CN115557910A - A kind of synthetic method of 6-azauracil - Google Patents

Abstract

The invention discloses a method for synthesizing 6-azouracil; it comprises the following steps: the first step is to use hydrazine carboxamide hydrochloride and glyoxylic acid aqueous solution as raw materials to react under alkaline conditions to form imine, and the reaction conditions are mild , the reaction conversion rate is high, and the raw material is cheap; the second step uses microwave irradiation to close the ring, and the conversion rate reaches 90% in half an hour at room temperature, which greatly shortens the reaction time and improves the reaction yield. The method of the invention has mild reaction conditions, is safe and reliable, and has good process stability.

Description

A kind of synthetic method of 6-azauracil

technical field

The invention relates to the field of organic medicine synthesis, in particular to a synthesis method of 6-azauracil (an important intermediate of etabepilone).

Background technique

Ethapirone is an anxiolytic drug, which belongs to the category of 5-HT1A receptor partial agonists. There is a great demand in experimental and clinical treatment.

In addition, 6-azauracil, as a 1,2,4-triazine derivative, can be used to inhibit HIV treatment and prevent HI (CN101035773); 6-azauracil derivatives can be used to treat viral infection, immune or inflammatory diseases , specifically involving modulation or agonism of toll-like receptors (TLRs) (EP2712866A1); 6-azauracil and uracil derivatives act together to inhibit 5SCD-1 enzymatic activity, minimizing drug therapy for metabolic syndrome Side effects in (WO2010006962A1); 6-azauracil and its derivatives are useful in the manufacture of drugs for inhibiting EGFR activity.

The existing synthetic conditions are mainly to react with hydrazine carboxamide hydrochloride and chloral to generate Schiff base, and the reaction conversion rate is not high (ChemicalPapersVolume73Issue6Pages1321-13312019 yield is only 58%), and then the second step ring closure yield Also only 62%, and the response time is long.

Contents of the invention

The object of the present invention is to provide a kind of synthetic method of 6-azauracil, to solve the problem raised in the above-mentioned background technology.

In order to achieve the above object, the present invention provides the following technical scheme: a kind of synthetic method of 6-azauracil, comprises the following steps:

The first step: mix 10mol, 1eq of hydrazine carboxamide hydrochloride and 10mol, 1eq of DIEA and dissolve in water, add 10mol, 1eq of 50% glyoxylic acid aqueous solution to the mixed solution under stirring at room temperature, after the addition is complete, the reaction The solution continued to stir for 6-10h, and the reaction was completed. Cool the reaction solution to 0-5°C, and a large amount of precipitates formed. The formed precipitates were collected by filtration, washed with water, and dried to obtain a light yellow product with a yield of 89% and a purity of 98.9%. Solid 2-[2-(aminocarbonyl)hydrazono]acetic acid compound 1.2g;

The second step: 10mol, 1eq of 2-[2-(aminocarbonyl)hydrazono]acetic acid was dissolved in 20mL of ethylene glycol, and 12mol, 1.2eq of potassium hydroxide was added under stirring at room temperature. After the addition was complete, the reaction solution was Microwave power 200W, irradiate at 25-35°C for 30min to react, after the reaction is completed, cool the reaction liquid to 0°C, a large amount of precipitate is formed, filter the precipitate, dissolve the precipitate in 20mL water and adjust the pH value to 2-3 with 1M HCl aqueous solution, After the aqueous solution was stirred at room temperature for 30 min, the solution was cooled to 0-5°C with ice salt, a large amount of precipitate formed, filtered, the filter cake was washed with water, and dried in vacuo to obtain a light yellow solid 6 with a yield of 90% and a purity of 99.0%. - Azauracil 1.0 g;

The specific synthesis reaction formula is:

Preferably, in the first step: 10mol, 1eq of hydrazine carboxamide hydrochloride and 10mol, 1eq of DIEA are mixed and dissolved in water, and 10mol, 1eq of 50% acetaldehyde is added to the mixture under stirring at room temperature Acid aqueous solution, after feeding, the reaction solution continued to stir for 8 hours. After the reaction was completed, the reaction solution was cooled to 3°C. A large amount of precipitate was formed. The formed precipitate was collected by filtration, washed with water, and dried. The yield was 89%, and the purity was 98.9%. 1.2 g of 2-[2-(aminocarbonyl)hydrazono]acetic acid compound as pale yellow solid.

Preferably, in the second step, 10mol and 1eq of 2-[2-(aminocarbonyl)hydrazono]acetic acid are dissolved in 20mL of ethylene glycol, and 12mol and 1.2eq of potassium hydroxide are added under stirring at room temperature After the addition, the reaction solution was irradiated with microwave power of 200W and 30-33°C for 30 minutes to react. After the reaction was completed, the reaction solution was cooled to 0°C, and a large amount of precipitate was formed. Filter the precipitate, dissolve the precipitate in 20mL of water and adjust the pH value with 1M HCl aqueous solution. Adjust to 2-3, stir the aqueous solution at room temperature for 30 minutes, then cool the solution to 3°C with ice salt, a large amount of precipitates are formed, filter, wash the filter cake with water, and dry in vacuo to obtain 90% yield and 99.0% purity 1.0 g of pale yellow solid 6-azouracil.

Preferably, in the second step, during the suction filtration, the washing liquid is directly added to the filter cake and then suction-filtered, and the washing liquid is added in a continuous manner, pumping while adding.

Compared with prior art, the beneficial effect of the present invention is:

The method of the invention has mild reaction conditions, is safe and reliable, and has good process stability. In the first step, hydrazine carboxamide hydrochloride and glyoxylic acid aqueous solution are used as raw materials to react under alkaline conditions to form imines. The reaction conditions are mild and the reaction conversion rate is high. , The raw material is cheap; the second step uses microwave irradiation, and the conversion rate reaches 90% in half an hour at room temperature, which greatly shortens the reaction time and improves the reaction yield.

detailed description

The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present invention, but not all of them. Based on the embodiments of the present invention, all other embodiments obtained by persons of ordinary skill in the art without making creative efforts belong to the protection scope of the present invention.

Example 1

A kind of synthetic method of 6-azauracil, comprises the following steps:

The first step: mix 10mol, 1eq of hydrazine carboxamide hydrochloride and 10mol, 1eq of DIEA and dissolve in water, add 10mol, 1eq of 50% glyoxylic acid aqueous solution to the mixed solution under stirring at room temperature, after the addition is complete, the reaction The solution continued to stir for 8 hours, and the reaction was completed. Cool the reaction solution to 0° C., and a large amount of precipitates formed. The formed precipitates were collected by filtration, washed with water, and dried to obtain a light yellow solid 2-[ 2-(aminocarbonyl)hydrazono]acetic acid compound 1.2g;

The second step: 10mol, 1eq of 2-[2-(aminocarbonyl)hydrazono]acetic acid was dissolved in 20mL of ethylene glycol, and 12mol, 1.2eq of potassium hydroxide was added under stirring at room temperature. After the addition was complete, the reaction solution was Microwave power 200W, irradiated at 28°C for 30min to react, the reaction was completed, the reaction solution was cooled to 0°C, a large amount of precipitate was formed, filtered the precipitate, dissolved in 20mL water and adjusted the pH value to 2 with 1M HCl aqueous solution, and the aqueous solution was at room temperature After stirring for 30 minutes, the solution was cooled to 2°C with ice salt, a large amount of precipitates formed, filtered, the filter cake was washed with water, and dried in vacuo to obtain 1.0 g of 6-azauracil as a pale yellow solid with a yield of 90% and a purity of 99.0%. ;

The specific synthesis reaction formula is:

Among them, the method of the present invention has mild reaction conditions, safety and reliability, and good process stability. In the first step, hydrazine carboxamide hydrochloride and glyoxylic acid aqueous solution are used as raw materials to react under alkaline conditions to form imines. The reaction conditions are mild and the reaction conversion High efficiency and cheap raw materials; the second step adopts microwave irradiation, and the conversion rate reaches 90% in half an hour at room temperature, which greatly shortens the reaction time and improves the reaction yield.

Example 2

A kind of synthetic method of 6-azauracil, comprises the following steps:

The first step: mix 10mol, 1eq of hydrazine carboxamide hydrochloride and 10mol, 1eq of DIEA and dissolve in water, add 10mol, 1eq of 50% glyoxylic acid aqueous solution to the mixed solution under stirring at room temperature, after the addition is complete, the reaction The solution continued to stir for 9 h, and the reaction was completed. Cool the reaction solution to 4° C., and a large amount of precipitates formed. The formed precipitates were collected by filtration, washed with water, and dried to obtain a light yellow solid 2-[ 2-(aminocarbonyl)hydrazono]acetic acid compound 1.2g;

The second step: 10mol, 1eq of 2-[2-(aminocarbonyl)hydrazono]acetic acid was dissolved in 20mL of ethylene glycol, and 12mol, 1.2eq of potassium hydroxide was added under stirring at room temperature. After the addition was complete, the reaction solution was Microwave power 200W, irradiated at 30°C for 30min to react, the reaction was completed, the reaction solution was cooled to 0°C, a large amount of precipitate was formed, filtered the precipitate, dissolved in 20mL water and adjusted the pH value to 3 with 1M HCl aqueous solution, and the aqueous solution was at room temperature After stirring for 30 minutes, the solution was cooled to 4°C with ice salt, a large amount of precipitates formed, filtered, the filter cake was washed with water, and dried in vacuo to obtain 1.0 g of 6-azouracil, a pale yellow solid with a yield of 90% and a purity of 99.0%. ;

The specific synthesis reaction formula is:

Among them, the method of the present invention has mild reaction conditions, safety and reliability, and good process stability. In the first step, hydrazine carboxamide hydrochloride and glyoxylic acid aqueous solution are used as raw materials to react under alkaline conditions to form imines. The reaction conditions are mild and the reaction conversion High efficiency and cheap raw materials; the second step adopts microwave irradiation, and the conversion rate reaches 90% in half an hour at room temperature, which greatly shortens the reaction time and improves the reaction yield.

Although the embodiments of the present invention have been shown and described, those skilled in the art can understand that various changes, modifications and substitutions can be made to these embodiments without departing from the principle and spirit of the present invention. and modifications, the scope of the invention is defined by the appended claims and their equivalents.

Claims (4)

1. A method for synthesizing 6-azauracil is characterized in that: the method comprises the following steps:

the first step is as follows: mixing 10mol and 1eq of hydrazine formamide hydrochloride and 10mol and 1eq of DIEA, dissolving in water, adding 10mol and 1eq of 50% glyoxylic acid aqueous solution into the mixed solution under stirring at room temperature, after the addition is finished, continuously stirring the reaction solution for 6-10h, finishing the reaction, cooling the reaction solution to 0-5 ℃, generating a large amount of precipitate, filtering and collecting the formed precipitate, washing with water, and drying to obtain 1.2g of a light yellow solid 2- [2- (aminocarbonyl) hydrazono ] acetic acid compound with the yield of 89% and the purity of 98.9%;

the second step: dissolving 10mol and 1eq of 2- [2- (aminocarbonyl) hydrazono ] acetic acid in 20mL of ethylene glycol, adding 12mol and 1.2eq of potassium hydroxide under stirring at room temperature, finishing the addition, irradiating the reaction solution at 25-35 ℃ for 30min under the microwave power of 200W for reaction, cooling the reaction solution to 0 ℃ after the reaction is finished, generating a large amount of precipitate, filtering the precipitate, dissolving the precipitate in 20mL of water, adjusting the pH value to 2-3 by using 1M of HCl aqueous solution, stirring the aqueous solution at room temperature for 30min, cooling the solution to 0-5 ℃ by using ice salt, generating a large amount of precipitate, filtering, washing a filter cake by using water, and drying in vacuum to obtain 1.0g of light yellow solid 6-azauracil with the yield of 90% and the purity of 99.0%;

the specific synthesis reaction formula is as follows:

2. the method for synthesizing 6-azauracil according to claim 1, wherein: in the first step: mixing 10mol and 1eq of hydrazine formamide hydrochloride and 10mol and 1eq of DIEA, dissolving in water, adding 10mol and 1eq of 50% glyoxylic acid aqueous solution into the mixed solution under stirring at room temperature, after the addition is finished, continuing stirring the reaction solution for 8 hours, finishing the reaction, cooling the reaction solution to 3 ℃, generating a large amount of precipitate, filtering and collecting the formed precipitate, washing with water, and drying to obtain 1.2g of 2- [2- (aminocarbonyl) hydrazono ] acetic acid compound which is a light yellow solid with the yield of 89% and the purity of 98.9%.

3. The method of claim 1, wherein the synthesis of 6-azauracil comprises: in the second step, 10mol and 1eq of 2- [2- (aminocarbonyl) hydrazono ] acetic acid are dissolved in 20mL of ethylene glycol, 12mol and 1.2eq of potassium hydroxide are added under the condition of stirring at room temperature, the reaction solution is irradiated at 30-33 ℃ under the microwave power of 200W for 30min to react after the addition is finished, the reaction solution is cooled to 0 ℃, a large amount of precipitate is generated, the precipitate is filtered, dissolved in 20mL of water, the pH value is adjusted to 2-3 by using 1M of HCl aqueous solution, the aqueous solution is stirred at room temperature for 30min, the solution is cooled to 3 ℃ by using ice salt, a large amount of precipitate is generated, the solution is filtered, a filter cake is washed by using water and dried in vacuum, and 1.0g of light yellow solid 6-azauracil with the yield of 90% and the purity of 99.0% is obtained.

4. The method for synthesizing 6-azauracil according to claim 1, wherein: and in the second step, directly adding a washing liquid on the filter cake during suction filtration, and then performing suction filtration, wherein the way of adding the washing liquid is continuous addition while adding the washing liquid.