-yl) malonic acid as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 4.80 (1H, s), 7.3-7.5 (1H, m), 7.47 (1H, d, J = 5.5 Hz), 7 77 (1H, d, J = 5.5 Hz), 7.89 (1H, s), 7.97 (1H, d, J = 8.3 Hz).

(3) To a xylene (2 ml) suspension of 0.10 g of 2- (1-benzothiophen-5-yl) malonic acid, 4 mg of p-toluenesulfonic acid monohydrate was added and then refluxed for 1 hour. The solvent was distilled off under reduced pressure, and cyclohexane was added to the resulting residue. The precipitate was collected by filtration to obtain 0.08 g of 2- (1-benzothiophen-5-yl) acetic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 2-1 (2).

Example 2-3

To a toluene (3 ml) solution of 0.21 g of ethyl cyanoacetate was added 0.41 g of potassium tert-butoxide, 0.30 g of 5-bromobenzothiophene and 0.02 g of palladium tetrakis (triphenylphosphine) (0), and then refluxed for 7.5 hours. Water was added to the reaction mixture and the pH was adjusted to 2 with hydrochloric acid. Ethyl acetate was added and insoluble material was filtered off. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) to obtain 0.16 g of ethyl 2- (1-benzothiophen-5-yl) -2-cyanoacetate as a pale yellow solid. colors.

¹ H-NMR (CDCl ₃ ) δ value: 1.29 (3H, t, J = 7.1 Hz), 4.25 (2H, m), 4.84 (1H, s), 7.37 (1H d, J = 5.4 Hz), 7.41 (1H, dd, J = 8.5, 1.7 Hz), 7.54 (1H, d, J = 5.4 Hz), 7.92 (1H, d, J = 8.5 Hz), 7.94 (1H, d, J = 1.7 Hz).

Example 2-4

To a toluene (25 ml) suspension of 0.16 g of dichlorobis (triphenylphosphine) palladium (II) was added 0.12 g of triphenylphosphine, 0.01 g of sodium borohydride, 5.79 g of potassium tert-butoxide and 2.92 g of ethyl cyanoacetate and stirred room temperature for 10 minutes. 5.00 g of 5-bromobenzothiophene and 25 ml of toluene were added, and then refluxed for 4 hours. 0.14 g of tetrakis (triphenylphosphine) palladium (0) was added, and then refluxed for 2 hours. Then, 25 ml of ethanol, 2.82 g of sodium hydroxide and 5 ml of water were added to the reaction solution, and then refluxed for 6 hours. 2.82 g of sodium hydroxide was added and then refluxed for 5 hours. 15 ml of water and 0.5 g of activated carbon were added to the reaction mixture, and insoluble material was filtered off. The aqueous layer was separated and 35 ml of ethanol was added to the solution. The pH was adjusted to 2 by adding 15 ml of hydrochloric acid. 15 ml of water was added to the mixture and it was stirred at 40 ° C. 30 ml of water was added and mixed. Then it was cooled. The precipitate was collected by filtration to obtain 3.38 g of 2- (1-benzothiophen-5-yl) acetic acid as a pale yellow solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 2-1 (2).

Example 2-5

To a 1.2-dimethoxyethane (25 ml) suspension of 0.16 g of dichlorobis (triphenylphosphine) palladium (II) was added 0.12 g of triphenylphosphine, 0.01 g of sodium borohydride, 5.53 g of potassium tert-butoxide and 3.48 g tert-butyl cyanoacetate and stirred at room temperature for 10 minutes. 5.00 g of 5-bromobenzothiophene was added and then refluxed for 2 hours. After 15 ml of water was added to the reaction mixture, the pH was adjusted to 1 by adding 2 ml of hydrochloric acid. The precipitate was collected by filtration to obtain 5.69 g of tert-butyl 2- (1-benzothiophen-5-yl) -2-cyanoacetate as a pale yellow solid.

¹ H-NMR (CDCl ₃ ) δ value: 1.45 (9H, s), 4.73 (1H, s), 7.36 (1H, d, J = 5.6 Hz), 7.39 (1H dd, J = 8.5, 2.0 Hz), 7.52 (1H, d, J = 5.6 Hz), 7.91 (1H, d, J = 8.5 Hz), 7.9 -8.0 (1H, m).

Example 2-6

To a 1,2-dimethoxyethane (1.00L) solution of 250 g of 5-bromobenzothiophene, 276 g of potassium tert-butoxide and 174 g of tert-butyl cyanoacetate were added. 8.23 g of dichlorobis (triphenylphosphine) palladium (II) and 6.15 g of triphenylphosphine were added to the mixture at 80-85 ° C, and then refluxed for 2 hours. Then, 500 ml of ethylene glycol, 250 ml of water, and 263 g of potassium hydroxide were added to the reaction mixture, and then refluxed for 4 hours. 1.50 L of water and 12.5 g of kieselguhr (cellulur, product of Advanced Minerals Company) were added to the reaction mixture. After insoluble matter was filtered off, 250 ml of toluene was added to the filtrate and the aqueous layer was separated. 375 ml of toluene and 375 ml of ethyl acetate were added to the aqueous layer, the pH was adjusted to 1 by addition of 505 ml of hydrochloric acid, and the organic layer was separated. The organic layer was treated with 12.5 g of activated carbon. The solvent was distilled off under reduced pressure, and toluene was added. The precipitate was collected by filtration to obtain 176 g of 2- (1-benzothiophen-5-yl) acetic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 2-1 (2).

Example 2-7

(1) To a 1,2-dimethoxyethane (3 ml) solution of 0.30 g of 4-bromobenzothiophene was added 0.33 g of potassium tert-butoxide, 0.21 g of tert-butyl cyanoacetate, 0.01 g of dichlorobis (triphenylphosphine) palladium (II ) and 0.01 g of triphenylphosphine and then refluxed for 40 minutes. 0.33 g of potassium tert-butoxide, 0.01 g of dichlorobis (triphenylphosphine) palladium (II) and 0.01 g of triphenylphosphine were added, and then refluxed for 30 minutes. The reaction mixture was added to a mixed solution of water and ethyl acetate and the pH was adjusted to 1 by the addition of 6 mol / L hydrochloric acid. The organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) to obtain 0.26 g of tert-butyl 2- (1-benzothiophen-4-yl) -2-cyanoacetate as a pale oily substance -Brown.

¹ H-NMR (CDCl ₃ ) δ value: 1.42 (9H, s), 5.03 (1H, s), 7.39 (1H, t, J = 7.8 Hz), 7.49 (1H d, J = 7.8 Hz), 7.54 (1H, d, J = 5.6 Hz), 7.59 (1H, d, J = 5.6 Hz), 7.92 (1H, d , J = 7.8 Hz).

(2) To an ethylene glycol (1.0 ml) solution of 0.25 g of tert-butyl 2- (1-benzothiophen-4-yl) -2-cyanoacetate was added 1.0 ml of a 40% (w / w) aqueous solution potassium hydroxide and 0.3 ml of water and was stirred at 95-105 ° C for 1 hour. Water and toluene were added to the reaction mixture, and the aqueous layer was separated. The pH was adjusted to 2 by adding 6 mol / L hydrochloric acid, and ethyl acetate was added to the mixture. The organic layer was separated and dried over anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. Cyclohexane was added to the resulting residue. The precipitate was collected by filtration to obtain 0.15 g of 2- (1-benzothiophen-4-yl) acetic acid as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 3.95 (2H, s), 7.2-7.4 (2H, m), 7.41 (1H, d, J = 5.5 Hz), 7 47 (1H, d, J = 5.5 Hz); 7.82 (1H, d, J = 7.8 Hz).

Example 3-1

50.2 g of sodium borohydride was suspended in 340 ml of tetrahydrofuran, a tetrahydrofuran (340 ml) solution of 170 g of (1-benzothiophen-5-yl) acetic acid and 65.1 g of sulfuric acid was successively dropped into the suspension and stirred at room temperature for 2 ,5 o'clock. To the resulting reaction mixture was added dropwise 85 ml of acetone and stirred for 30 minutes. 510 ml of water and 680 ml of toluene were added. The organic layer was separated, 510 ml of water was added and the pH was adjusted to 12 by adding 48 ml of a 20% (w / w) aqueous solution of sodium hydroxide. The organic layer was separated and washed with water, followed by distillation of the solvent. Cyclohexane and toluene were added. The precipitate was collected by filtration to obtain 135 g of 2- (1-benzothiophen-5-yl) ethanol as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 1.41 (1H, t, J = 6.0 Hz), 2.99 (2H, t, J = 6.5 Hz), 3.8-4.0 (2H, m), 7.22 (1H, dd, J = 8.3, 1.7 Hz), 7.30 (1H, d, J = 5.4 Hz), 7.44 (1H, d, J = 5.4 Hz), 7.6-7.7 (1H, m), 7.83 (1H, d, J = 8.3 Hz).

Example 3-2

2.95 g of sodium borohydride was suspended in 5 ml of 1,2-dimethoxyethane, a solution of 10 g (1-benzothiophen-5-yl) acetic acid and 11 ml of 6.9 were added dropwise a 1,2-dimethoxyethane (25 ml) solution. mol / L hydrogen chloride / 1,2-dimethoxyethane solution and stirred at room temperature for 1 hour. 5 ml of acetone was added dropwise to the resulting reaction mixture, and stirred for 30 minutes. 20 ml of water, 30 ml of toluene and 2 ml of 2 mol / L hydrochloric acid were added. Then, after the pH was adjusted to 9.5 by adding 20 ml of a 2 mol / L aqueous solution of sodium hydroxide, the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, followed by distillation of the solvent. Cyclohexane and toluene were added. The precipitate was collected by filtration to obtain 7.84 g of 2- (1-benzothiophen-5-yl) ethanol as a white solid.

Example 3-3

4.72 g of sodium borohydride was suspended in 40 ml of tetrahydrofuran, a tetrahydrofuran (60 ml) solution of 20 g of (1-benzothiophen-5-yl) acetic acid and 6.12 g of sulfuric acid was added dropwise to the suspension. The solution was heated to 66 ° C, after which approximately 40 ml of the solvent was distilled off under normal pressure and stirred at the same temperature for 1 hour. After cooling, 10 ml of acetone was added dropwise to the resulting reaction mixture and stirred for 30 minutes. 90 ml of water and 80 ml of toluene were added. The organic layer was separated, 60 ml of water was added, and the pH was adjusted to 13.6 by the addition of 5 ml of a 5 mol / L sodium hydroxide aqueous solution. The organic layer was separated, washed with water and then the solvent was distilled off, and cyclohexane and toluene were added. The precipitate was collected by filtration to obtain 16.5 g of 2- (1-benzothiophen-5-yl) ethanol as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 3-1.

Example 4-1

(1) To a toluene (5 ml) suspension of 0.23 g of a 40% (w / w) aqueous solution of benzyltrimethylammonium hydroxide was added 5.00 g of 2- (1-benzothiophen-5-yl) ethanol and 2 dropwise was added. 20 ml of acrylonitrile at 0-5 ° C, and then stirred at 0-20 ° C for 1 hour. To the resulting reaction mixture was added 0.125 ml of hydrochloric acid. 10 ml of propanol, 1.0 ml of water and 3.1 ml of sulfuric acid were added, and then refluxed for 6.5 hours. After cooling, 10 ml of water and 10 ml of toluene were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 15: 1-7: 1) to obtain 7.21 g of propyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate in as a colorless oily substance.

¹ H-NMR (CDCl ₃ ) δ value: 0.91 (3H, t, J = 7.4 Hz), 1.57-1.67 (2H, m), 2.58 (2H, t, J = 6.4 Hz), 2.99 (2H, t, J = 7.1 Hz), 3.71 (2H, t, J = 7.1 Hz), 3.74 (2H, t, J = 6, 4 Hz), 4.02 (2H, t, J = 6.7 Hz), 7.20 (1H, dd, J = 8.2, 1.6 Hz), 7.28 (1H, d, J = 5.6 Hz), 7.41 (1H, d, J = 5.6 Hz), 7.60-7.70 (1H, m), 7.78 (1H, d, J = 8.2 Hz) .

(2) To a methanol (12 ml) solution of 12.0 g of propyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate was added an aqueous (12 ml) solution of 2.76 g of potassium hydroxide and stirred at room temperature within 1.5 hours. The solvent was distilled off under reduced pressure from the resulting reaction mixture, and 36 ml of toluene and 36 ml of water were added to the residue. The pH was adjusted to 1.9 by the addition of 8 ml of 6 mol / L hydrochloric acid. The organic layer was separated, and then the solvent was distilled off under reduced pressure. 12 ml of toluene and 24 ml of cyclohexane were added. The precipitate was collected by filtration to obtain 8.91 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 2.63 (2H, t, J = 6.2 Hz), 3.00 (2H, t, J = 7.1 Hz), 3.72 (2H, t , J = 7.1 Hz), 3.74 (2H, t, J = 6.2 Hz), 7.20 (1H, dd, J = 8.4, 1.6 Hz), 7.27 (1H dd, J = 5.5, 0.6 Hz), 7.40 (1H, d, J = 5.5 Hz), 7.65-7.70 (1H, m), 7.78 (1H, d, J = 8.4 Hz).

Example 4-2

(1) To a toluene (5 ml) suspension of 5.00 g of 2- (1-benzothiophen-5-yl) ethanol was added 0.23 g of a 40% (w / w) aqueous solution of benzyltrimethylammonium hydroxide and 2.28 ml of tetrahydrofuran and 2.20 ml of acrylonitrile was added dropwise at 0-10 ° C., after which it was stirred at the same temperature for 1.5 hours. To the resulting reaction mixture was added 0.1 ml of hydrochloric acid, 10 ml of butanol and 5 ml of 50% (w / w) sulfuric acid, and then refluxed for 15 hours. After cooling, 15 ml of water was added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 10: 1) to obtain 6.65 g of butyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate as a colorless oily substance .

¹ H-NMR (CDCl ₃ ) δ value: 0.92 (3H, t, J = 7.4 Hz), 1.30-1.45 (2H, m), 1.50-1.65 (2H, m), 2.57 (2H, t, J = 6.3 Hz), 2.99 (2H, t, J = 7.1 Hz), 3.71 (2H, t, J = 7.1 Hz) , 3.74 (2H, t, J = 6.3 Hz), 4.06 (2H, t, J = 6.7 Hz), 7.21 (1H, dd, J = 8.3, 1.7 Hz), 7.28 (1H, dd, J = 5.4, 0.7 Hz), 7.41 (1H, d, J = 5.4 Hz), 7.65-7.70 (1H, m ), 7.78 (1H, d, J = 8.3 Hz).

(2) To a methanol (5 ml) solution of 5.00 g of butyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate was added an aqueous (5 ml) solution of 1.10 g of potassium hydroxide and stirred at room temperature within 2 hours. The solvent was distilled off under reduced pressure from the resulting reaction mixture, and 30 ml of toluene and 30 ml of water were added to the residue. The pH was adjusted to 1.6 by the addition of 3.5 ml of 6 mol / L hydrochloric acid. The organic layer was separated, and then the solvent was distilled off under reduced pressure. 15 ml of toluene and 30 ml of cyclohexane were added. The precipitate was collected by filtration to obtain 3.60 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 4-1 (2).

Example 4-3

(1) To a toluene (5 ml) suspension of 5.00 g of 2- (1-benzothiophen-5-yl) ethanol was added 0.23 g of a 40% (w / w) aqueous solution of benzyltrimethylammonium hydroxide and 2.28 ml of tetrahydrofuran and 2.22 ml of acrylonitrile was added dropwise at 5 ° C and then stirred at 0-15 ° C for 1.5 hours. To the resulting reaction mixture was added 0.13 ml of hydrochloric acid, 10 ml of methanol and 1.52 g of water. 9.47 g of hydrogen chloride was introduced into the resulting mixture, and then it was refluxed for 4 hours. After cooling, 15 ml of water and 10 ml of toluene were added to the reaction mixture. The organic layer was separated and dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: hexane: ethyl acetate = 5: 1) to obtain 7.36 g of methyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate as a colorless oily substance .

¹ H-NMR (CDCl ₃ ) δ value: 2.58 (2H, t, J = 6.4 Hz), 2.99 (2H, t, J = 7.1 Hz), 3.65 (3H, s ), 3.71 (2H, t, J = 7.1 Hz), 3.74 (2H, t, J = 6.4 Hz), 7.20 (1H, dd, J = 8.3, 1, 7 Hz), 7.28 (1H, d, J = 5.4 Hz), 7.41 (1H, d, J = 5.4 Hz), 7.65-7.70 (1H, m), 7 78 (1H, d, J = 8.3 Hz).

(2) To a methanol (5 ml) solution of 5.00 g of methyl 3- (2- (1-benzothiophen-5-yl) ethoxy) propionate was added an aqueous (5 ml) solution of 1.27 g of potassium hydroxide and stirred at room temperature within 2 hours. The solvent was distilled off under reduced pressure from the resulting reaction mixture, and 30 ml of toluene and 30 ml of water were added to the residue. The pH was adjusted to 1.0 by the addition of 5 ml of 6 mol / L hydrochloric acid. The organic layer was separated, and then the solvent was distilled off under reduced pressure. 11 ml of toluene and 30 ml of cyclohexane were added. The precipitate was collected by filtration to obtain 4.51 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 4-1 (2).

Example 4-4

To a toluene (50 ml) suspension of 50.0 g of 2- (1-benzothiophen-5-yl) ethanol was added 2.35 g of a 40% (w / w) aqueous solution of benzyltrimethylammonium hydroxide and 17.9 g of acrylonitrile was added dropwise at 8-15 ° C and stirred at 10-20 ° C for 1.5 hours. To the resulting reaction mixture was added 1.25 ml of hydrochloric acid, 100 ml of propanol and 5.05 g of water. 55.0 g of sulfuric acid was added dropwise and then refluxed for 6 hours. After cooling, 100 ml of water was added to the reaction mixture. The organic layer was separated. 50 ml of methanol was added thereto, and an aqueous (50 ml) solution of 31.5 g of potassium hydroxide was added dropwise, and then stirred at room temperature for 1.5 hours. To the resulting reaction mixture was added 75 ml of toluene and 75 ml of water. The aqueous layer was separated, 100 ml of toluene was added thereto, the pH was adjusted to 0.9 by the addition of 6 mol / L hydrochloric acid, and the organic layer was separated. After distilling off the solvent under reduced pressure, 50 ml of toluene and 125 ml of cyclohexane were added. The precipitate was collected by filtration to obtain 59.6 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 4-1 (2).

Example 4-5

To a toluene (260 ml) suspension of 260 g of 2- (1-benzothiophen-5-yl) ethanol was added 43.8 g of 2-propanol and 1.64 g of potassium tert-butoxide and stirred for 0.5 hours. After the reaction mixture was cooled to 15 ° C, 116 g of acrylonitrile was added dropwise to it and stirred at 15-25 ° C for 1 hour. 6.5 ml of hydrochloric acid, 520 ml of methanol and 78.9 g of water were added to the resulting reaction mixture. 310 g of hydrogen chloride were introduced into the resulting mixture at 10-25 ° C. and then refluxed for 3 hours. After cooling, 780 ml of water and 520 ml of toluene were added to the reaction mixture, and the organic layer was separated. To the organic layer was added dropwise 260 ml of methanol and an aqueous (260 ml) solution of 164 g of potassium hydroxide and stirred at 30-35 ° C for 2 hours. To the resulting reaction mixture was added 260 ml of water and the aqueous layer was separated. 520 ml of toluene and 260 ml of water were added to the aqueous layer, and 234 ml of hydrochloric acid was added dropwise, and the organic layer was separated. After 390 ml of solvent was distilled off from the organic layer under reduced pressure, 1040 ml of cyclohexane was added. The precipitate was collected by filtration to obtain 326 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 4-1 (2).

Example 4-6

To a toluene (360 ml) suspension of 180 g of 2- (1-benzothiophen-5-yl) ethanol was added 4.22 g of an aqueous solution of 40% (w / w) benzyltrimethylammonium hydroxide and 8.04 g of acrylonitrile was added dropwise at 30 ° C. After the reaction mixture was cooled to 20 ° C, 53.6 g of acrylonitrile was added dropwise thereto, and then it was stirred at 15-25 ° C for 2 hours. To the resulting reaction mixture was added 27 ml of hydrochloric acid and 180 ml of methanol. 97 g of hydrogen chloride were introduced into the resulting mixture at 10-25 ° C, stirred at 30-40 ° C for 30 minutes, and refluxed for 3 hours. After cooling, 360 ml of water was added to the reaction mixture, and the organic layer was separated. 180 ml of methanol and an aqueous (180 ml) solution of 113 g of potassium hydroxide were added dropwise to the organic layer and stirred at 30-35 ° C. for 2 hours. 360 ml of water was added to the reaction mixture, and the aqueous layer was separated. 360 ml of toluene was added to the aqueous layer and 151 ml of hydrochloric acid was added dropwise, and the organic layer was separated. After 126 ml of solvent was distilled off from the organic layer at normal pressure, 1080 ml of cyclohexane was added. The precipitate was collected by filtration to obtain 222 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 4-1 (2).

Example 5-1

10.0 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid was dissolved in 15 ml of 1,2-dimethoxyethane. 0.1 ml of N, N-dimethylformamide and 5.23 g of thionyl chloride were added to the solution and stirred at room temperature for 1.5 hours. This reaction solution was added dropwise to a mixed solution of 50 ml of water, 7.19 g of sodium hydroxide and 7.69 g of 1/2 3-azetidinol tartrate at 5-15 ° C. and stirred at the same temperature for 2 hours. Then added 90 ml of water. The precipitate was collected by filtration to obtain 11.0 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol as a white solid.

¹ H-NMR (CDCl ₃ ) δ value: 2.25-2.35 (2H, m), 2.96 (2H, t, J = 7.0 Hz), 3.65-3.80 (5H, m), 3.85-3.95 (1H, m), 4.05-4.15 (1H, m), 4.15-4.25 (1H, m), 4.40-4.50 ( 1H, m), 7.19 (1H, dd, J = 8.3, 1.5 Hz), 7.27 (1H, d, J = 5.4 Hz), 7.40 (1H, d, J = 5.4 Hz), 7.62-7.66 (1H, m), 7.78 (1H, d, J = 8.3 Hz).

Example 5-2

29.0 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid was suspended in 116 ml of toluene. 0.6 ml of N, N-dimethylformamide and 14.5 g of thionyl chloride were added to the suspension and stirred at room temperature for 2 hours. After that, 62 ml of the solvent was distilled off under reduced pressure. This reaction solution was added dropwise to a mixed solution of 87 ml of water, 13.9 g of sodium hydroxide and 25.7 g of 1/2 3-azetidinol tartrate at 10-20 ° C, and the mixture was stirred at 20-25 ° C for 1 hours and left overnight. After cooling the reaction solution, the pH was adjusted to 6 by the addition of 7 ml of acetic acid. After stirring at 10-15 ° C for 1 hour, a precipitate was collected by filtration to obtain 31.9 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol as solid white.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 5-1.

Example 5-3

50.0 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid was dissolved in 75 ml of 1,2-dimethoxyethane. 26.1 g of thionyl chloride was added to the solution, and then refluxed for 2 hours. After cooling, this reaction solution was added dropwise to a mixed solution of 125 ml of water, 20.0 g of sodium hydroxide and 25.2 g of 3-azetidinol hydrochloride at -5-10 ° C and stirred at 0-15 ° C for 30 minutes. Added 75 ml of water, heated to 40 ° C and dissolved. After cooling, the precipitate was collected by filtration to obtain 56.5 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol as a white solid.

The values of chemical shifts ¹ H-NMR spectrum in CDCl ₃ consistent with the values of example 5-1.

Example 6-1

To a suspension of 1.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol in bis (2-methoxyethyl) ether (5 ml) was added 0.37 g of borohydride sodium and then cooled to 10 ° C. 2.49 ml of chlorotrimethylsilane was added dropwise at 5-10 ° C. over 20 minutes and stirred at room temperature for 2.5 hours and at 40 ° C. for 4 hours. After cooling, 3.27 ml of 6.0 mol / L hydrochloric acid was added dropwise and stirred at 70-75 ° C. for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 10.0 by the addition of 2.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.36 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (5 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.72 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.65-1.75 (2H, m), 2.93 (2H, t, J = 6.9 Hz), 3.14 (2H, t, J = 7.4 Hz), 3.44 (2H, t, J = 6.0 Hz), 3.63 (2H, t, J = 6.9 Hz), 3.75-3.85 (2H, m), 4.15-4.25 (2H, m), 4.40-4.50 (1H, m), 6.06 (2H, s), 7.26 (1H, dd, J = 8, 3, 1.5 Hz), 7.41 (1H, d, J = 5.4 Hz), 7.73 (1H, d, J = 5.4 Hz), 7.70-7.75 (1H, m), 7.91 (1H, d, J = 8.3 Hz).

Example 6-2

To a 1,2-dimethoxyethane (5 ml) suspension of 1.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol was added 0.37 g of sodium borohydride, after which was cooled to 10 ° C. 2.49 ml of chlorotrimethylsilane was added dropwise at 5-10 ° C and stirred at room temperature for 2.5 hours and at 40 ° C for 4 hours. After cooling, 3.27 ml of 6.0 mol / L hydrochloric acid was added dropwise and stirred at 70-75 ° C. for 30 minutes. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 10.0 by the addition of 2.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.36 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (5 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.71 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

The values of chemical shifts ¹ H-NMR spectrum in DMSO-d ₆ consistent with the values of example 6-1.

Example 6-3

To a tetrahydrofuran (5 ml) suspension of 1.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol was added 0.37 g of sodium borohydride and tetrahydrofuran ( 1 ml) a solution of 0.75 ml of trifluoroacetic acid for 30 minutes and then refluxed for 2 hours. After cooling, 3.27 ml of 6.0 mol / L hydrochloric acid was added dropwise and then refluxed for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, and the aqueous layer was separated. Ethyl acetate was added to the aqueous layer and the pH was adjusted to 10.0 by addition of a 20% (w / w) aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.36 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (5 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.62 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

The values of chemical shifts ¹ H-NMR spectrum in DMSO-d ₆ consistent with the values of example 6-1.

Example 6-4

To a tetrahydrofuran (3 ml) suspension of 0.50 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol was added 0.19 g of sodium borohydride and then heated to 50 ° C. A tetrahydrofuran (1 ml) solution of 0.46 ml of dimethyl sulfate was added dropwise at 50-55 ° C. for 10 minutes and stirred at the same temperature for 2.5 hours. After cooling, 1.64 ml of 6.0 mol / L hydrochloric acid was added dropwise, and then it was refluxed for 1.5 hours. Ethyl acetate was added to the reaction mixture, and the pH was adjusted to 10.0 by the addition of a 20% (w / w) aqueous solution of sodium hydroxide. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.18 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (3.75 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.49 g of 1- (3- (2- (1-) maleate benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline substance.

The values of chemical shifts ¹ H-NMR spectrum in DMSO-d ₆ consistent with the values of example 6-1.

Example 6-5

To a suspension of 1.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol in bis (2-methoxyethyl) ether (5 ml) was added 0.37 g of borohydride sodium, after which it was cooled to 10 ° C. 2.46 ml of a 4.0 mol / L hydrogen chloride / dioxane solution was added dropwise at 5-15 ° C. for 12 minutes and stirred at the same temperature for 30 minutes, at room temperature for 3 hours and at 35-40 ° C for 6 hours. After cooling, 3.27 ml of 6.0 mol / L hydrochloric acid was added dropwise and stirred at 65-70 ° C. for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 10.0 by the addition of 2.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.36 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (5 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.86 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

Data ¹ H-NMR in DMSO-d ₆ consistent with the data of example 6-1.

Example 6-6

To a 1,2-dimethoxyethane (5 ml) suspension of 1.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol was added 0.37 g of sodium borohydride, after which was cooled to 10 ° C. 2.46 ml of a 4.0 mol / L hydrogen chloride / dioxane solution was added dropwise at 5-15 ° C. for 10 minutes and stirred at the same temperature for 1 hour, at room temperature for 3.5 hours and at 35 -40 ° C for 6 hours. After cooling, 3.27 ml of 6.0 mol / L hydrochloric acid was added dropwise and stirred at 65-70 ° C. for 1.5 hours. Water and ethyl acetate were added to the reaction mixture, and the pH was adjusted to 10.0 by the addition of 2.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated, washed successively with water and a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 0.36 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (5 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 0.93 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

Data ¹ H-NMR in DMSO-d ₆ consistent with the data of example 6-1.

Example 6-7

To a 1.2-dimethoxyethane (70 ml) suspension of 20.0 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol, 5.46 g of sodium borohydride was added, after which was cooled to 15 ° C. 20.6 ml of a 7.0 mol / L solution of hydrogen chloride / 1,2-dimethoxyethane was added dropwise at 15-20 ° C. for 40 minutes and stirred at room temperature for 1.5 hours and at 53-57 ° C. within 4 hours. After cooling, 65.5 ml of 6.0 mol / L hydrochloric acid was added dropwise and stirred at 65-70 ° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, 100 ml of water and 100 ml of ethyl acetate were added, and the pH was adjusted to 10.0 by the addition of 5.0 mol / L aqueous sodium hydroxide solution. After separation of the organic layer, it was washed with 50 ml of water and the pH was adjusted to 1.0 by the addition of 6.0 mol / L hydrochloric acid. The aqueous layer was separated and 50 ml of ethyl acetate was added thereto. The pH was adjusted to 10.0 by the addition of 5.0 mol / L aqueous sodium hydroxide. The organic layer was separated and anhydrous magnesium sulfate was added thereto. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. To the resulting residue was added 7.22 g of maleic acid and the mixture was solidified from a mixed solvent (100 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 19.2 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

Example 6-8

To a tetrahydrofuran (35.0 ml) suspension of 5.00 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol, 1.61 g of sodium borohydride was added and was added dropwise tetrahydrofuran (15 ml) solution of 2.09 g of sulfuric acid at room temperature for 30 minutes, and was stirred at 48-52 ° C for 7.5 hours. After cooling, 16.4 ml of 6.0 mol / L hydrochloric acid was added dropwise and then refluxed for 1 hour. The reaction mixture was concentrated under reduced pressure, water and ethyl acetate were added to the residue, and the pH was adjusted to 9.5 by the addition of 5.0 mol / L aqueous sodium hydroxide solution. The organic layer was separated and washed with a saturated aqueous solution of sodium chloride. Anhydrous magnesium sulfate and activated carbon were added to it. After the insoluble material was filtered off, the solvent was distilled off under reduced pressure. 1.81 g of maleic acid was added to the obtained residue, and the mixture was solidified from a mixed solvent (25 ml) of ethyl acetate: 2-propanol (4: 1) to obtain 4.82 g of 1- (3- (2- (1-benzothiophene) maleate 5-yl) ethoxy) propyl) azetidin-3-ol as a colorless crystalline solid.

Data ¹ H-NMR in DMSO-d ₆ consistent with the data of example 6-1.

Example 6-9

To a tetrahydrofuran (2.38 L) suspension of 340 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol was added 110 g of sodium borohydride and tetrahydrofuran (1, 02 L) a solution of 142 g of sulfuric acid at room temperature for 1 hour, and stirred at 45-55 ° C for 5 hours. After cooling, 170 ml of acetone was added and 204 ml of 36% hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for 3 hours and left overnight. 1.02 L of water was added to the reaction mixture, and 3.34 L of solvent was distilled off under reduced pressure. After cooling, 0.68 L of ethyl acetate was added, and an aqueous (0.68 L) solution of 147 g of sodium hydroxide was added at 14-22 ° C, and the mixture was stirred at 7-15 ° C for 30 minutes. The insoluble material was filtered off, washed with 0.34 L of ethyl acetate. The filtrate and washings were combined, and the organic layer was separated and washed with 0.68 L of water. After adding 2.04 L of 2-propanol to the organic layer, 3.01 L of solvent was distilled off under reduced pressure. 1.02 L of ethyl acetate and 34 g of activated carbon were added to the residue and stirred for 20 minutes. The insoluble material was filtered off and washed with 0.34 L of ethyl acetate. The filtrate and washings were combined, 116 g of maleic acid was added thereto. After the resulting reaction mixture was heated and dissolved, it was slowly cooled. The precipitate was collected by filtration to obtain 376 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol maleate as a colorless crystalline solid.

Data ¹ H-NMR in DMSO-d ₆ consistent with the data of example 6-1.

Example 6-10

To a tetrahydrofuran (250 ml) suspension of 50.0 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol, 13.6 g of sodium borohydride was added and 18. 5 g of sulfuric acid at room temperature for 3 hours and stirred at 45-55 ° C for 4.5 hours. After cooling, 15 ml of acetone was added, 120 ml of 6.0 mol / L hydrochloric acid was added dropwise, and then refluxed for 1 hour. 150 ml of water was added to the reaction mixture, and the solvent was distilled off under reduced pressure. 200 ml of ethyl acetate was added to the residue, and an aqueous (100 ml) solution of 43.9 g of sodium hydroxide was added dropwise at 10-21 ° C. The organic layer was separated, washed with the addition of a 20% aqueous solution of hydrogen chloride. 50.0 g of celite and 5.0 g of activated carbon were added thereto, and the mixture was stirred for 20 minutes. The insoluble material was filtered off and washed with 100 ml of ethyl acetate. The filtrate and washings were combined. 63 ml of ethyl acetate, 75 ml of 2-propanol and 17.1 g of maleic acid were added thereto. After the resulting reaction mixture was heated and dissolved, it was slowly cooled. The precipitate was collected by filtration to obtain 56.7 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol maleate as a colorless crystalline solid.

Data ¹ H-NMR in DMSO-d ₆ consistent with the data of example 6-1.

INDUSTRIAL APPLICABILITY

The method for producing 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol and its salts of the present invention has the following characteristics: (1) safety for the human body, (2) low environmental load and (3) the possibility of mass production and so on, therefore, the method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol and its salts is applicable in industrial production.

Claims (36)

1. The method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, characterized in that it involves the interaction of the derivative (phenylthio) acetic acid or its salts, represented by the general formula:

where X ¹ represents a halogen atom,
with a halogenating agent to obtain an acid halide represented by the general formula:

where X ² represents a halogen atom; X ¹ has the meanings given above,
then the intramolecular cyclization reaction of the halide in the presence of a Lewis acid, followed by a reduction reaction to obtain a dihydrobenzothiophene derivative represented by the general formula:

where X ¹ has the meanings given above,
then dehydration of the dihydrobenzothiophene derivative in the presence of an acid catalyst to obtain the 5-halogen-1-benzothiophene derivative represented by the general formula:

where X ¹ has the meanings given above,
then the binding of the 5-halogen-1-benzothiophene derivative to the malonic acid derivative or its salts represented by the general formula:

where R ² and R ³ , the same or different, represent an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group, in the presence of a base and a palladium catalyst, to obtain a benzothiophene derivative or its salts represented by the general formula:

where R ² and R ³ have the same meanings as above, then the interaction of the benzothiophene derivative or its salts with an acid or base, decarboxylation, if necessary, to obtain the benzothiophenacetic acid derivative or its salts represented by the general formula:

where R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group,
then hydrolysis of the benzothiophenoacetic acid derivative or its salts, if necessary, then reduction by the addition of an activator in the presence of an alkali metal borohydride to obtain 2- (1-benzothiophen-5-yl) ethanol, then the Michael addition reaction 2- (1-benzothiophen-5 -yl) ethanol using acrylonitrile in the presence of a base, reaction with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
then hydrolysis of the ester derivative of propionic acid in the presence of a base to obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, then the conversion of 3- (2- (1-benzothiophen-5-yl) ethoxy ) propionic acid or its salts into a reactive derivative, then reacting the reactive derivative with 3-azetidinol or its salts in the presence of a base to obtain 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3 -ol, then reduction of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol with the addition of by activating in the presence of an alkali metal borohydride. 2. The method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, characterized in that it involves the binding of a derivative of 5-halogen-1-benzothiophene represented general formula:

where X ¹ represents a halogen atom,
with a derivative of malonic acid or its salts represented by the general formula:

where R ² and R ³ , identical or different, represent an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group,
in the presence of a base and a palladium catalyst to obtain a benzothiophene derivative or its salts represented by the general formula:

where R ² and R ³ have the same meanings as above, then the interaction of the benzothiophene derivative or its salts with an acid or base, decarboxylation, if necessary, to obtain the benzothiophenacetic acid derivative or its salts represented by the general formula:

where R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group,
then hydrolysis of the benzothiophenoacetic acid derivative or its salts, if necessary, then reduction with the addition of an activator in the presence of an alkali metal borohydride to obtain 2- (1-benzothiophen-5-yl) ethanol, then the Michael addition of 2- (1-benzothiophen- 5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
then hydrolysis of the ester derivative of propionic acid in the presence of a base to obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, then the conversion of 3- (2- (1-benzothiophen-5-yl) ethoxy ) propionic acid or its salts into a reactive derivative, then reacting the reactive derivative with 3-azetidinol or its salts in the presence of a base to obtain 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3 -ol, then reduction of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol with the addition of by activating in the presence of an alkali metal borohydride. 3. The method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, characterized in that it includes the Michael addition reaction 2- (1-benzothiophene - 5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
then hydrolysis of the ester derivative of propionic acid in the presence of a base to obtain 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, then the conversion of 3- (2- (1-benzothiophen-5-yl) ethoxy ) propionic acid or its salts into a reactive derivative, then reacting the reactive derivative with 3-azetidinol or its salts in the presence of a base to obtain 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3 -ol, then reduction of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol with the addition of by activating in the presence of an alkali metal borohydride. 4. A method of obtaining a derivative of 5-halogen-1-benzothiophene represented by the general formula:

where X ¹ represents a halogen atom,
characterized in that it includes the interaction of the derivative (phenylthio) acetic acid or its salts represented by the general formula:

where X ¹ has the meanings given above,
with a halogenating agent to obtain an acid halide represented by the general formula:

where X ² represents a halogen atom; X ¹ has the meanings given above,
then the intramolecular cyclization reaction of the obtained halide in the presence of a Lewis acid, then reduction to obtain a dihydrobenzothiophene derivative represented by the general formula:

where X ¹ has the meanings given above,
then dehydration of the dihydrobenzothiophene derivative in the presence of an acid catalyst. 5. The production method according to any one of claims 1 to 4, characterized in that it comprises crystallization of crystals of a dihydrobenzophenone derivative represented by the general formula:

where X ¹ represents a halogen atom,
and the selection of crystals. 6. A method of obtaining a derivative of 5-halogen-1-benzothiophene represented by the general formula:

where X ¹ represents a halogen atom,
characterized in that it includes the dehydration of the dihydrobenzophenone derivative represented by the general formula:

where X ¹ has the meanings given above,
in the presence of an acid catalyst. 7. The production method according to claim 4 or 6, where X ¹ represents a bromine atom or an iodine atom. 8. A method of obtaining a benzothiophene derivative or its salts represented by the general formula:

where R ² and R ³ , identical or different, represent an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group,
characterized in that it includes the binding of a benzothiophene derivative represented by the general formula:

where X ¹ represents a halogen atom,
with a derivative of malonic acid or its salts represented by the general formula:

where R ² and R ³ have the same meanings as above,
in the presence of a base and a palladium catalyst. 9. The method of obtaining the benzothiophene derivative of claim 8, where X ¹ and a group represented by the general formula:

attached at the 4- or 5-position of the benzothiophene ring. 10. A method of obtaining a benzothiophene derivative according to claim 8 or 9, where X ¹ and a group represented by the general formula:

attached at the 5-position of the benzothiophene ring. 11. The production method according to claims 1 and 2, 8, where X ¹ represents a bromine atom or an iodine atom. 12. A method of obtaining a derivative of benzothiophenacetic acid or its salts, represented by the General formula:

where R ⁴ represents a hydrogen atom or unsubstituted or
substituted alkyl, cycloalkyl or aralkyl group,
characterized in that it includes the interaction of a benzothiophene derivative or its salts represented by the general formula:

where R ² and R ³ , the same or different, are an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group, with an acid or base, and decarboxylation, if necessary. 13. The method of producing a benzothiophenacetic acid derivative or its salts according to claim 12, wherein the group represented by the general formula:

and a group represented by the general formula:

attached at the 4- or 5-position of the benzothiophene ring. 14. A method of obtaining a derivative of benzothiophenacetic acid or its salts according to item 12 or 13, where the group represented by the general formula:

and a group represented by the general formula:

attached at the 5-position of the benzothiophene ring. 15. A method of obtaining a derivative of benzothiophenacetic acid or its salts, represented by the General formula:

where R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group,
characterized in that it includes the binding of a benzothiophene derivative represented by the general formula:

where X ¹ represents a halogen atom,
with a derivative of malonic acid or its salts represented by the general formula:

where R ² and R ³ , identical or different, represent an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group,
in the presence of a base and a palladium catalyst to obtain a benzothiophene derivative or its salts represented by the general formula:

where R ² and R ³ have the same meanings as above,
then the interaction of the benzothiophene derivative or its salts with an acid or base, and decarboxylation, if necessary. 16. The method of obtaining a derivative of benzothiophenacetic acid or its salts according to clause 15, where X ¹ group represented by the General formula:

and a group represented by the general formula:

attached at the 4- or 5-position of the benzothiophene ring. 17. A method for producing a benzotiofenuksusnoy acid or salts thereof according to claim 15 or 16, wherein X ¹ group represented by the general formula:

and a group represented by the general formula:

attached at the 5-position of the benzothiophene ring. 18. The production method according to clause 15, where X ¹ represents a bromine atom or an iodine atom. 19. The production method according to any one of claims 1 and 2, 8, 12 and 15, where R ² represents an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group or cyano group; R ³ represents an unsubstituted or substituted alkyloxycarbonyl, cycloalkyloxycarbonyl or aralkyloxycarbonyl group. 20. A method of obtaining 2- (1-benzothiophen-5-yl) ethanol, characterized in that it includes the hydrolysis of a derivative of benzothiophenacetic acid or its salts, represented by the general formula:

where R ⁴ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aralkyl group,
if necessary, and reduction with the addition of an activator in the presence of alkali metal borohydride. 21. A method for producing 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, characterized in that it includes a Michael addition reaction of 2- (1-benzothiophen-5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
then hydrolysis of the ester derivative of propionic acid in the presence of a base. 22. The method of obtaining 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, characterized in that it includes a Michael addition reaction of 2- (1-benzothiophen-5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
and hydrolysis of the ester derivative of propionic acid in the presence of a base according to any one of claims 1 to 3 and 21, wherein the acid used is sulfuric acid or hydrogen chloride. 23. The method of obtaining 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, characterized in that it includes a Michael addition reaction of 2- (1-benzothiophen-5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
and hydrolysis of the ester derivative of propionic acid in the presence of a base according to any one of claims 1 to 3 and 21, wherein the acid used is hydrogen chloride and R ¹ represents a hydrogen atom. 24. The method of obtaining 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or its salts, characterized in that it includes a Michael addition reaction of 2- (1-benzothiophen-5-yl) ethanol using acrylonitrile in the presence of a base, then reacting with an alcohol represented by the general formula:

where R ¹ represents a hydrogen atom or an unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of an acid to give an ester derivative of propionic acid represented by the general formula:

where R ¹ has the meanings given above,
and hydrolysis of the ester derivative of propionic acid in the presence of a base according to any one of claims 1 to 3 and 21, where the acid used is sulfuric acid, and R ¹ represents an ethyl group. 25. A method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, characterized in that it involves the reduction of 1- (3- (2- (1 -benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol with the addition of an activator in the presence of an alkali metal borohydride. 26. A method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, including the reduction of 1- (3- (2- (1-benzothiophen-5 -yl) ethoxy) propionyl) azetidin-3-ol with the addition of an activator in the presence of an alkali metal borohydride according to any one of claims 1 to 3 and 25, wherein the activator used is at least one compound selected from protonic acid, a methylating agent and silylating agent. 27. A method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, including the reduction of 1- (3- (2- (1-benzothiophen-5 -yl) ethoxy) propionyl) azetidin-3-ol with the addition of an activator in the presence of an alkali metal borohydride according to any one of claims 1 to 3 and 25, wherein the activator used is sulfuric acid. 28. A method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, including the reduction of 1- (3- (2- (1-benzothiophen-5 -yl) ethoxy) propionyl) azetidin-3-ol with the addition of an activator in the presence of an alkali metal borohydride according to any one of claims 1 to 3 and 25, wherein the alkali metal borohydride used is sodium borohydride. 29. A method of obtaining 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) azetidin-3-ol or its salts, including the reduction of 1- (3- (2- (1-benzothiophen-5 -yl) ethoxy) propionyl) azetidin-3-ol with the addition of an activator in the presence of an alkali metal borohydride according to any one of claims 1 to 3 and 25, where the amount of sulfuric acid used is 0.5-0.6 mol per mole of alkaline borohydride metal, and the method is characterized in that it includes the addition of sulfuric acid at 0-30 ° C for 10 minutes to 6 hours, and then the interaction at 30-70 ° C. 30. A derivative of dihydrobenzothiophene represented by the general formula:

where X ¹ represents a halogen atom. 31. The dihydrobenzothiophene derivative of claim 30, wherein X ¹ is a bromine atom. 32. A derivative of benzothiophene or a salt thereof represented by the general formula:

where R ² and R ³ , the same or different, represent a (C _1-4 ) alkyloxycarbonyl group or cyano group. 33. The benzothiophene derivative or a salt thereof according to claim 32, wherein R ² is a (C _1-4 ) alkyloxycarbonyl group or cyano group, and R ³ is a (C _1-4 ) alkyloxycarbonyl group. 34. The benzothiophene derivative or its salt according to claim 32 or 33, wherein the group represented by the general formula:

attached at the 4- or 5-position of the benzothiophene ring. 35. The benzothiophene derivative or its salt according to claim 32 or 33, wherein the group represented by the general formula:

attached at the 5-position of the benzothiophene cycle. 36. The ester derivative of propionic acid represented by the general formula:

where R ¹ represents a hydrogen atom or a (C _1-4 ) alkyl group.