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Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine

A technology of methylpyrimidine and synthesis method, applied in 4 fields, can solve the problems of complex synthesis process route, serious environmental pollution, unsuitable for industrial production and the like, and achieves the effect of simple synthesis process

Inactive Publication Date: 2012-04-04
太仓市运通化工厂
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In the prior art, there are many ways to synthesize 4,6-dihydroxy-2-methylpyrimidine, but the selected reagents have serious environmental pollution and high toxicity, and the synthesis process route is relatively complicated, which is not suitable for industrial production

Method used

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  • Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine
  • Synthesizing method of 4,6-dihydroxy-2-methylpyrimidine

Examples

Experimental program
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Effect test

Embodiment 1

[0015] 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%.

Embodiment 2

[0017] 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%.

Embodiment 3

[0019] 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%.

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Abstract

The invention discloses a synthesizing method of 4,6-dihydroxy-2-methylpyrimidine. The method comprises the following steps of adding sodium methoxide, dimethyl malonate and acetamidine hydrochloride in methanol under an ice-bath condition; removing the ice-bath; heating the mixture to 18-25 DEG C; reacting the mixture for 3-5 hours, distilling the reactant in reduced pressure to remove the methanol; adding water to dissolve the reactant; adjusting the PH value of the reactant to 1-2; and agitating the reactant at a temperature of 0 DEG C and devitrifying the reactant for 3-5 hours; filtering, washing and drying the product, obtaining white solid 4,6-dihydroxy-2-methylpyrimidine. In the invention, triphosgene is adopted to replace reagents such as POC13, phosgene and the like severely polluting the environment and with high toxicity, so that the synthesizing method provided by the invention is safe and easy to operate, the synthesizing process is simple and the synthesizing method is applicable to industrialization production.

Description

technical field [0001] The invention relates to the field of pharmaceutical intermediates, in particular to a method for synthesizing 4,6-dihydroxy-2-methylpyrimidine. Background technique [0002] 4,6-Dihydroxy-2-methylpyrimidine is an important intermediate of the anticancer drug dasatinib, the first approved treatment for adults with chronic myeloid leukemia who have failed or are intolerant to prior therapy medicine. In the prior art, there are many methods for synthesizing 4,6-dihydroxy-2-methylpyrimidine, but the selected reagents have serious environmental pollution and high toxicity, and the synthetic process routes are relatively complicated, which is not suitable for industrial production. Contents of the invention [0003] The present invention is just to overcome the above-mentioned deficiencies, and the technical problem to be solved is to provide a safe, simple process and a synthetic method of 4,6-dihydroxy-2-methylpyrimidine suitable for industrial product...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/54
Inventor 张卫东
Owner 太仓市运通化工厂
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