Novel synthesis method of Nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine

A technology of picoline and nevirapine, applied in the synthesis of pharmaceutical intermediates, the synthesis field of nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine, can solve the problem of high equipment requirements, long reaction steps and dangerous and other problems, to achieve the effect of simple operation, short reaction steps and mild reaction conditions

Inactive Publication Date: 2012-09-19
SHANGHAI SYNCORES TECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

To overcome the defects in the prior art that dangerous reactions a...

Method used

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  • Novel synthesis method of Nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine
  • Novel synthesis method of Nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine
  • Novel synthesis method of Nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0061] Example 1: Add 7.0 g (1.0 eq) of crotonaldehyde and 9.2 g (1.1 eq) of cyanoacetamide to 210 mL of dimethyl sulfoxide, then add 22.4 g (4.0 eq) of potassium tert-butoxide to the reaction in one go , the reaction temperature rises. Air was blown in, and the reaction was carried out at room temperature (about 15°C) overnight. At this time, LC-MS was used to monitor, and the target product was formed. The reaction was poured into water, the pH was adjusted to pH=5 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, the organic layers were combined, dried, and concentrated to obtain 8.52g of the target product 2-hydroxyl-3-cyano-4methylpyridine ( 27 ) solid, yield 60%.

[0062] 1 HNMR (DMSO); ppm: 2.4 (s,3H); 3.5 (bs,1H); 6.26 (m,1H).

Embodiment 2

[0063] Example 2: 7.0 g (1.0 eq) of crotonaldehyde and 18.4 g (2.0 eq) of cyanoacetamide were added to 210 mL of dimethyl sulfoxide, and then sodium tert-butoxide (4.0 eq) was added to the reaction at one time, The reaction temperature rises. Infuse air and react overnight at room temperature. At this time, LC-MS was used to monitor, and the target product was formed. The reaction was poured into water, the pH was adjusted to pH=5 with 2N hydrochloric acid, extracted 3 times with ethyl acetate, the organic layers were combined, dried, and concentrated to obtain 7.77g of the target product 2-hydroxyl-3-cyano-4methylpyridine ( 27 ) solid, yield 58%.

[0064] 1 HNMR (DMSO); ppm: 8.03 (d, J=2 Hz, 1H), 7.6 (d, J=2 Hz, 1H), 2.5 (s, 3H).

Embodiment 3

[0065] Example 3: 7.0 g (1.0 eq) of crotonaldehyde and 9.2 g (1.1 eq) of cyanoacetamide were added to 210 mL of methanol, and then 22.4 g (4.0 eq) of potassium tert-butoxide was added to the reaction at one time, and the reaction The temperature rises. Air was blown in and reacted overnight at 45°C. At this time, LC-MS was used to monitor, and the target product was formed. Spin the reaction system to dryness, add water and adjust the pH to pH=5 with 2N hydrochloric acid, extract 3 times with ethyl acetate, combine the organic layers, dry and concentrate to obtain 5.86g of the target product 2-hydroxy-3-cyano-4methyl Pyridine ( 27 ) solid, yield 40%.

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Abstract

The invention discloses a novel synthesis method of a Nevirapine key intermediate 2-chloro-3-amino-4-methyl pyridine and belongs to the pharmaceutical chemical field. The specific steps include that crotonic aldehyde and cyanoacetamide are subjected to ring closing reaction with the presence of strong alkaline reagents and oxygen to produce 2-hydroxy-3-cyano-4-methylpyridine; the 2-hydroxy-3-cyano-4-methylpyridine is reacted with phosphorus oxychloride to produce 2-chloro-3-amino-4-methylpyridine; the 2-chloro-3-amino-4-methylpyridine is hydrolyzed by concentrated sulfuric acid to obtain 2-chloro-3-formylamino-4-methylpyridine; and the 2-chloro-3-formylamino-4-methylpyridine is subjected to Hoffman amide degradation reaction to obtain the Nevirapine key intermediate 2-chloro-3-amino-4-methylpyridine. The technical scheme of the novel synthesis method of the Nevirapine key intermediate 2-chloro-3-amino-4-methyl pyridine has the advantages that sources of raw materials are wide, production cost is low, the reaction condition is mild, the operation is simple, the products are easy to purify, reaction steps are short, and the like, and the novel synthesis method is particularly suitable for large scale industrial production.

Description

technical field [0001] The invention relates to a new method for synthesizing a pharmaceutical intermediate, in particular to a new method for synthesizing a key intermediate of nevirapine, 2-chloro-3-amino-4-picoline, belonging to the field of medicine and chemical industry. Background technique [0002] Nevirapine (I), structural formula (I): [0003] [0004] The chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]-diazepine Zol-6-one is an 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. [0005] Since the synthesis and anti-HIV activity of Nevirapine (Nevirapine, I) in 1991, several synthetic methods have been developed, but the economical and industriali...

Claims

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Application Information

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IPC IPC(8): C07D213/73
Inventor 詹静黄鲁宁张席妮
Owner SHANGHAI SYNCORES TECH INC
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