Method for synthesizing 2-chloro-3-amino-4-methylpyridine by ethyl cyanoacetate and acetone

A technology of ethyl cyanoacetate and picoline, applied in the field of organic synthesis, can solve problems such as rising cost pressure, and achieve the effects of reducing steps, complicated operations, and reducing raw materials and operating costs

Inactive Publication Date: 2009-10-28
江苏鼎昊医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0025] At present, this method is widely used, but the original route has many reaction steps, a total of seven s

Method used

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  • Method for synthesizing 2-chloro-3-amino-4-methylpyridine by ethyl cyanoacetate and acetone
  • Method for synthesizing 2-chloro-3-amino-4-methylpyridine by ethyl cyanoacetate and acetone
  • Method for synthesizing 2-chloro-3-amino-4-methylpyridine by ethyl cyanoacetate and acetone

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Experimental program
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Embodiment 1

[0053] The first step, synthesis condensate I

[0054] Add 55g (0.49mol) of ethyl cyanoacetate (0.49mol), 90g of benzene, and 1.6g of piperidine into the reaction flask, heat up to reflux, add dropwise a mixture of 46g of acetone and 9.4g of glacial acetic acid, and reflux to separate water while adding dropwise. Then continue to reflux and divide the water until all the water is evaporated. After the reaction, cool down to 25°C, wash and separate the layers with 25ml of water, adjust the pH value of the organic phase to 8-9 with saturated sodium carbonate, and separate the layers at rest. Extract the aqueous phase with 50ml of benzene. The organic phases were combined and washed once with saturated sodium chloride solution, concentrated to dryness to obtain 71.5 g of condensate I (92% content, 95.4% molar yield), and 20 g of methanol was added after the condensate I was cooled;

[0055] Step 2: Synthesis of Condensate II

[0056] In a reaction bottle, under the protection of...

Embodiment 2

[0066] The other steps are the same, only the fourth step is changed:

[0067] Add 48g (0.24mol) of ethyl 2-chloro-4-methyl-nicotinate and 80g of ethylene glycol into the reaction device, raise the temperature to 120°C, pass ammonia gas for 24h, monitor the end point of the reaction by TLC, cool to room temperature, add 20g of water, separated into layers, the aqueous layer was extracted with 20ml of dichloromethane×3, the organic phases were combined and concentrated to obtain 34.8g of 2-chloro-4-methyl-nicotinamide (content 90.2%, molar yield 85.0%).

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Abstract

The invention relates to a method for synthesizing an important intermediate 2-chloro-3-amino-4-methylpyridine for an anti-AIDS medicament Nevirapine, and belongs to the technical field of organic synthesis. The method comprises the following process steps that: ethyl cyanoacetate and acetone are dehydrated and condensed to generate a condensation compound I under the action of a catalyst; dimethyl formamide, dimethyl sulfate and sodium methoxide solution react to generate N,N-dimethylformamiade dimethyl acetal (N,N-dimethyl formamide A), and then the N,N-dimethylformamiade dimethyl acetal reacts with the condensation compound I to generate conjugated enamine, namely a condensation compound II; the condensation compound II is cyclized by hydrochloric acid and ethanol to form a cyclic compound 2-chloro-4-methyl-ethyl nicotinate; the 2-chloro-4-methyl-ethyl nicotinate is ammonolyzed by ammonia gas to form 2-chloro-4-methyl-niacinamide; and the 2-chloro-4-methyl-niacinamide is subjected to Hofmann degradation reaction to form the 2-chloro-3-amino-4-methylpyridine. Compared with the prior synthesizing method, the method of the invention has the remarkable characteristic of reducing the reaction steps, and is suitable for large-scale industrialized production; the molar total yield of the five-step reaction is improved to 27 percent from the prior 24 percent; and the purity of the product reaches over 99 percent.

Description

(1) Technical field [0001] The invention relates to a method for synthesizing an important intermediate 2-chloro-3-amino-4-picoline of the anti-AIDS drug nevirapine. It belongs to the technical field of organic synthesis. (2) Background technology [0002] 2-Chloro-3-amino-4-picoline is the key intermediate of the anti-AIDS drug Nevirapine. Nevirapine, chemical name 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepine Zol-6-one is a non-nucleoside HIV reverse enzyme inhibitor (NNRTIs) developed by BoehringerIngelheim in Germany in the early 1990s. It can be used alone or in combination with drugs to treat adult HIV-infected patients and AIDS patients. It can effectively resist human immunodeficiency virus-1 (HIV-1), mainly to prevent HIV replication, and is currently one of the most widely used anti-AIDS drugs, mainly used to prevent mother-to-child virus transmission. Compared with other anti-AIDS drugs, nevirapine has strong antiviral effect, lo...

Claims

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Application Information

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IPC IPC(8): C07D213/73
Inventor 高桂祥徐志远朱一宽姚剑吕锦晨
Owner 江苏鼎昊医药科技有限公司
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