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Preparation method of 6-chlorine-3-methyluracil

A technology of methyluracil and methylurea, which is applied in the field of biopharmaceuticals, can solve the problems of less than 60% overall yield, environmental pollution of large methyl iodide, and low yield of synthesis process, and achieve simple reaction process and safety Good, high yield and high purity effect

Active Publication Date: 2018-09-28
EMEISHAN HONGSHENG PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the main production process uses malonic acid and N-methylurea as raw materials to obtain the target product through cyclization and chlorination, but the yield of this synthesis process is low, especially in the cyclization step, the overall yield is less than 60%.
[0004] Or, use 6-chlorouracil and methyl iodide to synthesize the target product, but use methyl iodide, which is more polluting to the environment, and the cost is more expensive

Method used

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  • Preparation method of 6-chlorine-3-methyluracil
  • Preparation method of 6-chlorine-3-methyluracil
  • Preparation method of 6-chlorine-3-methyluracil

Examples

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Effect test

Embodiment 1

[0041] Preparation of 1-methylbarbituric acid solid: Add 15g methylurea II and 11g sodium methoxide III to 500ml methanol solution, adjust the temperature to 50°C; keep the temperature, slowly add 24ml dimethyl malonate I dropwise for 2 hours; After the dropwise addition, the temperature was raised to 60°C for reflux reaction to generate 1-methylbarbituric acid IV; the reactant was cooled to 30°C, and the methanol was concentrated so that the total amount of methanol was concentrated to 60% of the total amount added initially, and 1-methylbarbituric acid IV was precipitated. Methyl barbituric acid solid IV crystals, filtered and dried;

[0042] Purification of 1-methylbarbituric acid crystals: control the temperature at 20°C, add hydrochloric acid to the dried 1-methylbarbituric acid solid IV crude product, the mass ratio of crystals to hydrochloric acid is 1:2.5; maintain the temperature Stir at 20°C, stir, centrifuge, and dry to obtain 1-methylbarbituric acid IV as a solid; ...

Embodiment 2

[0046] Preparation of 1-methylbarbituric acid solid: add 15g methylurea II and 11g sodium methoxide III to 500ml methanol solution, adjust the temperature to 40°C; keep the temperature, slowly add 24ml dimethyl malonate I dropwise for 1 hour; After the dropwise addition, the temperature was raised to 60°C for reflux reaction to generate 1-methylbarbituric acid IV; the reactant was cooled to 20°C, and the methanol was concentrated so that the total amount of methanol was concentrated to 80% of the total amount added initially, and 1-methylbarbituric acid IV was precipitated. Methyl barbituric acid solid IV crystals, filtered and dried;

[0047] Purification of 1-methylbarbituric acid crystals: control the temperature at 10°C, add hydrochloric acid to the dried 1-methylbarbituric acid solid IV crude product, the mass ratio of crystals to hydrochloric acid is 1:1.5; maintain the temperature Stir at 10°C, stir, centrifuge, and dry to obtain 1-methylbarbituric acid IV as a solid; t...

Embodiment 3

[0051] Preparation of 1-methylbarbituric acid solid: Add 15g methylurea II and 11g sodium methoxide III to 500ml methanol solution, adjust the temperature to 45°C; keep the temperature, slowly add 24ml dimethyl malonate I dropwise for 1.5h After the dropwise addition, the temperature was raised to 60°C for reflux reaction to generate 1-methyl barbituric acid IV; the reactant was cooled to 25°C, concentrated methanol, and the total amount of methanol was concentrated to 70% of the total amount added initially, and 1 -Methyl barbituric acid solid IV crystals, filtered and dried;

[0052] Purification of 1-methylbarbituric acid crystals: control the temperature at 15°C, add hydrochloric acid to the dried 1-methylbarbituric acid solid IV crude product, the mass ratio of crystals to hydrochloric acid is 1:2; maintain the temperature Stir at 15°C, stir, centrifuge, and dry to obtain 1-methylbarbituric acid IV as a solid; the yield is 90%, and the purity is 98%.

[0053] Preparation...

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Abstract

The invention discloses a preparation method of 6-chlorine-3-methyluracil. The preparation method comprises the following steps: cyclizing dimethyl malonate and N-methylurea under an alkaline condition of sodium methylate, acidifying and purifying the mixture to obtain an intermediate 1- methylbarbituric acid, and then chloridizing the intermediate through phosphorus oxychloride to obtain the product. The preparation method has the beneficial effects that the reaction process is more environmentally friendly, and a small number of byproducts are produced; furthermore, no reagents with heavy pollution are used; the reaction process is simple, high in safety and favorable for industrial production; finally, the yield of the finished product is higher.

Description

technical field [0001] The invention belongs to the field of biopharmaceuticals, in particular to a preparation method of 6-chloro-3-methyluracil. Background technique [0002] 6-Chloro-3-methyluracil is the key intermediate of alogliptin, a serine protease dipeptidyl peptidase IV inhibitor developed by Takeda Corporation of Japan, which mainly treats type 2 diabetes. Approved for marketing in China in November 2013, it is a new type of diabetes drug. [0003] At present, the main production process uses malonic acid and N-methylurea as raw materials to obtain the target product through cyclization and chlorination, but the yield of this synthesis process is low, especially in the cyclization step, the overall yield is less than 60%. [0004] Or, use 6-chlorouracil and methyl iodide to synthesize the target product, but use methyl iodide, which is more polluting to the environment, and the cost is relatively expensive. Contents of the invention [0005] In order to solve...

Claims

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Application Information

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IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 鲁成宪谯在银田健宏车尚泽
Owner EMEISHAN HONGSHENG PHARMA
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