JP2012046499A - Salt of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid or hydrate thereof and production method thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for producing 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid with a high purity, simply, safely and in a large amount and a high yield.SOLUTION: The 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid and 1-(3-(2-(1-benzothiophen-5-yl)ethoxy)propionyl)azetidin-3-ol are produced simply, safely, in a large amount, with a high purity and in a high yield by isolating a salt of 3-(2-(1-benzothiophen-5-yl)ethoxy)propionic acid, represented by the general formula (wherein, M represents a sodium ion, calcium ion or ammonium ion; and n represents 1 when M is a sodium ion or ammonium ion, and 2 when M is a calcium ion), or a hydrate thereof.

Description

  The present invention relates to a salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or a hydrate thereof, which is important as a pharmaceutical intermediate, and a method for producing the same.

3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid (hereinafter referred to as “intermediate A”) and 1- (3- (2- (1-benzothiophen-5-yl)) Ethoxy) propionyl) azetidin-3-ol (hereinafter referred to as “intermediate B”) is an important compound as a pharmaceutical production intermediate. For example, 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propyl) -3-azetidinol maleate (hereinafter referred to as “Compound 1”) developed as a therapeutic agent for neurodegenerative diseases. Can be produced by subjecting intermediate B obtained by reacting intermediate A to 3-azetidinol to a reduction reaction (Patent Documents 1 and 2).
Intermediate A is obtained by subjecting 2- (1-benzothiophen-5-yl) ethanol to a Michael addition reaction with acrylonitrile, followed by a reaction with an alcohol in the presence of an acid, followed by hydrolysis. (Patent Document 2). However, since the intermediate A is soluble in an organic solvent such as toluene, a step of concentrating the solvent is necessary to isolate the intermediate A as a solid. In addition, flammable and anesthetic cyclohexane must be used.

International Publication No. 03/035647 Pamphlet International Publication No. 2006/104088 Pamphlet

  In order to produce high-quality compound 1, high-purity raw materials are required. That is, there is a strong demand for a method by which intermediate A and intermediate B can be safely produced in a simple manner in a high yield, high purity, and in large quantities.

「式中、Ｒ^１は、水素原子、置換されていてもよいＣ_１−６アルキル基、置換されていてもよいＣ_３−８シクロアルキル基または置換されていてもよいアリール基を示す。」で表されるアルコールとの反応に付し、一般式［２］

「式中、Ｒ^１は、前記と同様の意味を有する。」で表されるプロピオン酸エステル誘導体とし、次いで、塩基の存在下、加水分解反応に付した後、塩基を作用させることにより、一般式［３］

「式中、Ｍは、ナトリウムイオン、カルシウムイオンまたはアンモニウムイオンを；ｎは、Ｍがナトリウムイオンまたはアンモニウムイオンの場合は１を、Ｍがカルシウムイオンの場合は２を示す。」で表される化合物またはその水和物が、簡便な方法で、高収率で、高純度で、大量に、安全に製造できることを見出した。さらに、得られた一般式［３］の化合物を単離した後、酸を作用させることによって、中間体Ａおよび中間体Ｂが、簡便な方法で、高収率で、高純度で、大量に、安全に製造できることを見出し、本発明を完成させた。 As a result of intensive studies, the present inventors have subjected 2- (1-benzothiophen-5-yl) ethanol to a Michael addition reaction with acrylonitrile in the presence of a base, and then in the presence of an acid, the compound represented by the general formula [ 1]

“In the formula, R ¹ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted aryl group.” To a reaction with an alcohol represented by the general formula [2]

In the formula, R ¹ has the same meaning as described above, and then subjected to a hydrolysis reaction in the presence of a base and then a base is allowed to act. Formula [3]

In the formula, M represents sodium ion, calcium ion or ammonium ion; n represents 1 when M is sodium ion or ammonium ion, and 2 when M is calcium ion. It was also found that the hydrate can be produced safely in a large amount with high yield and high purity by a simple method. Furthermore, by isolating the obtained compound of the general formula [3] and then reacting with an acid, intermediate A and intermediate B can be obtained in high yield, high purity, and in large quantities by a simple method. The present invention was completed by finding that it can be manufactured safely.

The compounds of the present invention are (1) manufactured easily, (2) manufactured in high yield, (3) manufactured in high purity, (4) manufactured in large quantities, (5) safe It has features such as being manufactured.
Moreover, the production method of the present invention is (1) simple, (2) high yield, (3) high purity, (4) can be produced in large quantities, (5) safe (6 (1) No solvent concentration step is required, (7) No flammable and anesthetic cyclohexane is used.
Furthermore, intermediate A and intermediate B can be safely produced from the compound of the present invention in a simple manner with a high yield, high purity, and in large quantities.
That is, the compound of the present invention is an important production intermediate of Compound 1, and the production method of the present invention is useful as an industrial production method of Intermediate A and Intermediate B.

Hereinafter, the present invention will be described in detail.
In this specification, unless otherwise stated, each term has the following meaning.
A halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
The C _1-6 alkyl group is a linear or branched C _1-6 such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl groups. An alkyl group is meant.
C _3-8 cycloalkyl group means a C _3-8 cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl groups.
An aryl group means a phenyl group or a naphthyl group.
The C _1-6 alkoxy group is linear or branched C _1-6 such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy and hexyloxy. Means an alkyloxy group;

Aliphatic hydrocarbons mean pentane, hexane or cyclohexane.
Aromatic hydrocarbons mean benzene, toluene or xylene.
Halogenated hydrocarbons mean methylene chloride, chloroform or dichloroethane.
Alcohol means methanol, ethanol, propanol, 2-propanol, butanol or 2-methyl-2-propanol.
Ethers mean diethyl ether, diisopropyl ether, dioxane, tetrahydrofuran, anisole, ethylene glycol dimethyl ether, diethylene glycol dimethyl ether or diethylene glycol diethyl ether.
Ketones mean acetone, 2-butanone or 4-methyl-2-pentanone.
Esters mean methyl acetate, ethyl acetate, propyl acetate or butyl acetate.
Amides mean N, N-dimethylformamide, N, N-dimethylacetamide or 1-methyl-2-pyrrolidone.
Nitriles mean acetonitrile.
The sulfoxide means dimethyl sulfoxide.

Inorganic acid means hydrochloric acid, sulfuric acid, phosphoric acid, hydrogen chloride or hydrogen bromide.
Organic carboxylic acid means acetic acid, trichloroacetic acid or trifluoroacetic acid.
Organic sulfonic acid means methanesulfonic acid, benzenesulfonic acid or p-toluenesulfonic acid.

The C _1-6 alkyl group, C _3-8 cycloalkyl group and aryl group of R ¹ are one or more groups selected from a halogen atom, a hydroxyl group, a C _1-6 alkyl group and a C _1-6 alkoxy group. May be substituted.

In the compound represented by the general formula [3] of the present invention, preferable compounds include the following compounds.
A compound in which M is sodium ion, calcium ion or ammonium ion is preferred.
When M is a sodium ion or an ammonium ion, n is preferably 1.
When M is a calcium ion, n is preferably 2.

「式中、Ｒ^１、Ｍおよびｎは、前記と同様の意味を有する。」 Next, the manufacturing method of this invention is demonstrated.
[Production Method 1]

“Wherein R ¹ , M and n have the same meaning as described above.”

[First step]
A compound of formula [5] can be produced by subjecting the compound of formula [4] to a Michael addition reaction with acrylonitrile in the presence of a base.
This reaction may be performed by the method described in Patent Document 2.

[Second step]
The compound of the general formula [2] can be produced by subjecting the compound of the formula [5] to a reaction with the alcohol of the general formula [1] in the presence of an acid.
This reaction may be performed by the method described in Patent Document 2.

[Third step]
The compound of general formula [2] or a hydrate thereof can be produced by hydrolyzing the compound of general formula [2] and then reacting with a base.

(3-1) Hydrolysis reaction The hydrolysis reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction. For example, aliphatic carbonization Examples thereof include hydrogens, aromatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols, sulfoxides and water, and these solvents may be used as a mixture.
Preferred solvents include aromatic hydrocarbons, mixed solvents of alcohols and water, and mixed solvents of alcohols and water, with toluene, methanol and water mixed solvents, and methanol and water mixed solvents being more preferred.
Although the usage-amount of a solvent is not specifically limited, 0.5-10 times amount (v / w) is preferable with respect to the compound of General formula [2], and 0.5-3 times amount (v / w) is more preferable.
This hydrolysis reaction is performed in the presence of a base.
Examples of the base used in this reaction include metal alkoxides such as sodium = methoxide, sodium = ethoxide, potassium = tert-butoxide and sodium = tert-butoxide; and sodium hydroxide, potassium hydroxide, barium hydroxide, carbonate Inorganic bases such as sodium and potassium carbonate are mentioned.
Preferred bases include inorganic bases, with sodium hydroxide and potassium hydroxide being more preferred.
The amount of the base used may be 1 mol or more, preferably 1 to 3 mol per mol of the compound of the general formula [2].
The reaction temperature is not particularly limited, but may be from 0 ° C. to the boiling point of the solvent, and preferably 10 to 40 ° C.
The reaction time is not particularly limited, but may be 10 minutes to 50 hours, and preferably 1 to 24 hours.

(3-2) Reaction with base The compound of general formula [3] or a hydrate thereof can be produced by allowing a base to act on the reaction mixture obtained by the hydrolysis reaction.

(3-2-1) When M is Calcium Ion By adding a base to the reaction mixture obtained by the hydrolysis reaction, the compound of the general formula [3] or a hydrate thereof can be produced.
Examples of the organic solvent used in this reaction include alcohols, sulfoxides and water, and these solvents may be used as a mixture.
Preferable organic solvents include alcohols and water, 2-propanol and water are preferable, and a mixed solvent of 2-propanol and water is more preferable.
The amount of the organic solvent used is preferably 1 to 10 times (v / w), more preferably 3 to 5 times (v / w) of the compound of the general formula [2].
Examples of the base used in this reaction include calcium chloride, calcium hydroxide and calcium acetate.
A preferred base is calcium acetate.
The amount of the base used may be 0.5 mol or more, preferably 0.5 to 2 mol, per mol of the compound of the general formula [2].
The base may be added as a solid, but is preferably added after being dissolved in an organic solvent and / or water.
The reaction temperature is not particularly limited, but may be from 0 ° C. to the boiling point of the solvent, and preferably 10 to 40 ° C.
The reaction time is not particularly limited, but may be 10 minutes to 50 hours, and preferably 1 to 24 hours.
The compound of the general formula [3] or the hydrate thus produced can be isolated by a usual method such as filtration.

(3-2-2) When M is a sodium ion or an ammonium ion After adding an acid to the reaction mixture obtained by the hydrolysis reaction, an organic solvent is added, and a base is added to the separated organic layer. A compound of formula [3] or a hydrate thereof can be produced.
Examples of the acid used in this reaction include inorganic acids, organic carboxylic acids, and organic sulfonic acids, and these acids may be used as a mixture.
Preferred acids include inorganic acids, and hydrochloric acid is preferred.
Examples of the organic solvent used in this reaction include aliphatic hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, alcohols and esters. These solvents are mixed. May be used.
Preferable organic solvents include aromatic hydrocarbons, alcohols and esters. Toluene, 2-propanol and ethyl acetate are preferred, and these solvents may be used as a mixture.
The amount of the organic solvent used is preferably 1 to 10 times (v / w), more preferably 3 to 5 times (v / w) of the compound of the general formula [2].
Examples of the base used in this reaction include sodium hydroxide and ammonia.
The amount of the base used may be 1 mol or more, preferably 1 to 3 mol per mol of the compound of the general formula [2].
Sodium hydroxide may be added as a solid, but is preferably added after being dissolved in an organic solvent and / or water.
As ammonia, it is preferable to use ammonia water and / or ammonia gas.
The reaction temperature is not particularly limited, but may be from 0 ° C. to the boiling point of the solvent, and preferably 10 to 40 ° C.
The reaction time is not particularly limited, but may be 10 minutes to 50 hours, preferably 1 to 24 hours.
The compound of the general formula [3] or the hydrate thus produced can be isolated by a usual method such as filtration.

  In the compounds of the present invention, when hydrates, solvates and various crystal forms exist, the present invention includes all of them.

  Next, a method for producing Intermediate A and Intermediate B from the compound of the general formula [3] of the present invention or a hydrate thereof will be described.

「式中、Ｍおよびｎは、前記と同様の意味を有する。」 [Production method A]

“Wherein M and n have the same meaning as described above.”

[First step]
Intermediate A can be produced by reacting a compound of general formula [3] or a hydrate thereof with an acid.
This reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction. For example, aliphatic hydrocarbons, aromatic hydrocarbons, Halogenated hydrocarbons, ethers, esters, ketones, water and the like can be mentioned, and these solvents may be used in combination.
Preferred solvents include one or more solvents selected from aromatic hydrocarbons, ethers, esters and ketones, and mixed solvents with water. From toluene, 1,2-dimethoxyethane, ethyl acetate and acetone. One or more selected solvents and a mixed solvent with water are more preferable.
Although the usage-amount of a solvent is not specifically limited, 1-10 times amount (v / w) is preferable with respect to the compound or its hydrate of General formula [3], and 3-5 times amount (v / w) is preferable. More preferred.
Examples of the acid used in this reaction include inorganic acids, organic carboxylic acids, and organic sulfonic acids, and these acids may be used as a mixture.
Preferred acids include inorganic acids, and hydrochloric acid is preferred.
The amount of the acid used may be 1 mol or more, preferably 1 to 3 mol per mol of the compound of the general formula [3] or its hydrate.
The reaction temperature is not particularly limited, but may be from 0 ° C. to the boiling point of the solvent, and preferably 10 to 40 ° C.
The reaction time is not particularly limited, but may be 10 minutes to 50 hours, preferably 1 to 24 hours.

The intermediate A thus obtained can be isolated by a usual method such as filtration. Intermediate A can be used in the next reaction as it is without isolation.
When M is a calcium ion, the method of using the intermediate A as it is without isolating the intermediate A is preferable.

[Second step]
A reactive derivative can be produced by reacting intermediate A with an activator.
Examples of reactive derivatives include acid halides, acid anhydrides, activated amides and activated esters, and acid halides are preferred.
Methods for producing reactive derivatives include, for example, production of acid halides using halogenating agents such as thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride; ethyl chloroformate, isobutyl chloroformate and pivaloyl chloride. Acid anhydrides by condensation with acid halides such as; production of activated amides by condensation with imidazole; production of activated amides by activated amidating agents such as carbonyldiimidazole; and p-nitrophenol and 2 -Production of active esters by condensation with mercaptobenzothiazole and the like.
As the production of the reactive derivative, the production of an acid halide using a halogenating agent is preferred, and the production of an acid chloride using thionyl chloride is more preferred.
The amount of the activator used varies depending on the type of the activator. For example, in the case of thionyl chloride, the amount of the activator may be 0.5 times or more, preferably 1 to 2 times the mole of intermediate A.
This reaction is usually carried out in the presence of a solvent, and the solvent used is not particularly limited as long as it does not affect the reaction. For example, aliphatic hydrocarbons, aromatic hydrocarbons, Halogenated hydrocarbons, ethers, esters, ketones, amides, nitriles, sulfoxides and the like may be mentioned, and these may be used in combination.
Preferable solvents include aromatic hydrocarbons and ethers, and toluene and 1,2-dimethoxyethane are more preferable.
The amount of the solvent used is not particularly limited, but is preferably 1 to 20 times (v / w), more preferably 1 to 10 times (v / w) of Intermediate A.
Although reaction temperature is not specifically limited, Preferably it is -60-150 degreeC, More preferably, it is -30-120 degreeC.
The reaction time is not particularly limited, but is 10 minutes to 50 hours, preferably 30 minutes to 20 hours.
The reactive derivative thus obtained can be isolated and purified, but it is preferable to proceed to the next reaction without isolation.

[Third step]
Intermediate B can be produced by reacting the reactive derivative with 3-azetidinol or a salt thereof in the presence of a base.
Examples of the base used in this reaction include organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and pyridine; and sodium hydroxide, water Examples thereof include inorganic bases such as potassium oxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate.
Preferred bases include inorganic bases, more preferably sodium hydroxide.
The base may be used in an amount of 1 mol or more, preferably 1 to 10 mol, with respect to Intermediate A.
The amount of 3-azetidinol or a salt thereof used may be 1-fold mol or more with respect to Intermediate A, and is preferably 1-2 mol.
Further, 3-azetidinol or a salt thereof is preferably used after being dissolved in an organic solvent and / or water.
Examples of the solvent for dissolving 3-azetidinol or a salt thereof include alcohols and water, and these may be used as a mixture.
As a preferable solvent, a mixed solvent of water and alcohols is preferable, and a mixed solvent of water and 2-propanol is more preferable.
The amount of the solvent used is not particularly limited, but is preferably 1 to 20 times (v / w), more preferably 1 to 10 times (v / w) of Intermediate A.
Although reaction temperature is not specifically limited, Preferably it is -60-100 degreeC, More preferably, it is -30-50 degreeC.
The reaction time is not particularly limited, but is 10 minutes to 50 hours, preferably 30 minutes to 20 hours.
Intermediate B thus obtained can be isolated by a usual method such as filtration.

Next, the usefulness of the compound of the present invention will be described.
(1) Purity test The compounds of Examples 1 to 6 and Comparative Examples 1 to 3 were used as test substances.
The purity of the test substance was measured by high performance liquid chromatography.

Measurement conditions for intermediate A Detector: UV absorption photometer Measurement wavelength: 230 nm
Column: XTerra RP18 3.5μm, inner diameter 4.6 x length 100mm
Column temperature: 40 ° C
Mobile phase: 40% CH ₃ CN 0.05mol / L phosphate buffer pH3.0
Flow rate: 1.0mL / min

Measurement conditions for intermediate B Detector: UV spectrophotometer Measurement wavelength: 230 nm
Column: SunFire C18 3.5μm, inner diameter 4.6 x length 100mm
Column temperature: 40 ° C
Mobile phase: 33% CH ₃ CN 0.02mol / L phosphate buffer pH3.0
Flow rate: 1.0mL / min

  The results are shown in Tables 1 and 2.

＊１）一般式［３］の化合物またはその水和物のＨＰＬＣ純度
＊２）中間体ＡのＨＰＬＣ純度
＊３）式［４］の化合物から一般式［３］の化合物またはその水和物の収率
＊４）一般式［３］の化合物またはその水和物から中間体Ａの収率
＊５）式［４］の化合物から中間体Ａの収率

* 1) HPLC purity of compound of general formula [3] or hydrate thereof * 2) HPLC purity of intermediate A * 3) From compound of formula [4] to compound of general formula [3] or hydrate thereof Yield * 4) Yield of intermediate A from compound of general formula [3] or hydrate thereof * 5) Yield of intermediate A from compound of formula [4]

In the production of the ammonium salt of the general formula [3] from the compound of the formula [4] (Example 1), the purity was 99.5% and the yield was 98%. In the production of intermediate A from the ammonium salt of the general formula [3] (Example 2), the purity was 99.5% and the yield was 98%. After isolating the ammonium salt of the general formula [3] from the compound of the formula [4], in the production of the intermediate A (Examples 1 and 2), the purity was 99.5% and the yield was 96%. .
In the production of the sodium salt of the general formula [3] from the compound of the formula [4] (Example 3), the purity was 99.9% and the yield was 99%. In the production of intermediate A from the sodium salt of the general formula [3] (Example 4), the purity was 99.9% and the yield was 98%. After isolating the sodium salt of the general formula [3] from the compound of the formula [4], in the production of the intermediate A (Examples 3 and 4), the purity was 99.9% and the yield was 97%. .
On the other hand, in the production in which the compound of the general formula [3] was not isolated (Comparative Examples 1 and 2), the purity of the intermediate A was 98.4 to 99.4%, and the yield was 85 to 89%.
By using the production method of the present invention, intermediate A can be produced with high purity and high yield.

＊１）一般式［３］の化合物またはその水和物のＨＰＬＣ純度
＊２）中間体ＡのＨＰＬＣ純度
＊３）中間体ＢのＨＰＬＣ純度
＊４）式［４］の化合物から一般式［３］の化合物またはその水和物の収率
＊５）一般式［３］の化合物またはその水和物から中間体Ｂの収率
＊６）式［４］の化合物から中間体Ｂの収率

* 1) HPLC purity of compound of general formula [3] or hydrate thereof * 2) HPLC purity of intermediate A * 3) HPLC purity of intermediate B * 4) From compound of formula [4] to general formula [3 Yield of compound or its hydrate * 5) Yield of intermediate B from compound of general formula [3] or hydrate * 6) Yield of intermediate B from compound of formula [4]

In the production of the calcium salt of the general formula [3] from the compound of the formula [4] (Example 5), the purity was 99.9% and the yield was 94%. In the production of intermediate B from the calcium salt of the general formula [3] (Example 6), the purity was 100% and the yield was 96%. In the production of intermediate C from the compound of formula [4] (Examples 5 and 6), the purity was 100% and the yield was 90%.
By using the production method of the present invention, intermediate B can be produced with high purity and high yield.

Next, although an example and a comparative example are given and explained, the present invention is not limited to these.
In each example, each abbreviation has the following meaning.
Bu: butyl, ^t Bu: tert-butyl, Me: methyl, Pr: propyl
DMSO-d ₆ : Heavy dimethyl sulfoxide
HPLC: High performance liquid chromatography

２−（１−ベンゾチオフェン−５−イル）エタノール150gおよび40％（w/w）ベンジルトリメチルアンモニウム＝ヒドロキシド水溶液3.52gのトルエン145mL溶液に19〜31℃でアクリロニトリル51.4gを滴下し、20〜23℃で１時間撹拌した。この反応混合物に塩酸22.5mLおよびメタノール150mLを加え、3〜25℃で塩化水素77.9gを導入後、2.5時間還流した。冷却後、反応混合物に水300mLおよびトルエン150mLを加えた。有機層を分取し、メタノール150mLを加え、20％（w/w）水酸化ナトリウム水溶液337gを滴下し、30℃で2.5時間撹拌した。この反応混合物に、水150mLを加え、塩酸でpH2.0に調整した。有機層を分取し、トルエン450mLを加え、19〜32℃でアンモニア17.6gを導入した。冷却後、析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸のアンモニウム塩の１水和物236gを得た。
¹H-NMR(400 MHz, D₂O)δ(ppm):
2.40(2H,t,J=6.8Hz),2.82(2H,dt,J=7.0,1.7Hz),3.57(2H,dt,J=7.0,2.7Hz),3.62(2H,dt,J=6.8,1.5Hz),7.06(1H,dd,J=8.3,1.2Hz),7.21(1H,dd,J=5.4,2.7Hz),7.39(1H,dd,J=5.4,3.4Hz),7.50-7.55(1H,m),7.68(1H,dd,J=8.3,2.9Hz).
HPLC純度：99.5％
水分値：6.6％ Example 1

Acrylonitrile (51.4 g) was added dropwise at 19 to 31 ° C. to a 145 mL solution of 2- (1-benzothiophen-5-yl) ethanol (150 g) and 40% (w / w) benzyltrimethylammonium hydroxide aqueous solution (3.52 g) at a temperature of 19 to 31 ° C. Stir at 23 ° C. for 1 hour. To this reaction mixture, 22.5 mL of hydrochloric acid and 150 mL of methanol were added, and 77.9 g of hydrogen chloride was introduced at 3 to 25 ° C., followed by refluxing for 2.5 hours. After cooling, 300 mL of water and 150 mL of toluene were added to the reaction mixture. The organic layer was separated, 150 mL of methanol was added, 337 g of a 20% (w / w) aqueous sodium hydroxide solution was added dropwise, and the mixture was stirred at 30 ° C. for 2.5 hours. To this reaction mixture, 150 mL of water was added, and the pH was adjusted to 2.0 with hydrochloric acid. The organic layer was separated, 450 mL of toluene was added, and 17.6 g of ammonia was introduced at 19 to 32 ° C. After cooling, the precipitate was collected by filtration to obtain 236 g of monohydrate of ammonium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
¹ H-NMR (400 MHz, D ₂ O) δ (ppm):
2.40 (2H, t, J = 6.8Hz), 2.82 (2H, dt, J = 7.0,1.7Hz), 3.57 (2H, dt, J = 7.0,2.7Hz), 3.62 (2H, dt, J = 6.8, 1.5Hz), 7.06 (1H, dd, J = 8.3,1.2Hz), 7.21 (1H, dd, J = 5.4,2.7Hz), 7.39 (1H, dd, J = 5.4,3.4Hz), 7.50-7.55 ( 1H, m), 7.68 (1H, dd, J = 8.3,2.9Hz).
HPLC purity: 99.5%
Moisture value: 6.6%

実施例１で得られた３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸のアンモニウム塩の１水和物25.0gを水108mLおよび酢酸エチル4.6mLに溶解し、室温で塩酸を9.29g滴下した。析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸21.5gを得た。
CDCl₃中における¹H-NMRは、比較例１の値と一致した。
HPLC純度：99.5％ Example 2

25.0 g of the monohydrate of ammonium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid obtained in Example 1 was dissolved in 108 mL of water and 4.6 mL of ethyl acetate, and at room temperature. 9.29 g of hydrochloric acid was added dropwise. The precipitate was collected by filtration to obtain 21.5 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
¹ H-NMR in CDCl ₃ agreed with the value of Comparative Example 1.
HPLC purity: 99.5%

２−（１−ベンゾチオフェン−５−イル）エタノール100gおよび40％（w/w）ベンジルトリメチルアンモニウム＝ヒドロキシド水溶液2.35gのトルエン100mL溶液に17〜31℃でアクリロニトリル34.2gを滴下し、21〜22℃で1時間撹拌した。この反応混合物に塩酸15mLおよびメタノール100mLを加え、2〜18℃で塩化水素52.7gを導入後、3.5時間還流した。冷却後、反応混合物に水200mLおよびトルエン100mLを加えた。有機層を分取し、メタノール100mLおよび20％（w/w）水酸化ナトリウム水溶液180mLを加え31〜38℃で1.5時間撹拌した。この反応混合物に、水200mLおよびトルエン100mLを加え、塩酸でpH2.1に調整した。有機層を分取し、２−プロパノール100mLおよび水酸化ナトリウム24.7gの水40mL溶液を滴下した。アセトン200mLを滴下後、析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸のナトリウム塩の３水和物182gを得た。
¹H-NMR(400 MHz, D₂O)δ(ppm)：2.40(2H,t,J=7.0Hz),2.76(2H,t,J=7.1Hz),3.43-3.53(2H,m),3.55-3.62(2H,m),6.92-7.01(1H,m),7.10-7.17(1H,m),7.25-7.34(1H,m),7.40-7.47(1H,m),7.60(1H,d,J=8.3Hz).
HPLC純度：99.9％
水分値：17.5％ Example 3

Acrylonitrile (34.2 g) was added dropwise to a 100 mL toluene solution of 100 g of 2- (1-benzothiophen-5-yl) ethanol and 2.35 g of 40% (w / w) benzyltrimethylammonium hydroxide aqueous solution at 17 to 31 ° C. Stir at 22 ° C. for 1 hour. To this reaction mixture, 15 mL of hydrochloric acid and 100 mL of methanol were added, and 52.7 g of hydrogen chloride was introduced at 2 to 18 ° C., followed by refluxing for 3.5 hours. After cooling, 200 mL of water and 100 mL of toluene were added to the reaction mixture. The organic layer was separated, 100 mL of methanol and 180 mL of 20% (w / w) sodium hydroxide aqueous solution were added, and the mixture was stirred at 31 to 38 ° C. for 1.5 hours. To this reaction mixture, 200 mL of water and 100 mL of toluene were added, and the pH was adjusted to 2.1 with hydrochloric acid. The organic layer was separated and a solution of 100 mL of 2-propanol and 24.7 g of sodium hydroxide in 40 mL of water was added dropwise. After adding 200 mL of acetone dropwise, the precipitate was collected by filtration to obtain 182 g of trihydrate of sodium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
¹ H-NMR (400 MHz, D ₂ O) δ (ppm): 2.40 (2H, t, J = 7.0 Hz), 2.76 (2H, t, J = 7.1 Hz), 3.43-3.53 (2H, m), 3.55-3.62 (2H, m), 6.92-7.01 (1H, m), 7.10-7.17 (1H, m), 7.25-7.34 (1H, m), 7.40-7.47 (1H, m), 7.60 (1H, d , J = 8.3Hz).
HPLC purity: 99.9%
Moisture value: 17.5%

実施例３で得られた３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸のナトリウム塩の３水和物36.2gを水110mLおよびアセトン10mLに溶解し、室温で6mol/L塩酸を20mL滴下した。析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸27.1gを得た。
CDCl₃中における¹H-NMRは、比較例１の値と一致した。
HPLC純度：99.9％ Example 4

36.2 g of the sodium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid obtained in Example 3 was dissolved in 110 mL of water and 10 mL of acetone, and 6 mol / 20 mL of L hydrochloric acid was added dropwise. The precipitate was collected by filtration to obtain 27.1 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
¹ H-NMR in CDCl ₃ agreed with the value of Comparative Example 1.
HPLC purity: 99.9%

２−（１−ベンゾチオフェン−５−イル）エタノール100gおよび40％（w/w）ベンジルトリメチルアンモニウム＝ヒドロキシド水溶液2.35gのトルエン95mL溶液に20〜30℃でアクリロニトリル34.2gを滴下し、24〜28℃で1時間撹拌した。この反応混合物に塩酸15mLおよびメタノール100mL加え、0〜21℃で塩化水素64.7gを導入後、3時間還流した。冷却後、反応混合物に水200mLおよびトルエン100mLを加えた。有機層を分取し、メタノール100mLを加え、水酸化カリウム63.0gの水100mL溶液を滴下し、26〜33℃で1時間撹拌した。この反応混合物に、水200mLを加えた。水層を分取し、酢酸23.6g、２−プロパノール200mLおよび水400mLを加え、70〜71℃で酢酸カルシウム１水和物49.4gの水200mL溶液を滴下した。冷却後、析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸の１／２カルシウム塩の１水和物151gを得た。
¹H-NMR(400 MHz, DMSO-d₆)δ(ppm)：2.24(2H,t,J=7.2Hz),2.87(2H,t,J=7.0Hz),3.52-3.63(4H,m),7.21(1H,d,J=8.4Hz),7.36(1H,d,J=5.4Hz),7.65-7.73(2H,m),7.85(1H,d,J=8.4Hz).
HPLC純度：99.9％
水分値：6.4％ Example 5

Acrylonitrile (34.2 g) was added dropwise at 20 to 30 ° C. to 95 mL of a toluene solution of 100 g of 2- (1-benzothiophen-5-yl) ethanol and 2.35 g of 40% (w / w) benzyltrimethylammonium hydroxide aqueous solution at 20 to 30 ° C. Stir at 28 ° C. for 1 hour. To this reaction mixture, 15 mL of hydrochloric acid and 100 mL of methanol were added, and 64.7 g of hydrogen chloride was introduced at 0 to 21 ° C., followed by refluxing for 3 hours. After cooling, 200 mL of water and 100 mL of toluene were added to the reaction mixture. The organic layer was separated, 100 mL of methanol was added, a solution of 63.0 g of potassium hydroxide in 100 mL of water was added dropwise, and the mixture was stirred at 26 to 33 ° C. for 1 hour. To this reaction mixture, 200 mL of water was added. The aqueous layer was separated, 23.6 g of acetic acid, 200 mL of 2-propanol and 400 mL of water were added, and a solution of 49.4 g of calcium acetate monohydrate in 200 mL of water was added dropwise at 70 to 71 ° C. After cooling, the precipitate was collected by filtration to obtain 151 g of monohydrate of ½ calcium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ (ppm): 2.24 (2H, t, J = 7.2 Hz), 2.87 (2H, t, J = 7.0 Hz), 3.52-3.63 (4H, m) , 7.21 (1H, d, J = 8.4Hz), 7.36 (1H, d, J = 5.4Hz), 7.65-7.73 (2H, m), 7.85 (1H, d, J = 8.4Hz).
HPLC purity: 99.9%
Moisture level: 6.4%

実施例５で得られた３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸の１／２カルシウム塩の１水和物115gにトルエン250mL、水200mLおよび塩酸35.7mLを加え、室温で0.5時間撹拌した。有機層を分取し、水で洗浄した。有機層を減圧下に溶媒113mLを留去後、塩化チオニル52.3gおよびトルエン13mLを加え、1時間還流した。冷却後、この反応混合物を水酸化ナトリウム36.8g、３−アゼチジノール塩酸塩48.1g、水100mLおよび２−プロパノール200mLの混合物に−5〜4℃で滴下し、トルエン50mLで洗浄後、4℃で0.5時間撹拌した。反応混合物に、トルエン200mLおよび水300mLを加え、38℃で有機層を分取した。水200mLを加え塩酸でpH2.6に調整し有機層を分取した。常圧下に溶媒を235mL留去後、トルエン400mLを加え、常圧下に溶媒を100mL留去した。冷却後、析出物を濾取し、白色固体の１−（３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオニル）アゼチジン−３−オール117gを得た。
CDCl₃中における¹H-NMRは、比較例３の値と一致した。
HPLC純度：100.0％ Example 6

To 115 g of the monohydrate of 1/2 calcium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid obtained in Example 5, 250 mL of toluene, 200 mL of water and 35.7 mL of hydrochloric acid were added. And stirred at room temperature for 0.5 hour. The organic layer was separated and washed with water. The organic layer was distilled off 113 mL of the solvent under reduced pressure, 52.3 g of thionyl chloride and 13 mL of toluene were added, and the mixture was refluxed for 1 hour. After cooling, the reaction mixture was added dropwise to a mixture of 36.8 g of sodium hydroxide, 48.1 g of 3-azetidinol hydrochloride, 100 mL of water and 200 mL of 2-propanol at −5 to 4 ° C., washed with 50 mL of toluene, and then washed with 0.5 at 4 ° C. Stir for hours. To the reaction mixture, 200 mL of toluene and 300 mL of water were added, and the organic layer was separated at 38 ° C. 200 mL of water was added, the pH was adjusted to 2.6 with hydrochloric acid, and the organic layer was separated. After 235 mL of the solvent was distilled off under normal pressure, 400 mL of toluene was added, and 100 mL of the solvent was distilled off under normal pressure. After cooling, the precipitate was collected by filtration to obtain 117 g of 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidin-3-ol as a white solid.
¹ H-NMR in CDCl ₃ agreed with the value of Comparative Example 3.
HPLC purity: 100.0%

２−（１−ベンゾチオフェン−５−イル）エタノール50.0gのトルエン50mL懸濁液に、40％（w/w）ベンジルトリメチルアンモニウム＝ヒドロキシド水溶液2.35gを加え、8〜15℃でアクリロニトリル17.9gを滴下し、10〜20℃で1.5時間撹拌した。この反応混合物に塩酸1.25mLを加えた後、プロパノール100mLおよび水5.05gを加え、硫酸55.0gを滴下後、6時間還流した。冷却後、反応混合物に水100mLを加えた。有機層を分取し、メタノール50mLを加え、水酸化カリウム31.5gの水50mL溶液を滴下し、室温で1.5時間撹拌した。この反応混合物に、トルエン75mLおよび水75mLを加えた。水層を分取し、トルエン100mLを加え、6mol/L塩酸でpH0.9に調整し、有機層を分取した。減圧下に溶媒を留去後、トルエン50mLおよびシクロヘキサン125mLを加えた。析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸59.6gを得た。
HPLC純度：98.4％ Comparative Example 1 (Patent Document 2, Example 4-4)

2.35 g of 40% (w / w) benzyltrimethylammonium hydroxide aqueous solution was added to 50 mL of toluene suspension of 50.0 g of 2- (1-benzothiophen-5-yl) ethanol, and 17.9 g of acrylonitrile at 8 to 15 ° C. Was added dropwise and stirred at 10 to 20 ° C. for 1.5 hours. After adding 1.25 mL of hydrochloric acid to the reaction mixture, 100 mL of propanol and 5.05 g of water were added, and 55.0 g of sulfuric acid was added dropwise, followed by refluxing for 6 hours. After cooling, 100 mL of water was added to the reaction mixture. The organic layer was separated, 50 mL of methanol was added, a solution of 31.5 g of potassium hydroxide in 50 mL of water was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. To this reaction mixture, 75 mL of toluene and 75 mL of water were added. The aqueous layer was separated, 100 mL of toluene was added, the pH was adjusted to 0.9 with 6 mol / L hydrochloric acid, and the organic layer was separated. After evaporating the solvent under reduced pressure, 50 mL of toluene and 125 mL of cyclohexane were added. The precipitate was collected by filtration to obtain 59.6 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid.
HPLC purity: 98.4%

２−（１−ベンゾチオフェン−５−イル）エタノール260gのトルエン260mL懸濁液に、２−プロパノール43.8gおよびカリウム＝ｔｅｒｔ−ブトキシド1.64gを加え、0.5時間撹拌した。反応混合物を15℃まで冷却後、アクリロニトリル116gを滴下し、15〜25℃で1時間撹拌した。反応混合物に塩酸6.5mL、メタノール520mLおよび水78.9gを加え、10〜25℃で塩化水素310gを導入後、3時間還流した。冷却後、反応混合物に水780mLおよびトルエン520mLを加え、有機層を分取した。有機層に、メタノール260mLおよび水酸化カリウム164gの水260mL溶液を滴下し、30〜35℃で2時間撹拌した。反応混合物に水260mLを加え、水層を分取した。水層に、トルエン520mLおよび水260mLを加え、塩酸234mLを滴下し、有機層を分取した。有機層から溶媒390mLを減圧下に留去し、シクロヘキサン1040mLを加え、析出物を濾取し、白色固体の３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸326gを得た。
HPLC純度：99.4％ Comparative Example 2 (Patent Document 2, Example 4-5)

To a suspension of 260 g of 2- (1-benzothiophen-5-yl) ethanol in 260 mL of toluene were added 43.8 g of 2-propanol and 1.64 g of potassium tert-butoxide, and the mixture was stirred for 0.5 hours. The reaction mixture was cooled to 15 ° C., 116 g of acrylonitrile was added dropwise, and the mixture was stirred at 15 to 25 ° C. for 1 hour. To the reaction mixture, 6.5 mL of hydrochloric acid, 520 mL of methanol and 78.9 g of water were added, and 310 g of hydrogen chloride was introduced at 10 to 25 ° C., followed by refluxing for 3 hours. After cooling, 780 mL of water and 520 mL of toluene were added to the reaction mixture, and the organic layer was separated. To the organic layer, a solution of 260 mL of methanol and 164 g of potassium hydroxide in 260 mL of water was added dropwise and stirred at 30 to 35 ° C. for 2 hours. 260 mL of water was added to the reaction mixture, and the aqueous layer was separated. To the aqueous layer, 520 mL of toluene and 260 mL of water were added, and 234 mL of hydrochloric acid was added dropwise to separate the organic layer. 390 mL of the solvent was distilled off from the organic layer under reduced pressure, 1040 mL of cyclohexane was added, and the precipitate was collected by filtration to obtain 326 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid as a white solid. It was.
HPLC purity: 99.4%

３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオン酸50.0gを１，２−ジメトキシエタン75mLに溶解し、塩化チオニル26.1gを加え、2時間還流した。冷却後、この反応液を水125mL、水酸化ナトリウム20.0gおよび３−アゼチジノール＝塩酸塩25.2gの混液に-5〜10℃で滴下し、さらに0〜15℃で30分間撹拌した。水75mLを加え、40℃に加熱溶解後冷却し、析出物を濾取し、白色固体の１−（３−（２−（１−ベンゾチオフェン−５−イル）エトキシ）プロピオニル）アゼチジン−３−オール56.5gを得た。
HPLC純度：99.7％ Comparative Example 3 (Patent Document 2, Example 5-3)

5-0.0 g of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid was dissolved in 75 mL of 1,2-dimethoxyethane, 26.1 g of thionyl chloride was added, and the mixture was refluxed for 2 hours. After cooling, this reaction solution was added dropwise to a mixed solution of 125 mL of water, 20.0 g of sodium hydroxide and 25.2 g of 3-azetidinol = hydrochloride at −5 to 10 ° C., and further stirred at 0 to 15 ° C. for 30 minutes. 75 mL of water was added, and the mixture was dissolved by heating at 40 ° C. and then cooled. The precipitate was collected by filtration and 1- (3- (2- (1-benzothiophen-5-yl) ethoxy) propionyl) azetidine-3- A total of 56.5 g was obtained.
HPLC purity: 99.7%

  The compound of the present invention is important for 1- (3- (2- (1- (benzothiophen-5-yl) ethoxy) propyl) -3-azetidinol maleate, which has been developed as a therapeutic agent for neurodegenerative diseases. It is a production intermediate and the production method of the present invention is useful as an industrial production method.

Claims (6)

2- (1-benzothiophen-5-yl) ethanol is subjected to a Michael addition reaction with acrylonitrile in the presence of a base, and then in the presence of an acid.

“In the formula, R ¹ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted aryl group.” In the reaction with the alcohol represented by the general formula

It is characterized in that a propionic acid ester derivative represented by “wherein R ¹ has the same meaning as described above”, then subjected to a hydrolysis reaction in the presence of a base, and then a base is allowed to act. General formula

3 wherein “M represents sodium ion, calcium ion or ammonium ion; n represents 1 when M is sodium ion or ammonium ion, and 2 when M is calcium ion”. A process for producing a salt of-(2- (1-benzothiophen-5-yl) ethoxy) propionic acid or a hydrate thereof. 2- (1-benzothiophen-5-yl) ethanol is subjected to a Michael addition reaction with acrylonitrile in the presence of a base, and then in the presence of an acid.

“In the formula, R ¹ represents a hydrogen atom, an optionally substituted C _1-6 alkyl group, an optionally substituted C _3-8 cycloalkyl group or an optionally substituted aryl group.” In the reaction with the alcohol represented by the general formula

Propionate derivative represented by “wherein R ¹ has the same meaning as described above” was obtained by subjecting it to a hydrolysis reaction in the presence of a base and then acting on a base. General formula

3 wherein “M represents sodium ion, calcium ion or ammonium ion; n represents 1 when M is sodium ion or ammonium ion, and 2 when M is calcium ion”. A salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid or a hydrate thereof is isolated and then reacted with an acid. Process for the preparation of thiophen-5-yl) ethoxy) propionic acid. General formula

3 wherein “M represents sodium ion, calcium ion or ammonium ion; n represents 1 when M is sodium ion or ammonium ion, and 2 when M is calcium ion”. -(2- (1-benzothiophen-5-yl) ethoxy) propionic acid salt or hydrate thereof. formula

A sodium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid represented by the formula: formula

A calcium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid represented by the formula: formula

An ammonium salt of 3- (2- (1-benzothiophen-5-yl) ethoxy) propionic acid represented by the formula: