JPS5939896A - Purification of 5-methyl-7-diethylamino-s-triazolo (1,5-a) pyrimidine - Google Patents

Abstract

PURPOSE:To obtain the titled high-purity compound (trapidil for short) suitable as a coronary vasodilator, by bringing crude trapidil into contact with an acid in the presence of water so that colored impurities are easily removed. CONSTITUTION:Crude trapidil is brought into contact with preferably 0.5- 10mol% acid such as hydrochlorid acid based on the crude trapidil in the presence of water(preferably 0.1-30pts.wt. water based on 1pt.wt. crude prapidil) preferably at 40-90 deg.C for <=1hr, to purify trapidil. The crude trapidil is preferably made into an aqueous solution, or a solution state of an organic acid such as hexane, chloroform, methanol, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for purifying 5-methyl-7-danitylamino-8-triazolo(1,5-a)pyrimidine (hereinafter abbreviated as trapidil).

Trapidil is known to have excellent medicinal efficacy as a coronary dilator. This method for producing trapidil has been proposed, for example, in publications such as British Patent No. 1148629, JP-A-56-7'9674, and JP-A-56-108772. These prior art documents also describe attempts to purify crude trapidil by repeating various operations such as extraction and 11) crystallization using various solvents. However, even by the methods specifically disclosed in these publications, crude trapidil is not purified sufficiently, and for example, the resulting trapidil is contaminated with colored impurities or is not sufficiently pure to be used as a pharmaceutical product. are often of insufficient quality.

As a result of intensive research into methods for obtaining high-quality purified products suitable as pharmaceuticals from crude trapidil, the present inventors found that
The present invention has been accomplished by discovering a method for purifying trapidil that is superior to conventional methods, in which colored impurities can be removed by a simple operation of bringing crude trapidil into contact with an acid in the presence of water.

To summarize the present invention, the gist of the present invention is a method for purifying crude trapidil and an acid, which is characterized by contacting the compound in the presence of water.

The crude trapidil may be produced by any method, for example, 5-methyl-7-substituted-s-triazolo in which the 7-position is substituted with a halogen, a mercapto group, an alkylmercapto group, an alkoxyl group, etc. (1,5-
a) Method of reacting pyrimidine and diethylamine, N
, N-diethyl acetate amide and 6-amino-1,2,4-
) A method of reacting with lyazole in the presence of a dehydrating agent, 5
Examples include a method in which crotonic acid diethylamide (or alkoxy) and 6-amino-1,2,4-) IJ azole are reacted in the presence of a condensing agent; Not done.

Examples of acids used in the method of the present invention include mineral acids such as hydrochloric acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, and propionic acid.

Among these acids, it is preferred to use hydrochloric acid. The amount of these acids used is usually in the range of 0.1 to 20 mol%, preferably in the range of 0.5 to 10 mol%, based on the crude trapidil. The contact between the crude Trapidil and the acid needs to be carried out in the presence of water, and the amount of water used is usually 0.01 parts by weight per 1 part by weight of the crude Trapidil.
In the range from 0.1 to 50 parts by weight, preferably from 0.1 to 30 parts by weight.
Parts by weight range.

In the method of the present invention, when the crude trapidil and the acid are brought into contact with each other in the presence of water, it is preferable that the crude trapidil is in a solution state, and the crude trapidil is preferably in the form of an aqueous solution or an organic solvent inert to the acid and trapidil. It is preferable to use a solution of The crude Trapidil was added to J
When used in a liquid state, the organic solvent is preferably a solution of a water-immiscible solvent. Examples of the organic solvent include hydrocarbons such as hexane, heptane, benzene, toluene, and xylene, norogenated hydrocarbons such as 1,2-dichloroethane, dichloromethane, chloroform, and chlorobenzene, ethers such as diethyl ether and diisopropyl ether, methanol, and ethanol. Alcohol such as isopropyl alcohol.

What can be exemplified? The solvent can be used as a single solvent or in a mixed solvent system of two or more solvents. Among these organic solvents, hydrocarbons are preferably used.

In the method of the present invention, contact of crude trapidil with an acid is carried out by stirring, shaking, or the like.

The temperature during the contact treatment is usually in the range of 20 to 100°C, preferably 40 to 90°C. The time required for the contact treatment is usually one hour or less to achieve a sufficient purification effect.

In the method of the present invention, it is possible to obtain purified trapidil, which is highly purified and has an extremely low degree of coloration and is suitable as a pharmaceutical, by subjecting the mixture to contact with an acid and then subjecting it to conventional methods such as extraction and crystallization. can.

Next, the method of the present invention will be specifically explained using examples.

Reference Example 1 [Production method of crude trapidil] 5-, methyl-7-hydroxy-8-triazolo (it
s-a) Pyrimidine 150g% dichloroethane 300m
#, 168 g of phosphorus oxychloride was stirred for 5.5 hours under a nitrogen atmosphere. The reaction mixture was mixed with 420% sodium bicarbonate.
The mixture was added dropwise to 1.54 g of water at 50°C, stirred for 0.5 hours, and then extracted with 500 me of chloroform. 161 g of diethylamine was added dropwise into the organic layer for 50 min.
Stirred at °C for 1 hour. The reaction mixture was washed with 500 J of water, and the organic layer was concentrated under reduced pressure to obtain 164 g of crude trapidil with a purity of 94%. This crude trapidil is colored orange-red and has an absorbance of E at 427 nm.
1% (427 nm) was 1.02 C1n.

Example 1 Crude trapidil prepared in Reference Example 1 50. 100m
After dissolving No. 5 in water, 15 ml of 36% salt LWO was added, and the mixture was vigorously stirred with 200 g of xylene at 80'C for 15 minutes. After standing for 10 minutes, separate the organic layer to 80% by weight.
Concentrated. The mixture was stirred and cooled to 20°C, and the precipitated crystals were collected from door to door. By recrystallizing the crystal from xylene, 1
35 g of colorless trapidil with a 0% aqueous solution having a Hazen number (hereinafter simply referred to as Hazen number) of 30 and a purity of 99.5% was obtained.

Comparative Example 1 When the same method as in Example 1 was carried out except that the crude trapidil was not treated with 36% hydrochloric acid, 35 g of slightly yellow trapidil with a Hazen number of 200 and a purity of 99.2% was obtained. Ta.

Example 2 When treated in the same manner as in Example 1 except that 1 ml of 36% hydrochloric acid was used, the Hazen number was 25 and the purity was 99.
32 g of 7% colorless trapidil were obtained.

Examples 3 to 4 Colorless trapidil was obtained by treating in the same manner as in Example 1 except for using the acid shown in Table 1.

Table 1 Example 5 50 g of crude trapidil described in Reference Example 1 was mixed with xylene 2
00g and 1% at 80°C with 5ml of 1N hydrochloric acid.
After stirring for 5 minutes, the liquid was separated. After concentrating the organic layer by 80% by weight, it was cooled to 20° C., and the precipitated crystals were collected from door to door. By recrystallizing the crystals from xylene, 33 g of colorless trapidil with a 10% aqueous solution having a Hazen number of 30 and a purity of 99.5% was obtained.

Comparative Example 2 When treated in the same manner as in Example 5 except that 5 m5 of water was used instead of 1N hydrochloric acid and the liquid was separated by stirring,
35 g of slightly yellow trapidil, a 10% aqueous solution with a Hazen number of 250 and a purity of 99.2%, was obtained.

Examples 6 to 7 Colorless trapidil was obtained in the same manner as in Example 5 except that the acid shown in Table 2 was used instead of INHCe.

Table 2 Applicant: Mitsui Petrochemical Industries, Ltd. Agent Kazu Yamaguchi

Claims (1)

[Claims] (1) Crude 5-methyl-7-ethylamino-8
- A method for purifying the compound, which comprises bringing triazolo(1,5-a)pyrimidine into contact with an acid in the presence of water.