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

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

 

The technical FIELD TO WHICH the INVENTION RELATES

The present invention relates to a new process for the preparation of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts used as drugs for diseases of the Central nervous system and peripheral nervous system.

BACKGROUND of INVENTION

1-(3-(2-(1-Benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts thereof have nervousity action, action, promoting nerve regeneration, and the effect on axon and applicable as medicines for diseases of the Central nervous system and peripheral nervous system.

As methods for obtaining the compounds are known, for example, (1) the manner of interaction of 5-(2-(3-chloropropoxy)ethyl)-1-benzothiophene with 3-azetidinol or its salts, (2) method of exposure to 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 of complex balancerationality or exposure to its reduction reaction of the sodium borohydride in the presence of a complex of tetrahydrofuran with nortryptaline complex, and the like (patent document 1).

However, method (1) has the following disadvantages: (A) low yield, (B) has required the terrain in complex treatment methods, such as chromatography on a column of silica gel, (C) in the excreted a lot of waste, and so on.

Furthermore, the method (2) may not satisfy the conditions of the industrial way of production, because it has the following disadvantages: (A) the method is used as the reagent complex with tetrahydrofuran borane and tetrahydrofuran complex with boron TRIFLUORIDE and so on, which are harmful to the human body, legkonastraivaemy, highly toxic and metastability, (B) requires caution in handling and storage of these chemicals and special equipment, and so on.

In addition, as a method of obtaining 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salt used in the above method (2), known, for example, the following methods: (3) method of exposure to 2-(1-benzothiophen-5-yl)ethanol reaction joining Michael using tert-butyl acrylate, followed by the exposure of his de-tert-bottling plant, (4) method of exposure to 2-(1-benzothiophen-5-yl)ethanol reaction accession Michael using Acrylonitrile, followed by the exposure of its hydrolysis by acid, and the like (patent document 1).

However, the method (3) and (4) may not satisfy the conditions of the industrial mode of production, because they have the following shortcomings in the way the (3): (A) produces by-products resulting from the transesterification of acrylic acid, (B) require special equipment and handling due to the release of large quantities of fuel Isobutanol gas during the reaction de-tert-bottled, in method (4): low yield of hydrolysis acid, and so forth.

As a method of obtaining 2-(1-benzothiophen-5-yl)ethanol used in the above methods (3) and (4), known, for example, the following methods: (5) method of exposure to 5-methyl-1-benzothiophene bromirovanii N-bromosuccinimide and interaction with cenocoeliinae obtaining (1-benzothiophen-5-yl)acetonitrile, then exposure to hydrolysis, then the exposure of reduction reaction (non-patent document 1, 2, 3), (6) the way the interaction of 5-bromo-1-benzothiophene with magnesium to obtain a Grignard reagent, then the exposure of its interaction with ethylene oxide (patent document 2), (7) method of exposure to 5-(1-benzothiophen)carbaldehyde Wittig reaction using methoxyethylamine, then the exposure of its hydrolysis to obtain (1-benzothiophen-5-yl)acetaldehyde, then the exposure of his response recovery (patent document 3), and so on.

However, the methods (5)-(7) may not satisfy the conditions of the industrial mode of production, because they have the following disadvantages: (A) intermediate compounds have the annoying effect, (B) use of highly toxic reagent (qi is rosediana), (C) use of carcinogenic reagent (ethylene oxide), (D) use of flammable reagents (utility, Grignard reagent), (E) the reaction processes are complex, and so on.

On the other hand, as methods of deriving benzodioxane acid or its salts are known, for example, the following methods: (8) the method of exposure to hydroxyl groups benzothiophene galogenirovannyie, then the exposure of its interaction with cenocoeliinae with getting benzothiazolethiol, then the exposure of its hydrolysis (non-patent document 3), (9) the method of exposure 7-oxo-4,5,6,7-tetrahedralisation obtained from 3-bromothiophene, the reaction of the reformed using ethylbromoacetate, then exposure to the particular dehydration using sulfur and exposure of its hydrolysis, and so on (non-patent document 4).

However, the methods (8) and (9) cannot satisfy the conditions of the industrial mode of production, because they have the following disadvantages: (A) intermediate compounds have the annoying effect, (B) use of highly toxic reagent (cyanocobalamine), (C) therefore, require complex processing wastes, (D) there are many stages of the process, (E) low output (F) requires a high reaction temperature, (G) uses complex reaction processes and so on.

<> In addition, as a method of obtaining a derivative of 5-halogen-1-benzothiophene known, for example, the following methods: (10) the manner of interaction between 4-halogenfree with dimethylacetal 2-halogenated in the presence of a base to obtain dimethylacetal 2-(4-halogenfrei)acetaldehyde, then the exposure for the reaction of intramolecular cyclization in the presence of polyphosphoric acid, and the like (non-patent document 5, patent document 4, patent document 5).

However, the method (10) may not satisfy the conditions of the industrial way of production, because it has the following disadvantages: (A) require complex methods of separation, such as distillation or chromatography on a column of silica gel, and so forth, because the obtained intermediate compounds are oily substances, (B) require complex processing in the process of implementation of the cyclization reaction using phosphate compounds, because the formed complex by-products, (C) require complex methods, such as distillation or chromatography on a column of silica gel and so on, for the Department of derivatives of 5-halogen-1-benzothiophene from the resulting by-products, because their derivatives have a low melting point, (D) produce large quantities of liquid waste, is the quiet contain phosphorus compounds, require complicated processes, and so on.

As a method of producing 4-halogenfree used in the above method (10), known, for example, (11) the method of exposure of thioanisole galogenirovannyie chlorine or bromine, then the exposure of its demethylation large excess of chlorine (patent document 6), (12) the method of conducting communication (4 halogenfrei)acetic acid with sodium sulfide in the presence of sodium hydroxide (patent document 7), (13) the method of conducting interaction monohalogenated with monochloride sulfur in the presence of zinc chloride to obtain degalogenirovaniya, then the exposure of its reaction recovery chloroethanol acid and zinc (patent document 8), (14) the method of implementation of the interaction of 1,4-dehalogenase with sodium hydrosulfide in 1-methyl-2-pyrrolidone (patent document 9), and so on.

However, the methods (11)-(14) can not satisfy the conditions of the industrial mode of production, because they have the following disadvantages: (A) low yield, (B) isomers are formed, (C) requires a high reaction temperature, (D) used reagents, providing a greater load on the environment, such as chlorine or sulfide, and so forth.

Further, as a method of obtaining derived benzothiophene derived from (phenylthio)acetic acid is you or its salts are known, for example, the following methods: (15) a method of exposure for the reaction of intramolecular cyclization in the presence of a Lewis acid, then the exposure for the reaction of recovery, then the exposure for the reaction of dehydration, and the like (patent document 10).

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

[patent document 1]

International publication No. 03/035647, brochure

[patent document 2]

EP 0129478, newsletter

[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 # H 08-143533, newsletter

[patent document 7]

JP # H 05-178816, newsletter

[patent document 8]

JP # H 05-140086, newsletter

[patent document 9]

JP # H 04-182463, newsletter

[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 Depending 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.2446-2455

DISCLOSED IS E of the INVENTION

The PROBLEM SOLVED by the PRESENT INVENTION

The present invention is to create a new way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol and its salts, ensuring the safety for the human body, low impact on the environment and the possibility of mass production.

The WAY to solve the PROBLEM

During the intensive and consistent research came to the conclusion that the way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts of 2-(1-benzothiophen-5-yl)ethanol, the method of obtaining 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts differs in that it includes exposure to 2-(1-benzothiophen-5-yl)ethanol reaction accession Michael using Acrylonitrile in the presence of a base, then placing his interaction with alcohol represented by the General formula [1]:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,

in the presence of acid to obtain ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

then the exposure ester derivative of propionic key is lots of hydrolysis in the presence of a base;

moreover, the specified ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

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

the way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol or salts differs in that it includes the transformation of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts in a reactive derivative, then the engagement reactive derivative with 3-azetidinol or its salts in the presence of a base, and then bicrystalline crystals from the reaction mixture;

the way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts differs in that it includes exposure to 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol reaction recovery with the addition of activator in the presence of alkali metal borohydride; and

the way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts differs in that it includes exposure to 2-(1-benzothiophen-5-yl)ethanol reaction joining Michael using Acrylonitrile in the presence of a base, then placing his interaction with alcohol, before the purposes of the General formula [1]:

where R1has the values defined above,

in the presence of acid to obtain ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

then the exposure ester derivative of propionic acid hydrolysis in the presence of a base to obtain 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts, then its transformation into a reactive derivative, then the engagement 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 the exposure for the reaction of recovery with the addition of activator in the presence of the alkali metal borohydride.

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

where X1represents a halogen atom,

differs in that it includes the implementation of synergies derived (phenylthio)acetic acid or its salt represented by the General formula [3]:

/p>

where X1has the values defined above,

with a halogenation agent to obtain gelegenheid represented by the General formula [4]:

where X2represents a halogen atom, X1has the values defined above,

then the exposure received gelegenheid reactions intramolecular cyclization in the presence of a Lewis acid, then its exposure reduction reaction of obtaining derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

and exposure derived dihydrobenzofuran dehydration reaction in the presence of an acid catalyst;

moreover, the specified derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

is an important intermediate compound in the method of obtaining the derivative of 5-halogen-1-benzothiophene represented by the General formula [6]:

where X1has the values defined above;

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

where X1has the values defined above,

can be obtained is about a simple method with high purity, crystallization and isolation of crystals of a particular derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

then the exposure of the crystals of the reaction and dehydration;

the method of obtaining the derived benzothiophene or its salt represented by the General formula [9]:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano,

differs in that it includes linking the derived benzothiophene represented by the General formula [7]:

where X1has the values defined above,

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

where R2and R3have the meanings defined above;

the method of deriving benzodioxane acid or its salt represented by the General formula [10]:

where R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group,

the fact differentiates itself here, that includes the implementation of synergies derived benzothiophene or its salt represented by the General formula [9]:

where R2and R3have the meanings given above,

with acid or base, exposure derived benzothiophene or its salts decarboxylation reaction, if necessary;

derived benzothiophene represented by the General formula [9]:

where R2and R3have the meanings given above,

is an important intermediate compound in the method of deriving benzodioxane acid or its salt represented by the General formula [10]:

where R4has the values defined above;

the method of obtaining 2-(1-benzothiophen-5-yl)ethanol differs in that it includes exposure derived benzodioxane acid or its salt represented by the General formula [11]:

where R4has the values defined above,

hydrolysis, if necessary, then the exposure for the reaction of recovery with the addition of activator in the presence of alkali metal borohydride; and

the method of obtaining 2-(1-benzothiophen-5-yl)ethanol differs in that it includes the implementation of synergies derived (phenyl is IO)acetic acid or its salts, represented by the General formula [3]:

where X1has the values defined above,

with a halogenation agent to obtain gelegenheid represented by the General formula [4]:

where X1and X2have the meanings given above,

then the exposure received gelegenheid reactions intramolecular cyclization in the presence of a Lewis acid, then its exposure reduction reaction of obtaining derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

then the exposure derived dihydrobenzofuran dehydration reaction in the presence of an acid catalyst to obtain the derived 5-halogen-1-benzothiophene represented by the General formula [6]:

where X1has the values defined above,

then linking derivative of 5-halogen-1-benzothiophene with a derivative of malonic acid or its salt represented by the General formula [8]:

where R2and R3have the meanings given above,

in the presence of base and palladium catalyst to obtain the derived benzothiophene or its salts, presents a total of four who Ulai [12]:

where R2and R3have the meanings given above,

then the implementation of synergies derived benzothiophene with acid or base, the exposure of its decarboxylation reaction, if necessary, to obtain the derived benzodioxane acid or its salt represented by the General formula [11]:

where R4has the values defined above,

then the exposure derived benzodioxane acid or its salts hydrolysis, if necessary, then the exposure for the reaction of recovery with the addition of activator in the presence of alkali metal borohydride.

Next, the method of obtaining 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or salts differs in that it includes the implementation of synergies derived (phenylthio)acetic acid or its salt represented by the General formula [3]:

where X1has the values defined above,

with a halogenation agent to obtain gelegenheid represented by the General formula [4]:

where X1and X2have the meanings given above,

then the exposure received gelegenheid reactions intramolecular cyclization in the presence of sour is s Lewis, then placing his reaction recovery derivatization of dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

then the exposure derived dihydrobenzofuran dehydration reaction in the presence of an acid catalyst to obtain the derived 5-halogen-1-benzothiophene represented by the General formula [6]:

where X1has the values defined above,

then linking derivative of 5-halogen-1-benzothiophene with a derivative of malonic acid or its salt represented by the General formula [8]:

where R2and R3have the meanings given above,

in the presence of base and palladium catalyst to obtain the derived benzothiophene or its salt represented by the General formula [12]:

where R2and R3have the meanings given above,

then the implementation of synergies derived benzothiophene with acid or base, the exposure of its decarboxylation reaction, if necessary, to obtain the derived benzodioxane acid or its salt represented by the General formula [11]:

where R4have meant what I defined above,

then the exposure derived benzodioxane acid or its salts hydrolysis, if necessary, then the exposure for the reaction of recovery with the addition of activator in the presence of alkali metal borohydride to obtain 2-(1-benzothiophen-5-yl)ethanol, then exposure to 2-(1-benzothiophen-5-yl)ethanol reaction joining Michael using Acrylonitrile in the presence of a base, then placing his interaction with alcohol represented by the General formula [1]:

where R1has the values defined above,

in the presence of acid to obtain ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

then the exposure ester derivative of propionic acid hydrolysis 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 in a reactive derivative, then the engagement of 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)propioni is)azetidin-3-ol, and then exposure to 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol reaction recovery with the addition of activator in the presence of alkali metal borohydride.

The EFFECT of the INVENTION

The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)-3-azetidinol or its salts of the present invention has the following characteristics: (1) provides a high yield, (2) does not require chromatography on a column of silica gel, (3) a small content of the waste, (4) do not use reagents that are harmful and cause problems related to stability, and so forth, and this method is applicable in industrial production.

The method of obtaining 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) provides a high output and so on, and this method is applicable in industrial production.

The method of deriving benzodioxane acid or its salt represented by the General formula [10] according to the present invention has the following characteristics: (1) the process does not use irritating intermediate compounds, (2) use of highly toxic reagents (cyanocobalamine), (3) does not require complex processing waste (4) the number of stages is small, (5) provides a high yield, (6) does not require high temperature reactions, (7) the reaction process is simple and so on, and this method is applicable as an industrial production method.

The method of obtaining derivatives of 5-halogen-1-benzothiophene represented by the General formula [6] according to the present invention has the following characteristics: (1) a small amount of by-products, (2) purification can be performed by a simple method such as extraction and crystallization, (3) therefore, do not require complex methods of purification, such as distillation or chromatography on a column of silica gel, and so forth, and this method is applicable in industrial production.

The BEST WAY of carrying out the INVENTION

Further, the present invention is described in more detail.

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

the term "alkyl group" means an unbranched or branched C1-12alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl or the like;

the term "cycloalkyl group" means C3-8cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or the like;

those who min "kalkilya group" means apC 1-6alkyl group, for example benzyl, diphenylmethyl, trityl, phenethyl, naphthylmethyl or the like;

the term "alkoxygroup" means an unbranched or branched C1-6alkyloxy, for example methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentane or the like;

the term "allyloxycarbonyl group” means an unbranched or branched C1-12allyloxycarbonyl group, such as methoxycarbonyl, etoxycarbonyl, 1,1-dimethylpropanolamine, isopropoxycarbonyl, 2-ethylhexyloxymethyl, tert-butoxycarbonyl, tert-pentyloxybenzoyl or the like;

the term "cycloalkylcarbonyl group" means C3-8cycloalkylcarbonyl group, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexyloxycarbonyl or the like;

the term "aracelikarsaalyna group" means apC1-6allyloxycarbonyl group, such as benzyloxycarbonyl, ventilatsioonil or the like;

the terms "aryl group" means a group, for example phenyl, naphthyl or the like;

the term "Alchemilla group” means C2-12alkenylphenol group, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl or the like, the COO is responsible.

Alkyl, cycloalkyl and aryl groups, R1can be substituted by at least one group selected from a halogen atom, hydroxyl group, nitro group, alkyl groups, cycloalkyl group, alkoxygroup, alkenylphenol group and the aryl group or the like.

Allyloxycarbonyl, cycloalkylcarbonyl and aracelikarsaalyna group, R2and R3can be substituted by at least one group selected from a halogen atom, hydroxyl group, nitro group, alkyl groups, cycloalkyl group, alkoxygroup, alkenylphenol group and the aryl group or the like.

Alkyl, cycloalkyl and kalkilya group, R4can be substituted by at least one group selected from a halogen atom, hydroxyl group, nitro group, alkyl groups, cycloalkyl group, alkoxygroup, alkenylphenol group and the aryl group or the like.

In the present invention, the preferred methods of obtaining are the following methods.

To obtain 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts by the method of production, including exposure to 2-(1-benzothiophen-5-yl)ethanol reaction joining Michael in the presence of a base using Acrylonitrile, then the implementation of its interaction with with the IRTA, represented by the General formula [1]:

where R1has the values defined above,

in the presence of acid to obtain ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

and exposure of the ester derivative of propionic acid hydrolysis in the presence of a base, the method of obtaining, in which R1represents a hydrogen atom or alkyl group is preferred, method of production, in which R1represents a hydrogen atom, methyl group, ethyl group, or through a group, is more preferable, and the method of obtaining, in which R1represents a hydrogen atom or ethyl group is more preferred.

The method of obtaining, in which the acid used is an inorganic acid is preferred, and the method of obtaining, in which the used acid is a sulfuric acid or hydrogen chloride, is preferred.

When the acid is hydrogen chloride, the preferred method of production, in which R1represents a hydrogen atom.

When acid is chamois what I acid, preferred is a method of obtaining, in which R1represents an ethyl group.

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

Method of production, which used the activator is a proton acid such as sulfuric acid and hydrogen chloride, and so forth, is preferred, and the method of production, which used the activator is a sulfuric acid, is preferred.

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

To obtain the derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

the method of obtaining, VK is chushim the implementation of synergies derived (phenylthio)acetic acid or its salts, represented by the General formula [3]:

where X1has the values defined above,

with a halogenation agent to obtain gelegenheid represented by the General formula [4]:

where X1and X2have the meanings given above,

then the exposure received gelegenheid reactions intramolecular cyclization in the presence of a Lewis acid, then the exposure for the reaction of recovery, method of production, in which X1represents a chlorine atom, a bromine atom or an iodine atom is preferred, method of production, in which X1represents a bromine atom or an iodine atom is preferable, and the method of obtaining, in which X1represents a bromine atom is more preferred.

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

where X1has the values defined above,

the method of production, including exposure derived dihydrothiophene represented by the General formula [5]:

where X1has the values defined above,

the dehydration reaction in the presence of an acid catalyst, method of production, in which X1the submitted is a chlorine atom, a bromine atom or an iodine atom is preferred, method of production, in which X1represents a bromine atom or an iodine atom is preferable, and the method of obtaining, in which X1represents a bromine atom is more preferred.

To highlight the way bicrystalline crystals derived dihydrobenzofuran represented by the General formula [5], is the preferred method of separation by crystallization him from aliphatic hydrocarbons such as hexane and cyclohexane, and so forth, a method of separation by crystallization from hexane and cyclohexane is preferable, and a method of separation by crystallization from cyclohexane is even more preferred.

To obtain the derived benzothiophene or its salt represented by the General formula [9]:

where R2and R3have the meanings given above,

method of production, including exposure derived benzothiophene represented by the General formula [7]:

where X1has the values defined above,

binding assays with a derivative of malonic acid or its salt represented by the General formula [8a] in the presence of a palladium catalyst and base:

where R3arepresents an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group; R2has the values defined above,

is preferred, method of production, in which R2represents allyloxycarbonyl group, aracelikarsaalyna group, or cyano; R3arepresents allyloxycarbonyl group or aracelikarsaalyna group is more preferred, method of production, in which R2represents a C1-4allyloxycarbonyl group, apC1-4allyloxycarbonyl group, or cyano, R3arepresents a C1-4allyloxycarbonyl group or apC1-4allyloxycarbonyl group is even more preferred.

The method of obtaining, in which X1represents a chlorine atom, a bromine atom or an iodine atom is preferred, and the method of obtaining, in which X1represents a bromine atom or an iodine atom, is preferable.

The method of obtaining, in which X1attached at the 4 - or 5-position benzothiophene cycle is preferred, and the method of obtaining, in which X1attached in the 5-position benzothiophene cycle, is preferable.

For receiving the Oia derived benzodioxane acid or its salts, represented by the General formula [10]:

where R4has the values defined above,

method of production, including the implementation of synergies derived benzothiophene or its salt represented by the General formula [9a]:

where R2and R3ahave the meanings given above,

with acid or base, the exposure of its decarboxylation reaction, if necessary, is preferred, method of production, in which R2represents allyloxycarbonyl group, aracelikarsaalyna group, or cyano, R3arepresents allyloxycarbonyl group or aracelikarsaalyna group is more preferable, and the method of obtaining, in which R2represents a C1-4allyloxycarbonyl group, apC1-4allyloxycarbonyl group, or cyano, R3arepresents a C1-4allyloxycarbonyl group or apC1-4allyloxycarbonyl group is even more preferred.

The method of obtaining, in which the group represented by the General formula:

where R2and R3ahave the meanings defined above, attached at the 4 - or 5-position benzothiophene cycle is preferred, and SP is a way to obtain, in which the group is attached in the 5-position benzothiophene cycle, is preferable.

The method of obtaining, in which the group represented by the General formula:

where R4has the values defined above, attached at the 4 - or 5-position benzothiophene cycle is preferred, and the method of obtaining, in which the group is attached in the 5-position benzothiophene cycle, is preferable.

The method of obtaining, in which R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group is preferred, method of production, in which R4represents a hydrogen atom, alkyl group or aracelio group is preferred, and the method of obtaining, in which R4represents a hydrogen atom, a C1-4alkyl group or apC1-4alkyl group, is preferable.

As the preferred connection for the specified ester propionic acid derivative represented by the General formula [2]:

where R1has the values defined above,

use the following connection.

The compound in which R1represents an atom of hydrogen and an alkyl group, is preferred, a compound in which R1represents a hydrogen atom, methyl group, ethyl group, or through a group, is more preferable, and a compound in which R1represents a hydrogen atom or ethyl group is more preferred.

As the preferred connection for the specified derived dihydrobenzofuran represented by the General formula [5]:

where X1has the values defined above,

use the following connection.

The compound in which X1represents a chlorine atom, a bromine atom or an iodine atom is preferable, a compound in which X1represents a bromine atom or an iodine atom is preferable, and a compound in which X1represents a bromine atom is more preferred.

As the preferred connection for the specified derived benzothiophene or its salt represented by the General formula [9]:

where R2and R3have the meanings given above,

use the following connection.

The compound in which R2represents allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano,is preferred the compound in which R2represents allyloxycarbonyl group, aracelikarsaalyna group, or cyano, is more preferred, and a compound in which R2represents a C1-4allyloxycarbonyl group, apC1-4allyloxycarbonyl group, or cyano, is even more preferred.

The compound in which R3represents allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group is preferred, a compound in which R3represents allyloxycarbonyl group or aracelikarsaalyna group is more preferred, and a compound in which R3represents a C1-4allyloxycarbonyl group or apC1-4allyloxycarbonyl group is even more preferred.

Connection in which the group represented by the General formula:

where R2and R3have the meanings given above,

attached at the 4 - or 5-position benzothiophene cycle is preferred, and a compound in which the group is attached in the 5-position benzothiophene cycle, is preferable.

As typical compounds of General formula [9] or their salts according to the present image is meniu specified, for example, the following connections.

In the table Et is an ethyl group,tBu represents a tert-boutelou group.

TABLE 1

Further explanation of the methods of obtaining of the present invention.

[Method of obtaining 1]

where X1and X2have the meanings given above.

The compound of General formula [5] can be obtained by conversion of compounds of General formula [3] or its salts in gelegenheid, then the exposure received gelegenheid reactions intramolecular cyclization in the presence of a Lewis acid, then the exposure for the reaction of recovery.

The compound of General formula [5] can be easily converted into a compound of General formula [6] the exposure of its dehydration reaction in the presence of an acid catalyst.

The compound of General formula [3] or its salts, for example, can be obtained easily and with good yield, by engagement of thiophenol with Chloroacetic acid in the presence of a base to obtain (phenylthio)acetic acid, then the exposure (phenylthio)acetic is islote halogenation reaction or interaction of 4-halogenfree with Chloroacetic acid in the presence of a base.

In addition, the salt of the compounds of General formula [3], are not particularly limited, but suggest, for example, salts with alkali metal such as sodium, potassium, cesium and the like;

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

ammonium salt;

and salts with 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 explained below in more detail.

The intramolecular cyclization reaction:

The compound of General formula [13] can be obtained by conducting a compound of General formula [3] or its salt with a halogenation agent to obtain gelegenheid, then the exposure received gelegenheid reactions intramolecular cyclization in the presence of Lewis acid.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like;

nitro compounds such as nitromethane, nitrobenzene and the like;

and carbon disulphide to etomu such, moreover, these solvents can be used in a mixture.

The preferred solvents are available aliphatic halogenated hydrocarbons, and dichloromethane is preferable.

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

As the halogenation agent used in this reaction are available, for example, phosphorus oxychloride, oxybromide phosphorus, trichloride phosphorus, pentachloride phosphorus, thionyl chloride, thienylboronic and oxalicacid, and thionyl chloride is preferred.

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

As the Lewis acid used in this reaction are available, 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.

Kolichestvoparkov Lewis acid may be equal to or greater than 1 mol per mol of compound of General formula [3] or its salts, and is preferably 1-5 mol.

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

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

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

The compound of General formula [13], obtained in the manner described above, can be isolated and purified, but preferably move on to the next reaction without isolation.

Response and recovery:

The compound of General formula [5] can be obtained by exposure to compounds of General formula [13] reaction of recovery. This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic halogenated hydrocarbons such as dichloromethane, chloroform, dichloroethane and the like;

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

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

the sulfoxidov, such as dimethyl sulfoxide and the like;

alcohols, such as methanol, ethanol, propane is, 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, and these solvents may be used in mixture.

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

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

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

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

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

the metal hydride, such as diisobutylaluminium, trialkylaluminium, soy is inania hydride stanila, gedrosian and the like;

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

the complex compound of aluminum hydride, such as sociallyengaged and the like;

and borane, alkylboron, and the like.

The preferred reductant is offered integrated connection borohydride, and sodium borohydride is preferred.

The amount of reducing agent varies depending on the type of reducing agent, but, for example, in the case of complex compounds of borohydride it can be equal to or to exceed 0.25 mol per mol of compound of General formula [13], and more preferably it is equal to 0.25 to 2 mol.

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

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

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

The compound of General formula [5], obtained in the manner described above, can be used as it is in the next reaction without separation, but it is preferable to select it bicrystalline crystal.

The method of crystallization of the aliphatic hydrocarbons, the x as hexane, cyclohexane and the like, is preferred method of crystallization from hexane or cyclohexane is preferable, and a method of crystallization from cyclohexane is even more preferred.

The dehydration reaction:

The compound of General formula [6] can be obtained by exposure to compounds of General formula [5] the 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 has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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-methoxyethoxy) ether, dioxane and the like;

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

the sulfoxidov, 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, ethano is, 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, and these solvents may be used in mixture.

The preferred solvents are available ketones, acetone is preferred.

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

As the acid catalyst used in this reaction are available, for example, acid Bronsted, such as chloromethane acid, sulfuric acid, methanesulfonate acid, triftormetilfullerenov acid, p-toluensulfonate acid, dichloracetic acid, and the like;

and a Lewis acid such as aluminum chloride, boron TRIFLUORIDE, trichloride boron, and the like, and p-toluensulfonate acid is preferred.

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

The reaction temperature is not particularly restricted, but it is located between

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

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

[Method of obtaining 2]

where R2, R3and X1have the meanings given above.

The compound of General formula [8] or its salts, for example, diethylmalonate, di(tert-butyl)malonate, ethylcyanoacrylate, tert-butylcyanoacrylate, malononitrile and the like, commercially available.

The compound of General formula [9] or its salt can be obtained by exposure to compounds of General formula [7] binding assays with compound of General formula [8] or its salts in the presence of a base and a palladium catalyst, in the presence or in the absence of ligand, in the presence or in the absence of reductant.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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

ethers, such as tetrahydrofuran, 1,2-Dimitar iatan, bis(2-methoxyethoxy) 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;

the sulfoxidov, 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 may be used in mixture.

The amount used of the solvent is not particularly limited, but preferably it is 1 to 20-fold amount by weight of compounds of General formula [7], and more preferably is 1-10 times the specified volume (vol./mass.).

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

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;

organic base, Taco is as triethylamine, N,N-diisopropylethylamine, pyridine and the like.

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

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

inorganic palladium salt such as palladium chloride;

organic palladium salt such as palladium acetate;

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

and organopalladium complex on the polymer, such as bis(acetate)triphenylphosphorane(II)deposited on the polymer, di(acetate)dicyclohexylphosphino(II)deposited on the polymer, and the like.

The amount of palladium catalyst is not particularly restricted, but preferably it is of 0.0001-1 mol per mol of compound of General formula [7], and more preferably it is from 0.005 to 0.1 mol.

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

tricyclohexylphosphine, such as tricyclohexylphosphine and the like;

triarylphosphine, such as triphenylphosphine, trailerteen and the like;

trialkylphosphine, such as trimethylphosphite, triethylphosphite, tributylphosphite and the like;

tricyclohexylphosphine, such as tricyclohexylphosphine and the like;

triarylphosphite, such as triphenylphosphite and the like;

salt imidazole, such as 1,3-bis(2,4,6-trimetilfenil)imidazolidone and the like;

the diketones, such as acetylacetone, activerelation and the like;

amines, such as trimethylamine, triethylamine, Tripropylamine, triisopropanolamine and the like;

1,1'-bis(diphenylphosphino)ferrocene

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

The amount of ligand is not particularly restricted, but preferably it is equal to 0.0001 to 2 mol per mol of compound of General formula [7], and more preferably it is from 0.005 to 0.2 mol.

As the reducing agent used, if required, in this reaction, are available, for example, the complex compound of borohydride such as lithium borohydride, sodium borohydride, calcium borohydride, triacetoxyborohydride, matrilineality and the like.

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

The amount of compounds of General formula [8] is 1-5 mol per mol of compound of General formula [7], and more preferably it is equal to 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 General formula [9] or its salt obtained in the manner described above, can be used as it is in the next reaction without isolation.

[Method of obtaining 3]

where R2, R3and R4have the meanings given above.

The compound of General formula [10] or its salt can be prepared by the interaction of the compounds of General formula [9] or its salt with acid or base in the presence or in the absence of water, in the presence or in the absence of alcohol, exposure to its decarboxylation reaction, if necessary.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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

ethers, such as tetrahydrofuran, 1,2-Dimitar iatan, bis(2-methoxyethoxy) 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;

the sulfoxidov, 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, and these solvents may be used in mixture.

The amount used of the solvent is not particularly limited, but preferably it is 1-50-fold amount by weight of compounds of General formula [9] or its salt, and more preferably it is 1 to 15 times the specified volume (vol./mass.).

As the acid used in this reaction offers an inorganic acid, such as chloromethane acid, sulfuric acid, phosphoric acid, hydrogen chloride, bromovalerate and the like;

organic carboxylic acid, such as acetic acid, trichloroacetic acid, triperoxonane to the slot, and the like,

and organic sulfonic acid, such as methanesulfonate acid, p-toluensulfonate acid and the like.

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

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

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

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 used of the base is 2 to 10 mol per mol of compound of 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 restricted, but preferably it is 0.5-5 times the amount by weight of compounds of General formula [9] or its salts, to ensure that water functions of solvent.

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

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

The number of alcohol are not particularly limited, but preferably it is 0.5-5 times the amount by weight of compounds of General formula [9] or its salts, to ensure that the alcohol function of 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, carry out the heat.

As the acid used, if required, in this reaction, are available, for example, inorganic acid, such as chloromethane acid, sulfuric acid, phosphoric acid, hydrogen chloride, bromovalerate and the like;

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

and organic sulfonic acid, such as methanesulfonate acid, p-toluensulfonate acid and the like.

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

In addition, the acid may be used is as a solvent.

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

Moreover, the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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

ethers, such as tetrahydrofuran, 1,2-dimethoxyethane, bis(2-methoxyethoxy) 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;

the sulfoxidov, 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, and these solvents may be used in mixture.

This reaction can be carried out at 50-200°C, and preferably at 50-150°C 1 min what are you up to 24 hours.

[Method 4]

where R4has the values defined above.

2-(1-Benzothiophen-5-yl)ethanol compounds of the formula [15] can be obtained by exposure to compounds of General formula [11] or its salt hydrolysis, if necessary, and turn it into (1-benzothiophen-5-yl)acetic acid or its salts of the compounds of formula [14], then the exposure (1-benzothiophen-5-yl)acetic acid or its salts of reduction reaction with the addition of activator in the presence of alkali metal borohydride.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis(2-methoxyethoxy) ether, dioxane and the like, and tetrahydrofuran is preferred.

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

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

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

The number used will dissolve the La is not particularly limited, but preferably it is 1 to 20-fold amount by weight of the compounds of formula [14] or its salts, and preferably equal to 2-10 times the specified volume (vol./mass.).

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

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

As the activator used in this reaction are available, for example, a proton acid such as sulfuric acid, hydrogen chloride, triperoxonane acid and the like, and sulfuric acid and hydrogen chloride are preferred.

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

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

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

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

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

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

In addition, the hydrolysis reaction of compounds of General formula [11] or its salts, which can be carried out, if necessary, can be performed by itself, for example, the compound of the formula [14] or its salt can be obtained by exposure of their hydrolysis in the presence of a base.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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

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

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

the sulfoxidov, 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 may be used in mixture.

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

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

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

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

As predpochtite the high grounds offered neorganicheskoi base, and sodium hydroxide and potassium hydroxide are preferred.

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

This reaction is preferably performed by adding water.

The amount of added water can be equal to or greater than 1 mol per mol of compound of General formula [11] or its salt is preferably 0.1 to 10 times the specified volume (vol./mass.), and more preferably it is equal to 0.3 to 2 times the specified volume (vol./mass.), to ensure that water functions of solvent.

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

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

The compound of the formula [14] or its salt obtained in the above manner can be isolated from the reaction mixture after the reaction in the usual way.

For example, after the reaction, they can be isolated by acidification with dilute chloroethanol acid, extraction with an organic solvent, such as toluene, with the subsequent removal process is Italia.

In addition, they can be isolated as a salt by adding a base in the extract.

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

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

ammonium salt,

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

The preferred salt is proposed salt of an alkali metal such as sodium and potassium, and sodium salt is preferred.

[Method of obtaining 5]

where R1has the values defined above.

3-(2-(1-Benzothiophen-5-yl)ethoxy)propionic acid compounds of the formula [17] or its salt can be obtained by exposure to the compounds of formula [15] the reactions proceed by Michael using Acrylonitrile in the presence of a base to obtain the compounds of formula [16], then the exposure to the compounds of formula [16] interaction with alcohol of General formula [1] in the presence of acid, then converting it into a compound of General formula [2] and exposure to compounds of General formula [2] is eacli hydrolysis in the presence of a base.

This method of obtaining explained below in more detail.

The reaction joining Michael:

The compound of the formula [16] can be obtained by exposure to the compounds of formula [15] the reactions proceed by Michael 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 has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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-methoxyethoxy) ether, dioxane and the like;

the sulfoxidov, such as dimethyl sulfoxide and the like;

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

The preferred solvents are offered a single solvent of aromatic hydrocarbons and a mixed solvent of aromatic hydrocarbons, ethers and tertiary alcohols, and a single solvent of aromatic Ugledar the Dov, a mixed solvent of aromatic hydrocarbons and ethers and mixed solvent of aromatic hydrocarbons and tertiary alcohols are preferred, and toluene, a mixed solvent of toluene and tetrahydrofuran, a mixed solvent of toluene and tert-butanol are added and mixed solvent of toluene and tert-amyl alcohol are more preferred.

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

In addition, as an additive to the above solvents can be mixed primary alcohols, such as a small amount of methanol and ethanol and the like;

secondary alcohols such as 2-propanol and the like;

and water, and the like.

The amount of the additive is equal to or less than 0.5 times the amount by weight of the compounds of formula [15], and more preferably it is equal to or less than 0.1 times the specified volume (vol./mass.).

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

the metal alkoxide is, such as sodium methoxide, ethoxide sodium tert-piperonyl potassium tert-piperonyl sodium and the like;

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

As the preferred Foundation offers organic substrate and a metal alkoxide, and more preferred are the hydroxide designed and tert-piperonyl potassium.

The amount of base 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 to 0.1 mol.

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

As the catalyst, if required, offer generally known salt of Quaternary ammonium, preferably tetrabutylammonium, benzyltrimethylammonium and benzyltriethylammonium.

The amount of catalyst 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 to 0.1 mol.

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

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

The reaction temperature is not particularly restricted, but it may be in the range from 0°C to a temperature equal to or above the boiling point of the solvent, and is preferably 0-35°C.

The reaction time is not particularly restricted, but it is in the interval from 1 minute to 24 hours and preferably from 30 minutes to 4 hours.

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

The reaction of esterification:

The compound of General formula [2] can be obtained by exposure to the compounds of formula [16] interaction with alcohol of General formula [1] in the presence of acid.

As the acid used in this reaction are available, for example, inorganic acid, such as chloromethane acid, sulfuric acid, hydrogen chloride, bromovalerate and the like,

and organic sulfonic acid, such as methanesulfonate acid, p-toluensulfonate acid and the like.

The preferred acid is proposed inorganic acid, and sulfuric acid and hydrogen chloride are more preferred.

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

As the alcohol of General formula [1]used in this reaction are offered alkalemia alcohols with an unbranched chain, such as methanol, ethanol, propanol, butanol, pentanol and the like;

alkalemia alcohols with branched-chain, such as isobutyl alcohol and the like;

substituted alkalemia alcohols, such as methoxyethanol, chloroethanol, cyclohexanediol and the like;

and Arakelova alcohols such as benzyl alcohol, finitely alcohol and the like.

The preferred alcohol is offered alkalemia alcohols with an unbranched chain, and methanol, ethanol, propanol and butanol are preferable.

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

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

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

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

As the solvent used offer though especially this limit, the same solvent as for the reactions of addition to Michael.

The reaction temperature is not particularly restricted, but it may be in the range from 0°C to a temperature equal to or above the boiling point of the solvent, and is preferably 20-150°C.

The reaction time is not particularly restricted, but it is in the range from 10 minutes to 50 hours, and preferably ranges from 1-24 hours.

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

Hydrolysis reaction:

The compound of General formula [17] or its salt can be obtained by hydrolysis of compounds 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 has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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

halogenated Ugledar the water, such as dichloromethane, chloroform and the like;

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

the sulfoxidov, 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 may be used in mixture.

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

The amount used of the solvent is not particularly limited, but preferably is 0.5 to 10 times the amount by weight of compounds of General formula [2], and more preferably it is 0.5-3 times the specified volume (vol./mass.).

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

As predpochtitel the CSO Foundation serves inorganic base, and sodium hydroxide and potassium hydroxide are preferred.

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

This reaction is preferably carried out with addition of water.

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

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

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

The compound of the formula [17] or its salt obtained in the above manner can be isolated from the reaction mixture after the reaction in the usual way.

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

Chrome is also they can be isolated as a salt by adding a base in the extract.

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

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

ammonium salt,

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

The preferred salt is proposed salt with alkaline metal such as sodium and potassium, and the like, and sodium salt is more preferable.

[Methods of obtaining 6]

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

This method of obtaining explained below in more detail.

Transformation into a reactive derivative:

The compound of the formula [17] or its salt can be converted into reactio the but-able-derived implementation of its interaction with the activator.

As the reactive derivative are offered, for example, gelegenheid, anhydride, activated amide, and the activated ester and the like, and gelegenheid is preferred.

As a way of turning compounds in reactive derivative are offered, for example, the transformation in gelegenheid using a halogenation agent such as thionyl chloride, oxalicacid, trichloride phosphorus, pentachloride phosphorus, and the like;

becoming anhydride condensation galogenangidridy acid, such as ethylchloride, isobutylacetate, pivaloyloxy and the like;

transformation into activated amide using condensation with imidazole and activated agent amidation, such as carbonyldiimidazole and the like,

and become activated ester condensation with p-NITROPHENOL, 2-mercaptobenzothiazoles, and the like.

As a way of turning into a reactive derivative, it is preferable transformation in gelegenheid using a halogenation agent, and more preferred is turning into an acid chloride using thionyl chloride.

The amount of activator used in said conversion varies depending on the IDA activator, but, for example, in the case of thionyl chloride it can be equal to or greater than 0.5 mol per mol of 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 has no adverse effect on the reaction, is not particularly limited, but suggest, for example, aliphatic hydrocarbons such as hexane, cyclohexane and the like;

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-methoxyethoxy) ether, dioxane and the like;

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

the sulfoxidov, 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 may be used in mixture.

The preferred solvents are available aromatic hydrocarbons such as benzene, toluene and xylene, and the like, and ethers such as tetrahydrofuran, 1,2-dimetho sietan, bis(2-methoxyethoxy) ether, dioxane and the like, and toluene and 1,2-dimethoxyethane are preferred.

The amount used of the solvent is not particularly limited, but preferably it is 1 to 20-fold amount by weight of the compounds of formula [17] or its salts, and more preferably is 1-10 times the specified volume (vol./mass.).

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

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

Reactive derivative of the compound of the formula [17] or its salt obtained in the above manner can be isolated and purified, but preferably move on to the next reaction without isolation.

The amidation reaction:

The compound of the formula [18] can be obtained by engagement of the solution reactive derivative of the compound of the 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 are available, for example, an organic base such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), pyridine, and the like;

and neo is organic base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.

As the preferred Foundation offers neorganicheskoi base, and sodium hydroxide is more preferable.

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

Number 3-azetidinol or its salts may be equal to or greater than 1 mol per mol of 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 aqueous solution.

The amount of water containing dissolved 3-azetidinol or its salts are not particularly restricted, but preferably it is 1 to 20-fold amount by weight of the compounds of formula [17] or its salts, and preferably is 1-10 times the specified volume (vol./mass.).

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

After the reaction, the compound of the formula [18], obtained described the above, can be isolated and purified by crystallization from the reaction mixture by performing processing, such as neutralization of the reaction mixture and diluted with water, if necessary with subsequent operation of heating and cooling.

[Method of obtaining 7]

1-(3-(2-(1-Benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol compounds of the formula [19] or its salt can be obtained by exposure to the compounds of formula [18] reaction recovery with the addition of activator, such as a proton acid, meteorologi agent and cilleruelo agent and the like in the presence of alkali metal borohydride.

This reaction is usually carried out in the presence of a solvent, and the solvent used, if it has no adverse effect on the reaction, is not particularly limited, but suggest, for example, ethers such as tetrahydrofuran, 1,2-dimethoxyethane, bis(2-methoxyethoxy) ether, dioxane and the like, and tetrahydrofuran is preferred.

In addition, these solvents may 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 things like the th.

The amount used of the solvent is preferably 1 to 20-fold amount by weight of the compounds of formula [18], and more preferably it is equal to 3-10 times the specified volume (vol./mass.).

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

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

As the activator used in this reaction are available, for example, a proton acid such as sulfuric acid, hydrogen chloride, triperoxonane acid and the like,

metymirumi agent, such as dimethylsulfate and the like,

and similitude agent, such as trimethylsilyloxy and the like.

As the preferred activator is proposed proton acid such as sulfuric acid, hydrogen chloride, and the like, and sulfuric acid is more preferable.

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

in Addition, add activator varies depending on the type of activator, but in the case of sulfuric acid, it is preferably in the range from 10 minutes to 6 hours, and more preferably it ranges from 30 minutes to 4 hours.

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

In addition, when the amount of alkali metal borohydride is 2.0 to 2.2 mol per mol of compound of the formula [18] and the amount of sulfuric acid is 0.5 to 0.6 mol per mol of the alkali metal borohydride, and the time of addition of sulfuric acid dropwise is 1-4 hours, can be obtained compound of the formula [19] or its salt with high purity, thanks to the additional suppression of the formation of by-products.

The reaction temperature is not particularly restricted, but it may be in the range from -20 to 150°C, and is preferably 0-70°C.

After addition of the activator at 0-30°C is the preferred implementation of the interaction at 30-70°C, and more preferred after you add the activator at 0-30°C is the implementation of interaction at 40-60°C.

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

In the present invention as the site is titeling retrieval method is proposed the following method:

the method of obtaining suspendirovanie the compounds of formula [18] in the air (3-10 times the specified volume (vol./mass.)), the addition of alkali metal borohydride (2-3 mol), the addition of the activator at 0-30°C and then for interaction with 30-70°C for 1-20 hours is preferred, the method of obtaining suspendirovanie the compounds of formula [18] in the air (3-10 times the specified volume (vol./mass.)), the addition of sodium borohydride (2-3 mol), adding a proton acid (0.5 to 1 mol per mol of sodium borohydride) at 0-30°C and then for interaction with 30-70°C for 1-20 hours is preferable, and the method of obtaining suspendirovanie the compounds of formula [18] in tetrahydrofuran (3-10 times the specified volume (vol./mass.)) the addition of sodium borohydride (2.0 to 2.2 mol), sulfuric acid (0.5 to 0.6 mol per mol of sodium borohydride), by adding sulfuric acid at 0-30°C for 1-4 hours, and then the engagement at 40-60°C for 1-20 hours is more preferable.

After the reaction, the compound of the formula [19] or its salt obtained in the manner described above, can be selected in the usual way.

For example, after the reaction, they can be distinguished by the addition of 6.0 mol/l chloroethanol acid to decompose the excess reducing agent, cooled to room temp the atmospheric temperature, then the alkalization reaction mixture with an aqueous solution of sodium hydroxide, extraction with an organic solvent such as ethyl acetate, and then removing the solvent from the extract.

In addition, they can be isolated as a salt by adding an acid in the extract.

As for the salts of the compounds of formula [19], the salt, if it is commonly known as salt basic group such as amino group is not particularly limited, but suggest, for example, salts of mineral acids, such as chloromethane acid, Hydrobromic acid, nitric acid, sulfuric acid and the like,

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

and salts of sulfonic acid, such as methanesulfonate acid, benzolsulfonat acid, toluensulfonate acid, mesitylenesulfonic acid, naphthalenesulfonate acid and the like.

As the preferred salt offers a pharmacologically acceptable salt, and a salt of maleic acid is preferable.

If the compounds of the present invention there isomer (n is an example, optical isomer, hydrate, MES and various kinds of crystal forms, all of them are covered by the present invention.

In addition, if the compounds used in the production method, described above, there are isomer (for example, optical isomer, hydrate, MES and various kinds of crystal forms, all of them can be used in the production method of the present invention.

Examples

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

Relations in luttich mixtures taken by volume. In the absence of specific instructions to the media in chromatography on a column of silica gel represents B.W. silica gel BW-127ZH or PSQ100B (product of Fuji Silysia Chemical Ltd.).

Abbreviations in the examples mean the following: Me: methyl, Et: ethyl, Pr: propyl, Bu: butyl,tBu: tert-butyl, DMSO-d6: dimethylsulfoxide-d6.

Reference example 1

To water (275 ml) suspension 546 g thiophenol was added dropwise water (550 ml) solution of 585 g of potassium hydroxide at a temperature not exceeding 20°C. Then, to the mixture was added dropwise water (825 ml) solution of 492 g of Chloroacetic acid and the mixture was stirred at 80-90°C for 3 hours. After cooling, the reaction mixture pH was brought to 1.5 chlorotoluron the th acid and was added to the mixture 1650 ml of dichloromethane and 550 ml of water. The organic layer was separated and added to her anhydrous magnesium sulfate. Was filtered, the insoluble material and the filtrate was added 5,95 g of iron chloride(III), then was added dropwise 832 g of bromine at 5-10°C and the mixture was stirred at room temperature for 5 hours. After cooling the reaction solution to 5°C and to it was added dropwise water (825 ml) solution of 187 g of sodium sulfite and the pH was brought up to 1.2 chloroethanol acid. After stirring at 5-10°C. for 1 hour the precipitate was collected by filtration to obtain a solid substance. To the obtained solid substance was added 2000 ml of a mixture of toluene and water was removed by heating and azeotropic distillation. The reaction mixture was cooled to 5°C within 2 hours. After stirring at the same temperature for 1 hour, the crystalline precipitate was collected by filtration to obtain 1108 g (4 pampanito)acetic acid in a solid white color.

1H-NMR (CDCl3) δ value: the 3.65 (2H, s), 7,25-to 7.35 (2H, m), 7,40-7,50 (1H, m).

Reference example 2

To water (600 ml) solution at 88.9 g of sodium hydroxide was added to 200 g of 4-bromothiophene and was added dropwise water (300 ml) solution of 105 g of Chloroacetic acid, and the mixture was stirred at 60-70°C for 1 hour. After cooling the reaction mixture to 40°C) was added thereto 140 ml of chlorotoluron the th acid and 600 ml of toluene and the mixture was then heated to 80°C. The organic layer was separated and was slowly cooled to 5°C. After stirring at the same temperature for 1 hour and the crystalline precipitate was collected by filtration to obtain 243 g (4 pampanito)acetic acid in a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of reference example 1.

Example 1-1

To dichloromethane (750 ml) suspension of 250 g (4 pampanito)acetic acid was added 2.5 ml of N,N-dimethylformamide and 132 g of thionyl chloride and the mixture is then boiled under reflux for 1 hour. After cooling the reaction mixture to 20°C and to it was added dropwise dichloromethane (1500 ml) suspension of 148 g of aluminium chloride 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 1310 ml of water and 188 ml chloroethanol acid while cooling. The organic layer was separated, was added thereto 1250 ml of water and brought the pH to 3.0 by the addition of 5% aqueous potassium carbonate solution. The organic layer was separated and cooled to 5°C. was Added thereto and 15.3 g of sodium borohydride, and 500 ml of methanol and the mixture was stirred at 10-20°C for 2 hours. To the reaction solution was added to 750 ml of water, then brought the mixture to pH 7.0 by adding acetic acid and left the Yali at room temperature over night. To the reaction solution was added 200 ml of 5% aqueous potassium hydroxide solution and the organic layer was separated. To the organic layer were added to 25.0 g of activated charcoal and the mixture was stirred at room temperature. Was filtered, the insoluble material, and drove away from the filtrate the solvent. To the obtained residue was added cyclohexane, precipitated precipitated crystals were collected by filtration to obtain 194 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol in the form of a solid pale red color.

1H-NMR (CDCl3) 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), and 5.30-of 5.40 (1H, m), 7,11 (1H, d, J=8,3 Hz), 7,35 (1H, DD, J=8,3, 2.0 Hz), to 7.50 (1H, d, J=2.0 Hz).

Example 1-2

To acetone (600 ml), a solution of 300 g of 5-bromo-2,3-dihydro-1-benzothiophen-3-ol was added 12.4 g of monohydrate p-toluensulfonate acid and the mixture is then boiled under reflux for 2 hours. To the reaction solution was added 15.0 g of activated charcoal and the mixture was stirred. Was filtered, the insoluble material was washed its 300 ml of acetone. The filtrate and wash water were combined and to the mixture was added dropwise 2700 ml of water at 5-15°C. the Precipitate was collected by filtration to obtain 268 g of 5-bromo-1-benzothiophene in the form of a solid pale purple color.

1H-NMR (CDCl3) δ value: 7,27 (1H, d, J=5.4 Hz), 7,44 (1H, DD, J=8,5,1,9 Hz), of 7.48 (1H, d, J=5.4 Hz), 7,74 (1H, d, J=8.5 Hz), of 7.97 (1H, d, J=1.9 Hz).

Example 2-1

(1) To 1,2-dimethoxyethane (10 ml) suspension of 0.02 g of Tris(dibenzylideneacetone)diplegia(0) was added 0.11 g of 10% (wt./mass.) mix three(tert-butyl)phosphine/hexane, to 1.76 g of cesium carbonate, 0.50 g of 5-bromination and 0.45 g of diethylmalonate and the mixture is then boiled under reflux for 2 hours. To the reaction mixture were added water and ethyl acetate, and then brought the mixture to pH 2 by adding 2 mol/l chloroethanol acid. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 10:1) to obtain the 0,69 g of diethyl 2-(1-benzothiophen-5-yl)malonate in a solid white color.

1H-NMR (CDCl3) δ value: of 1.27 (6H, t, J=7,1 Hz), 4,1-4,3 (4H, m), to 4.73 (1H, s), 7,33 (1H, d, J=5.4 Hz), 7,40 (1H, DD, J=8,3, 2.0 Hz), was 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 etilenglikolevye (1.0 ml) suspension of 0.25 g of diethyl 2-(1-benzothiophen-5-yl)malonate was added 1.0 ml of 40% (wt./mass.) an aqueous solution of potassium hydroxide and 0.3 ml of water and the mixture is then boiled under reflux for 2 hours. To the reaction mixture were added water and toluene and separated water layer. Brought the pH to 2 with 6 mol/l chlorine is vodorodnoi acid was added to the water layer in ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. The resulting residue is suspended in 5 ml of xylene was added to a suspension of 0.01 g of monohydrate p-toluensulfonate acid, and the mixture is then boiled under reflux for 30 minutes. Drove away under reduced pressure, the solvent and the obtained residue was added toluene and cyclohexane. The precipitate was collected by filtration to obtain 0.02 g of 2-(1-benzothiophen-5-yl)acetic acid in the form of a solid pale yellow color.

1H-NMR (CDCl3) 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 1,2-dimethoxyethane (10 ml), a solution of 0.11 g of 10% (wt./mass.) three(tert-butyl)phosphine/hexane was added 0.02 g of Tris(dibenzylideneacetone)diplegia(0), of 1.76 g of cesium carbonate, 0.50 g of 5-bromination and 0.61 g of tert-butylmalonate and the mixture is then boiled under reflux for 2 hours. Then added thereto, 0.02 g of Tris(dibenzylideneacetone)diplegia(0) and 0.11 g of 10% (wt./mass.) three(tert-butyl)phosphine/hexane and then boiled under reflux 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 brought the pH to 3 by addition of 6 mol/l chloroethanol is islote. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 20:1) obtaining of 0.49 g of di(tert-butyl) 2-(1-benzothiophen-5-yl)malonate in a solid white color.

1H-NMR (CDCl3) δ value: of 1.47 (18H, s)4,55 (1H, s), 7,32 (1H, d, J=5.4 Hz), 7,39 (1H, DD, J=8,5) and 1.7 Hz), the 7.43 (1H, d, J=5.4 Hz), to 7.84 (1H, d, J=1.7 Hz), 7,86 (1H, d, J=8,5 Hz).

(2) To 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 monohydrate p-toluensulfonate acid and then boiled under reflux for 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 in a solid white color.

1H-NMR (CDCl3) δ value: 4,80 (1H, s), 7,3-7,5 (1H, m), 7,47 (1H, d, J=5.5 Hz), to 7.77 (1H, d, J=5.5 Hz), 7,89 (1H, s), of 7.97 (1H, d, J=8,3 Hz).

(3) To kelloway (2 ml) suspension of 0.10 g of 2-(1-benzothiophen-5-yl)malonic acid was added 4 mg of the monohydrate of p-toluensulfonate acid and then boiled under reflux for 1 hour. Drove away under reduced pressure, the solvent and the obtained residue was added cyclohexane. The precipitate was collected by filtration to obtain 0.08 g of 2-(1-benzothiophen-5-yl)acetic acid is in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 2-1 (2).

Example 2-3

To a toluene (3 ml) solution of 0.21 g of ethylcyanoacrylate added 0,41 g of tert-butoxide potassium, of 0.30 g of 5-bromination and 0.02 g of tetrakis(triphenylphosphine)palladium(0) and then boiled under reflux for 7.5 hours. To the reaction mixture were added water and brought the pH up to 2 chloroethanol acid. Added ethyl acetate and was filtered, the insoluble material. The organic layer was separated, washed with water and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 5:1) to obtain 0.16 g of ethyl 2-(1-benzothiophen-5-yl)-2-cyanoacetate in the form of a solid pale yellow color.

1H-NMR (CDCl3) δ value: of 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) and 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 toluene (25 ml) suspension of 0.16 g dichlorobis(triphenylphosphine)palladium(II) was added 0.12 g of triphenylphosphine, 0.01 g sodium borohydride, 5,79 g of tert-butoxide potassium and of 2.92 g of ethylcyanoacrylate and stirred at room temperature for 10 minutes. Doba is Lyali of 5.00 g of 5-bromination and 25 ml of toluene and then boiled under reflux for 4 hours. Added 0.14 g tetrakis(triphenylphosphine)palladium(0) and then boiled under reflux for 2 hours. Then to the reaction solution was added 25 ml of ethanol, 2,82 g of sodium hydroxide and 5 ml of water and then boiled under reflux for 6 hours. Added 2,82 g of sodium hydroxide and then boiled under reflux for 5 hours. To the reaction mixture was added 15 ml of water and 0.5 g of activated carbon was filtered and the insoluble material. The aqueous layer was separated and the solution was added 35 ml of ethanol. Brought the pH to 2 by addition of 15 ml chloroethanol acid. Was added to a mixture of 15 ml of water and stirred it at 40°C. was Added 30 ml of water and stirred. Then it was cooled. The precipitate was collected by filtration to obtain to 3.38 g of 2-(1-benzothiophen-5-yl)acetic acid in the form of a solid pale yellow color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 2-1 (2).

Example 2-5

To 1,2-dimethoxyethane (25 ml) suspension of 0.16 g dichlorobis(triphenylphosphine)palladium(II) was added 0.12 g of triphenylphosphine, 0.01 g sodium borohydride, 5.53 g of tert-butoxide potassium and of 3.48 g of tert-butylcyanoacrylate and stirred at room temperature for 10 minutes. Was added to 5.00 g of 5-bromination and then boiled under reflux in the course is 2 hours. After the reaction mixture was added 15 ml of water, the pH was brought to 1 by adding 2 ml chloroethanol acid. The precipitate was collected by filtration to obtain 5,69 g of tert-butyl 2-(1-benzothiophen-5-yl)-2-cyanoacetate in the form of a solid pale yellow color.

1H-NMR (CDCl3) δ value: a 1.45 (9H, s), to 4.73 (1H, s), of 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), to $ 7.91 (1H, d, J=8.5 Hz), of 7.9 to 8.0 (1H, m).

Example 2-6

To 1,2-dimethoxyethane (1,00L) to a solution of 250 g of 5-bromination was added 276 g of tert-butoxide potassium and 174 g of tert-butylcyanoacrylate. Was added to the mixture 8,23 g dichlorobis(triphenylphosphine)palladium(II) and x 6.15 g of triphenylphosphine at 80-85°C and then boiled under reflux for 2 hours. Then to the reaction mixture was added 500 ml of ethylene glycol, 250 ml of water and 263 g of potassium hydroxide and then boiled under reflux for 4 hours. To the reaction mixture was added to 1.50 l of water and 12.5 g of diatomaceous earth (Tellur, Advanced Minerals Company). After filtered, the insoluble material, the filtrate was added 250 ml of toluene and separated water layer. To the aqueous layer was added 375 ml of toluene and 375 ml of ethyl acetate, the pH was brought to 1 by addition of 505 ml chloroethanol acid and the organic layer was separated. The organic layer was treated with 12.5 g of activated charcoal. Drove under reduced pressure Rast is oritel was added toluene. The precipitate was collected by filtration to obtain 176 g of 2-(1-benzothiophen-5-yl)acetic acid in a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 2-1 (2).

Example 2-7

(1) To 1,2-dimethoxyethane (3 ml) solution of 0.30 g of 4-bromination was added 0.33 g of tert-butoxide potassium, 0.21 g of tert-butylcyanoacrylate, 0.01 g of dichlorobis(triphenylphosphine)palladium(II) and 0.01 g of triphenylphosphine and then boiled under reflux for 40 minutes. Added 0.33 g of tert-butoxide potassium, 0.01 g of dichlorobis(triphenylphosphine)palladium(II) and 0.01 g of triphenylphosphine and then boiled under reflux for 30 minutes. The reaction mixture was added to a mixed solution of water and ethyl acetate and brought the pH to 1 by addition of 6 mol/l chloroethanol acid. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 5:1) to obtain 0.26 g of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate in the form of oily substances pale brown color.

1H-NMR (CDCl3) δ value: of 1.42 (9H, s)of 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), to 7.59 (1H, d, J=5.6 Hz), 7,92 (1H, d, J=78 Hz).

(2) To etilenglikolevye (1.0 ml) solution of 0.25 g of tert-butyl 2-(1-benzothiophen-4-yl)-2-cyanoacetate was added 1.0 ml of 40% (wt./mass.) an aqueous solution of potassium hydroxide and 0.3 ml of water and stirred at 95-105°C for 1 hour. To the reaction mixture were added water and toluene and separated water layer. Brought the pH to 2 by addition of 6 mol/l chloroethanol acid and to the mixture was added ethyl acetate. The organic layer was separated and dried over anhydrous magnesium sulfate, and then drove away under reduced pressure the solvent. To the obtained residue was added cyclohexane. The precipitate was collected by filtration to obtain 0.15 g of 2-(1-benzothiophen-4-yl)acetic acid in a solid white color.

1H-NMR (CDCl3) 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

In 340 ml of tetrahydrofuran suspended of 50.2 g of sodium borohydride, the suspension was dropping consistently tertrahydrofuran ring (340 ml) solution of 170 g (1-benzothiophen-5-yl)acetic acid and of 65.1 g of sulfuric acid and stirred at room temperature for 2.5 hours. In the resulting reaction mixture was added dropwise 85 ml of acetone and stirred for 30 minutes. Added 510 ml of water and 680 ml of toluene. The organic layer was separated, added 510 ml of water and brought the pH to 12 by addition of 48 ml of 20% (wt./mass.) water is th solution of sodium hydroxide. The organic layer was separated and washed with water followed by distillation of the solvent. Added cyclohexane and toluene. The precipitate was collected by filtration to obtain 135 g of 2-(1-benzothiophen-5-yl)ethanol in the form of a solid white color.

1H-NMR (CDCl3) 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) and 1.7 Hz), 7,30 (1H, d, J=5.4 Hz), 7,44 (1H, d, J=5.4 Hz), and 7.6 to 7.7 (1H, m), 7,83 (1H, d, J=8,3 Hz).

Example 3-2

In 5 ml of 1,2-dimethoxyethane suspended 2,95 g sodium borohydride, to the suspension was added dropwise 1,2-dimethoxyethane (25 ml) solution of 10 g (1-benzothiophen-5-yl)acetic acid and 11 ml of 6.9 mol/l solution of hydrogen chloride/1,2-dimethoxyethane and stirred at room temperature for 1 hour. To the obtained reaction mixture was added dropwise 5 ml of acetone and stirred for 30 minutes. Was added 20 ml of water, 30 ml of toluene and 2 ml of 2 mol/l chloroethanol acid. Then, after the pH was brought to 9.5 by adding 20 ml of 2 mol/l aqueous sodium hydroxide solution, separated the organic layer. The organic layer was dried over anhydrous magnesium sulfate, followed by distillation of the solvent. Added cyclohexane and toluene. The precipitate was collected by filtration to obtain to 7.84 g of 2-(1-benzothiophen-5-yl)ethanol in the form of a solid white color.

Example 3-3

In 40 ml of tetrahydrofuran suspended 4,72 g sodium borohydride, to suspen the AI was added dropwise tertrahydrofuran ring (60 ml) solution of 20 g (1-benzothiophen-5-yl)acetic acid and 6,12 g of sulfuric acid. The solution was heated to 66°C, and then drove about 40 ml of the solvent at normal pressure and stirred at the same temperature for 1 hour. After cooling, to the resulting reaction mixture was added dropwise 10 ml of acetone and stirred for 30 minutes. Added 90 ml of water and 80 ml of toluene. The organic layer was separated, was added 60 ml of water and brought the pH to 13.6 by adding 5 ml of 5 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed with water and then drove the solvent, was added cyclohexane and toluene. The precipitate was collected by filtration to obtain 16.5 g of 2-(1-benzothiophen-5-yl)ethanol in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 3-1.

Example 4-1

(1) To toluene (5 ml) suspension of 0.23 g of 40% (wt./mass.) the aqueous hydroxide solution designed was added to 5.00 g of 2-(1-benzothiophen-5-yl)ethanol was added dropwise 2,20 ml of Acrylonitrile at 0-5°C, and then stirred at 0-20°C for 1 hour. To the obtained reaction mixture was added with 0.125 ml chloroethanol acid. Added 10 ml of propanol, 1.0 ml of water and 3.1 ml of sulfuric acid and then boiled under reflux for 6.5 hours. After cooling, to the reaction mixture were added 10 ml of water and 10 ml of toluene, the Organic layer was separated and dried over anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 15:1 to 7:1) to obtain the 7,21 g of propyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate as colorless oily substance.

1H-NMR (CDCl3) δ value: of 0.91 (3H, t, J=7.4 Hz), 1,57-to 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), was 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-of 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 water (12 ml) solution of 2.76 g of potassium hydroxide and stirred at room temperature for 1.5 hours. From the obtained reaction mixture is kept under reduced pressure, the solvent and to the residue was added 36 ml of toluene and 36 ml of water. Brought the pH to 1.9 by addition of 8 ml of 6 mol/l chloroethanol acid. The organic layer was separated, and then drove away under reduced pressure the solvent. Added 12 ml of toluene and 24 ml of cyclohexane. The precipitate was collected by filtration to obtain 8,91 g 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

1H-NMR (CDCl3) δ value: 2,63 (2H, t, J=6.2 Hz), of 3.00 (2H, t, J=7,1 Hz), and 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 G is), 7,27 (1H, DD, J=5,5, 0.6 Hz), 7,40 (1H, d, J=5.5 Hz), 7,65-of 7.70 (1H, m), 7,78 (1H, d, J=8,4 Hz).

Example 4-2

(1) To toluene (5 ml) suspension of 5.00 g of 2-(1-benzothiophen-5-yl)ethanol was added to 0.23 g of 40% (wt./mass.) an aqueous solution of hydroxide designed and 2,28 ml of tetrahydrofuran and added dropwise 2,20 ml of Acrylonitrile at 0-10°C, then stirred at the same temperature for 1.5 hours. To the obtained reaction mixture was added 0.1 ml chloroethanol acid, 10 ml of butanol and 5 ml of 50% (wt./mass.) sulfuric acid and then boiled under reflux for 15 hours. After cooling, to the reaction mixture was added 15 ml of water. The organic layer was separated and dried over anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced pressure the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 10:1) obtaining of 6.65 g of butyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate as colorless oily substance.

1H-NMR (CDCl3) δ value: to 0.92 (3H, t, J=7.4 Hz), 1,30-1,45 (2H, m), 1,50-of 1.65 (2H, m), to 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) and 1.7 Hz), 7,28 (1H, DD, J=5,4, 0.7 Hz), 7,41 (1H, d, J=5.4 Hz), 7,65-of 7.70 (1H, m), 7,78 (1H, d, J=8,3 Hz).

(2) To methanol (5 ml) solution of 5.00 g of butyl 3-(2-(1-benzothia the EN-5-yl)ethoxy)propionate was added water (5 ml) solution of 1.10 g of potassium hydroxide and stirred at room temperature for 2 hours. From the obtained reaction mixture is kept under reduced pressure, the solvent and to the residue was added 30 ml of toluene and 30 ml of water. Brought the pH to 1.6 by the addition of 3.5 ml of 6 mol/l chloroethanol acid. The organic layer was separated, and then drove away under reduced pressure the solvent. Added 15 ml of toluene and 30 ml of cyclohexane. The precipitate was collected by filtration receipt of 3.60 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 4-1 (2).

Example 4-3

(1) To toluene (5 ml) suspension of 5.00 g of 2-(1-benzothiophen-5-yl)ethanol was added to 0.23 g of 40% (wt./mass.) an aqueous solution of hydroxide designed and 2,28 ml of tetrahydrofuran and added dropwise 2,22 ml of Acrylonitrile at 5°C and then stirred at 0-15°C for 1.5 hours. To the obtained reaction mixture was added to 0.13 ml chloroethanol acid, 10 ml of methanol and 1.52 g of water. In the obtained mixture was introduced for 9.47 g of hydrogen chloride and then boiled under reflux for 4 hours. After cooling, to the reaction mixture was added 15 ml of water and 10 ml of toluene. The organic layer was separated and dried over anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced d is the pressure of the solvent. The obtained residue was purified by chromatography on a column of silica gel (eluent: hexane:ethyl acetate = 5:1) obtaining of 7.36 g of methyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate as colorless oily substance.

1H-NMR (CDCl3) δ value: of 2.58 (2H, t, J=6.4 Hz), 2,99 (2H, t, J=7,1 Hz), the 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) and 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 methanol (5 ml) solution of 5.00 g of methyl 3-(2-(1-benzothiophen-5-yl)ethoxy)propionate was added water (5 ml) solution of 1.27 g of potassium hydroxide and stirred at room temperature for 2 hours. From the obtained reaction mixture is kept under reduced pressure, the solvent and to the residue was added 30 ml of toluene and 30 ml of water. Brought the pH to 1.0 by adding 5 ml of 6 mol/l chloroethanol acid. The organic layer was separated, and then drove away under reduced pressure the solvent. Added 11 ml of toluene and 30 ml of cyclohexane. The precipitate was collected by filtration to obtain 4,51 g 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 4-1 (2).

Example 4-4

To toluene (50 ml) suspension of 50.0 g of 2-(1-benzothiophen-5-yl)ethanol was added 2.35 g of 40% (wt./mass.) water plants the ora hydroxide designed and added dropwise to 17.9 g of Acrylonitrile at 8-15°C and was stirred at 10-20°C. for 1.5 hours. To the obtained reaction mixture was added 1.25 ml chloroethanol acid, 100 ml of propanol and of 5.05 g of water. Was added dropwise 55,0 g of sulfuric acid and then boiled under reflux for 6 hours. After cooling, to the reaction mixture were added 100 ml of water. The organic layer was separated. Add to it 50 ml of methanol and added dropwise water (50 ml) solution of 31.5 g of potassium hydroxide and then stirred at room temperature for 1.5 hours. To the obtained reaction mixture was added 75 ml of toluene and 75 ml of water. The aqueous layer was separated, was added 100 ml of toluene, the pH is brought to 0.9 by adding 6 mol/l chloroethanol acid and the organic layer was separated. After distillation under reduced pressure of the solvent was added 50 ml of toluene and 125 ml of cyclohexane. The precipitate was collected by filtration to obtain to 59.6 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 4-1 (2).

Example 4-5

To toluene (260 ml) suspension of 260 g of 2-(1-benzothiophen-5-yl)ethanol was added while 43.8 g of 2-propanol and 1.64 g of tert-butoxide potassium and stirred for 0.5 hours. After cooling the reaction mixture to 15°C and to it was added dropwise 116 g of Acrylonitrile and stirred at 15-25°C in those which begins 1 hour. To the obtained reaction mixture was added to 6.5 ml chloroethanol acid, 520 ml of methanol and 78,9 g of water. In the resulting mixture was injected 310 g of hydrogen chloride at 10-25°C and then boiled under reflux for 3 hours. After cooling, to the reaction mixture was added 780 ml of water and 520 ml of toluene and the organic layer was separated. To the organic layer was added dropwise 260 ml of methanol and water (260 ml) solution of 164 g of potassium hydroxide and stirred at 30-35°C for 2 hours. To the obtained reaction mixture was added to 260 ml of water and the separated aqueous layer. To the aqueous layer was added 520 ml of toluene and 260 ml of water was added dropwise 234 ml chloroethanol acid, and the organic layer was separated. After the organic layer had slipped away under reduced pressure 390 ml of solvent was added to 1040 ml of cyclohexane. The precipitate was collected by filtration to obtain 326 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 4-1 (2).

Example 4-6

To 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% (wt./mass.) hydroxide designed and added dropwise of 8.04 g of Acrylonitrile at 30°C. After cooling the reaction mixture to 20°C and to it was added dropwise 53,6 the city of acre is lonitrile and then stirred at 15-25°C for 2 hours. To the obtained reaction mixture was added 27 ml chloroethanol acid and 180 ml of methanol. In the resulting mixture was injected 97 g of hydrogen chloride at 10-25°C, stirred at 30-40°C for 30 minutes and boiled under reflux for 3 hours. After cooling, to the reaction mixture was added 360 ml of water and the organic layer was separated. To the organic layer was added dropwise to 180 ml of methanol and water (180 ml) solution of 113 g of potassium hydroxide and stirred at 30-35°C for 2 hours. To the reaction mixture was added 360 ml of water and the separated aqueous layer. To the aqueous layer was added 360 ml of toluene and added dropwise 151 ml chloroethanol acid, and the organic layer was separated. After the organic layer is kept at normal pressure 126 ml of solvent was added to 1080 ml of cyclohexane. The precipitate was collected by filtration to obtain 222 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid in the form of a solid white color.

The values of chemical shifts1H-NMR spectrum in CDCl3consistent with the values of example 4-1 (2).

Example 5-1

In 15 ml of 1,2-dimethoxyethane was dissolved 10.0 g of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid. Was added to a solution of 0.1 ml of N,N-dimethylformamide and 5,23 g of thionyl chloride and stirred at room temperature for 1.5 hours. This reaction solution to allali dropwise to a mixed solution of 50 ml of water, 7,19 g of sodium hydroxide and 7.69 g 1/2 tartrate 3-azetidinol at 5-15°C and stirred at the same temperature for 2 hours. Then add 90 ml of water. The precipitate was collected by filtration receipt of 11.0 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol in the form of a solid white color.

1H-NMR (CDCl3) δ value: of 2.25 to 2.35 (2H, m), 2,96 (2H, t, J=7.0 Hz), 3,65-of 3.80 (5H, m), 3,85-of 3.95 (1H, m), 4,05-to 4.15 (1H, m), 4,15-of 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

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

The values of chemical shifts1NMR spectrum in CDCl 3consistent with the values of example 5-1.

Example 5-3

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

The values of chemical shifts1H-NMR spectrum in CDCl3consistent 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-methoxyethanol) ether (5 ml) was added and 0.37 g of sodium borohydride and then cooled to 10°C. was Added dropwise 2,49 ml of chlorotrimethylsilane at 5-10°C for 20 minutes and stirred at room temperature for 2.5 h and at 40°C for 4 hours. After cooling, was added dropwise with 3.27 ml of 6.0 mol/l chloroethanol acid and stirred at 70-75°C for 30 minutes. To the reaction mixture were added water and ethyl acetate, and to the-Odile pH to 10.0 by adding a 2.0 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride. Added anhydrous magnesium sulfate and activated charcoal. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 0.36 g of maleic acid and the mixture was utverjdali mixed solvent (5 ml) ethyl acetate:2-propanol (4:1) to obtain 0,72 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colourless crystalline substance.

1H-NMR (DMSO-d6) δ value: of 1.65 and 1.75 (2H, m), with 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 to of 3.85 (2H, m), 4,15-of 4.25 (2H, m), 4,40-4,50 (1H, m), the 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 to 7.75 (1H, m), to $ 7.91 (1H, d, J=8,3 Hz).

Example 6-2

To 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 and 0.37 g of sodium borohydride, and then was cooled to 10°C. was Added dropwise 2,49 ml of chlorotrimethylsilane at 5-10°C and was stirred at room temperature for 2.5 h and at 40°C for 4 hours. After cooling, was added dropwise with 3.27 ml of 6.0 mol/l chloroethanol acid and stirred at 70-75°C for 30 minutes. To the reaction mixture were added water and ethyl acetate and brought the pH to 10.0 by adding a 2.0 mol/l aqueous solution of hydroxide NAT the Oia. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride. Added anhydrous magnesium sulfate and activated charcoal. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 0.36 g of maleic acid and the mixture was utverjdali mixed solvent (5 ml) ethyl acetate:2-propanol (4:1) to give 0.71 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

The values of chemical shifts1H-NMR spectrum in DMSO-d6consistent with the values of example 6-1.

Example 6-3

To tetrahydrofuranate (5 ml) suspension of 1.00 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added and 0.37 g of sodium borohydride was added dropwise tertrahydrofuran ring (1 ml) solution of 0.75 ml triperoxonane acid for 30 minutes and then boiled under reflux for 2 hours. After cooling, was added dropwise with 3.27 ml of 6.0 mol/l chloroethanol acid and then boiled under reflux for 1.5 hours. To the reaction mixture were added water and ethyl acetate and the separated aqueous layer. To the aqueous layer was added ethyl acetate and brought the pH to 10.0 by the addition of 20% (wt./mass.) an aqueous solution of sodium hydroxide. The organic layer was separated, the industry is Ali successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 0.36 g of maleic acid and the mixture was utverjdali mixed solvent (5 ml) ethyl acetate:2-propanol (4:1) obtaining of 0.62 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

The values of chemical shifts1H-NMR spectrum in DMSO-d6consistent with the values of example 6-1.

Example 6-4

To tetrahydrofuranate (3 ml) suspension of 0.50 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added to 0.19 g of sodium borohydride and then was heated to 50°C. was Added dropwise tertrahydrofuran ring (1 ml) solution and 0.46 ml of dimethylsulfate at 50-55°C for 10 minutes and stirred at the same temperature for 2.5 hours. After cooling, was added dropwise 1,64 ml of 6.0 mol/l chloroethanol acid and then boiled under reflux for 1.5 hours. To the reaction mixture were added ethyl acetate and brought the pH to 10.0 by the addition of 20% (wt./mass.) an aqueous solution of sodium hydroxide. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced pressure, dissolve the spruce. To the obtained residue was added 0.18 g of maleic acid and the mixture was utverjdali from a mixed solvent of (3.75 ml) ethyl acetate:2-propanol (4:1) obtaining of 0.49 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

The values of chemical shifts1H-NMR spectrum in DMSO-d6consistent 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-methoxyethanol) ether (5 ml) was added and 0.37 g of sodium borohydride, and then was cooled to 10°C. was Added dropwise 2,46 ml of 4.0 mol/l solution of hydrogen chloride/dioxane 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 in for 6 hours. After cooling, was added dropwise with 3.27 ml of 6.0 mol/l chloroethanol acid and stirred at 65-70°C for 1.5 hours. To the reaction mixture were added water and ethyl acetate and brought the pH to 10.0 by adding a 2.0 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride. Added anhydrous magnesium sulfate and activated charcoal. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue, obavljale 0.36 g of maleic acid and the mixture was utverjdali mixed solvent (5 ml) ethyl acetate:2-propanol (4:1) to obtain the 0,86 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline matter.

Data1H-NMR in DMSO-d6match this example 6-1.

Example 6-6

To 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 and 0.37 g of sodium borohydride, and then was cooled to 10°C. was Added dropwise 2,46 ml of 4.0 mol/l solution of hydrogen chloride/dioxane at 5-15°C for 10 minutes and stirred at the same temperature for 1 hour, at room temperature for 3.5 hours at 35-40°C for 6 hours. After cooling, was added dropwise with 3.27 ml of 6.0 mol/l chloroethanol acid and stirred at 65-70°C for 1.5 hours. To the reaction mixture were added water and ethyl acetate and brought the pH to 10.0 by adding a 2.0 mol/l aqueous solution of sodium hydroxide. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride. Added anhydrous magnesium sulfate and activated charcoal. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 0.36 g of maleic acid and the mixture was utverjdali mixed solvent (5 ml) ethyl acetate:2-propanol (4:1) obtaining of 0.93 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

Data1H-NMR in DMSO-d6corresponded with D. the authorized example 6-1.

Example 6-7

To 1,2-dimethoxyethane (70 ml) suspension of 20.0 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added 5,46 g of sodium borohydride, and then was cooled to 15°C. was Added dropwise to 20.6 ml of 7.0 mol/l solution of hydrogen chloride/1,2-dimethoxyethane at 15-20°C for 40 minutes and was stirred at room temperature for 1.5 hours and at 53-57°C for 4 hours. After cooling, was added dropwise 65,5 ml of 6.0 mol/l chloroethanol acid and stirred at 65-70°C for 1 hour. The reaction mixture was concentrated under reduced pressure, was added 100 ml of water and 100 ml of ethyl acetate and brought the pH to 10.0 by the addition of 5.0 mol/l aqueous solution of sodium hydroxide. After separation of the organic layer washed with 50 ml of water and brought the pH to 1.0 by the addition of 6.0 mol/l chloroethanol acid. The aqueous layer was separated and added to it 50 ml of ethyl acetate. Brought the pH to 10.0 by the addition of 5.0 mol/l aqueous solution of sodium hydroxide. The organic layer was separated and was added anhydrous magnesium sulfate. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 7,22 g of maleic acid and the mixture was utverjdali mixed solvent (100 ml) ethyl acetate:2-propanol (4:1) to give 19.2 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as escitalo crystalline substance.

Example 6-8

To tetrahydrofuranate (35,0 ml) suspension of 5.00 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added to 1.61 g of sodium borohydride was added dropwise tertrahydrofuran ring (15 ml) solution of 2.09 g of sulfuric acid at room temperature for 30 minutes, and stirred at 48-52°C for 7.5 hours. After cooling, was added dropwise to 16.4 ml of 6.0 mol/l chloroethanol acid and then boiled under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, was added to the residue water and ethyl acetate and brought the pH to 9.5 by the addition of 5.0 mol/l aqueous solution of sodium hydroxide. The organic layer was separated and washed his saturated aqueous sodium chloride. Was added anhydrous magnesium sulfate and activated charcoal. After filtered, the insoluble material, kept under reduced pressure the solvent. To the obtained residue was added 1,81 g of maleic acid and the mixture was utverjdali mixed solvent (25 ml) ethyl acetate:2-propanol (4:1) to obtain the 4,82 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

Data1H-NMR in DMSO-d6match this example 6-1.

Example 6-9

To tetrahydrofuranate (2.38 l) suspension of 340 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propion the l)azetidin-3-ol was added 110 g of sodium borohydride was added dropwise tertrahydrofuran ring (1,02 l) solution of 142 g of sulfuric acid at room temperature for 1 hour, and stirred at 45-55°C for 5 hours. After cooling, was added 170 ml of acetone and added dropwise 204 ml of 36% chloroethanol acid, and the mixture was stirred at room temperature for 3 hours and left over night. To the reaction mixture were added 1,02 l of water and kept under reduced pressure 3,34 l of solvent. After cooling, was added to 0.68 l of ethyl acetate and added dropwise water (0.68 liter) solution of 147 g of sodium hydroxide at 14-22°C and the mixture was stirred at 7-15°C for 30 minutes. Was filtered, the insoluble material was washed 0.34 l of ethyl acetate. The filtrate and wash water were combined, and the organic layer was separated and washed 0,68 l of water. Once added to the organic layer 2,04 l 2-propanol drove under reduced pressure 3,01 l of solvent. Was added to the residue 1,02 l of ethyl acetate and 34 g of activated carbon and stirred for 20 minutes. Was filtered, the insoluble material was washed him 0.34 l of ethyl acetate. The filtrate and wash water were combined, was added 116 g of maleic acid. After the resulting reaction mixture was heated and dissolved, it is slowly cooled. The precipitate was collected by filtration to obtain 376 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

Data1H-NMR in DMSO-d6match data is m example 6-1.

Example 6-10

To tetrahydrofuranate (250 ml) suspension of 50.0 g of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol was added to 13.6 g of sodium borohydride was added dropwise to 18.5 g of sulfuric acid at room temperature for 3 hours and stirred at 45-55°C for 4.5 hours. After cooling, was added 15 ml of acetone, was added dropwise to 120 ml of 6.0 mol/l chloroethanol acid and then boiled under reflux for 1 hour. To the reaction mixture was added 150 ml of water and kept under reduced pressure the solvent. Was added to the residue 200 ml of ethyl acetate and added dropwise to water (100 ml) solution for 43.9 g of sodium hydroxide in 10-21°C. the Organic layer was separated and washed by adding 20% aqueous solution of hydrogen chloride. Was added to 50.0 g of celite and 5.0 g of activated charcoal, and the mixture was stirred for 20 minutes. Was filtered, the insoluble material was washed in 100 ml of ethyl acetate. The filtrate and wash water were combined was added 63 ml of ethyl acetate, 75 ml of 2-propanol and 17.1 g of maleic acid. After the resulting reaction mixture was heated and dissolved, it is slowly cooled. The precipitate was collected by filtration to obtain 56.7 g of the maleate of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol as a colorless crystalline substance.

Data1H-NMR in DMSO-d6sootvetstvovala example 6-1.

INDUSTRIAL APPLICABILITY

The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol and its salts of the present invention has the following characteristics: (1) the security for the human body, (2) low load on the environment, and (3) the possibility of mass production and so on, therefore, the way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol and its salts applicable in industrial production.

1. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, characterized in that it includes the interaction derived (phenylthio)acetic acid or its salt represented by the General formula:

where X1represents a halogen atom,
with a halogenation agent to obtain gelegenheid represented by the General formula:

where X2represents a halogen atom; X1has the values defined above,
then the reaction is intramolecular cyclization of gelegenheid in the presence of a Lewis acid followed by reduction with obtaining derived dihydrobenzofuran represented by the General formula:

where X1has the values defined above,
then dehydration derived dihydrobenzo the thiophene in the presence of an acid catalyst to obtain the derived 5-halogen-1-benzothiophene, represented by the General formula:

where X1has the values defined above,
then linking derivative of 5-halogen-1-benzothiophene with a derivative of malonic acid or its salt represented by the General formula:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano, in the presence of base and palladium catalyst to obtain the derived benzothiophene or its salt represented by the General formula:

where R2and R3have the same meanings as above, then the interaction derived benzothiophene or its salts with an acid or a base, decarboxylation, if necessary, to obtain the derived benzodioxane acid or its salt represented by the General formula:

where R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group,
then hydrolysis derived benzodioxane acid or its salts, if necessary, and then restore the addition of activator in the presence of borohydride alkaline metallic obtaining 2-(1-benzothiophen-5-yl)ethanol then the reaction accession for Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined above,
then the 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 in a reactive derivative, then the interaction of 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-Ola, then recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride.

2. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, characterized in that it includes binding derivative of 5-halogen-benzothiophene, represented by the General formula:

where X1represents a halogen atom,
with a derivative of malonic acid or its salt represented by the General formula:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano,
in the presence of base and palladium catalyst to obtain the derived benzothiophene or its salt represented by the General formula:

where R2and R3have the same meanings as above, then the interaction derived benzothiophene or its salts with an acid or a base, decarboxylation, if necessary, to obtain the derived benzodioxane acid or its salt represented by the General formula:

where R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group,
then hydrolysis derived benzodioxane acid or its salts, if necessary, then restore with the addition of activator in the presence of alkali metal borohydride to obtain 2-(1-benzothiophen-5-yl)ethanol, and then implement the function of joining Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, then interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined above,
then the 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 in a reactive derivative, then the interaction of 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-Ola, then recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride.

3. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, characterized in that it comprises the reaction of accession for Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, then interaction with alcohol, p is redstavleny General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined above,
then the 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 in a reactive derivative, then the interaction of 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-Ola, then recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride.

4. A method of obtaining a derivative of 5-halogen-1-benzothiophene represented by the General formula:

where X1represents a halogen atom,
characterized in that it includes the interaction derived (phenylthio)acetic acid or its salt represented by the General formula:

where X1has the values defined above,
with a halogenation agent to obtain gelegenheid represented by the General formula:

where X2represents a halogen atom; X1has the values defined above,
then the reaction is intramolecular cyclization of the obtained gelegenheid in the presence of a Lewis acid, and then recovering with obtaining derived dihydrobenzofuran represented by the General formula:

where X1has the values defined above,
then dehydration derived dihydrobenzofuran in the presence of an acid catalyst.

5. The way of getting any one of claims 1 to 4, characterized in that it includes bicrystalline crystals derived dihydrobenzofuran represented by the General formula:

where X1represents 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 X1represents a halogen atom,
characterized in that it includes dehydration derived dihydrobenzofuran represented by the General formula:

where X1has the values defined above, in the presence of an acid catalyst.

7. The method of receiving according to claim 4 or 6, where X1represents a bromine atom or an iodine atom.

8. The method of obtaining the derived benzothiophene or its salt represented by the General formula:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano,
characterized in that it includes linking the derived benzothiophene represented by the General formula:

where X1represents a halogen atom,
with a derivative of malonic acid or its salt represented by the General formula:

where R2and R3have the same meanings as above,
in the presence of a base and a palladium catalyst.

9. The method of obtaining the derived benzothiophene of claim 8, where X1and a group represented by the General formula:

attached at the 4 - or 5-position benzothiophene cycle.

10. The method of obtaining the derived benzothiophene of claim 8 or 9, where X1and a group represented by the General formula:

attached in the 5-position benzothiophene cycle.

11. The way to receive the deposits according to claims 1 and 2, 8, where X1represents a bromine atom or an iodine atom.

12. The method of deriving benzodioxane acid or its salt represented by the General formula:

where R4represents a hydrogen atom or unsubstituted or
substituted alkyl, cycloalkyl or aracelio group,
characterized in that it includes the interaction derived benzothiophene or its salt represented by the General formula:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano, with acid or base, and decarboxylation, if necessary.

13. The method of deriving benzodioxane acid or its salts indicated in paragraph 12, where the group represented by the General formula:

and a group represented by the General formula:

attached at the 4 - or 5-position benzothiophene cycle.

14. The method of deriving benzodioxane acid or its salt according to item 12 or 13, where the group represented by the General formula:

and a group represented by the General formula:

the connected inany in the 5-position benzothiophene cycle.

15. The method of deriving benzodioxane acid or its salt represented by the General formula:

where R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group,
characterized in that it includes linking the derived benzothiophene represented by the General formula:

where X1represents a halogen atom,
with a derivative of malonic acid or its salt represented by the General formula:

where R2and R3identical or different, represent an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano,
in the presence of base and palladium catalyst to obtain the derived benzothiophene or its salt represented by the General formula:

where R2and R3have the same meanings as above,
then the interaction derived benzothiophene or its salts with an acid or a base, and decarboxylation, if necessary.

16. The method of deriving benzodioxane acid or its salts according to § 15, where X1the group represented by the General formula:

and a group represented by the General formula:

attached at the 4 - or 5-position benzothiophene cycle.

17. The method of deriving benzodioxane acid or its salt according to item 15 or 16, where X1the group represented by the General formula:

and a group represented by the General formula:

attached in the 5-position benzothiophene cycle.

18. The way of getting 15, where X1represents a bromine atom or an iodine atom.

19. The way of getting any one of claims 1 and 2, 8, 12 and 15, where R2represents an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group, or cyano; R3represents an unsubstituted or substituted allyloxycarbonyl, cycloalkylcarbonyl or aracelikarsaalyna group.

20. The method of obtaining 2-(1-benzothiophen-5-yl)ethanol, characterized in that it comprises the hydrolysis of a derivative benzodioxane acid or its salt represented by the General formula:

where R4represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aracelio group,
if necessary, and restore with the addition of activator in presets is under the borohydride of an alkali metal.

21. The method of obtaining 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts, characterized in that it comprises the reaction of accession for Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, then interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined above,
then the 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 comprises the reaction of accession for Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, then interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester derivative of propionic acid, made the by the General formula:

where R1has the values defined 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 or hydrogen chloride.

23. The method of obtaining 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts, characterized in that it comprises the reaction of accession for Michael 2-(1-benzothiophen-5-yl)ethanol using Acrylonitrile in the presence of a base, then interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined 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 it is used the acid is hydrogen chloride, and R1represents a hydrogen atom.

24. The method of obtaining 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or its salts, characterized in that it comprises the reaction of accession for Michael 2-(1-benzothiophen-5-yl)ethanol use is using Acrylonitrile in the presence of a base, then interaction with alcohol represented by the General formula:

where R1represents a hydrogen atom or unsubstituted or substituted alkyl, cycloalkyl or aryl group,
in the presence of acid to obtain ester propionic acid derivative represented by the General formula:

where R1has the values defined 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 R1represents an ethyl group.

25. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, characterized in that it includes the recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride.

26. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, including the recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride, according to any one of claims 1 to 3 and 25, where used, the activator is at least one compound selected from a proton acid, meteorologi agent and cilleruelo and the enta.

27. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, including the recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride, according to any one of claims 1 to 3 and 25, where used, the activator is a sulfuric acid.

28. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, including the recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride, according to any one of claims 1 to 3 and 25, where used, the alkali metal borohydride is sodium borohydride.

29. The way to obtain 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propyl)azetidin-3-ol or its salts, including the recovery of 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol with the addition of activator in the presence of alkali metal borohydride, according to any one of claims 1 to 3 and 25, where the number of used sulfuric acid is 0.5 to 0.6 mol per mol of the alkali metal borohydride, and the method is characterized by the fact that includes adding sulfuric acid at 0-30°C for from 10 min to 6 h, and then the interaction at 30-70°C.

30. Derived dihydrobenzofuran represented by the General formula:

where X1represents and what Ohm halogen.

31. Derived dihydrobenzofuran on item 30, where X1represents a bromine atom.

32. Derived benzothiophene or its salt represented by the General formula:

where R2and R3identical or different, represent a (C1-4)allyloxycarbonyl group, or cyano.

33. Derived benzothiophene or its salt p, where R2is a (C1-4)allyloxycarbonyl group, or cyano, and R3is a (C1-4)allyloxycarbonyl group.

34. Derived benzothiophene or its salt p or 33, where the group represented by the General formula:

attached at the 4 - or 5-position benzothiophene cycle.

35. Derived benzothiophene or its salt p or 33, where the group represented by the General formula:

attached in the 5-position benzothiophene cycle.

36. Ester propionic acid derivative represented by the General formula:

where R1represents a hydrogen atom or (C1-4)alkyl group.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (II) and to their pharmaceutically acceptable salts. In formula R1 means phenyl optionally substituted on one or more carbon atoms with one or more R9; where R9 is specified of halogen, amino, C1-6alkyl and C1-6alkoxy, one of R2 and R3 represents -C(=O)NR6R7, and the other represents -NHC(=O)NHR4; R4 and R6 represent N, and R7 represents piperidine-3-yl. Besides the invention refers to a pharmaceutical composition containing the compound of the invention, to application of the compound for preparing a drug, and also to an intermediate compound of formula (XI) or its salts, where A represents thienyl ring.

EFFECT: preparation of new compounds exhibiting inhibitory properties with respect to SNK1 kinase.

7 cl, 263 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula (1) , where substitutes are as defined in paragraph 1 of the invention. The compounds have fungicide properties. The method of obtaining formula (1) compounds is described, in which n equals 0. Described also is a fungicide composition based on formula (1) compounds and a phytopathogenic fungus control method which uses compounds in paragraph 1 or a composition based on the said compounds.

EFFECT: obtaining novel compounds which can be used as fungicides.

24 cl, 312 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1), their tautomers and pharmaceutically acceptable salts. The disclosed compounds have thromobopoietin receptor agonist properties. In formula (1) , A is a nitrogen atom or CH, when A is a nitrogen atom, B is NR9 (where R9 is a C1-10 alkyl group), and when A is CH, B is a sulphur atom, R1 is a phenyl group (the phenyl group is substituted with one or more substitutes selected from a group consisting of halogen atoms, C1-10 alkyl groups and C1-10 alkoxy groups (C1-10 alkyl groups and C1-10 alkoxy groups are unsubstituted or substituted with one or more halogen atoms)), L1 is bond, X is OH, R2 is a C1-10 alkyl group, L2 is a bond, L3 is NH, L4 is a bond or NH, Y is a sulphur atom, and when L4 is a bond, R3 is a piperidinyl group, a piperazinyl group (the piperidinyl group and the piperazinyl group are substituted with substitutes selected from a group containing C1-10 alkoxycarbonyl groups, carboxyl group, hydroxyl groups, di-C1-10 alkylaminocarbonyl groups, C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups (C1-10 alkylaminocarbonyl groups and C1-10 alkyl groups are substituted with a substitute selected from a group containing pyridyl groups, hydroxyl groups and carboxyl groups)), or when L4 is NH, R3 is a C1-10 alkyl group (C1-10 alkyl group is substituted with a substitute selected from a group containing C1-10 alkoxy groups, C1-10 alkoxycarbonyl groups or carboxyl groups).

EFFECT: obtaining a thrombopoietin receptor activator which is a formula (1) compound and a medicinal agent which contains the disclosed compound as an active ingredient.

10 cl, 3 tbl, 47 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to compounds of formula I or to pharmaceutically acceptable salts thereof, where Ar is imidazole or pyrazole, where the said Ar can be substituted with substitute(s) selected from a group consisting of a C1-C6 alkyl group, a phenyl group and a halogen atom, each of Y1, Y2 and Y3 is a carbon ot nitrogen atom, A is an oxygen atom, a sulphur atom or a group of formula -SO2-, R1 is a hydrogen atom, a C1-C6 alkyl group which can be substituted with one phenyl group (where the said phenyl group can be substituted with one substitute selected from a group consisting of a halogen atom and a C1-C6 alkyl group), or a phenyl group, R2 is a C1-C6 alkyl group, R3 is (i) a C1-C18 alkyl group, (ii) C2-C8 alkenyl group, (iii) C2-C8 alkynyl group, (iv) C3-C8 cycloalkyl group, (v) C1-C6 alkyl group substituted with 1-3 substitutes selected from a group given in paragraph 1 of the formula of invention, or (vi) a phenyl group, a naphthyl group, a pyrazolyl group, a pyridyl group, an indolyl group, a quinolinyl group or an isoquinolinyl group, where each of the said groups can be substituted with 1-3 substitutes selected from a group given in paragraph 1, R4 is a hydrogen atom or a C1-C6 alkyl group, and R5 is (i) C1-C10 alkyl group, (ii) C1-C10 alkyl group which is substituted with one or two substitutes selected from a group given in paragraph 1, (iii) C2-C8 alkenyl group which can be substituted with a phenyl group, or (iv) phenyl group, naphthyl group, thienyl group, pyrrolyl group, pyrazolyl group, pyridyl group, furanyl group, benzothienyl group, isoquinolinyl group, isoxazolyl group, thiazolyl group, benzothiadiazolyl group, benzoxadiazolyl group, phenyl group, condensed with a 5-7-member saturated hydrocarbon ring which can contain one or two oxygen atoms as ring members, uracyl group or tetrahydroisoquinolinyl group, where each of the said groups can be substituted with 1-5 substitutes selected from a group given in paragraph 1, provided that when Ar is a group of formula 5, which can be substituted with a C1-C6 alkyl group, R5 is not a C1-C10 alkyl group, and the formula (I) compound is not 5-(3,5-dichlorophenylthio)-4-isopropyl-2-methane-sulfonylaminomethyl-1-methyl-1H-imidazole or 5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-2-p-toluene-sulfonylaminomethyl-1H-imidazole. The invention also relates to a pharmaceutical composition based on the formula I compound and to formula II compounds, radicals of which are defined in the formula of invention.

EFFECT: obtaining novel compounds with inhibitory effect on the bond between S1P and its Edg-1 (SIP1) receptor.

32 cl, 43 tbl, 18 ex

FIELD: chemistry.

SUBSTANCE: invention refers to compounds of the formula (I): , where R1 is C1-C8alkyl optionally substituted with one to three substitutes selected out of substitute group A; R2 is C1-C6alkyl or C1-C6alkoxyC1-C6alkyl; R3 is C1-C6alkyl or C1-C6alkoxy; or R2 and R3 together with adjoining carbon atoms form optionally substituted non-aromatic 5-10-member carbon ring; R4 is hydrogen; G is group represented by the formula: or the rest as provided in the invention claim; and to pharmaceutical composition, application of claimed compounds, and method of atopic dermatitis prevention or treatment.

EFFECT: novel compounds useful as atopic dermatitis treatment medication and antipruritic medicines.

24 cl, 75 ex, 290 tbl

FIELD: chemistry.

SUBSTANCE: present invention relates to cyclic derivatives of aminobenzoic acid and to their pharmaceutically acceptable salts of general formula , in which ring Ar is a phenyl group, a 5-member aromatic heterocyclic group containing 1-2 heteroatoms selected from nitrogen, sulphur and oxygen, or a benzothiazolyl group; where the said groups can have 1-2 substitutes selected from a group comprising lower alkyl; a phenyl group; a phenyl group substituted with 1-2 halogens; a phenyl group substituted with a lower alkoxy group; a phenyl group substituted with a halogen-substituted lower alkyl group; a phenoxy group substituted with a halogen; a halogen; Z is an oxygen atom or -(CH2)-n (where n equals 0, 1 or 2); Y is C1-C4 alkylene, C2-C4 alkenylene or general formula (2) -T-A-U- (2) in which T is a single bond, C1-C4 alkylene or C2-C4 alkenylene; U is single bond, C1-C4 alkylene; values of the rest of radicals are given in the formula of invention.

EFFECT: obtaining a PPARα, agonist which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid, and an agent which reduces the level of lipids which contains an active ingredient in form of at least one cyclic derivative of aminobenzoic acid.

12 cl, 16 tbl, 184 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: described are novel thiophene derivatives of formula (1) and pharmaceutically acceptable salts thereof, where A is -CH2CH2-, -NH-CH2-, -CH2-O or -CH2NH-, R1 is hydrogen or alkyl, when X is C-R4, R1 additionally represents halogen, and when A is -CH2-CH2- or -CH2NH, R1 additionally represents alkoxy, R2 is hydrogen, alkoxy, fluoralkoxy, hydroxyalkoxy, hydroxyalkyl, di-(hydroxy)alkoxy, pyridinyl-3-methoxy, pyridinyl-4-methoxy, R3 is hydrogen, alkyl, trifluoromethyl, and when X is C-R4, R3 additionally represents halogen, and when A is -CH2-CH2-, R3 additionally represents alkoxy, X is N or C-R4, R4 is hydrogen, alkyl, alkoxy or halogen, R5 is methyl or ethyl. Also described are isomers of the said compounds, an initial compound for synthesis of formula (1) compound, which has agonistic effect on S1P1/EDG1 receptors, as well as a pharmaceutical composition based on formula (1) compound and use of formula (1) compound.

EFFECT: obtaining a pharmaceutical composition for preventing or treating diseases or disorders associated with activated immune system.

19 cl, 2 tbl, 167 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of a therapeutic agent which is an α-amino-amide compound of formula (I):

, in which R is a phenyl ring which is optionally substituted with one or two substitutes independently selected from halogen, hydroxy, cyano, C1-C6-alkyl, C1-C6-alkoxy or trifluoromethyl; R1 is hydrogen or C1-C6-alkyl; R2 and R3 are independently selected from hydrogen, C1-C4-alkyl; R4 and R5 independently denote hydrogen, C1-C6-alkyl; X is O or S; Y and Z, taken together with X and a phenyl ring bonded to Y and X, form a 5-7-member saturated heterocycle containing O or S atoms, or Y and Z denote hydrogen; or its isomers, mixtures and pharmaceutically acceptable salts for preparing a medicinal agent for treating lower urinary tract disorders.

EFFECT: obtaining a pharmaceutical composition based on the said compounds.

8 cl, 6 ex

FIELD: chemistry, pharmacology.

SUBSTANCE: claimed invention relates to sulfamate derivatives of benzothiophene, obtained by method including stages: 1) conversion of 6-methoxybenzothiophene (3); , where R3 represents monobromine-derivative using N-bromosuccinimide and APTS in standard conditions; 2) conversion of said monobromine-derivative by interaction with Mg in Et2O in argon atmosphere into magnesium-organic bromide and its further condensation with ketone or aldehyde selected from group, consisting of cyclopentanone, cyclohexanone, cycldecanone, 4-methylcyclohexanone, 2-methylcyclohexanone, 2,2-dimethylcyclopentanone, 2-adamantanone, propanal, hexanal, cyclohexane carboxaldehyde, cycloheptancarboxaldehyde in Et2O obtaining corresponding hydroxyl-substituted methoxybenzothiophene in standard conditions; 3) processing said hydroxy-substituted methoxybenzothiophene with triethylsilane in argon atmosphere in dichlomethane obtaining corresponding substituted methoxybenzothiophene; 4) optional alkylating of corresponding substituted methoxybenzothiophene using standard conditions obtaining corresponding substituted methoxybenzothiophene, carrying (C1-C6)alkyl or (C3-C12)cycloalkyl; removal of protective group from substituted methoxybenzothiophene, obtained at stage 3) or stage 4) in presence of tribromborane in standard conditions; conversion of obtained hydroxy-compound into corresponding sulfamate by processing with sodium hydrate and amidochlorsulfonic acid, or interaction with sulfamoylchloride in dimethylacetamide; 7) optional oxidation of obtained compound with hydrogen peroxide in trifluoracetic acid in standard conditions. Compounds can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders. Also described are pharmaceutical composition based on compounds I and application of the latter.

EFFECT: obtaining compounds which can be used as inhibitors of steroid sulfatase enzyme in production of medication for treatment or prevention of estrogen-depending disorders.

43 cl, 1 dwg, 10 tbl, 67 ex

FIELD: chemistry.

SUBSTANCE: invention relates to production of heterocyclic ketones of formula or or their mixes, wherein R1 and R2 are hydrogen, alkyl, C6-C10 aryl; or R1 and R2 together form cyclic ring system;R3 C1-C40 alkyl; X sulfur; by interaction of heterocyclic compound of the formula (II) with α, β-unsaturated carboxylic acid or with anhydride of an acid in a liquid reactionary medium which includes a strong organic acid selected from the group includingC1-C8 alkylsulfonic acid and a water absorber selected from the group including phosphorus pentoxide, a strong organic acid possessing higher acidity, compared to carbolyxic acid; the process is effected by adding simultaneously the compounds of formula (II), acids or anhydride to the reactionary medium specified above, at temperature from 50 to 110°C. Replaced heterocyclic ketones make the important initial compounds on receiving heterocyclic metallocene catalysts for polymerization of α-olefines.

EFFECT: new compounds possess useful biological properties.

5 cl, 2 tbl, 5 ex

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

Ethynylbenzoate // 2079495
The invention relates to light-sensitive pesticides, specifically to some ethynylbenzoate

The invention relates to heteroalicyclic alkanoyl derivatives, which have a biocidal effect, and more particularly to aminoalcohols derived molecules containing heteroalicyclic ring system, to methods of their synthesis, their new intermediates, containing pharmaceutical compositions and to their use as biocidal agents, in particular anticancer agents

The invention relates to heteroalicyclic alkanols derived, and in particular to methods of obtaining new polycyclic biocidal compounds of General formula I

ArCH2Other where Ar is 2-benzo/b/oil/2,1-d/thiophene-5-yl; 2-benzo/db/oil/2,3-d/furan-6-yl; 2-benzo/b/oil/1,2-d/furan-5-yl; 2-/7-methyl, 7H-benzo/with/carbazole-10-yl/methyl, 2-/benzo/b/oil/2,1-d/furan-5-yl; R= -H3or their salts, which can be used as anticancer agents

The invention relates to a method for producing novel compounds that have biological activity similar to the activity retinova acid, more specifically, to methods and intermediate products used in the synthesis dogsleding acetylene compounds with similar retinova acid activity

FIELD: organic chemistry, medicine, endocrinology.

SUBSTANCE: invention relates to novel compounds representing C-glycoside derivatives and their salts of the formula: wherein ring A represents (1) benzene ring; (2) five- or six-membered monocyclic heteroaryl ring comprising 1, 2 or 4 heteroatoms chosen from nitrogen (N) and sulfur (S) atoms but with exception of tetrazoles, or (3) unsaturated nine-membered bicyclic heterocycle comprising 1 heteroatom representing oxygen atom (O); ring B represents (1) unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (2) saturated or unsaturated five- or six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O; (3) unsaturated nine-membered bicyclic carbocycle, or (4) benzene ring; X represents a bond or lower alkylene wherein values for ring A, ring B and X correlate so manner that (1) when ring A represents benzene ring then ring B is not benzene ring, or (2) when ring A represents benzene ring and ring B represents unsaturated eight-nine-membered bicyclic heterocycle comprising 1 or 2 heteroatoms chosen from N, S and O and comprising benzene ring or unsaturated nine-membered bicyclic carbocycle comprising benzene ring then X is bound to ring B in moiety distinct from benzene ring comprised in ring B; each among R1-R4 represents separately hydrogen atom, -C(=O)-lower alkyl or lower alkylene-aryl; each R5-R11 represents separately hydrogen atom, lower alkyl, halogen atom, -OH, =O, -NH2, halogen-substituted lower alkyl-sulfonyl, phenyl, saturated six-membered monocyclic heterocycle comprising 1 or 2 heteroatoms chosen from N and O, lower alkylene-OH, lower alkyl, -COOH, -CN, -C(=O)-O-lower alkyl, -O-lower alkyl, -O-cycloalkyl, -O-lower alkylene-OH, -O-lower alkylene-O-lower alkyl, -O-lower alkylene-COOH, -O-lower alkylene-C(=O)-O-lower alkyl, -O-lower alkylene-C(=O)-NH2, -O-lower alkylene-C(=O)-N-(lower alkyl)2, -O-lower alkylene-CH(OH)-CH2(OH), -O-lower alkylene-NH, -O-lower alkylene-NH-lower alkyl, -O-lower alkylene-N-(lower alkyl)2, -O-lower alkylene-NH-C(=O)-lower alkyl, -NH-lower alkyl, -N-(lower alkyl)2, -NH-lower alkylene-OH or NH-C(=O)-lower alkyl. Indicated derivatives can be used as inhibitor of co-transporter of Na+-glucose and especially as a therapeutic and/or prophylactic agent in diabetes mellitus, such as insulin-dependent diabetes mellitus (diabetes mellitus 1 type) and non-insulin-dependent diabetes mellitus (diabetes mellitus 2 type), and in diseases associated with diabetes mellitus, such as insulin-resistant diseases and obesity.

EFFECT: valuable medicinal properties of compounds.

11 cl, 41 tbl, 243 ex

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