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Preparation method of aminomethylpyrazine compound

A technology for aminomethylpyrazine and compounds, which is applied in the field of preparation of aminomethylpyrazine compounds, and can solve the problems that 2-chloro-3-methylpyrazine is expensive, not suitable for industrial production, and the product quality is not high , to achieve the effects of stable post-processing, controllable quality and stable reaction yield

Active Publication Date: 2021-11-09
CGENETECH (SUZHOU CHINA) CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The existing process raw material 2-chloro-3-methylpyrazine is expensive, highly toxic cyanide and phosphorus oxychloride are used in the process, high temperature and high pressure hydrogenation conditions, expensive palladium carbon, and easy to produce disubstituted coupling Impurities, the quality of the final product is not high and the purity is low, it is neither safe nor environmentally friendly, and is not suitable for industrial production

Method used

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  • Preparation method of aminomethylpyrazine compound
  • Preparation method of aminomethylpyrazine compound
  • Preparation method of aminomethylpyrazine compound

Examples

Experimental program
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Effect test

preparation example

[0058]

[0059] Compound 1 (75Kg, 694.4mol, 1eq) was dissolved in chloroform (550Kg), NCS (74.2Kg, 556mol, 0.8eq) and azobisisobutylcyanide (1.1Kg, 6.94mol, 0.01eq) were added, heated to The reaction began to reflux at 60°C. After continuing the reaction for 4 hours, the temperature was lowered appropriately, and NCS (37.1Kg, 278mol, 0.4eq) and azobisisobutyrocyanide (1.1Kg, 6.94mol, 0.01eq) were added again to make the reaction stable. The impurities are controlled below 5%, and the temperature is raised to reflux again for about 4 hours. TLC (PE / EA=2:1) ​​detects that about 20-30% of the raw materials remain in the reaction. Continue the reaction for 2 hours to detect that the reaction is complete. Cool and stir to room temperature or 10 At about ℃, filter the next day, wash the filter residue with a small amount of chloroform, combine the mother liquor, and spin dry under reduced pressure at 40-50℃ to obtain a viscous reddish-brown oil. After cooling, add 50Kg of tertiary...

Embodiment 2

[0074] 1) Preparation example of compound 2:

[0075]

[0076] Compound 1 (7.5Kg, 69.4mol, 1eq) was dissolved in chloroform (55Kg), NCS (3.7Kg, 27.8mol, 0.4eq) and azobisisobutylcyanide (0.11Kg, 0.69mol, 0.01eq) were added, Heat to 60°C and the reaction starts to reflux. After continuing to react for 4 hours, cool down appropriately, and add NCS (3.7Kg, 27.8mol, 0.4eq) and azobisisobutylcyanide (0.11Kg, 0.69mol, 0.01eq) again to make the reaction stable , the disubstituted impurity is controlled below 5%, and the temperature is raised again to reflux for about 4 hours. TLC (PE / EA=2:1) ​​detects that about 20-30% of the raw materials are left in the reaction, and the reaction is continued for 2 hours. The reaction is complete, cooled and stirred until At room temperature or around 10°C, filter the next day, wash the filter residue with a small amount of chloroform, combine the mother liquor, and spin dry under reduced pressure at 40-50°C to obtain a viscous reddish-brown oil...

Embodiment 3

[0090] 1) Preparation example of compound 2:

[0091]

[0092] Compound 1 (7.5Kg, 69.4mol, 1eq) was dissolved in chloroform (55Kg), NCS (4.6Kg, 34.7mol, 0.5eq) and azobisisobutylcyanide (0.11Kg, 0.69mol, 0.01eq) were added, heated The reaction started to reflux at 60°C. After continuing the reaction for 4 hours, the temperature was lowered appropriately, and NCS (4.6Kg, 34.7mol, 0.5eq) and azobisisobutylcyanide (0.11Kg, 0.69mol, 0.01eq) were added again to make the reaction stable. The disubstituted impurity is controlled below 5%, and the temperature is refluxed again for about 4 hours. TLC (PE / EA=2:1) ​​detects that about 20-30% of the raw materials remain in the reaction. Continue the reaction for 2 hours to detect that the reaction is complete. Cool and stir to room temperature Or about 10°C, filter the next day, wash the filter residue with a small amount of chloroform, combine the mother liquor, and spin dry under reduced pressure at 40-50°C to obtain a viscous reddis...

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PUM

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Abstract

The invention relates to a preparation method of an aminomethylpyrazine compound, which comprises the following steps of: by taking 2, 3-dimethylpyrazine as an initial raw material, under the initiation of AIBN, adding NCS (N-Chlorosuccinimide) in batches to realize monochlorination, then carrying out Gabriel reaction to obtain 2-methyl-3-aminomethylpyrazine, and then carrying out trifluoroacetylation and polyphosphoric acid cyclization to obtain 8-methyl-3-(trifluoromethyl) imidazole [1, 5-a] pyrazine.

Description

technical field [0001] The invention relates to the field of medicine, in particular to a preparation method of aminomethylpyrazine compounds. Background technique [0002] 8-Methyl-3-(trifluoromethyl)imidazol[1,5-a]pyrazine (1435487-57-2) is a commonly used pharmaceutical and chemical intermediate. The conventional preparation method uses 2-chloro-3-methyl Pyrazine is used as the starting material, and it is prepared through a series of reactions such as sodium cyanide substitution, high-pressure hydrogenation reduction, trifluoroacetylation, and phosphorus oxychloride ring closure. The specific process is as follows. [0003] [0004] The existing process raw material 2-chloro-3-methylpyrazine is expensive, highly toxic cyanide and phosphorus oxychloride are used in the process, high temperature and high pressure hydrogenation conditions, expensive palladium carbon, and easy to produce disubstituted coupling Impurities, the quality of the final product is not high and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 郝岩余强丁炬平张福治潘慧平
Owner CGENETECH (SUZHOU CHINA) CO LTD