JP3205975B2 - Method for producing pyrazinecarboxamide - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a process for producing pyrazinecarboxamide, which is simple and uses very little by-products such as pyrazinemonocarboxylic acid, using ammonia water or an ammonia solution of an organic solvent, and is industrially advantageous. Pyrazincarboxamide is a compound useful as a drug such as a tuberculosis drug.

[0002]

2. Description of the Related Art As a conventional method for producing pyrazinecarboxamide, a method is known in which a pyrazinecarboxylic acid ester is dissolved in an appropriate organic solvent, and a small excess amount of ammonia gas is blown into this. However, this method has a problem that a long time is required for the reaction or that pyrazine monocarboxylic acid is easily produced as a by-product when moisture is present. Further, addition of an ammonium salt or the like as a catalyst has been proposed, but there has been a problem that the addition of the catalyst is not very welcomed from the use as a pharmaceutical. JP-A-62-111871 proposes a method of hydrolyzing 2-cyanopyrazine with an aqueous solution of sodium hydroxide to obtain pyrazinecarboxamide. However, since pyrazine monocarboxylic acid is produced as a by-product, pyrazinecarboxamide can be obtained with high purity. Has a problem that the yield has to be sacrificed to some extent.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to solve these problems and to produce pyrazinecarboxamide from pyrazine carboxylate with high purity and high yield in an industrially advantageous and efficient manner in a short time. And

[0004]

The present invention provides a compound of the general formula [I]

Embedded image Wherein R represents a lower alkyl group; and a pyrazine carboxylate represented by the general formula [II] characterized by reacting dropwise with a high-concentration aqueous ammonia or an ammonia solution of an organic solvent.

Embedded image The method for producing a pyrazinecarboxamide represented by the formula:

[0005] The properties of the pyrazine carboxylic acid ester as a raw material compound are not limited, but a liquid ester is preferable even at a low temperature in order to facilitate dropping. In particular, the use of isobutyl ester is preferable since there is little or no by-product of pyrazine monocarboxylic acid. Isobutyl ester and isopropyl ester are disclosed in Japanese Patent Application No.
-23635. It is preferable that the concentration of the ammonia solution used is high. If the concentration is low, unreacted ester tends to remain and the reaction time becomes long. When aqueous ammonia is used, a commercially available product having a concentration of 25 to 28% can be used. The same applies to an ammonia solution of an organic solvent, and an ammonia solution of about 20% is preferably used. As the organic solvent, any inert organic solvent can be used. Preferably, alcohols such as methanol and ethanol are used. The amount of ammonia is sufficient if the contained ammonia is at least 1 mole of the ester.
Since the reaction time is short, it is preferably used at least 3 times the molar amount. The reaction temperature may be room temperature or lower. Particularly, since the by-product of pyrazine monocarboxylic acid depends on the reaction temperature, the reaction is carried out under ice cooling or lower if necessary. The reaction is carried out by dropping a pyrazine carboxylate into aqueous ammonia or an ammonia solution of an organic solvent. By doing so, the by-product of pyrazine carboxylic acid can be greatly suppressed, and conversely, it is not preferable to add aqueous ammonia to the pyrazine monocarboxylic acid ester.
Since the reaction proceeds quickly, a short reaction time is sufficient. Since pyrazine monocarboxylic acid by-produced easily escapes to the mother liquor in the presence of ammonia, the carboxamide crystals can be easily removed by filtration and then washed with water or an organic solvent to obtain high-purity pyrazine carboxamide. The filtered mother liquor can be reused in the reaction by blowing in ammonia gas and replenishing the consumed ammonia.

[0006]

Next, the present invention will be described in more detail with reference to examples. The progress of the reaction was determined by high performance liquid chromatography (HP
LC). For compounds, NMR,
Confirmed by IR and HPLC. Example 1 A flask was charged with 35 ml of 25% aqueous ammonia, and
Cooled to ° C. 13.8 g of methyl pyrazine carboxylate was added thereto over about 20 minutes with stirring. After further aging for about 30 minutes, the crystals were filtered, washed with a small amount of water, and dried to obtain white pyrazinecarboxamide crystals.
1.5 g were obtained. 190 ° C

Example 2 In the same manner as in Example 1, 18 g of pyrazine carboxylate isobutyl ester was dropped and reacted in place of methyl pyrazine carboxylate to give a pyrazinecarboxamide crystal 1
1.7 g were obtained. Melting point: 190 ° C. The filtrate was further concentrated to about 10 ml, cooled and filtered to obtain 0.4 g of secondary crystals. 190 ° C

Example 3 In the same manner as in Example 1, 8.3 g of isopropyl pyrazine carboxylate was added dropwise instead of methyl pyrazine carboxylate to give 5.16 g of pyrazinecarboxamide crystals. 190 ° C

Example 4 A flask was charged with 20 ml of methanol and cooled to 5 ° C. with ice. 4.1 g of ammonia gas was blown into this, followed by stirring 6 g of isobutyl pyrazine carboxylate,
It was dropped in about 5 minutes. After further aging for 1 hour, filtration,
After washing with a small amount of methanol and drying, 3.94 g of white crystals of pyrazinecarboxamide were obtained. Melting point 190 ° C. Further concentrate the filtrate to about 5 ml, cool and filter,
0.15 g of secondary crystals were obtained. Melting point 190 [deg.] C. The pyrazine monocarboxylic acid in the filtered mother liquor was analyzed by HPLC and found to be 0.1% or less.

Comparative Example 1 18 g of isobutyl pyrazine carboxylate was dissolved in 100 ml of isobutanol, and 8.5 g of ammonia gas was blown in at room temperature over 2 hours. Further at room temperature 30
After aging for a time, the generated crystals were filtered and dried to obtain 12 g of white pyrazinecarboxamide. Melting point: 190 ° C. Further, the filtrate was concentrated to dryness to obtain 0.2 g of pyrazinecarboxamide containing 0.1 g of pyrazinemonocarboxylic acid. It can be seen that the reaction time is longer when the concentration of ammonia is lower than in the comparative example, and that pyrazine carboxylic acid is easily produced as a by-product when the dropping is reversed.

[0011]

According to the present invention, pyrazinecarboxamide can be obtained industrially and efficiently from pyrazine carboxylate with high purity, high yield and in a short time.

──────────────────────────────────────────────────続 き Continuing from the front page (72) Inventor Michinori Takebayashi 2767-12 Niihama, Kojima Shioike, Kurashiki-shi, Okayama Nippon Soda Co., Ltd. Mizushima Plant (58) Field surveyed (Int. Cl. ⁷ , DB name) C07D 241/24 A61K 31/4965 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the general formula [I] Wherein R represents a lower alkyl group; and a pyrazine carboxylate represented by the general formula [II]: wherein the pyrazine carboxylate is reacted dropwise with ammonia water or an ammonia solution of an organic solvent. A method for producing a pyrazinecarboxamide represented by the formula: 2. The method for producing a pyrazinecarboxamide according to claim 1, wherein the pyrazine carboxylate is isobutyl pyrazine carboxylate or isopropyl pyrazine carboxylate.