JP2000229901A - New method for production of phenoxyalkylhalide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a derivative of phenoxyalkylhalide in high purity and yield useful as a synthetic intermediate for tamsulosin hydrochloride by reacting a halogenide to a specific (alkoxyphenoxy)ethyl compound. SOLUTION: The (C) derivative of phenoxyalkylhalide of formula II (X is a halogen) is obtained by reacting (B) the halogenide to the (alkoxyphenoxy) ethyl compound expressed by formula I (R is a lower alkyl; and Y is a leaving group). The substituted sulfamoyl phenethylamines (e.g. tamsulosin hydrochloride) (E) of formula IV can be obtained by reacting amine compound (D) of formula III (R1 and R3 are each H or a lower alkyl; R2 is OH, a lower alkyl or the like; and R6 is H or a halogen) to the obtained component (C) [e.g. (o- ethoxyphenoxy)ethyl bromide]. The component (E) is a compound having adrenoreceptor blocking action.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to (R) -5- [2-
[[2- (o-ethoxyphenoxy) ethyl] amino]
Phenoxyalkyl halide derivatives, particularly useful as an industrially superior intermediate for the production of a series of sulfamoyl-substituted phenethylamine derivatives, including -2-methylethyl] -2-methoxybenzenesulfonamide hydrochloride (general name "tamsulosin hydrochloride"), , 2- (o-ethoxyphenoxy) ethyl halide and a novel process for producing the sulfamoyl-substituted phenethylamine derivative via the intermediate.

[0002]

2. Description of the Related Art Heretofore, as a general method for producing a phenoxyalkyl halide, a method of condensing phenol and an alkylenedihalide has been known. That is,
J. Med. Chem. 8 (3) 356-367 (19
65) describes reacting o-methoxyphenol with ethylene dihalide in the presence of sodium hydroxide. However, in order to produce a phenoxyalkyl halide, a method of reacting a lower alkoxyphenol and an alkylene dihalide in the presence of an alkali was additionally tested by the present inventors, and the alkylene dihalide was condensed with two alkoxyphenols. A large amount of 1,2-bis (alkoxyphenoxy) ethane, which is a dimer, is formed as a by-product, which lowers the production rate of the target product, and further requires subsequent purification by distillation. Further, when ethylene 1,2-dibromide is used in an amount of 2 equivalents to o-ethoxyphenol according to the experimental examples in the above-mentioned literature, the desired product 2- (o-ethoxyphenoxy) is used.
The other dimer of ethyl bromide, 1,2-bis (o-
Ethoxyphenoxy) ethane was by-produced. In order to suppress the by-product formation of the dimer, it is necessary to use a large excess of alkylene dihalide with respect to the alkoxyphenol. However, the amount of vinyl halide formed by decomposition of the alkylene dihalide by alkali is lower. Since it is a substance that is easily scattered at the boiling point, it has a problem in terms of environmental protection or health and safety. In addition, distillation and purification at high temperature and high vacuum, which are indispensable for removing a large amount of by-product dimers, require special equipment in industrial production, and therefore have a large negative effect on scale expansion, operability, and economic effects. And it was.

On the other hand, a phenoxyalkyl halide, which is an object compound of the present invention, is a compound useful as an important intermediate for producing an amine derivative by reacting with an amino compound such as benzylamine. For example, Japanese Patent Publication No. 62-52742 discloses that a sulfamoyl-substituted phenethylamine derivative having an excellent α-adrenergic receptor blocking action and useful as a hypotensive agent can be obtained by reacting a corresponding amine derivative. I have. Among these compounds having an α-adrenergic receptor blocking action, tamsulosin hydrochloride has been developed by the present applicant company, and has already been marketed as a therapeutic agent for dysuria associated with prostatic hypertrophy. Certain phenoxyalkyl halide derivatives and tamsulosin
It has been desired to develop a production method for producing the hydrochloride itself at low cost and with good yield.

[0004]

An object of the present invention is to provide a novel process for producing a phenoxyalkyl halide derivative represented by the general formula (I). Another object of the present invention is to provide a novel process for producing tamsulosin hydrochloride, particularly using the general formula (I), which is the target compound of the present invention.

[0005]

Means for Solving the Problems The present inventors have prepared a novel process for producing a phenoxyalkyl halide derivative and a compound represented by the general formula (I):
The present invention has been completed as a result of intensive studies on a novel method for producing tamsulosin hydrochloride using phenol.

[0006]

That is, the present invention relates to the following production method. 1) An (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II)

Embedded image (Wherein, R represents a lower alkyl group and Y represents a leaving group. The same applies hereinafter.) The following general formula characterized by reacting a halide:
A method for producing the phenoxyalkyl halide derivative represented by (I). (Hereinafter, referred to as production method 1.)

Embedded image (Wherein X represents a halogen atom.) 2) (Alkoxyphenoxy) ethyl alcohol represented by the following general formula (III):

Embedded image After reacting a sulfonyl halide to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II),

Embedded image The following general formula characterized by reacting a halide
A method for producing the phenoxyalkyl halide derivative represented by (I). (Hereinafter, it is referred to as manufacturing method 2.)

Embedded image 3) a lower alkoxyphenol represented by the following general formula (IV)

Embedded image Reaction of ethylene carbonate or ethylene oxide with the following general formula (I
(Alkoxyphenoxy) ethyl alcohol represented by II),

Embedded image Further, after reacting an alkylsulfonyl halide to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II),

Embedded image The following general formula characterized by reacting a halide
A method for producing the phenoxyalkyl halide derivative represented by (I). (Hereinafter referred to as Production Method 3.)

Embedded image 4) An (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II)

Embedded image A phenoxyalkyl halide represented by the following general formula (I) for reacting an alkali metal halide,

Embedded image Amine compound (V) represented by the following general formula

Embedded image (Wherein R ₁ and R ₃ represent a hydrogen atom or a lower alkyl group;
₂ represents a hydroxyl group, a lower alkyl group, or —O-lower alkyl group, and R ₆ represents a hydrogen atom or a halogen atom. The same applies hereinafter) to produce a sulfamoyl-substituted phenethylamine derivative represented by the following general formula (hereinafter referred to as Production Method 4).

Embedded image

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of the group represented by the general formula of the present invention, a lower alkyl group means a linear or branched alkyl group having 1 to 5 carbon atoms. Examples are methyl, ethyl, propyl, isopropyl, butyl, pentyl, isopentyl and the like, preferably methyl, ethyl, propyl and the like. The halogen atom includes fluorine, chlorine, bromine and the like. Hereinafter, the production method of the present invention will be described in detail. In addition, since the manufacturing method 1 and the manufacturing method 2 are included in each step of the manufacturing method 3 (the manufacturing method 1 is the third step of the manufacturing method 3, and the manufacturing method 2 is the second and third steps of the manufacturing method 3), the manufacturing method 3 will be described in the following description of the manufacturing method. And Production Method 4 will be described in detail.

1) Manufacturing method 3

Embedded image In the first step of the present production method, an equivalent to excess amount of ethylene carbonate or ethylene oxide is reacted with a lower alkoxyphenol represented by the general formula (IV) in the presence or absence of a base at room temperature or under heating to obtain a compound of the general formula (III) Is a step of obtaining (alkoxyphenoxy) ethyl alcohol represented by

A base may be added to make the reaction proceed smoothly. The base in this case is not particularly limited as long as it is an organic or inorganic base, but preferably,
Inorganic bases, for example, carbonates such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate, hydroxides such as sodium hydroxide and potassium hydroxide, metal hydrides such as sodium hydride and lithium hydride, tetrabromide And quaternary ammonium salts such as butyl ammonium.

The reaction solvent is not limited as long as it does not participate in the reaction. Preferably, the reaction is carried out at a high temperature in order to promote the reaction, so that a solvent having a high boiling point, for example, dimethylformamide, dimethylacetamide, Dimethyl sulfoxide or a mixed solvent thereof is exemplified.
This reaction can be carried out in the absence of a solvent, if necessary. The reaction time is about several hours to 24 hours.

The (alkoxyphenoxy) ethyl alcohol obtained in this way is isolated or not isolated, and is directly subjected to the next step.

In the second step of the present process, an equivalent to excess amount of a sulfonyl halide is reacted with (alkoxyphenoxy) ethyl alcohol represented by the general formula (III) in the presence or absence of a base under cooling to room temperature. The general formula (I
This is a step of obtaining the (alkoxyphenoxy) ethylsulfonyl compound represented by I).

The sulfonyl halide is a sulfonylating agent such as methanesulfonyl chloride, ethanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonyl chloride or sulfonic anhydride thereof. Therefore, the compound represented by the general formula (II) In the formula, the leaving group represented by Y includes a methylsulfonyloxy group, a toluenesulfonyloxy group and the like. A base may be added to make this reaction proceed smoothly. The base in this case is not particularly limited as long as it is an organic or inorganic base, but is preferably an organic base, for example, triethylamine, trimethylamine, pyridine, picoline, lutidine and the like. As the reaction solvent, a solvent that does not participate in the reaction, for example, dimethylformamide, dimethylamide, dioxane, tetrahydrofuran, dichloroethane, chloroform, carbon tetrachloride, dimethoxymethane, dimethoxyethane, ethyl acetate, benzene, toluene, acetonitrile, dimethyl sulfoxide and the like These mixed solvents are mentioned. The reaction time is about several minutes to 24 hours. The (alkoxyphenoxy) ethylsulfonyl compound thus obtained can be isolated or can be directly subjected to the next step without isolation.

In the third step of the present process, an (alkoxyphenoxy) ethylsulfonyl compound represented by the general formula (II) is reacted with an equivalent amount or an excess amount of a halide at room temperature or under heating to obtain the desired compound of the present invention. This is a step of obtaining a phenoxyalkyl halide represented by the formula (I).

Examples of the halide include lithium bromide, potassium bromide, magnesium bromide, calcium bromide, tetrabutylammonium bromide and the like. The reaction solvent is not particularly limited as long as it is a solvent inert to the reaction, and examples thereof include acetone, methyl ethyl ketone, ethyl acetate, benzene, toluene, tetrahydrofuran, dichloroethane, chloroform, carbon tetrachloride, acetonitrile, and dimethyl sulfoxide. . The reaction time is about 1 hour to 24 hours, and the reaction temperature is from room temperature to heating. The target compound (I) thus obtained
Can be isolated and purified by well-known methods, for example, extraction, precipitation, chromatography, fractional crystallization, recrystallization and the like. Industrially, purification by recrystallization is preferred.

2) Production method 4

Embedded image

In this production method, an (alkoxyphenoxy) ethylsulfonyl compound represented by the general formula (II) is converted into the target compound (I) of the present invention, and then reacted with an amine compound represented by the general formula (V). This is a method for producing a sulfamoyl-substituted phenethylamine derivative represented by the formula (VI).

That is, an equimolar amount or an excess amount of the amine compound represented by the general formula (V) with respect to the compound of the present invention (I) obtained in the third step of the above-mentioned Production Method 3 is added at room temperature to under heating or by heating. The reaction can be carried out by refluxing. The reaction solvent is not particularly limited as long as it is a solvent that does not participate in the reaction, such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, and ethanol. In addition, upon the reaction, addition of an organic base such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, triethylamine, dimethylaniline, potassium carbonate, sodium hydrogen carbonate, sodium carbonate, etc., in order to make the reaction proceed smoothly May be advantageous. For the specific embodiment of this production method, see Examples described later and JP-B-62-52742.

[0019]

EXAMPLES The present invention will be described below in more detail with reference to examples, but the present invention is not limited to the examples.

(Example 1) o-ethoxyphenol 5
0 g (1.0 equivalent), 38.2 g (1.2 equivalent) of ethylene carbonate, and 2.5 g (0.05 equivalent) of potassium carbonate in DMF
250 ml and stirred at about 110 ° C. overnight to give 2- (o
-Ethoxyphenoxy) ethanol is obtained. After cooling,
500 ml of ethyl acetate and 54.9 g of triethylamine
After adding (1.5 equivalents), 58.0 g (1.4 equivalents) of methanesulfonyl chloride are added dropwise at 0 ° C. or lower. After dripping, 1000 ml of water and 200 ml of methyl ethyl ketone
The organic layer was dispersed in the above mixture, and the organic layer was washed with 500 ml of a 10% aqueous sodium bromide solution. The obtained organic layer was concentrated to obtain 2- (o-ethoxyphenoxy) ethyl methanesulfonate. After concentration, methyl ethyl ketone
250 ml and lithium bromide monohydrate 75.9 g (2.
(0 equivalent), and warm to about 90 ° C. for about 3 hours.
After cooling, the mixture was dispersed in 500 ml of water and 150 ml of ethyl acetate.
It wash | cleans sequentially by 00 ml and then 300 ml of water, and concentrates the obtained organic layer. The concentrated residue was recrystallized from an 85% aqueous methanol solution (300 ml) and dried under vacuum to obtain 2- (o-
72.4 g of ethoxyphenoxy) ethyl bromide
(Melting point: 44-45 ° C., purity: 99.1%).

Example 2 To 2- (o-ethoxyphenoxy) ethyl methanesulfonate obtained in the same manner as in Example 1, methyl ethyl ketone and lithium bromide monohydrate were added, and the mixture was heated to about 90 ° C. Heat for about an hour. After cooling, the mixture was dispersed in water and ethyl acetate, and the extracted organic layer was washed successively with a 1% aqueous potassium carbonate solution and then with water.
The obtained organic layer is concentrated. The concentrated residue is recrystallized from an 85% aqueous methanol solution and dried under vacuum to obtain 2- (o-ethoxyphenoxy) ethyl bromide. This compound and R
(-)-5-[(2-amino-2-methyl) ethyl]-
Dissolve 2-methoxybenzenesulfonamide in ethanol and heat to reflux. After the reaction, the solvent is distilled off, the residue is made alkaline with 10% aqueous sodium hydroxide, the precipitated oil is extracted with ethyl acetate, and the extract is washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solution is distilled off, purified by a conventional method, and treated with ethanol hydrochloride to give (R) -5- [2-[[2- (o-ethoxyphenoxy) ethyl] amino] -2-methylethyl] -2-. Obtain methoxybenzenesulfonamide hydrochloride.

[0022]

According to the process of the present invention, a high purity of the target compound (I) useful as an intermediate for producing a series of sulfamoyl-substituted phenethylamine derivatives having an α-adrenergic receptor blocking action, particularly tamsulosin hydrochloride, is obtained. And a high yield (the yield from the compound represented by the general formula (IV) is 8
0% or more). In addition, a highly versatile raw material can be used without using an alkyl dihalide as a raw material. Since the alkali decomposition product vinyl halide (having a high volatility) is not produced as a by-product, it is excellent in environmental conservation and safety assurance in industrial production. Further, since dimer is not formed as an impurity, the production scale can be easily expanded because general-purpose equipment can be used without special distillation equipment at high temperature and high vacuum which is indispensable for removing dimer. As a result, productivity and energy efficiency are improved, and the cost is reduced economically. Further, since the target compound (I) is not exposed to the high temperature during distillation, it is an excellent production method in that secondary problems such as decomposition do not occur. Therefore, it can be said that this is an extremely excellent production method for industrially producing tamsulosin hydrochloride as a final product as well as the target compound (I). The route to the series of sulfamoyl-substituted phenethylamine derivatives containing tamsulosin hydrochloride as the final substance via the target compound (I) is the above-mentioned production method 4.

Claims (5)

[Claims] 1. An (alkoxyphenoxy) ethyl compound represented by the following general formula (II): (Wherein, R represents a lower alkyl group and Y represents a leaving group. The same applies hereinafter.) The following general formula characterized by reacting a halide:
A method for producing the phenoxyalkyl halide derivative represented by (I). Embedded image (In the formula, X means a halogen atom.) 2. An (alkoxyphenoxy) ethyl alcohol represented by the following general formula (III): After reacting a sulfonyl halide to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II), (Wherein, Y represents a leaving group; the same applies hereinafter) The following general formula wherein a halide is reacted:
A method for producing the phenoxyalkyl halide derivative represented by (I). Embedded image (In the formula, X means a halogen atom.) 3. A lower alkoxyphenol represented by the following general formula (IV): (Wherein, R represents a lower alkyl group; the same applies hereinafter) Ethylene carbonate or ethylene oxide is reacted and the following general formula (I
(Alkoxyphenoxy) ethyl alcohol represented by II), Further, an alkylsulfonyl halide is reacted to give an (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II). (Wherein, Y represents a leaving group; the same applies hereinafter) The following general formula wherein a halide is reacted:
A method for producing the phenoxyalkyl halide derivative represented by (I). Embedded image (In the formula, X means a halogen atom.) 4. An (alkoxyphenoxy) ethylsulfonyl compound represented by the following general formula (II): (Wherein, R represents a lower alkyl group, Y represents a leaving group, and the same applies hereinafter) By reacting a halide, a phenoxyalkyl halide represented by the following general formula (I) is obtained. (Wherein, R represents a lower alkyl group, X represents a halogen atom, and the same applies hereinafter). In addition, an amine compound (V) represented by the following general formula: (Wherein R ₁ and R ₃ represent a hydrogen atom or a lower alkyl group;
₂ represents a hydroxyl group, a lower alkyl group, or —O-lower alkyl group, and R ₆ represents a hydrogen atom or a halogen atom. The same applies hereinafter) to produce a sulfamoyl-substituted phenethylamine derivative represented by the following general formula. Embedded image 5. The compound represented by the general formula (I) is 2-
The method according to any one of claims 1 to 4, which is (o-ethoxyphenoxy) ethyl bromide.