JPS6125713B2 - - Google Patents

Description

[Detailed Description of the Invention] The present invention is characterized in that 2-cyanopyrazine is used as a raw material and is reacted in aqueous ammonia with stirring at a reaction temperature of 60°C to 90°C to produce pyrazinamide. The present invention relates to a method for producing pyrazinamide.

Conventionally, in the production of pyrazine amide, the most common method is (a) stirring and reacting pyrazine carboxylic acid ester in aqueous ammonia to form pyrazine amide and alcohol (Japanese Pharmacopoeia, 9th revised edition). Other methods include (b) a method in which pyrazine and formamide are reacted with peroxide and iron salt in the presence of concentrated sulfuric acid (Japanese Patent Publication No. 47-4457), and (c) a method in which 2-cyanopyrazine is treated with ammonia (Acta). .Polon.Pharm.33.
However, in the method (a) using pyrazine carboxylic acid ester as a raw material, the raw material pyrazine carboxylic acid is produced through a number of steps, and the pyrazine amide The manufacturing method is complicated, and the method (b) of reacting pyrazine and formamide uses peroxides with a high risk of explosion, and concentrated sulfuric acid and iron salts have the drawback of being difficult to handle in the manufacturing process. In addition, the method (c) using 2-cyanopyrazine as a starting material is superior to the methods (a) and (b) above because it is a liquid raw material and is easier to handle, but it is simply simpler. When the reaction is carried out by stirring and mixing with ammonia, the pyrazine amide produced is accompanied by by-products that are insoluble in hot water, which significantly impairs the quality of the pyrazine amide and has the disadvantage that the yield is also poor. As a result of research to improve this point, the present inventors discovered that extremely pure pyrazine amide can be obtained from 2-cyanopyrazine by maintaining the reaction temperature at 60 to 90°C. I reached it.

Generally, nitrile groups that exist as substituents in organic compounds are often converted into amide groups using various catalysts, but the catalysts usually used are sulfuric acid or sodium hydroxide. Ammonia is rarely used. actual,
Even when benzonitrile, phthalonitrile and aqueous ammonia are reacted, the reaction hardly proceeds under normal conditions, and it is quite difficult to convert cyanopyrazine into an amide group. However, even if the nitrile group substituted on the pyrazine nucleus is attempted to be converted into an amide group with a catalyst of sulfuric acid or sodium hydroxide, the desired pyrazine amide is hardly produced;
Research has revealed that when ammonia is used as a catalyst, it has the specificity of producing pyrazine amide in good yield only by limiting the reaction conditions.

According to the research results of Dr. I. Sawlewicz described in the above ACTA.POLON.PHARM.Nr1.1976, when ammonia water and cyanopyrazine are reacted, N,
N-dipyrazinoimidoamine is produced, and this N,
It has been shown that pyrazinamide is produced when N-dipyrazinoimidoamine is further reacted with aqueous ammonia. This research suggests that pyrazinamide is produced when cyanopyrazine is reacted with ammonia water, but it is unclear from this known fact alone when producing the pyrazinamide that we are aiming for. Therefore, there is no progress towards implementation. Therefore, the present inventors conducted more detailed research on the reaction of cyanopyrazine with aqueous ammonia, and discovered reaction conditions that allow pyrazinamide to be produced from cyanopyrazine in one step without going through N,N-dipyrazinoimide amine. This led to the establishment of an industrially advantageous manufacturing method.

The present invention will be explained in detail below.

The main raw material used in the present invention is 2-cyanopyrazine, water is used as an auxiliary raw material, and ammonia is used as a catalyst. The target pyrazine amide is a nitrile group of 2-cyanopyrazine with one molecule of water added, and ammonia only acts as a catalyst for this water addition reaction. In the method of the present invention, the main raw material, cyanopyrazine, and 2 to 17% ammonia water are placed in a container equipped with an ammonia blowing pipe, and the temperature is raised while stirring, and the reaction temperature is maintained at 60 to 90°C.
A solution of pyrazine amide is obtained by stirring and reacting for about 1 hour while blowing ammonia gas. As this solution is cooled, pyrazine amide crystals begin to precipitate. After the crystals are filtered and separated, the filtrate is concentrated, and the remaining dissolved pyrazine amide precipitates out. The pyrazine amide crystals collected from the filtrate are washed with water and dried to produce pyrazine amide. The yield varies depending on the ratio of cyanopyrazine and aqueous ammonia, but it is
Good yields up to 90% can be obtained. The purity of the obtained pyrazinamide is more than 98%.

The concentration of ammonia water used in the present invention is the concentration that indicates saturation solubility at the reaction temperature, and a concentration lower than that can of course be used, but it is disadvantageous because the reaction rate becomes slow and the reaction time becomes longer. Therefore, in order to maintain saturated solubility, it is preferable to blow ammonia gas into the reaction vessel little by little during the reaction.

The amount of ammonia water to be used can be 5 to 100 times that of cyanopyrazine under normal pressure, but it is preferable that the pyrazine amide produced after the reaction is completely dissolved as a condition to suppress the formation of impurities. If the concentration is too close, the yield of pyrazine amide will decrease and the amount of pyrazine amide to be concentrated and extracted will increase, which is not preferable. Therefore,
The most preferred ratio is 6 to 20 times.

The reaction temperature in this reaction can be used from room temperature to 90°C, but from room temperature to about 40°C, N,N-dipyrazinoimide amine is rapidly produced, but the subsequent reaction to pyrazinamide is slow and difficult to use. This is a very disadvantageous manufacturing method. Also, from 40℃
The formation of pyrazinamide at reaction temperatures between 60 °C is
It occurs more quickly as the temperature approaches 60°C, but it takes a considerable amount of time, and the obtained pyrazine amide contains impurities that are insoluble in hot water, so in order to obtain high purity pyrazine amide, purification is required by recrystallization. The need arises. Therefore, the optimum range for the reaction temperature in this reaction is 60°C to 90°C.

Next, Examples will be described to explain the present invention in more detail.

Example 1 Add 28% ammonia water to a 500 c.c. four-necked flask equipped with a stirrer, thermometer, and ammonia gas blowing tube.
Add 150 c.c. and 15 g of 2-cyanopyrazine and heat to 80-90°C on an oil bath. The reaction was allowed to proceed for 1.5 hours under strong stirring while blowing ammonia gas into the off-gas to the extent that almost no ammonia was discharged. Next, the oil bath is removed and the mixture is cooled with ice water to precipitate needle-shaped crystals. This was collected by filtration, washed with water, and dried to obtain 13.2 g of crystals. When the filtrate was concentrated by distillation under reduced pressure to 26 g, further crystals were precipitated, and after drying, 1.1 g of crystals were obtained. The melting point of the obtained white crystals was 188-190°C, which is in good agreement with the literature value of 189-191°C, and the infrared absorption spectrum measured by the KBr method also indicates that it is a pyrazine amide.

The yield of pyrazine amide by this method was 14.3 g, which was 81.3% of the raw material cyanopyrazine.

Example 2 In the apparatus of Example 1, 15 g of 2-cyanopyrazine and 28
% ammonia water and bring the contents to 60-70℃.
Ammonia gas was blown in while maintaining this temperature with stirring, and the mixture was allowed to react for 3 hours, and then cooled with ice water to precipitate crystals. The crystals were collected by filtration, and the filtrate was distilled under reduced pressure to concentrate to 25 g. The crystals crystallized were combined with the crystals obtained by filtration and dried to yield 16.2 g (yield: 92.2%). The melting point of this crystal was 187-189°C, and it was confirmed by infrared absorption spectrum that it was pyrazine amide.

Example 3 In the apparatus of Example 1, 30 g of 2-cyanopyrazine and 28
% ammonia water was added, ammonia gas was blown in while stirring while maintaining the temperature at 40°C, and when the reaction was allowed to proceed for 1 hour, white crystals were precipitated. This was collected by filtration, washed with water, and dried to obtain 30.7 g of crystals. The melting point of this substance was 175-189°C, and as a result of infrared absorption spectrum analysis, it was estimated that it was an imide compound, not pyrzinamide. The filtrate was concentrated by vacuum distillation, and a small amount of crystals produced was analyzed by infrared absorption spectroscopy and confirmed to be pyrazinamide.

Claims (1)

[Claims] 1 2-cyanopyrazine in ammonia water for 60 minutes
A method for producing pyrazine amide, which comprises reacting at a reaction temperature of 90°C to 90°C.