CN116143710A

CN116143710A - Preparation method of 2-amino-5-methylpyrazine

Info

Publication number: CN116143710A
Application number: CN202211377517.3A
Authority: CN
Inventors: 汤健志; 刘相国; 蔡蓉蓉
Original assignee: Suzhou Qiusuo Biotechnology Co ltd
Current assignee: Suzhou Qiusuo Biotechnology Co ltd
Priority date: 2022-11-04
Filing date: 2022-11-04
Publication date: 2023-05-23

Abstract

The invention belongs to the technical field of medicine synthesis, and relates to a preparation method of 2-amino-5-methyl pyrazine, wherein S1 is prepared by esterification: dissolving raw material 5-methyl pyrazine-2-formic acid and a methylation reagent in an acidic system for reaction, reacting at 60 ℃ overnight, adjusting pH to be alkaline, and extracting with an organic solvent to obtain an intermediate A; s2, substitution: dissolving the intermediate A and hydroxylamine hydrochloride in methanol, stirring and mixing uniformly to obtain a solution, dripping alkali liquor into the solution, reacting for 2-5h at 50-100 ℃, filtering and drying to obtain an intermediate B; s3, dehydration: dissolving the intermediate B and strong base weak acid salt in DMF, reacting for 1-5h at 50-100 ℃, filtering, and spin-drying to obtain the product 2-amino-5-methylpyrazine. The yield of the 2-amino-5-methyl pyrazine prepared by the method can reach more than 75wt%, the reaction condition is mild, the method has great advantages in mass production, the next reaction can be carried out without purifying by a silica gel column, and the preparation efficiency is high.

Description

Preparation method of 2-amino-5-methylpyrazine

Technical Field

The invention relates to the technical field of medicine synthesis, in particular to a preparation method of 2-amino-5-methyl pyrazine.

Background

2-amino-5-methyl pyrazine is an important novel heterocyclic organic intermediate, is an important industrial raw material, and is widely applied to industries such as medicines, pesticides, dyes and the like. Because pyrazine ring has biological activity and has irreplaceable functions of other groups or functional groups in the aspect of synthesizing medicines, the pyrazine ring is a hot spot field in medical research. In addition, the 2-amino-5-methyl pyrazine has special chemical properties and medicinal activity, is an intermediate of a plurality of medicines and pesticides, and has very broad application prospect. It can also be used as medicine and medicine intermediate, hair dyeing auxiliary agent, polymer stabilizer, antioxidant and anti-fog agent of photosensitive material, etc. In the existing synthesis technology, 2-amino-5-methyl pyrazine is mainly obtained by reducing raw material 5-methyl pyrazine-2-carboxamide by LAH (lithium aluminum hydride) or bromine. The reaction steps are shown in the following figures:

however, the yields of these methods are not high. Lithium aluminum hydride is active in nature, is violent in reaction, causes fire disaster due to improper quenching, and bromine is toxic, so that the production risk is high due to the influence.

There is therefore a need to develop a new process to solve the above problems.

Disclosure of Invention

The main purpose of the invention is to provide a preparation method of 2-amino-5-methyl pyrazine, which can obtain 2-amino-5-methyl pyrazine with high yield, and the preparation is safer and more environment-friendly.

The invention realizes the aim through the following technical scheme: a preparation method of 2-amino-5-methyl pyrazine comprises the following steps:

s1, esterification: dissolving raw material 5-methyl pyrazine-2-formic acid and a methylation reagent in an acidic system, reacting overnight at 60 ℃, adjusting pH to be alkaline, and extracting with an organic solvent to obtain an intermediate A;

s2, substitution: dissolving the intermediate A and hydroxylamine hydrochloride in methanol, stirring and mixing uniformly to obtain a solution, dripping alkali liquor into the solution, reacting for 2-5h at 50-100 ℃, filtering and drying to obtain an intermediate B;

s3, dehydration: dissolving the intermediate B and strong base weak acid salt in DMF, reacting for 1-5h at 50-100 ℃, filtering, and spin-drying to obtain the product 2-amino-5-methylpyrazine.

Specifically, the methylating agent is methanol, dimethyl carbonate or methyl iodide.

Specifically, the acid of the acid system adopts concentrated sulfuric acid, dilute hydrochloric acid, concentrated hydrochloric acid or concentrated nitric acid.

Specifically, in step S2, the alkali solution is one of a methanol suspension of sodium hydroxide, an ethyl acetate suspension of potassium carbonate, and a methanol suspension of sodium bicarbonate, wherein the dosage of the alkaline substance is 1.0-4.0eq.

Specifically, the strong alkali weak acid salt is one of potassium carbonate, potassium phosphate and sodium carbonate, and the dosage is 1.0eq.

The technical scheme of the invention has the beneficial effects that:

the yield of the 2-amino-5-methyl pyrazine prepared by the method can reach more than 75wt%, the reaction condition is mild, the method has great advantages in mass production, the next reaction can be carried out without purifying by a silica gel column, and the preparation efficiency is high.

Detailed Description

The present invention will be described in further detail with reference to specific examples.

Example 1:

s1, placing raw material 5-methyl pyrazine-2-formic acid (20 g,144.79 mmol) and methanol (200 ml) into a 250ml reaction bottle, uniformly stirring, and dropwise adding concentrated sulfuric acid (148 mmol) while stirring until the solution is dark brown. The reaction was heated to 60 ℃ and reacted overnight.

Stopping heating, cooling the reaction solution to room temperature, distilling under reduced pressure, removing most of the solvent, adding distilled water, and stirring uniformly. The pH of the system was adjusted to 8 with saturated sodium carbonate solution, and extraction was performed by adding ethyl acetate (100 ml. Times.4). After the organic layers were combined, the upper insoluble matter was removed by filtration, and the solvent was dried under reduced pressure to give 15g of intermediate A (active ingredient methyl 5-methylpyrazine-2-carboxylate).

S2, placing a crude product (15.00 g,98.59 mmol) of 5-methyl pyrazine-2-methyl formate, hydroxylamine hydrochloride (13.7 g,197.17 mmol) and methanol (70 ml) into a reaction bottle, uniformly stirring, and cooling to about 0 ℃. A suspension of sodium hydroxide (394.35 mmol) in methanol (70 ml) was added dropwise. After the addition, naturally heating to room temperature, and stirring and reacting for 2h. After stopping the reaction, the pH of the system is regulated to 2 by dilute hydrochloric acid, and the mixture is concentrated under reduced pressure to precipitate a solid. After filtration, the residue was washed with distilled water and dried in an oven at 65℃to give 7.8g of intermediate B (active ingredient N-hydroxy-5-methylpyrazine-2-carboxamide).

S3, adding the intermediate N-hydroxy-5-methylpyrazine-2-carboxamide (7.8 g,50.9 mmol), potassium carbonate (50.9 mmol) and 25ml DMF into a reaction bottle, and stirring for 3h to generate a large amount of solid insoluble matters. After filtration, the solvent was dried by spinning to give 4.3g of 2-amino-5-methylpyrazine as a product in 77.5wt%.

The reaction process of the steps is as follows:

example 2:

s1, placing raw materials of 5-methylpyrazine-2-formic acid (20 g,144.79 mmol) and dimethyl carbonate (200 ml) into a 250ml reaction bottle, uniformly stirring, and dropwise adding dilute hydrochloric acid (184 mmol) while stirring until the solution is dark brown. The reaction was heated to 60 ℃ and reacted overnight.

Stopping heating, cooling the reaction solution to room temperature, distilling under reduced pressure, removing most of the solvent, adding distilled water, and stirring uniformly. The pH of the system was adjusted to 9 with sodium hydroxide solution, and ethanol was added for extraction (100 ml. Times.4). After combining the organic layers, the upper insoluble material was removed by filtration and the solvent was dried under reduced pressure to give 18.18g of intermediate A.

S2, placing the intermediate A (18.18 g,119.5 mmol), hydroxylamine hydrochloride (16.61 g,239.0 mmol) and methanol (80 ml) into a reaction bottle, uniformly stirring, and cooling to about 0 ℃. A suspension of sodium bicarbonate (358.5 mmol) in methanol (70 ml) was added dropwise. After the addition, naturally heating to room temperature, and stirring for reaction for 3h. After stopping the reaction, the pH of the system is regulated to 2 by dilute hydrochloric acid, and the mixture is concentrated under reduced pressure to precipitate a solid. After filtration, the residue was washed with distilled water and dried in an oven at 50 ℃ to give 9.7g of intermediate B.

S3, adding the intermediate B (9.69 g,63.29 mmol), potassium phosphate (63.29 mmol) and 30ml DMF into a reaction bottle, and stirring for 1h to generate a large amount of solid insoluble matters. After filtration, the solvent was dried by spinning to give 5.5g of 2-amino-5-methylpyrazine as a product in a yield of 79.2wt%.

Example 3:

s1, placing raw materials of 5-methyl pyrazine-2-formic acid (20 g,144.79 mmol) and methyl iodide (200 ml) into a 250ml reaction bottle, uniformly stirring, and dropwise adding concentrated hydrochloric acid (225 mmol) while stirring until the solution is dark brown. The reaction was heated to 60 ℃ and reacted overnight.

Stopping heating, cooling the reaction solution to room temperature, distilling under reduced pressure, removing most of the solvent, adding distilled water, and stirring uniformly. The pH of the system was adjusted to 11 with saturated sodium carbonate solution, and extraction was performed by adding ethyl acetate (100 ml. Times.4). After the organic layers were combined, the upper insoluble matter was removed by filtration, and the solvent was dried under reduced pressure to obtain 25.60g of intermediate A.

S2, placing the intermediate A (25.60 g,168.2 mmol), hydroxylamine hydrochloride (23.37 g,336.4 mmol) and methanol (70 ml) into a reaction bottle, uniformly stirring, and cooling to about 0 ℃. A suspension of potassium carbonate (336.4 mmol) in ethyl acetate (70 ml) was added dropwise. After the addition, naturally heating to room temperature, and stirring and reacting for 5h. After stopping the reaction, the pH of the system is regulated to 2 by dilute hydrochloric acid, and the mixture is concentrated under reduced pressure to precipitate a solid. After filtration, the residue was washed with distilled water and dried in an oven at 100℃to give 11.5g of intermediate B.

S3, adding the intermediate B (11.49 g,75.04 mmol), potassium carbonate (75.04 mmol) and 25ml DMF into a reaction bottle, and stirring for 3h to generate a large amount of solid insoluble matters. After filtration, the solvent was dried by spinning to give 6.4g of 2-amino-5-methylpyrazine as a product in a yield of 76.8wt%.

Example 4:

s1, placing raw material 5-methyl pyrazine-2-formic acid (35 g,253.37 mmol) and methanol (200 ml) into a 250ml reaction bottle, uniformly stirring, and dropwise adding concentrated nitric acid (28.7 g, 268 mmol) while stirring until the solution is dark brown. The reaction was heated to 60 ℃ and reacted overnight.

Stopping heating, cooling the reaction solution to room temperature, distilling under reduced pressure, removing most of the solvent, adding distilled water, and stirring uniformly. The pH of the system was adjusted to 10 with saturated sodium carbonate solution, and extraction was performed with ethyl acetate (100 ml. Times.4). After combining the organic layers, the upper insoluble material was removed by filtration and the solvent was dried under reduced pressure to give 28.66g of intermediate A.

S2, placing the intermediate A (28.66 g,188.3 mmol), hydroxylamine hydrochloride (26.17 g,376.6 mmol) and methanol (70 ml) into a reaction bottle, stirring uniformly, and cooling to about 0 ℃. A suspension of sodium hydroxide (188.3 mmol) in methanol (90 ml) was added dropwise. After the addition, naturally heating to room temperature, and stirring and reacting for 4h. After stopping the reaction, the pH of the system is regulated to 2 by dilute hydrochloric acid, and the mixture is concentrated under reduced pressure to precipitate a solid. After filtration, the residue was washed with distilled water and dried in an oven at 75 ℃ to give 13.0g of intermediate B.

S3, adding the intermediate B (13.0 g,84.83 mmol), potassium carbonate (84.83 mmol) and 35ml DMF into a reaction bottle, and stirring for 5h to generate a large amount of solid insoluble matters. After filtration, the solvent was dried by spinning to give 7.3g of 2-amino-5-methylpyrazine as a product in a yield of 75.1wt%.

The reagent for adjusting the pH in the step S1 can be replaced by other alkaline substances commonly used by the person skilled in the art, and the extraction reagent can also be replaced by other organic solvents commonly used by the person skilled in the art, without limiting the steps.

In conclusion, the yield of the 2-amino-5-methyl pyrazine prepared by the method can reach more than 75wt%, the reaction condition is mild, the method has great advantages in mass production, the next reaction can be performed without purifying by a silica gel column, and the preparation efficiency is high.

What has been described above is merely some embodiments of the present invention. It will be apparent to those skilled in the art that various modifications and improvements can be made without departing from the spirit of the invention.

Claims

1. A preparation method of 2-amino-5-methyl pyrazine is characterized in that: the method comprises the following steps:

s1, esterification: dissolving raw material 5-methyl pyrazine-2-formic acid and a methylation reagent in an acidic system for reaction, reacting at 60 ℃ overnight, adjusting pH to be alkaline, and extracting with an organic solvent to obtain an intermediate A;

2. The method for producing 2-amino-5-methylpyrazine, according to claim 1, characterized in that: the methylating agent is methanol, dimethyl carbonate or methyl iodide.

3. The method for producing 2-amino-5-methylpyrazine, according to claim 1, characterized in that: the acid of the acid system adopts concentrated sulfuric acid, dilute hydrochloric acid, concentrated hydrochloric acid or concentrated nitric acid.

4. The method for producing 2-amino-5-methylpyrazine, according to claim 1, characterized in that: in the step S2, the alkali liquor is one of a methanol suspension of sodium hydroxide, an ethyl acetate suspension of potassium carbonate and a methanol suspension of sodium bicarbonate, wherein the dosage of alkaline substances is 1.0-4.0eq.

5. The method for producing 2-amino-5-methylpyrazine, according to claim 1, characterized in that: the strong alkali weak acid salt is one of potassium carbonate, potassium phosphate and sodium carbonate, and the dosage is 1.0eq.