JPS5929691A - Purification of 5-methyl-7-diethylamino-s-triazolo(1,5-a) pyrimidine - Google Patents

Abstract

PURPOSE:To prepare 5-methyl-7-diethylamino-s-triazolo[1,5-a]pyridine(trapidil for short) useful as a coronary vasodilator, having high purity and high quality, by bringing crude trapidil into contact with a sulfur compound having a reducing action. CONSTITUTION:Crude trapidil is brought into contact with a sulfur compound (e.g., 5-20wt% NaHSO3, Na2SO3, etc. is preferably used) having reducing action in the presence of preferably 20-100 times as much water as the sulfur compound by weight, to purify trapidil. Crude trapidil is used as an aqueous solution, and the contact of it with the sulfur compound is carried out preferably at 20- 90 deg.C for 1.0-6hr.

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 is described, for example, in British Patent No. 1148629 and Japanese Patent Application Laid-open No. 56-79'6.
This method has been proposed in publications such as No. 74 and Japanese Unexamined Patent Publication No. 56-108772. These prior art documents also describe attempts to purify crude trapidil by repeating various operations such as extraction and recrystallization 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.

In view of these current circumstances, the present inventors have conducted intensive studies on a method for obtaining high-quality, highly purified purified products suitable for use as pharmaceuticals from crude trapidil in good yield.
The inventors have discovered that the above object can be achieved by contacting purified trapidil with a specific sulfur compound, and have arrived at the method of the present invention.

To summarize the present invention, the gist of the present invention is a method for distilling crude trapidil and a sulfur compound having a reducing action, which is characterized by contacting the compound in the presence of water. .

Good too. For example, a method of reacting diethylamine with 5-methyl-7-substituted-5-)riazolo(1,5-a)pyrimidine in which the 7-position is substituted with a halogen, mercapto group, alkylmercapto group, alkoxyl group, etc., N,N -Method of reacting diethyl acetate amide and 6-amino-1,2,4-triazole in the presence of a dehydrating agent 3-Halo(or alkoxy)crotonic acid diethylamide and 3-amino-1,2,4-)riazolole The method of the present invention is not limited to these methods, but the method of the present invention is not limited to these methods.

In the method of the present invention, specifically, the sulfur compounds having a reducing action used include Na2S1Na2S2, N
aH8, NaH3O6, Na2SO3, Na2S2O4
, Na S OZn (H'5O3), and Rongalit C. 23X can be exemplified. Among these sulfur compounds, it is preferable to use metal sulfite compounds such as NaH3O6 and Na25o5 because they have a remarkable purification effect. The amount of these sulfur compounds used is usually 1 to 50% by weight, preferably 5 to 20% by weight based on crude trapidil.

In the method of the present invention, it is necessary to carry out the contact treatment of the crude trapidil and the sulfur compound in the presence of water. The proportion of water present during the contact is usually 5 to 200 times the weight of the sulfur compound, preferably 20 times the weight of the sulfur compound.
The amount ranges from 100 to 100 times by weight, and the amount is preferably such that the sulfur compound is dissolved. Of course, when the crude trapidil is used in the form of an aqueous solution or a water-containing solution, it is not necessarily necessary to add water again.

In the method of the present invention, when the crude trapidil and the sulfur compound are brought into contact with each other, the crude trapidil is preferably in a solution state, and may be in an aqueous solution state, and has a reducing action. Although it may be in the form of a solution of an organic solvent inert to sulfur compounds, it is particularly preferable that it be in the form of an aqueous solution. When the crude trapidil is used in the form of a solution in the organic solvent, the solution is preferably a solution in a non-aqueous solvent.

Specific examples of organic solvents include a wide range of solvents such as hydrocarbons such as hexane, benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform and ethylene dichloride, alcohols such as methanol and ethanol, and carbon disulfide. can. These solvents can also be used as a mixed solvent of two or more.

In the method of the present invention, a solution of the crude trapidil,
The mixture of the sulfur compound, water, and optionally a solvent is usually brought into contact under stirring or shaking conditions. The temperature during contact treatment is not particularly limited, but is usually 1.
0°C to 150°C, preferably 20°C to 90°
It is in the range of C. The time for contact treatment varies depending on the type of sulfur compound used and the temperature, but is usually 0.5
A sufficient purification effect can be obtained within a range of from 1.0 to 30 hours, preferably from 1.0 to 6 hours.

41 According to the method of the present invention, by subjecting the mixture to contact with a sulfur compound and subjecting it to conventional extraction and crystallization operations, trapidil of high quality and purity with a low degree of coloring and suitable for use as a pharmaceutical product can be obtained. Next, the present invention will be specifically explained with reference to Examples.

In addition, the absorbance of trapidil shown in the example is 4 (450n
m) is 1% by weight of trapidil using a 1 cIn cell.
The absorbance of an aqueous solution at a wavelength of 450 nm is 0.667%, and K (427 nm) is 1α using a one-stroke cell.The wavelength of a 0.667% by weight aqueous solution of trapidil is 427 nm.
This is the absorbance at

5-methyl-7-hydroxy-8-triazolo[1,5
-a) 300.8 g of pyrimidine, 750 g of ethylene dichloride, and 636 g of phosphorus oxychloride were heated and stirred at 90° C. to 88° C. for 5 hours under a nitrogen stream. Add this solution to a mixture of 1400 g water and 840 g sodium bicarbonate for 2 hours.
The mixture was added dropwise at 0°C and further stirred at the same temperature for 1.0 hour. 00 g of chloroform door was added to this reaction mixture to separate it into an organic layer and an aqueous layer. Diethylamine 32 in the organic layer
2g was dropped at 30'C, and after the dropping was completed, it was heated to 5°C for 1.
Stirred for 0 hours. Next, this reaction mixture was washed with 500 g of water and the organic layer was dried to give 6.0 g of crude trapidil.
21g was obtained (purity 95.8%).

This corresponds to a yield of trapidil of 75%.

\ Example 1 Crude trapidil (4 (450: nm) 11.611,
Purity 95.8%) 5. 1 g of C was dissolved in 20 g of xylene, 5.0 g of an aqueous solution containing 0.5 g of NaH3O was added, the mixture was stirred at 80'C for 1.0 hour, and the xylene was distilled off from the xylene layer, resulting in 4 trapidil with a purity of 98%. ．．
9g was obtained, and the absorbance of this trapidil was 'l! (450n
m) was 0.320.

Comparative Example 1 The same operation as in Example 1 was performed except that NaH8O3 was not added. As a result, 4.75 g of trapidil with a purity of 98% was obtained, and its absorbance was E4 (450
nm) was 0.600.

Examples 2 to 9 50 g of crude trapidil having the absorbance shown in Table 1 was added to 100 g of water.
Dissolved in g. After adding 5 g of the various sulfur compounds shown in Table 1 to this solution and stirring at the temperature shown in Table 1 for 6 hours, the absorbance of this solution was measured, and the results shown in Table 1 were obtained.

7- Table 1. Absorbance after treatment with sulfur compounds Example 10 Crude trapidil (w OA, 67% (427 nm) 1
．． 00) Dissolve 50g in 100g of water to make NaH8O
When 35.0 g of the solution was added and stirred at 80°C for 5.0 hours, the absorbance of this solution was E? (M″% (4271m) is 0.
It was reduced to 220.

Then, 200 g of xylene was added and extracted at 80'C.

When 150 g of xylene was distilled off from the xylene layer and trapidil was crystallized from the remaining 8-solution, 52 g of trapidil was obtained as colorless crystals. The purity of this thing is 9
9.2%, and the absorbance (at AC427nm) is 0.
It was 030.

Applicant: Mitsui Petrochemical Industries, Ltd. Agent Kazu Yamaguchi

Claims (1)

[Claims] (1) Crude 5-methyl-7-danitylamino-8
- A method for purifying a triazolo(1,5-a)pyrimidine and a sulfur compound having a reducing action in the presence of water 0