A method for preparing 2-chloro-3-cyano-4-picoline

A picoline and cyano technology, applied in the field of preparing 2-chloro-3-cyano-4-picoline, can solve the problems of phosphorus oxychloride easy to corrode production equipment, not suitable for industrial production, and environmental protection , to achieve the effect of shortening processing time, low cost and low cost

Active Publication Date: 2020-05-26
YANCHENG DESANO PHARMA CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] Because the above-mentioned routes all need to use highly toxic phosphorus oxychloride, a large amount of waste water will be generated, which not only has environmental protection problems, but also phosphorus oxychloride is easy to corrode production equipment, which is not suitable for industrial production

Method used

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  • A method for preparing 2-chloro-3-cyano-4-picoline
  • A method for preparing 2-chloro-3-cyano-4-picoline
  • A method for preparing 2-chloro-3-cyano-4-picoline

Examples

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Embodiment 1

[0039] Example 1: 4,4-dicyano-3-methyl-3-butenal dimethyl acetal and 1,1-dicyano-4-methoxy-2-methyl-1,3- Preparation of mixtures of butadiene

[0040]

[0041] Add 100.0g of sodium methoxide and 1500mL of toluene to the reaction flask, add 140mL of acetone dropwise at room temperature, and add 140mL of methyl formate dropwise. After the dropwise addition, keep stirring for 30 minutes; heat up to 50°C and continue stirring for 3 hours; naturally cool down to At room temperature, a light yellow suspension was obtained.

[0042] In another reaction bottle, add 800mL of 15wt% hydrogen chloride methanol solution, slowly add the light yellow suspension obtained in the previous step reaction, after the dropwise addition, naturally warm up to room temperature, and continue to stir for 4 hours; cool down to 0°C, drop Add 28wt% sodium methoxide methanol solution; filter, and concentrate the filtrate to 1 / 3 of the original volume under reduced pressure to obtain a mixture of acetoace...

Embodiment 2

[0044] Embodiment 2: Preparation of 2-chloro-3-cyano-4-methylpyridine

[0045]

[0046] Under ice-bath conditions, feed hydrogen chloride gas into 300 mL of ethanol until saturation, slowly add the reddish-brown oily substance obtained in Example 1, after the addition, continue the heat preservation reaction at 10 ° C for 8 hours; add the reaction mixture dropwise to 1.5 In L water, keep warm and continue stirring for 1 hour; filter with suction, wash the filter cake with ice water, and dry in vacuo to obtain 178.0 g of 2-chloro-3-cyano-4-methylpyridine with an HPLC purity of 99.5%.

Embodiment 3

[0047] Embodiment 3: Preparation of 2-chloro-3-cyano-4-methylpyridine

[0048] Under ice-bath conditions, first add 480 mL of ethanol solution to the reaction flask, then slowly add the reddish-brown oil obtained in Example 1, after the addition is complete, add 300 grams of acetyl chloride dropwise at 10°C to generate hydrogen chloride, and continue the insulation reaction for 50 hour; the reaction mixture was added dropwise to 2L of water, and the insulation continued to stir for 1 hour; suction filtration, the filter cake was washed with ice water, and dried in vacuo to obtain 174.5 g of 2-chloro-3-cyano-4-picoline, HPLC purity 99.3%.

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Abstract

The invention discloses a method for preparing 2-chloro-4-methylpyridine-3-carbonitrile. The method comprises the following steps: at -20 DEG C to 50 DEG C, a hydrogen chloride solution is used for treating raw materials containing 4,4-dicyano-3-methyl-3-butenal dimethyl acetal. 2-chloro-4-methylpyridine-3-carbonitrile whose HPLC purity reaches 99% or above can be conveniently obtained, which has important meanings for subsequent preparation of high purity 2-chloro-4-methylpyridine-3-carbonitrile and nevirapine; the method has the advantages of short process route, simple operation, high yield, low cost, etc., a highly toxic product phosphorous oxychloride is avoided, discharge of waste water is reduced, and the method is very suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing 2-chloro-3-cyano-4-picoline, belonging to the technical field of medicinal chemistry. Background technique [0002] Nevirapine is a HIV-1 non-nucleoside reverse transcriptase inhibitor (Non-NucleosideReverse Transcriptase Inhibitor, NNRTI), the chemical name is 11-cyclopropyl-5,11-dihydro-4-methyl-6H- Dipyrido[3,2-b:2',3'-e][1,4]diazepine-6-one, its structural formula is as follows: [0003] [0004] In the method for synthesizing nevirapine, many synthetic routes all need to go through the key intermediate 2-chloro-3-amino-4-picoline, and the main route of industrialized production of 2-chloro-3-amino-4-picoline at present as follows: [0005] [0006] It can be seen that 2-chloro-3-cyano-4-methylpyridine is an important intermediate for the industrial production of nevirapine. [0007] The method for the synthesis of 2-chloro-3-cyano-4-picoline disclosed in the prior art mainly contains the fol...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/85C07D213/73C07C255/15C07C253/30
Inventor 李竟鹏赵楠华嗣凯
Owner YANCHENG DESANO PHARMA CO LTD
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