JPH0237358B2 - 55MECHIRUU77JECHIRUAMINOOSSTORIAZORO * 1 * 55A * PIRIMIJINNOSEISEIHO - Google Patents

Description

[Detailed description of the invention]

The present invention provides 5-methyl-7-diethylamino-
The present invention relates to a method for purifying s-triazolo[1,5-a]pyrimidine (hereinafter abbreviated as trapidil). Trapidil is known to have excellent medicinal efficacy as a coronary dilator. This method of producing trapidil is described in, for example, British Patent No. 1148629, Japanese Patent Application Publication No.
This method has been proposed in publications such as No. 56-79674 and JP-A-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 documents, crude trapidil is not purified sufficiently, and for example, the resulting trapidil is contaminated with colored impurities or is not of high enough purity to be used as a pharmaceutical product. They are often of insufficient quality to serve as food. In view of these current circumstances, the present inventors have conducted intensive studies on methods for obtaining high-quality, highly purified purified products suitable for use as pharmaceuticals from crude Trapidil in a high yield. The inventors have discovered that the above object can be achieved by contact treatment with a 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 purifying crude trapidil and a sulfur compound having a reducing action, which is characterized by contacting the compound in the presence of water. The crude trapidil used in the method of the present invention may be produced by any method. For example, the 7th position is a halogen, a mercapto group,
A method for reacting 5-methyl-7-substituted-s-triazolo[1,5-a]pyrimidine substituted with an alkylmercapto group, alkoxyl group, etc. with diethylamine, and N,N-diethyl acetate amide and 3
-Method of reacting amino-1,2,4-triazole in the presence of a dehydrating agent 3-Halo (or alkoxy)crotonic acid diethylamide and 3-amino-
Examples include a method of reacting 1,2,4-triazole in the presence of a condensing agent, etc.
The method of the present invention is not limited to these methods. In the method of the present invention, the sulfur compounds having a reducing action used include Na ₂ S,
_{Na2S2 , NaHS} , _NaHSO3 , _{Na2SO3 , Na2S2O4 ,}
Examples include Na ₂ S ₂ O ₃ , Zn (HSO ₃ ), and Rongarit C. Among these sulfur compounds, it is preferable to use metal sulfite compounds such as NaHSO ₃ and Na ₂ SO ₃ 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 ratio of water present during the contact is usually 5 to 5 to the sulfur compound.
The amount is preferably in the range of 200 times by weight, preferably 20 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, it is preferable that the crude trapidil is in a solution state,
It may be in the form of an aqueous solution or a solution of an organic solvent inert to the sulfur compound having a reducing action, but it is particularly preferable to 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 be done. These solvents can also be used as a mixed solvent of two or more. In the method of the present invention, a mixture consisting of the solution of crude trapidil, the sulfur compound, water and optionally a solvent are brought into contact, usually under stirring or shaking conditions. The temperature during the contact treatment is not particularly limited, but is usually in the range of 10°C to 150°C, preferably 20°C to 90°C. The contact treatment time varies depending on the type of sulfur compound used and the temperature, but is usually 0.5 to 30 hours.
A sufficient purification effect can be obtained preferably within a range of 1.0 to 6 hours. 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 as a pharmaceutical product is obtained. be able to. Next, the present invention will be specifically explained with reference to Examples. In addition, the absorbance of trapidil E1% 1cm (450nm) shown in the example represents the absorbance of a 1% by weight aqueous solution of trapidil at a wavelength of 450nm using a 1cm cell, and E0.667 1cm (427nm) represents the absorbance at a wavelength of 450nm using a 1cm cell. This is the absorbance at a wavelength of 427 nm of the 0.667% by weight aqueous solution of trapidil used. Reference Example 1 [Preparation method of crude trapidil] 300.8 g of 5-methyl-7-hydroxy-s-triazolo[1,5-a]pyrimidine, 750 g of ethylene dichloride, and 366 g of phosphorus oxychloride were heated at 90°C to 88°C under a nitrogen stream. The mixture was heated and stirred for 5 hours. This solution was added dropwise to a mixture of 1400 g of water and 840 g of sodium bicarbonate at 20°C, and the mixture was further stirred at the same temperature for 1.0 hour. 1700 g of chloroform was added to this reaction mixture to separate it into an organic layer and an aqueous layer. Add 322g of diethylamine to the organic layer at 30°C, and after the addition is complete.
Stirred at 50°C for 1.0 hour. The reaction mixture was then washed with 500 g of water and the organic layer was dried to obtain 321 g of crude trapidil (purity 95.8%).
This corresponds to a 75% yield of trapidil. Example 1 Crude trapidil [E1% 1 cm (450 nm) 0.611,
Dissolve 5.0g of purity 95.8% in 20g of xylene.
Add 5.0 g of an aqueous solution containing 0.5 g of NaHSO ₃ and heat at 80°C.
After stirring for 1.0 hour, xylene was distilled off from the xylene layer to obtain 4.9 g of trapidil with a purity of 98%.
The absorbance of trapidil is E1% 1cm (450nm).
It was 0.320. Comparative Example 1 The same operation as in Example 1 was carried out without adding NaHSO ₃ . As a result, purity
4.75 g of 98% trapidil was obtained, and its absorbance E
1% 1cm (450nm) was 0.600. Examples 2 to 9 50g of crude Trapidil with the absorbance shown in Table 1 was added to water.
5 g of the various sulfur compounds shown in Table 1 were added to this solution dissolved in 100 g of the sulfur compound at the temperature shown in Table 1.
After stirring for a period of time, the absorbance of this solution was measured, and the results shown in Table 1 were obtained.

【table】

[Table] Example 10 Crude Trapidil [E0.667 1cm (427nm) 1.00]
When 50 g of the solution was dissolved in 100 g of water, 5.0 g of NaHSO ₃ was added, and the mixture was stirred at 80° C. for 5.0 hours, the absorbance E0.667 of this solution at 1 cm (427 nm) was reduced to 0.220. Next, 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 solution, 32 g of trapidil was obtained as colorless crystals. The purity of this substance is 99.2% and the absorbance E5% 1cm (427nm) is 0.030
It was hot.

Claims (1)

[Claims] 1. Crude 5-methyl-7-diethylamino-s
- A method for purifying a triazolo[1,5-a]pyrimidine and a sulfur compound having a reducing action in the presence of water.