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Preparation method for nevirapine intermediate

A technology of nevirapine and intermediates, applied in the field of material synthesis, can solve the problems of high wastewater content, treatment of phosphorus oxychloride odor, etc., achieve short production cycle, reduce the discharge of three wastes, and achieve the effects of high yield and purity

Inactive Publication Date: 2018-12-28
湖北宇阳药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The purpose of the present invention is to overcome the defect in the prior art, and provides a kind of preparation method of nevirapine intermediate, in chlorination reaction, direct chlorine gas, has solved the waste water content too high difficult to handle and the odor problem of phosphorus oxychloride stench , and by controlling the reaction temperature and material ratio, the one-time yield of the product can reach 90.1%

Method used

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  • Preparation method for nevirapine intermediate
  • Preparation method for nevirapine intermediate
  • Preparation method for nevirapine intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] 1. The first step is to synthesize hydroxyl compounds:

[0031] Put in purified water and ammonia water, cool down to below 15°C after feeding, start to add 99% methyl cyanoacetate dropwise for about 1 hour (to generate cyanoacetamide), then add 99% diethyl methyl ester (methyl acetoacetate) dropwise , polycondensation reaction) the dropping time is about 1 hour, after the dropping is finished, keep warm at 10-15°C for 30 minutes, then raise the temperature to 20-25°C, keep warm at this temperature for 1 hour, then slowly raise the temperature to 70- 75°C and keep at this temperature for 3 hours. The system precipitated needle-like material, and cooled to 20°C for suction filtration, pumped the mother liquor into another kettle and raised the temperature to 60-65°C, adjusted the pH value to 7 with sulfuric acid, stirred for half an hour, and the pH remained unchanged, then cooled to 15°C for suction filtration, and the mother liquor into the sewage treatment station. ...

Embodiment 2

[0040] 1. The first step is to synthesize hydroxyl compounds:

[0041] Put in purified water and ammonia water, cool down to below 15°C after feeding, start to add 99% methyl cyanoacetate dropwise for about 1 hour (to generate cyanoacetamide), then add 99% diethyl methyl ester (methyl acetoacetate) dropwise , polycondensation reaction) the dropping time is about 1 hour, after the dropping is finished, keep warm at 10-15°C for 30 minutes, then raise the temperature to 20-25°C, keep warm at this temperature for 1 hour, then slowly raise the temperature to 70- 75°C and keep at this temperature for 3 hours. The system precipitated needle-like material, and cooled to 20°C for suction filtration, pumped the mother liquor into another kettle and raised the temperature to 60-65°C, adjusted the pH value to 7 with sulfuric acid, stirred for half an hour, and the pH remained unchanged, then cooled to 15°C for suction filtration, and the mother liquor into the sewage treatment station. ...

Embodiment 3

[0050] 1. The first step is to synthesize hydroxyl compounds:

[0051] Put in purified water and ammonia water, cool down to below 15°C after feeding, start to add 99% methyl cyanoacetate dropwise for about 1 hour (to generate cyanoacetamide), then add 99% diethyl methyl ester (methyl acetoacetate) dropwise , polycondensation reaction) the dropping time is about 1 hour, after the dropping is finished, keep warm at 10-15°C for 30 minutes, then raise the temperature to 20-25°C, keep warm at this temperature for 1 hour, then slowly raise the temperature to 70- 75°C and keep at this temperature for 3 hours. The system precipitated needle-like material, and cooled to 20°C for suction filtration, pumped the mother liquor into another kettle and raised the temperature to 60-65°C, adjusted the pH value to 7 with sulfuric acid, stirred for half an hour, and the pH remained unchanged, then cooled to 15°C for suction filtration, and the mother liquor into the sewage treatment station. ...

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Abstract

The invention provides a preparation method for a nevirapine intermediate. The preparation method comprises: performing a cyclization reaction of ammonia water, methyl cyanoacetate and methyl acetoacetate to form a compound hydroxyl: 2,6-dihydroxy-3-cyano-4-methylpyridine; adding triethylamine dropwise, introducing chlorine gas at the temperature until the reaction is complete, and obtaining 2,6-dichloro-3-cyano-4-methylpyridine; adding concentrated sulfuric acid, heating to 120 DEG C to react for 3-5 h, and then cooling to 60 DEG C; adding water to perform hydrolysis reaction, and obtaining 2,6-dichloro-3-amido-4-methylpyridine; adding a degradation reagent sodium hypochlorite, and obtaining a nevirapine intermediate 2,6-dichloro-3-amino-4- methylpyridine by Hofmann reaction. According tothe preparation method, commonly used phosphorus oxychloride is replaced with the directly introduced chlorine gas, which solves the problems that the wastewater content is too high, it is difficultto perform treatment and the odor of phosphorus oxychloride is bad, and the one-time yield of the product is 90.1%.

Description

technical field [0001] The invention relates to the technical field of substance synthesis, in particular to a preparation method of a nevirapine intermediate. Background technique [0002] Nevirapine (Nevirapine, I), the chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1 ,4]-diazepine-6-one, is HIV-1 non-nucleoside reverse transcriptase inhibitor. On June 24, 1996, it was approved by the FDA to treat HIV infection in adults with nucleoside drugs. Nevirapine binds directly to the reverse transcriptase of HIV-1 and blocks RNA-dependent and DNA-dependent DNA polymerase activity by cleaving the catalytic end of the enzyme. [0003] The application number is: "CN201010611305.8", the name is "a method for preparing nevirapine", which discloses a method for preparing nevirapine, including: A. 2-chloro-3-pyridine with the structure shown in formula (II) Carboxylic acid reacts with carbonyl diimidazole to generate active amide; B, the active amide ...

Claims

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Application Information

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IPC IPC(8): C07D213/73
CPCC07D213/73
Inventor 钱坚锋任旭忠叶塽
Owner 湖北宇阳药业有限公司
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