JP3592747B2 - N-tert-butyl-2,3-pyrazinedicarboxamide and method for producing the same - Google Patents

Description

（式中、Ｂｕ^ｔはｔｅｒｔ−ブチル基を表わす。）で示されるＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドに関し、更に２，３−ジシアノピラジンを硫酸の存在下、ｔｅｒｔ−ブチルアルコール又はイソブチレンと反応させることを特徴とする式（１）のＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドの製造法に関する。
【０００６】
以下に本発明を詳細に説明する。
本発明の式（１）のＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドの製造法における反応を実施するには、２，３−ジシアノピラジンと硫酸の混合物中にｔｅｒｔ−ブチルアルコール又はイソブチレンを導入しながら反応させる方法、或は逆に硫酸中にｔｅｒｔ−ブチルアルコール又はイソブチレンを導入し、次にこの混合物中に２，３−ジシアノピラジンを加えながら反応させる方法が適用できる。
【０００７】
前者の反応方法について更に説明する。
先ず硫酸中に撹拌しながら２，３−ジシアノピラジンを分割添加して、硫酸溶液を得る。硫酸は５０〜１００％の硫酸を使用することができるが、７０〜９０％硫酸水溶液が好ましい。硫酸の使用量は２，３−ジシアノピラジン１モルに対して２モル以上、好ましくは２〜５モル、より好ましくは３．３〜５モルであり、かかる使用量は高収率で目的のＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドを得るのに好適である。２，３−ジシアノピラジン１モルに対する硫酸の使用量が２モルより少ないと、収率は低下する。
【０００８】
次に、以上のようにして得られた硫酸溶液中に、引き続き撹拌下、ｔｅｒｔ−ブチルアルコールを滴下するか、或はイソブチレンを導入管を通して導入する。ｔｅｒｔ−ブチルアルコール又はイソブチレンの使用量は２，３−ジシアノピラジン１モルに対して当モル以上であり、経済的な観点から１〜２モル程度が適当である。反応温度は０〜９０℃で行うことができるが、低温側で行うのが高収率を達成するために好ましい。好ましい反応温度は０〜５０℃、より好ましくは０〜２０℃である。反応時間は、ｔｅｒｔ−ブチルアルコールを用いる場合は、０．５〜５時間でｔｅｒｔ−ブチルアルコールを滴下し、その後同温度に保って０〜１０時間で反応を完結させる。又、イソブチレンを使用する場合は、５〜１０時間でイソブチレンを導入し、その後同温度に保って０〜２時間で反応を完結させる。このようにして反応を行うと、目的とするＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドが高収率で生成する。
【０００９】
生成物の単離の一態様を示すと、反応液を水中に、或は反応液中に水を加え、次にアルカリを加えて中和すると結晶が析出する。析出した結晶をろ別して水洗し、乾燥するとＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドの粗結晶が得られる。この粗結晶を水、イソプロピルアルコール等の溶媒で再結晶を行うことにより、Ｎ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドの精製された結晶を得ることができる。
【００１０】
【実施例】
以下、実施例を示し本発明を説明するが、本発明は以下の実施例に限定されるものではない。
実施例１
８０％硫酸水溶液２６．４ｇ（０．２１５モル）中に、撹拌下、内温を５〜１０℃に保ちながら２，３−ジシアノピラジン８．０ｇ（０．０６１モル）を分割して加え、引き続き内温を５〜１０℃に保ちながら、撹拌下、ｔｅｒｔ−ブチルアルコール５．５ｇ（０．０７４モル）を１時間かけて滴下し、更に同温度で０．５時間反応を続けた。反応終了後、反応液を水７５ｇ中に加えて水溶液とした。この水溶液を液体クロマトグラフィーで分析した結果、上記反応によりＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミド１０．９ｇ（０．０４９モル、収率８０％）が生成した。
【００１１】
上記水溶液に更に水５０ｇを加え、次に水酸化ナトリウム水溶液で中和すると結晶が析出した。この結晶をろ別し、水洗後、乾燥して粗結晶９．５ｇを得た。得られた粗結晶を水３９ｇ中に加え、５０℃に加熱して溶解した。この水溶液をトルエンで洗浄して不純物をトルエン層へ除去した。分液後、水層をろ過し、ろ液を１０℃に冷却すると結晶が析出した。析出した結晶をろ別し、乾燥してＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドの結晶６．３ｇを得た。
【００１２】

^１Ｈ−ＮＭＲ（溶媒：Ｄ_２Ｏ、ｐｐｍ）：
１．４５（９Ｈ、ｓ、ｔｅｒｔ−ブチル）
８．７７（２Ｈ、ｓ、ピラジン環のＨ）
ＥＩＭＳ： ｍ／ｅ ２２２（Ｍ^＋ ）
ＣＩＭＳ（イソブタン）： ｍ／ｅ ２２３（Ｍ^＋ ＋Ｈ）
【００１３】
【発明の効果】
本発明によれば、医薬品の中間体等に有用な新規化合物であるＮ−ｔｅｒｔ−ブチル−２，３−ピラジンジカルボキサミドを提供することができ、又本発明の製造方法により当該化合物を高収率で製造することができる。[0001]
[Industrial applications]
The present invention relates to a novel compound, N-tert-butyl-2,3-pyrazinedicarboxamide, and a method for producing the same. The compound of the present invention is a compound useful as an intermediate such as a pharmaceutical. From the compound of the present invention, 3- (N-tert-butylcarbamoyl) -2-pyrazinecarboxylic acid can be obtained by partial hydrolysis of the compound, and further 3- (N-tert-butylcarbamoyl) -2 can be obtained. -N-tert-butyl-2-pyrazinecarboxamide can be produced by subjecting pyrazinecarboxylic acid to a decarboxylation reaction. All of these compounds are useful as intermediates for pharmaceuticals and the like. For example, N-tert-butyl-2-pyrazinecarboxamide can be converted to this hydride, N-tert-butyl-2-piperazinecarboxamide (see JP-A-1-117869). 5- (2-N'-tert-butylcarboxamide-1-piperazinyl) pentanamide derivative, which is an active ingredient of the HIV protease inhibitor described in 5-279337.
[0002]
[Prior art]
The compound of the present invention is a novel compound not described in any literature.
[0003]
[Problems to be solved by the invention]
An object of the present invention is to provide a novel compound, N-tert-butyl-2,3-pyrazinedicarboxamide, and a method for producing the same.
[0004]
[Means for Solving the Problems]
The present inventors have found that the novel compound N-tert-butyl-2,3-pyrazinedicarboxamide is a compound useful as an intermediate for pharmaceuticals and the like, as described above, and that 2,3-dicyanopyrazine is used as a raw material. The present inventors have found that N-tert-butyl-2,3-pyrazinedicarboxamide can be obtained in a high yield by carrying out a Ritter reaction.
[0005]
That is, the present invention provides the following formula (1):
Embedded image

(Wherein, Bu ^t represents. A tert- butyl group) relates N-tert- butyl-2,3 pyrazine dicarboxamide represented by further presence of 2,3-dicyano-pyrazine sulfate, tert- butyl alcohol Or a method for producing N-tert-butyl-2,3-pyrazinedicarboxamide of the formula (1), characterized by reacting with isobutylene.
[0006]
Hereinafter, the present invention will be described in detail.
In order to carry out the reaction in the process for producing N-tert-butyl-2,3-pyrazinedicarboxamide of the formula (1) of the present invention, tert-butyl alcohol or isobutylene is mixed in a mixture of 2,3-dicyanopyrazine and sulfuric acid. Or, conversely, a method of introducing tert-butyl alcohol or isobutylene into sulfuric acid and then reacting while adding 2,3-dicyanopyrazine to the mixture.
[0007]
The former reaction method will be further described.
First, 2,3-dicyanopyrazine is added portionwise with stirring in sulfuric acid to obtain a sulfuric acid solution. As the sulfuric acid, 50 to 100% sulfuric acid can be used, but a 70 to 90% sulfuric acid aqueous solution is preferable. The amount of sulfuric acid used is 2 mol or more, preferably 2 to 5 mol, more preferably 3.3 to 5 mol per mol of 2,3-dicyanopyrazine. Suitable for obtaining -tert-butyl-2,3-pyrazinedicarboxamide. If the amount of sulfuric acid used is less than 2 moles per mole of 2,3-dicyanopyrazine, the yield decreases.
[0008]
Next, tert-butyl alcohol is added dropwise to the sulfuric acid solution obtained as described above while stirring, or isobutylene is introduced through an inlet tube. The amount of tert-butyl alcohol or isobutylene to be used is at least equimolar to 1 mol of 2,3-dicyanopyrazine, and is suitably about 1 to 2 mol from an economic viewpoint. The reaction can be carried out at a temperature of 0 to 90 ° C., but is preferably carried out at a low temperature in order to achieve a high yield. A preferred reaction temperature is 0 to 50 ° C, more preferably 0 to 20 ° C. When tert-butyl alcohol is used, tert-butyl alcohol is added dropwise in 0.5 to 5 hours, and then the reaction is completed at 0 to 10 hours while maintaining the same temperature. When isobutylene is used, isobutylene is introduced in 5 to 10 hours, and then the temperature is maintained at the same temperature to complete the reaction in 0 to 2 hours. When the reaction is performed in this manner, the desired N-tert-butyl-2,3-pyrazinedicarboxamide is produced in high yield.
[0009]
In one embodiment of the isolation of the product, crystals are precipitated when the reaction solution is added to water or water is added to the reaction solution and then neutralized by adding an alkali. The precipitated crystals are collected by filtration, washed with water, and dried to obtain crude crystals of N-tert-butyl-2,3-pyrazinedicarboxamide. By recrystallizing this crude crystal with a solvent such as water or isopropyl alcohol, a purified crystal of N-tert-butyl-2,3-pyrazinedicarboxamide can be obtained.
[0010]
【Example】
Hereinafter, the present invention will be described with reference to Examples, but the present invention is not limited to the following Examples.
Example 1
8.0 g (0.061 mol) of 2,3-dicyanopyrazine was dividedly added to 26.4 g (0.215 mol) of an 80% aqueous sulfuric acid solution while stirring while maintaining the internal temperature at 5 to 10 ° C. Subsequently, 5.5 g (0.074 mol) of tert-butyl alcohol was added dropwise over 1 hour with stirring while maintaining the internal temperature at 5 to 10 ° C., and the reaction was continued at the same temperature for 0.5 hour. After completion of the reaction, the reaction solution was added to 75 g of water to make an aqueous solution. As a result of analyzing this aqueous solution by liquid chromatography, 10.9 g (0.049 mol, 80% yield) of N-tert-butyl-2,3-pyrazinedicarboxamide was produced by the above reaction.
[0011]
When 50 g of water was further added to the above aqueous solution and then neutralized with an aqueous sodium hydroxide solution, crystals precipitated. The crystals were separated by filtration, washed with water and dried to obtain 9.5 g of crude crystals. The obtained crude crystals were added to 39 g of water, and dissolved by heating to 50 ° C. This aqueous solution was washed with toluene to remove impurities to the toluene layer. After liquid separation, the aqueous layer was filtered, and the filtrate was cooled to 10 ° C. to precipitate crystals. The precipitated crystals were collected by filtration and dried to obtain 6.3 g of crystals of N-tert-butyl-2,3-pyrazinedicarboxamide.
[0012]

¹ H-NMR (solvent: D ₂ O, ppm):
1.45 (9H, s, tert-butyl)
8.77 (2H, s, H of pyrazine ring)
EIMS: m / e 222 (M ⁺ )
CIMS ^{(isobutane): m / e 223 (M} + + H)
[0013]
【The invention's effect】
According to the present invention, it is possible to provide N-tert-butyl-2,3-pyrazinedicarboxamide, which is a novel compound useful as an intermediate or the like of pharmaceuticals, and to produce the compound with high yield by the production method of the present invention. Can be manufactured at a rate.

Claims (2)

Formula (1) characterized in that 2,3-dicyanopyrazine is reacted with tert-butyl alcohol or isobutylene in the presence of sulfuric acid.

(Wherein, Bu ^t represents a tert- butyl group.) The method of producing N-tert- butyl-2,3 pyrazine dicarboxamide represented by. The method according to claim 1, wherein the reaction is carried out at 0 to 50 ° C using 2 to 5 mol of sulfuric acid per 1 mol of 2,3-dicyanopyrazine.