JPH07285921A - Production of 2-amino-n-(beta-hydroxyphenethyl)acetamide derivative - Google Patents

Abstract

PURPOSE:To easily obtain a 2-amino-N-(beta-hydroxyphenethyl)acetamide derivative in high yield and purity by reaction of hexamethylenetetramine with a 2- halogeno-N-(p-hydroxy-2,5-dimethoxyphenethyl) acetamide followed by hydrolyzing the resultant adduct. CONSTITUTION:A 2-halogeno-N-(beta-hydroxy-2,5-dime thoxyphene) acetamide of formula I (X<1> is a halogen) is reacted with hexamethylenetetramine of formula (CH2)6N4 followed by hydrolyzing the resultant adduct to obtain the objective 2-amino-N-(beta-hydroxyphenethyl)acetamide derivative (midodrine) of formula II. The compound of formula I can be easily obtained by Schotten-Baumann reaction of a haloacetyl halide of formul-a X<1>CH2C0X<2> (X<2> is a halogen) with 1-(2,5-dimethoxyphenyl)-2-aminoethanol of formula III. By this method, the objective midodrine can be obtained in high yield and purity in an industrially highly advantageous way in a short process by extremely simple operations without the need for using any risky raw material.

Description

Detailed Description of the Invention

[0001]

The present invention relates to 2-amino-N- (β
-Hydroxyphenethyl) acetamide derivative.

[0002]

[Prior art and its problems]

[0003]

[Chemical 3]

The 2-amino-N- (β-hydroxyphenethyl) acetamide derivative represented by is a so-called prodrug obtained by modifying a phenylethanolamine derivative having a selective α-receptor stimulating action with glycine, and is generally called midodrine. It is called by name. This midodrine is an extremely useful compound as a therapeutic agent for hypotension.

Conventionally, as a method for producing midodrine, for example, the method described in Japanese Patent Publication No. 57-47986 and the method described in US Pat. No. 3,340,298 are known. The former method is an expression

[0006]

[Chemical 4]

2-Chloro-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide represented by the following formula was reacted with sodium azide to obtain the following formula:

[0008]

[Chemical 5]

A method for producing midodrine by reducing 2-azido-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide represented by The latter method is a method of producing midodrine by removing a protecting group after reacting a protected glycine derivative with phenylethanolamine which is a base without substitution of nitrogen.

However, all of these methods have drawbacks and are not industrially advantageous methods. That is, according to the former method, an azide compound is used as an intermediate, but the alkyl azide is generally unstable to heat and mechanical shock, and its handling requires caution. Further, sodium azide as a raw material reacts with an acid to have strong toxicity and generate explosive hydrogen azide. Also, the latter method is a conventional laboratory method for peptide synthesis, but the use of a protecting group necessitates a multistep synthesis process, and furthermore, produces middrine in high yield and high purity. Is difficult to do.

[0011]

In view of the above situation, the present inventor has made earnest studies to develop an industrially advantageous method for producing midodrine, and as a result, is represented by the following general formula (4). 2-halogeno-N- (β-hydroxy-2,5
-The target midodrine can be easily obtained in high yield and high purity by hydrolyzing an adduct obtained by reacting -dimethoxyphenethyl) acetamide with hexamethylenetetramine represented by the formula (5). Found out. The present invention has been completed based on such knowledge.

That is, the present invention has the general formula

[0013]

[Chemical 6]

[In the formula, X ¹ represents a halogen atom. ] 2-halogeno-N- (β-hydroxy-2,5 represented by
2-dimethoxyphenethyl) acetamide is reacted with hexamethylenetetramine represented by the formula (CH ₂ ) ₆ N ₄ (5), and then the resulting adduct is hydrolyzed to give the 2-amino-formula represented by the formula (1). It relates to a method for producing a 2-amino-N- (β-hydroxyphenethyl) acetamide derivative, which comprises obtaining an N- (β-hydroxyphenethyl) acetamide derivative.

In the present invention, 2-halogeno-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide of the general formula (4) used as a starting material is a known compound, for example, a compound represented by the formula:

[0016]

[Chemical 7]

1- (2,5-dimethoxyphenyl) -2-aminoethanol represented by the general formula X ¹ CH ₂ COX ² (7) [wherein X ² represents a halogen atom]. X ¹ is the same as above. ] It is a compound that can be easily produced by reacting a haloacetyl halogen compound represented by the following by the Schotten-Baumann reaction.

Hexamethylenetetramine of the general formula (5) used as the other starting material in the present invention is also a known compound. The compound is industrially inexpensive, easily available, and extremely stable.

The 2-halogeno-N- (β-of the general formula (4)
The reaction of hydroxy-2,5-dimethoxyphenethyl) acetamide with hexamethylenetetramine of the general formula (5) is generally carried out in a suitable solvent. As the solvent used, conventionally known solvents can be widely used as long as they do not participate in the reaction, for example, methanol, ethanol,
Alcohols such as isopropyl alcohol, ethers such as tetrahydrofuran and dioxane, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride, esters such as ethyl acetate and methyl acetate, ketones such as acetone and methyl ethyl ketone,
Examples thereof include acetonitrile and dimethylformamide. The use ratio of the compound of the general formula (4) and the compound of the general formula (5) is not particularly limited and may be appropriately selected from a wide range, but usually the former is 0.8 to 1 mol per mol.
It is recommended to use about 1.2 mol. This reaction is carried out from room temperature near the boiling point of the solvent used, but usually 30 to 7
About 0 ° C is suitable. The reaction time varies depending on the reaction temperature and the like and cannot be generally stated, but it is usually several hours.

The adduct produced by the above reaction is filtered,
Although it can be easily removed from the reaction mixture by a conventional means such as concentration, the hydrolysis reaction can be continued as it is without isolating the adduct. In this case, the desired midodrine can be produced in a substantially one-step reaction, which is extremely advantageous industrially.

For the hydrolysis reaction, the same solvent as that used in the reaction between the compound of the general formula (4) and the compound of the general formula (5) can be used. Further, this hydrolysis reaction is carried out in the presence of an ordinary acid, for example, a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid. The amount of the acid used may be usually about 1 to 10 times mol, preferably about 4 times mol, per mol of the compound to be hydrolyzed. The reaction temperature is usually room temperature to 100 ° C., and the reaction is generally completed in 1 to 24 hours.

Although midodrine is usually used as an acid addition salt, the desired acid addition salt can be produced all at once by using the above acid during hydrolysis.

[0023]

EFFECTS OF THE INVENTION According to the present invention, the desired midodrine can be obtained in a high yield and a high purity by using a short process and an extremely simple operation without using a dangerous raw material, and therefore, it is industrially extremely advantageous. It can be manufactured.

[0024]

EXAMPLES The present invention will be further clarified with reference to the following examples.

Example 1 5.4 g of 2-chloro-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide was added to 25 ml of acetonitrile, 3 g of hexamethylenetetramine was added thereto, and the mixture was stirred at 40 ° C. for 5 hours. did. The precipitated crystals were filtered and dried at 50 ° C. to obtain 8.1 g of white crystals having a melting point of about 158 ° C.

The crystals were suspended in 30 ml of ethanol, and 8.3 g of 35% hydrochloric acid was added while cooling. After stirring overnight at room temperature, the crystals were filtered off. 23.4m of this crystal
1 and 12.5 ml of methanol were dissolved by heating. After cooling, the precipitated crystals were filtered, washed with cold water, and then dried at 60 ° C to obtain white crystals of midodrine hydrochloride.

Yield: 4.6 g, yield 79%, melting point: about 2
00 ° C The infrared absorption spectrum obtained above is 3340c.
m ^-1 , 1665 cm ^-1 , 1570 cm ^-1 , 1500 cm
^-1 and 1220 cm ^-1 have absorption peaks,
It was identical with that synthesized by the method described in JP-A-47986.

Example 2 3 g of hexamethylenetetramine was dissolved in 30 ml of ethanol, and 2-chloro-N- (β-hydroxy-
2,5-dimethoxyphenethyl) acetamide 5.4 g
Was added, and the mixture was stirred in a water bath at 40 ° C for 6 hours. Next, while cooling with ice water, 8.8 g of 35% hydrochloric acid was added, and the mixture was aged by stirring at room temperature overnight. The precipitated crystals were filtered, washed with isopropyl alcohol, and dried at 60 ° C. The obtained crude midodrine hydrochloride (7.3 g) was dissolved in water (23 ml) and methanol (5 ml) by heating, and the crystals precipitated after cooling were filtered and dried at 50 ° C.

Yield: 3.4 g, 58% yield The physical properties of this product were completely in agreement with those of the compound obtained in Example 1.

Example 3 A mixture of 6.4 g of 2-bromo-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide, 3 g of hexamethylenetetramine and 30 ml of acetonitrile was stirred at room temperature for 1 hour to react spontaneously. As a result, a uniform solution was obtained, and crystals were precipitated again. Acetonitrile was distilled off under reduced pressure, ethanol was added to the residue, and 35% hydrochloric acid was added while cooling with ice water. After aging overnight at room temperature, the crystals were filtered. The obtained crystals were recrystallized from 24 ml of water and 2.4 ml of methanol to obtain white crystals of midodrine hydrochloride.

Yield: 5.1 g, 87% yield The physical properties of this product were completely the same as those of the compound obtained in Example 1.

Claims (1)

[Claims] 1. A general formula: [In the formula, X ¹ represents a halogen atom. ] 2-
Halogeno-N- (β-hydroxy-2,5-dimethoxyphenethyl) acetamide is reacted with hexamethylenetetramine of the formula (CH ₂ ) ₆ N ₄ and then the resulting adduct is hydrolyzed. 2] 2-amino-N- (β-hydroxyphenethyl) acetamide derivative represented by
A method for producing an amino-N- (β-hydroxyphenethyl) acetamide derivative.