JPS5945668B2 - Novel method for producing (3-carbomethoxypropyl)-trimethylammonium chloride hydrate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is based on the following formula [(CH3ゝN-CH2(H2(H2-COOGLeCl
・Represented by H2O (3-carbomethoxypropyl)
- A novel method for producing trimethylammonium chloride hydrate.

(3-Carbomethoxypropyl)monotrimethylammonium chloride (hereinafter abbreviated as CPT) has an acetylcholine-like action and a local vasodilatory action, and is a useful pharmaceutical agent as a hair root function activator. It is known that the anhydride and monohydrate of CPT have significantly different physical properties.

According to the inventors' research on the hygroscopicity of CPT, the hygroscopicity when left under conditions of relative humidity of 40% is
With T anhydride, it is more than 9% after 24 hours and about 1 after 48 hours.
1%, showing more than 12% after 72 hours, whereas CPT
- In the case of aqueous salt, it was 1% or less after 24 hours, 3% or less after 48 hours, 4% or less after 96 hours, and 5% or less even after 180 hours. As described above, CPT anhydride easily absorbs moisture and is difficult to handle during production and storage, whereas monohydrate has various advantages due to its low humidity. But C
PT-hydrate salt is produced from CPT anhydride, and no method for directly producing it is known yet. Methods for producing CPT anhydride include, for example, a method in which γ-halogenobutyric acid lower alkyl ester is reacted with a trimethylamine solution in an acetone solvent, and the resulting crude crystals are isolated and purified using methanol (see Japanese Patent Publication No. 17961/1983); A method of reacting γ-trimethylammonium butyric acid chloride with a lower alcohol in the presence of para-toluenesulfonic anhydride and isolating and purifying it using a mixed solvent of methanol-acetone or dimethylformamide-acetone (Japanese Patent Application Laid-Open No. 48-5714) (see official bulletin) is known.

By treating the CPT anhydride thus obtained with a water-containing organic solvent, CPT-hydrate can be produced (see Japanese Patent Laid-Open No. 7418/1983).

However, when producing CPT monohydrate by these methods, the CPT anhydride is separated and dried and then recrystallized again from a water-containing organic solvent, which increases the number of processing steps and makes the operation complicated. Due to the low yield, C
There are drawbacks such as a low yield of PT monohydrate. As a result of research into the production of this monohydrate, the present inventors found that CPT monohydrate can be obtained directly by reacting γ-chlorobutyric acid methyl ester with a gaseous state of trimethylamine in a moisture-containing atmosphere. .

According to the method of the present invention, CPT monohydrate can be obtained in good yield and high purity by simple and economical means. When carrying out the present invention, it is preferable to pass an inert gas containing moisture, such as air or nitrogen gas, into the γ-chloroacetic acid methyl ester after or simultaneously with the introduction of the trimethylamine gas.

Venting time varies depending on the moisture content of the inert gas, etc.
2 to 4 when using an inert gas with a relative humidity of 40% or more
Time is enough. Usually, 1.2 to 3 moles of water per mole of additional water required are applied by introducing moisture-containing air into the reactor. It is preferable to add desired moisture to the air used through a humidifier. The reaction temperature is preferably 30°C or higher, particularly 50 to 105°C. The reaction can be carried out under normal pressure, reduced pressure or increased pressure, and the solvent is not particularly required, but alcohols such as methanol, ethanol, propanol, etc., ketones such as acetone, methyl ethyl ketone, dimethylformamide, etc., and mixtures thereof may be used. It can also be used.

Separation of the products is carried out in a conventional manner. Example 0.25 mol (about 159) of trimethylamine gas was blown into 32 g of γ-chlorobutyric acid methyl ester under ice cooling and stirring within about 0.5 hours, and then the reactor was sealed and the internal temperature was gradually raised. and heat at 60°C for 3 hours.

Claims (1)

[Claims] 1. A method for producing (3-carbomethoxypropyl)-trimethylammonium chloride hydrate, which comprises reacting γ-chlorobutyric acid methyl ester with trimethylamine gas in a moisture-containing atmosphere.