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Method for synthesizing N-methyl pyrimidone

A technology of methylpyrimidinone and synthesis method, applied in the field of chemical synthesis, to achieve the effect of simplifying post-processing

Inactive Publication Date: 2010-12-15
陈岱岭
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The technical problem to be solved in the present invention is to overcome the defects of the existing synthetic methods and provide a synthetic method of N-methylpyrimidinone with high yield, easy scale application and low cost

Method used

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  • Method for synthesizing N-methyl pyrimidone
  • Method for synthesizing N-methyl pyrimidone
  • Method for synthesizing N-methyl pyrimidone

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0015] Embodiment 1 synthetic hydroxypyrimidinone

[0016]

[0017] Suspend 5.8 g of amidoxime in 24 ml of methanol, and add 3.13 g of dimethyl acetylenedicarboxylate dropwise. Stir at 30° C. for 1.5 hours. After the reaction was detected by TLC, about 16 ml of methanol was evaporated under reduced pressure, then 30 ml of xylene was added, and about 15 ml was evaporated under reduced pressure. Finally, the temperature was raised to reflux (above 125° C.) for 5 hours. Allow to cool below 60°C, add 3ml of methanol, then gradually add 30ml of methyl tert-butyl ether, stir evenly, cool to 0-5°C, and keep warm for 5 hours. The precipitated crystals were filtered, and then the mother liquor was cooled to 0° C. and kept for 5 hours. Filter the crystallization that separates out, merge with next time product, obtain 5.8g hydroxypyrimidinone product altogether, productive rate 69.5%.

Embodiment 2

[0018] The N-methylation of embodiment 2 hydroxypyrimidinones

[0019]

[0020] 23g of hydroxypyrimidinone was dissolved in 260ml of pyridine, and 29.32g of benzoic anhydride was added dropwise. Stir overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was dissolved in 30 ml of ethyl acetate, washed successively with dilute hydrochloric acid, sodium bicarbonate solution and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 21 g of a brown product.

[0021] To a solution of 0.34 g of lithium hydride in 178.5 ml of dioxane was added the benzoyl-protected hydroxypyrimidinone obtained previously. The mixture was aged at 38°C for 1 hour and cooled to room temperature. Add 5ml of dimethyl sulfate and heat at 55-60°C for 4 hours. Cool to room temperature, add 1 drop of glacial acetic acid, then add 200ml of water and 200ml of ethyl acetate. After shaking, the two phase...

Embodiment 3

[0022] The N-methylation of embodiment 3 hydroxypyrimidinones

[0023]

[0024] Dissolve 14.0 g of benzoyl-protected hydroxypyrimidinone in 700 ml of dry tetrahydrofuran, add 5.2 g of cesium carbonate and 4.04 ml of dimethyl sulfate, and stir at 60° C. for 1 hour. The solvent was evaporated from the reaction mixture, and 200 ml of ethyl acetate was added to dissolve it. Washed successively with dilute hydrochloric acid, water and brine, dried over anhydrous sodium sulfate, and evaporated to dryness under reduced pressure, the crude N-methylated product obtained was treated in the same manner as in Example 2 to obtain 4.6 g of N-methylpyrimidinone, Yield 41%.

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Abstract

This invention discloses a method for synthesizing N-methyl pyrimidone, comprising the following steps of: (1) steaming away a solvent, reheating and closing a ring after amidoxime reacts with dimethyl acetylene dicarboxylic acid ester in an alcohols solvent; (2) cooling down the reaction products after closing the ring, adding the solvent for crystallization twice, and filtering the separated crystal, wherein the obtained crystal is hydroxyl pyrimidone; (3) generating pyrimidone protected by the acylation of the hydroxyl by reaction between the hydroxyl pyrimidone with organic acid acyl in the presence of alkali; and (4) reacting the pyrimidone protected by the acylation of the hydroxyl with dimethyl sulphate under the catalysis of the hydride or cesium carbonate so as to obtain N-methyl pyrimidone. In the synthesizing method, the once total yield of the generated hydroxyl pyrimidone can be increased to 69.5%; in the step of methylation, the proected hydroxyl greatly reduces the degree of the side reaction of the methylation, the dimethyl sulphate is changed as the methylating agent so that the yield is close to the original technique, and the cost is reduced greatly; in addition, the post-treatment is simplified, and this invention is suitable for the mass production.

Description

technical field [0001] The invention relates to a chemical synthesis method, in particular to a synthesis method of an anti-HIV drug intermediate. Background technique [0002] Hydroxypyrimidinone and N-methylpyrimidinone are important intermediates for the synthesis of a new class of anti-HIV drug, retapaline. WO03035077 reported its synthesis method, which is to react the aminoisobutyronitrile amidoxime protected by amino group with dimethylacetylene dicarboxylate in methanol, after the adduct is formed, only azeotropic distillation is used, and xylene is used to replace solvent methanol , and then staged heating and ring closure to generate hydroxypyrimidinone. This method requires strict control of the heating process, which takes up to ten hours, and then adds a crystallization mixed solvent, and then needs to cool down in stages. After 20 hours of cooling and crystallization process, the product can be obtained. The technological process is too complicated, and indus...

Claims

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Application Information

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IPC IPC(8): C07D239/557
Inventor 陈岱岭
Owner 陈岱岭
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