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Method for synthetizing 4,6-dichloro-2-methyl pyridine

A methylpyrimidine and synthesis method technology, applied in 4 fields, can solve the problems of complex synthesis process route, serious environmental pollution, high toxicity, etc., and achieve the effect of simple synthesis process

Inactive Publication Date: 2012-05-02
太仓市运通化工厂
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In the prior art, there are multiple synthetic methods for 4,6-dichloro-2-methylpyrimidine, and some of the chlorinated reagents selected are also different, mainly POCl3, phosgene, etc. These reagents have serious environmental pollution and are more toxic. Large, and the synthesis process route is relatively complicated, not suitable for industrial production

Method used

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  • Method for synthetizing 4,6-dichloro-2-methyl pyridine
  • Method for synthetizing 4,6-dichloro-2-methyl pyridine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Add 150ml of methanol to a 500ml three-necked flask, and add 18.4g (0.34mol) of sodium methoxide while stirring under ice bath conditions, and add 13.2g (0.1mol) of dimethyl malonate and acetamidine salt after the dissolution is complete Acetate 9.45g (0.1mol), then remove the ice bath and heat up to 18-25°C for 4h reaction, the solution is milky white, after the reaction is completed, methanol is distilled off under reduced pressure (30-35°C), then add 50mL water to dissolve, and use 4mol / L dilute hydrochloric acid to adjust the pH to 1~2. At this time, a white solid precipitated. Stir and crystallize at 0°C for 4 hours, filter with suction, wash with ice water and ice methanol at 0~5°C, and dry to obtain a white solid. 10.8 g of 4,6-dihydroxy-2-methylpyrimidine, the yield is 86%.

[0021] In a 250mL three-necked flask, add 10g (0.08mol) of 4,6-dihydroxy-2-methylpyrimidine obtained above, 29.8g (0.2mol) of N,N-diethylaniline and 60mL of dichloroethane to reflux , and...

Embodiment 2

[0023] Add 1060ml of methanol to a 3L three-necked flask, and add 108.2g (2mol) of sodium methylate while stirring under ice bath conditions, and add 105.6g (0.8mol) of dimethyl malonate and acetamidine hydrochloride after the dissolution is complete Salt 113.4g (1.2mol), then remove the ice bath and heat up to 18-25°C for 5h reaction, the solution is milky white, after the reaction is completed, methanol is distilled off under reduced pressure (30-35°C), then add 400mL water to dissolve, and use 4mol / L dilute hydrochloric acid to adjust the pH to 1-2. At this time, a white solid precipitated out. Stir and crystallize at 0°C for 4 hours, filter with suction, wash with ice water and ice methanol at 0-5°C, and dry to obtain a white solid 4 , 6-dihydroxy-2-methylpyrimidine 86g, the yield is 87%.

[0024] Add 100 g (0.8 mol) of 4,6-dihydroxy-2-methylpyrimidine obtained above and 238.4 g (1.6 mol) of N, N-diethylaniline and 400 mL of dichloroethane into a 3 L three-necked flask, an...

Embodiment 3

[0026] Add 3960ml of methanol into a 10L three-necked flask, and add 608.8g (11.25mol) of sodium methoxide while stirring under ice bath conditions, and add 330g (2.5mol) of dimethyl malonate and acetamidine hydrochloride after the dissolution is complete Salt 472.5g (5mol), then remove the ice bath and heat up to 18-25°C for 5h reaction, the solution is milky white, after the reaction is completed, methanol is distilled off under reduced pressure (30-35°C), then add 50mL water to dissolve, and use 4mol / L Dilute hydrochloric acid to adjust the pH to 1-2. At this time, a white solid precipitated out. Stir and crystallize at 0°C for 5 h, filter with suction, wash with ice water and ice methanol at 0-5°C, and dry to obtain white solid 4. 250 g of 6-dihydroxy-2-methylpyrimidine, the yield is 86%.

[0027] In a 10L three-necked flask, add 300g (2.4mol) of 4,6-dihydroxy-2-methylpyrimidine obtained above, 1072.8g (7.2mol) of N,N-diethylaniline and 2400mL of dichloroethane to reflux ...

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Abstract

The invention discloses a method for synthetizing 4,6-dichloro-2-methyl pyridine, which comprises the following steps of: under the ice-bath condition, adding sodium methoxide, dimethyl malonate and acetamidine hydrochloride into methanol; removing the ice bath, heating to a temperature of 18 to 25 DEG C and performing a reaction for 3 to 5 hours; carrying out reduced pressure distillation to remove the methanol; adding water for dissolving; regulating a pH value of the obtained solution to the range of 1 to 2; under the condition of a temperature of 0 DEG C, carrying out stirring and crystallization for 3 to 5 hours; carrying out extraction filtering, washing and drying to obtain white solid 4,6-dyhydroxyl-2-methyl pyridine; adding N,N-diethyl aniline and dichloroethane into the obtained 4,6-dyhydroxyl-2-methyl pyridine; heating to the reflux condition; then slowly adding a solution of triphosgene dichloroethane; performing a reflux reaction for 6 to 8 hours; washing reaction liquid; drying, filtering and concentrating an organic layer; and carrying out recrystallization and decolorization treatment on the obtain solid 4,6-dichloro-2-methyl pyridine. In the method, triphosgene is adopted to replace reagents with serious pollution to the environment and large toxicity, such as POC13, phosgene and the like. The method is safe, is easy to operate, has a simple synthetic process and is suitable for the industrial production.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a synthesis method of 4,6-dichloro-2-methylpyrimidine. Background technique [0002] 4,6-Dichloro-2-methylpyrimidine is an important intermediate for the anticancer drug dasatinib, the first approved treatment for adult-stage chronic myeloid leukemia who have failed or are intolerant to prior therapy Drug. In the prior art, there are multiple synthetic methods for 4,6-dichloro-2-methylpyrimidine, and some of the chlorinated reagents selected are also different, mainly POCl3, phosgene, etc. These reagents are serious to environmental pollution and more toxic. Large, and the synthetic process route is all relatively complicated, is not suitable for industrialized production. Contents of the invention [0003] The present invention is just to overcome the above-mentioned disadvantages, and the technical problem to be solved is to provide a safe, simple process and a s...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/30
Inventor 张卫东
Owner 太仓市运通化工厂
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