JP2001288174A - Method for producing N-alkyl-2-piperazinecarboxamide - Google Patents

Abstract

(57) Abstract: A method for producing an N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid to obtain a target compound in high yield and high purity. Providing a way. SOLUTION: In a method for producing N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid, an N-alkyl-2-piperazinecarboxamide having a higher boiling point than water from an aqueous reaction solution. Extract with alcohol.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to an N-alkyl-2 compound.
The invention relates to a process for producing piperazinecarboxamide. More specifically, the present invention relates to an improvement in a method for producing an N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid to extract a target product from an aqueous reaction solution.

[0002] Among N-alkyl-2-piperazinecarboxamides, for example, Nt-butyl-2-piperazinecarboxamide (hereinafter sometimes abbreviated as BAP) is
For example, it is a compound useful as an intermediate for pharmaceutical production, such as an HIV protease inhibitor described in WO952162.

[0003]

2. Description of the Related Art As a method for producing BAP, for example, N-
Method for reducing tert-butyl-2-pyrazinecarboxamide under high pressure in the presence of a platinum catalyst
No. 7869) has been proposed. However, this method is not industrially preferable because an expensive platinum catalyst is used and the reaction is performed under a high pressure of 100 atm.

[0004] Therefore, as an improved method, there has been proposed a method of producing BAP by reacting 2-cyanopiperazine with tert-butyl alcohol in the presence of sulfuric acid. This method is more economically advantageous than the above high pressure reduction method.
Is excellent. However, in this method,
In addition to the target product, it is necessary to extract the target BAP with an organic solvent from an aqueous reaction solution containing unreacted alcohol, water and acid. As the organic solvent, chloroform or isopropyl alcohol has been used.

[0005]

However, chloroform is not preferred in terms of environmental health. In addition, as for isopropyl alcohol, alcohol is removed from the alcohol extract by azeotropic distillation, salt cake is added to the obtained aqueous solution of BAP, and salting out is performed. There is a problem that BAP becomes colored. Further, when the salting-out method is employed, a step of further separating BAP and sodium sulfate is required, and it is difficult to completely separate the sodium sulfate from sodium sulfate.

The present invention relates to the reaction of 2-cyanopiperazine with an alkanol in the presence of an acid to give an N-alkyl-2-
An object of the present invention is to provide a method for producing piperazinecarboxamide, which can obtain a target substance in high yield and high purity.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies in view of such circumstances, and as a result, as a solvent for extracting BAP from an aqueous reaction solution, instead of isopropyl alcohol,
By using an alcohol having a higher boiling point than water, it was found that the extraction operation was simple and the coloring of the product BAP was reduced without the need for sodium sulfate, and the present invention was completed.

That is, the gist of the present invention is to provide a method for producing N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid. A method for producing N-alkyl-2-piperazinecarboxamide, wherein carboxamide is extracted with an alcohol having a higher boiling point than water.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
The present invention relates to a method for producing an N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid. Is also characterized by using a high-boiling alcohol.

The 2-cyanopiperazine used as a raw material can be easily synthesized by reacting ethylenediamine with 2-chloroacrylonitrile, for example, according to the method described in JP-A-8-187790. The other raw material, alkanol, is not particularly limited, but specific examples thereof include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, and sec-butanol. Tert-butanol, hexanol, octanol and the like. Of these, tert-butanol is preferably used.

Hereinafter, as a typical example, a case where tert-butyl alcohol is used as an alkanol to produce BAP will be described. 2-cyanopiperazine and ter
The reaction with t-butyl alcohol is usually carried out by dropping tert-butyl alcohol into a mixture of acid and 2-cyanopiperazine, or conversely, dropping 2-cyanopiperazine into a mixture of acid and tert-butyl alcohol. Or,
Alternatively, the reaction is performed by dropping an acid into a mixture of 2-cyanopiperazine and tert-butyl alcohol.

As the acid, sulfuric acid, orthophosphoric acid, formic acid or Lewis acid can be used, but sulfuric acid is preferred. The reaction proceeds with about 10% dilute sulfuric acid,
It is preferable to use 50 to 90% sulfuric acid from the viewpoint of yield. The amount of the acid used is preferably not less than the theoretical amount necessary for neutralizing the amino group of 2-cyanopiperazine and subjecting the cyano group to alcoholysis. For example, in the case of sulfuric acid, the amount is preferably 1 mol of 2-cyanopiperazine. On the other hand, 2 mol or more, preferably 2 to 20 mol of sulfuric acid is used. The most preferred amount is 5 to 5.
The amount is 15 mol, and such an amount is suitable for obtaining a target substance in a high yield. When the amount of sulfuric acid used is 1 mol or less per 1 mol of 2-cyanopiperazine, the yield decreases.

The amount of tert-butyl alcohol used is
The amount is preferably at least equimolar to 1 mol of 2-cyanopiperazine, and about 1 to 4 mol is appropriate from an economic viewpoint. The reaction temperature is generally 0 to 80 ° C, preferably 0 to 80 ° C.
５０50 ° C. 2-cyanopiperazine or tert-
The reaction is completed when butyl alcohol or an acid is added dropwise for 0.5 to 5 hours and then kept at the same temperature for 0 to 10 hours.

With respect to the reaction aqueous solution thus obtained,
After adding an aqueous solution of an alkali such as caustic soda to neutralize preferably to pH 7 to 14, more preferably to pH 10 to 14, still more preferably to pH 12 to 14, the reaction aqueous solution, preferably about 0.5 to 50 wt. %, More preferably 1 to 20% by weight of an alcohol having a higher boiling point than water is added to extract BAP. The extraction may be performed two or more times as necessary.

The alcohol having a higher boiling point than water is not particularly limited, but specific examples thereof include those having 4 to 4 carbon atoms such as n-butanol, pentanol, methyl isobutyl carbinol, and isoamyl alcohol.
8 alcohols. Of these, n
-Butanol and isoamyl alcohol are preferred, and n-
Butanol is particularly preferred.

With respect to the alcohol extract, after the aqueous phase is separated, azeotropic dehydration is performed while adding an appropriate amount of the same alcohol to the alcohol solution. After dehydration, if BAP is precipitated in the alcohol solution, an appropriate amount of the same alcohol is added and the precipitated BAP is redissolved. Then, insoluble matter is filtered off. If not precipitated, the insoluble matter is filtered off as it is. The alcohol extract usually contains salts such as sodium sulfate, which are derived from the above-described neutralization step of the aqueous solution of BAP reaction. However, since the solubility of salts in alcohol is lower than that of BAP, such an insoluble matter is easily separated by filtration. Can be removed in a simple manner.

The alcohol solution from which the insoluble matter has been removed is concentrated, and the precipitated BAP is filtered off and dried, so that the content of impurities is usually 3% by weight or less.
Preferably 1% by weight or less of BAP can be obtained as a production. In addition, as an impurity, usually piperazine-
2-carboxamide and N-octyl-2-piperazinecarboxamide.

Also, if desired, the BAP of the obtained product
Can be recrystallized to obtain a higher purity.

[0019]

The present invention will be described more specifically with reference to examples and comparative examples, but the present invention is not limited to these examples unless it exceeds the gist. (Reference Example 1: Synthesis of CPN-S) 130 g of EDA (ethylenediamine) and 189 g of toluene were charged into a separable flask equipped with a stirring blade and a cooler equipped with a 1 L jacket, and 63 g of 2-chloroacrylonitrile (C) was stirred.
AN) was added dropwise to synthesize 2-cyanopiperazine (CPA). Subsequently, the CPN was extracted twice with 125 g of water,
565 g of a 35% aqueous sulfuric acid solution was added dropwise to the aqueous phase for acid precipitation,
Isolated as 2-cyanopiperazine monosulfate (CPN-S). This can be continuously used for the litter reaction in a wet state or a dry state as shown in the following examples.

(Example 1) 4 L equipped with a stirring blade and a cooler
925 g of 67% in a jacketed separable flask
After charging sulfuric acid, 163 g of wet CPN-S (8.5% liquid content, 98% dry purity) synthesized in the same manner as in Reference Example 1
And 63 g of tert-butanol was added to the slurry.
Was added dropwise at 35 ° C. over 3 hours and aged at the same temperature for 13 hours. After adding 110 g of water thereto, 2209 g of a 25% aqueous sodium hydroxide solution was added to adjust the pH to 13, and Nt
tert-butyl-2-piperazinecarboxamide (BA
P) was synthesized. The reaction yield was 85%. N-Butanol (n-BuOH, boiling point 118 ° C.) 1
BAP was extracted by adding 74 g. The reaction solution was colored brown, but a considerable amount of coloring components remained in the aqueous phase even at the time of extraction, and the n-BuOH phase was only slightly colored.
Subsequently, the aqueous phase was removed by a liquid separation operation, and the obtained n-B
Azeotropic dehydration was performed while adding 490 g of n-BuOH to the uOH phase. After confirming the end of dehydration with a moisture meter,
After adding 530 g of n-BuOH to redissolve the precipitated BAP and filtering out insolubles mainly composed of sodium sulfate,
This was concentrated, crystallized, filtered and dried to obtain 91 g of BAP. The isolation yield was 82%, and the purity was 99.6%, which was high yield and high purity.

(Embodiment 2) 1. equipped with a stirring blade and a cooler
520 g of 6 in a 5 L jacketed separable flask
After charging 5% sulfuric acid, 80 g of dry CPN-S (purity 100%) synthesized in the same manner as in Reference Example 1 was added, and 34 g of tert-butanol was added dropwise to this slurry at 35 ° C over 3 hours, and overnight. It was left to mature. After adding 76 g of water thereto, a 25% aqueous sodium hydroxide solution was added to 1230.
g to pH 13 to synthesize N-tert-butyl-2-piperazinecarboxamide (BAP). The reaction yield was 86%. N-Butanol (n
-BuOH) was added to extract BAP, and the n-BuOH phase obtained by performing the liquid separation operation was further charged with 365 g of n-BuOH.
Azeotropic dehydration was performed while adding BuOH. After confirming the completion of the dehydration with a moisture meter, 280 g of n-BuOH was added to redissolve the precipitated BAP, and the insoluble matter was filtered. This was concentrated, crystallized, filtered and dried to obtain 49 g of BAP.
I got The isolation yield was 81% and the purity was 99.6%, which was high yield and high purity. In addition, n-B distilled off by azeotropic dehydration
Although uOH is separated from water, the quality after the separation is such that it can be sufficiently recycled according to gas chromatography.

(Example 3) 1 L equipped with a stirring blade and a cooler
225g of 65% in a jacketed separable flask
After charging sulfuric acid, 35 g of dry CPN-S (purity 100%) synthesized in the same manner as in Reference Example 1 was added, and 15 g of tert-butanol was added dropwise to this slurry at 35 ° C. over 3 hours, and left overnight. And matured. After adding 27 g of water thereto, 540 g of a 25% aqueous sodium hydroxide solution was added to adjust the pH to 13, and N-tert-butyl-2-piperazinecarboxamide (BAP) was synthesized. The reaction yield was 84%. To this aqueous solution, 42 g of isoamyl alcohol (IAA, boiling point 132 ° C.) was added to extract BAP. Like n-butanol, the IAA phase was only slightly colored. Subsequently, while adding 246 g of IAA to the IAA phase obtained by performing the liquid separation operation,
Azeotropic dehydration was performed. After confirming the completion of dehydration with a moisture meter, 123 g of IAA was added, the precipitated BAP was redissolved, and the insoluble matter was filtered.
Drying gave 21.6 g of BAP. 83 isolated yield
%, Purity was 99.5%, which was high yield and high purity.

(Comparative Example 1) 4 L equipped with a stirring blade and a cooler
1250 g of 71 in a jacketed separable flask
% Sulfuric acid, and wet CPN-S synthesized in the same manner as in Reference Example 1 (liquid content 34%, dry purity 100%) 31
7 g was added, and tert-butanol 8 was added to the slurry.
9 g was dropped at 35 ° C. over 3 hours to react. After adding 158 g of water thereto, 3.2 kg of a 25% aqueous sodium hydroxide solution was added to adjust the pH to 11, and N-tert-butyl-2-piperazinecarboxamide (BAP) was synthesized. The reaction yield was 84%. 400 g of isopropyl alcohol (IPA, boiling point 82 ° C.) was added to the aqueous solution to extract BAP. The reaction was colored brown,
Upon extraction with IPA, the aqueous phase became clear and colorless, and the IPA phase was colored dark brown. When this extract is concentrated, I
PA was distilled off, and 400 g of a BAP aqueous solution was obtained.
Since BAP dissolves well in water, sodium sulfate is added thereto, salted out and filtered to obtain 230 g of a crude BAP cake. This cake had a liquid content of 20% and a dry purity of only 82%, was colored brown, and required further purification. The crude BAP cake was suspended in 4.5 kg of ethyl acetate, 46 g of activated carbon was added, and the temperature was raised to 65 ° C. to dissolve the BAP. After holding for 1 hour, the activated carbon and insolubles were filtered hot at 65 ° C., and the filtrate was concentrated under reduced pressure. When the distillate reached 2.6 kg, the concentration was stopped, and the precipitate was cooled to 5 ° C. and the precipitated crystals were filtered to obtain wet BAP, which contained impurities and was dissolved again in ethyl acetate to obtain a wet BAP. And then dry to BA
105 g of P were obtained. Although the purity was 99.2%, the isolation yield was as low as 68%, and required extremely complicated operations and a large amount of an organic solvent. Had to be disadvantaged.

Example 4 An experiment was conducted in the same manner as in Example 1 except that methyl isobutylcarbinol (boiling point: 132 ° C.) was used instead of n-butanol, and the purity was 99.0%.
Was obtained in an isolated yield of 82%. Example 5 An experiment was conducted in the same manner as in Example 1 except that n-pentanol (boiling point: 130 ° C.) was used instead of n-butanol, and BAP having a purity of 99.1% was isolated at a yield of 83%.
I got it.

[0025]

According to the present invention, in a method for producing N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid, the target compound is obtained in high yield and high purity. Can be obtained at

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Hitoshi Matsuda 1-1 Kurosaki Castle Stone, Yahata-nishi-ku, Kitakyushu Mitsubishi Chemical Corporation Kurosaki Office (72) Inventor Hideyoshi Hashimoto 1-1 1-1 Kurosaki Castle Stone, Yawata-Nishi-ku, Kitakyushu City Mitsubishi Chemical F term in Kurosaki Office Co., Ltd. (reference) 4H039 CA19 CA42 CA71 CD10 CD30 CL00

Claims (6)

[Claims] 1. A method for producing an N-alkyl-2-piperazinecarboxamide by reacting 2-cyanopiperazine with an alkanol in the presence of an acid, wherein N-alkyl-2-piperazinecarboxamide is prepared from an aqueous reaction solution at a higher concentration than water. N, characterized by extraction with a boiling alcohol
A method for producing an alkyl-2-piperazinecarboxamide. 2. The method according to claim 1, wherein water is azeotropically removed from the alcohol extract. 3. The method according to claim 2, wherein insolubles contained in the alcohol extract after azeotropic dehydration are removed by filtration. 4. The method according to claim 3, wherein the insolubles are filtered, the alcohol extract is concentrated, and the precipitated N-alkyl-2-piperazinecarboxamide is filtered off. 5. The process according to claim 1, wherein impurities in the finally obtained N-alkyl-2-piperazinecarboxamide are not more than 3% by weight. 6. An alcohol having a higher boiling point than water having 4 carbon atoms.
The method according to any one of claims 1 to 5, wherein the alcohol is an alcohol of the formula: