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Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate

A technology of heterocyclic compounds and dimethyl carbonate, which is applied in the field of methylation of pyrimidine heterocyclic compounds, can solve problems that no one has raised, and achieve the effects of simple operation, easy industrial production, and easy recycling

Inactive Publication Date: 2010-12-08
DONGHUA UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although the patent CN01808303.X and the report Synthetic Communications. (2005, 35: 3021-3026) show that dimethyl carbonate DMC can be used for N-methylation on nitrogen-containing heterocycles, no one has proposed the use of DMC for pyrimidine heterocycles The sulfhydryl group on the compound undergoes a methylation reaction

Method used

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  • Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate
  • Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate
  • Method for carrying out methylation to pyrimidine heterocyclic compound containing sulfhydryl by dimethyl carbonate

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Experimental program
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Effect test

Embodiment 1

[0025] Preparation of 2-methylthiopyrimidine

[0026] In a 150ml reaction flask, add 2-mercaptopyrimidine (11.2g, 0.1mol), potassium carbonate (5.0g, 0.036mol), tetrabutylammonium bromide (2g), dimethyl carbonate (10.8g, 0.12mol) , gradually warming up to 75~110 ​​℃ under stirring, react for 0.5~3 hours, TLC or HPLC monitoring; After the reaction, cool down to room temperature, add water (20~50ml), stir for 0.5 hour, stand for stratification, separate the organic phase, The aqueous phase was extracted with methyl tert-butyl ether or diethyl ether (10-30 ml), the organic phases were combined, washed twice with water (20-50 ml), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, the solvent was recovered, and the product was dried in vacuo 12.1 g were obtained, and the yield was 96%.

Embodiment 2

[0028] Preparation of 4,6-dimethyl-2-methylthiopyrimidine

[0029] In a 150ml reaction flask, add 4,6-dimethyl-2-mercaptopyrimidine (28g, 0.2mol), potassium carbonate (2.5g, 0.018mol), tetrabutylammonium bromide (5g), dimethyl carbonate (32.4g, 0.36mol), gradually heat up to 75~110 ​​℃ under stirring, react for 0.5~3 hours, monitor by TLC or HPLC; After the reaction is finished, cool down to room temperature, add water (20~50ml), stir for 0.5 hours, stand for aliquots layer, separate the organic phase, extract the aqueous phase with methyl tert-butyl ether or diethyl ether (10-30 ml), combine the organic phases, wash twice with water (20-50 ml), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure , the solvent was recovered, and 30.2 g of the product was obtained by vacuum drying with a yield of 98%.

Embodiment 3

[0031] Preparation of 4,6-dimethoxy-2-methylthiopyrimidine

[0032] In a 150ml reaction flask, add 4,6-dimethoxy-2-mercaptopyrimidine (51.7g, 0.3mol), potassium carbonate (7.5g, 0.054mol), tetrabutylammonium bromide (8g), dicarbonate Methyl ester (43.2g, 0.48mol) was gradually warmed up to 75~110°C under stirring, reacted for 0.5~10 hours, monitored by TLC or HPLC; after the reaction was finished, cooled to room temperature, added water (20~50ml), stirred for 0.5 hours, and kept the Separate the layers, separate the organic phase, extract the aqueous phase with methyl tert-butyl ether or diethyl ether (10-30 ml), combine the organic phases, wash twice with water (20-50 ml), dry over anhydrous sodium sulfate, filter, reduce It was concentrated under pressure, the solvent was recovered, and the product was vacuum-dried to obtain 31.3 g with a yield of 56%.

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Abstract

The invention relates to a method for carrying out methylate to sulfydryl-contained pyrimidine heterocyclic compounds by methyl carbonate, which comprises the steps: (1) the sulfydryl-contained pyrimidine heterocyclic compounds and the methyl carbonate are mixed according to the mol ratio of 1:10 to 20, and added with catalyst, the dosage of which is 3 to 80 percent of the gross weight of the reactants, and then added with alkali, the mol ratio of which to the sulfydryl-contained pyrimidine heterocyclic compounds is 1 to 2:1, then the mixture is stirred and the temperature is raised to 50 to 130 DEG C for reaction for 0.5 to 15 hours, and TLC or HPLC is used for monitoring; and (2) after the reaction is finished, the temperature is reduced to room temperature, 20 to 50ml of water is added, and the mixture is stirred for 0.5 hour and rested for delamination, the organic phases are separated out while the aqueous phase is extracted by using 10 to 30ml of methyl tert-butyl ether or aether, then the organic phases are combined, washed by 20 to 50ml of water for two times, dried by anhydrous sodium sulfate, filtered and concentrated by pressure reduction, and the solvent is recycled, thus obtaining the final product. The preparation method has the advantages of simple and safe operation, easy solvent recovery, high product yield, environmental protection and being suitable for industrial production.

Description

technical field [0001] The invention belongs to the field of preparation of methylation of pyrimidine heterocyclic compounds containing mercapto group, in particular to a method for methylation of pyrimidine heterocyclic compounds containing mercapto group by dimethyl carbonate. Background technique [0002] 4,6-Disubstituted-2-methylthiopyrimidine is an important intermediate in the synthesis of plant growth regulators, herbicides, fungicides and medicinal products. Related reports PCT Int. Appl., 2003013545 and Bollettino Chimico Farmaceutico. (2004, 143(7): 275-279) show that methylation by 4,6-disubstituted-2-mercaptopyrimidine, the selected methylation The reagent is methyl iodide or dimethyl sulfate. However, methyl iodide and dimethyl sulfate are highly toxic, and methyl iodide is expensive. These reagents have serious hidden dangers in actual reaction operations and environmental protection. Japanese Patent JP2008184397 discloses that in the presence of sulfuric ac...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/38C07D239/60C07D239/28
Inventor 朱利民谢建刚李树白权静郑妍
Owner DONGHUA UNIV