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The preparation method of 6-chloro-3-methyluracil

A technology of methyl uracil and methyl urea, applied in the field of pharmaceutical chemical synthesis, can solve the problems of increasing production cost, low yield and the like, and achieves the effects of reducing usage, improving yield and convenient post-processing

Active Publication Date: 2020-09-04
ZHEJIANG XIANFENG TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In April 2010, it was approved by the Ministry of Health, Labor and Welfare of Japan. On January 25, 2013, it was approved by the FDA for the treatment of type II diabetes. Intermediate, but the method yield of preparing 6-chloro-3-methyluracil in the prior art is low, and this has just improved the production cost of whole process

Method used

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  • The preparation method of 6-chloro-3-methyluracil
  • The preparation method of 6-chloro-3-methyluracil
  • The preparation method of 6-chloro-3-methyluracil

Examples

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Effect test

Embodiment 1

[0028] The present embodiment provides a kind of preparation method of 6-chloro-3-methyluracil, specifically, comprises the following steps:

[0029] Step 1: Add 20.0g of methylurea, 110g of methanol and 102g of sodium methoxide into a 500mL four-neck flask, stir to dissolve, then add 47.6g of diethyl malonate, heat up and reflux for 6 hours, then cool to 20°C, add acetic acid Adjust the pH value of the reaction solution to 5.0, add 30mL of water, keep the reaction solution at 20°C for 15 minutes, cool the reaction solution to 10°C, and keep the temperature for 15 minutes, filter with suction, and dry to obtain 40.8g of white to off-white loose powder -like intermediate 1, the yield is 92.1%;

[0030] Step 2: Take 20.0g of intermediate 1 and add it to a 250mL four-necked bottle, then add 80g of acetonitrile and 2.5g of water in sequence, and then add 50.0g of phosphorus oxychloride dropwise, control the temperature at 10°C during the dropwise addition, and complete the dropwis...

Embodiment 2

[0034] The present embodiment provides a kind of preparation method of 6-chloro-3-methyluracil, specifically, comprises the following steps:

[0035] Step 1: Add 20.0g of methylurea, 110g of methanol and 117g of sodium methoxide into a 500mL four-neck flask, stir to dissolve, then add 51.9g of diethyl malonate, heat up and reflux for 10 hours, then cool to 30°C, add acetic acid Adjust the pH value of the reaction solution to 8.0, add 30mL of water, keep the reaction solution at 30°C for 45 minutes, cool the reaction solution to 12°C, and keep the temperature for 30 minutes, filter with suction, and dry to obtain 41.0g of white to off-white loose powder -like intermediate 1, the yield is 92.5%;

[0036] Step 2: Take 20.0g of intermediate 1 and add it to a 250mL four-necked bottle, then add 80g of acetonitrile and 2.5g of water in sequence, and then add 50.0g of phosphorus oxychloride dropwise, control the temperature at 5°C during the dropwise addition, and complete the dropwis...

Embodiment 3

[0040] The present embodiment provides a kind of preparation method of 6-chloro-3-methyluracil, specifically, comprises the following steps:

[0041] Step 1: Add 20.0g of methylurea, 110g of methanol and 110g of sodium methoxide into a 500mL four-neck flask, stir to dissolve, then add 49.7g of diethyl malonate, heat up and reflux for 8 hours, then cool to 25°C, add acetic acid Adjust the pH value of the reaction solution to 6.5, add 30mL of water, keep the reaction solution at 25°C for 30 minutes, cool the reaction solution to 11°C, and keep the temperature for 25 minutes, filter with suction, and dry to obtain 41.3g of white to off-white loose powder -like intermediate 1 with a yield of 93.2%;

[0042] Step 2: Take 20.0g of intermediate 1 and add it to a 250mL four-necked bottle, then add 80g of acetonitrile and 2.5g of water in sequence, and then add 50.0g of phosphorus oxychloride dropwise, control the temperature at 8°C during the dropwise addition, and complete the dropwi...

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Abstract

The invention belongs to the technical field of medicine chemosynthesis, and relates to a preparation method of 6-chloro-3-methyluracil. The method comprises the following steps that 1, methylurea, anorganic solvent and alkali are added into a reaction container for stirring and dissolution, then malonic acid or malonic ester is added, heating and reflux are conducted, then cooling is conducted,acid is added to adjust a pH value of reaction liquid, water is added, the reaction liquid is cooled, suction filtration is conducted, and drying is conducted to obtain a white to off-white first intermittent in a shape of loose powder; 2, phosphorus oxychloride is used for chloridizing the first intermittent to obtain a crude product; 3, the crude product prepared in the step 2 is subjected to decoloration by means of activated carbon to obtain a finished product. According to the preparation method of the 6-chloro-3-methyluracil, the product in the step 1 precipitates in a form of sodium salt, that is to say, the first intermittent is 1-sodium methylbarbiturate, compared with the prior art where a first intermittent precipitates in a form of 1-methylbarbituric acid, the preparation method of the 6-chloro-3-methyluracil has the advantages that the yield is obviously improved, moreover, in the step 2, acetonitrile is used as the solvent, the phosphorus oxychloride usage is reduced, post-treatment is convenient, and meanwhile, the product has a good crystal form, and is easy to filter.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and relates to a preparation method of 6-chloro-3-methyluracil. Background technique [0002] Alogliptin, chemical name: 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-di Oxo-1(2H)-pyrimidinyl]methyl]benzonitrile benzoate. Alogliptin benzoate (Alogliptinbenzoate) is a serine protease dipeptidyl peptidase IV (DPP-IV) inhibitor developed by Japan's Takeda Company, which can maintain glucagon-like peptide 1 (GLP-1) and glucose-dependent The level of insulin-promoting polypeptide (GIP) can promote the secretion of insulin, thereby exerting the effect of lowering blood sugar. In April 2010, it was approved by the Ministry of Health, Labor and Welfare of Japan. On January 25, 2013, it was approved by the FDA for the treatment of type II diabetes. intermediate, but the method for preparing 6-chloro-3-methyluracil in the prior art has a low yield, which increases...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/553
CPCC07D239/553
Inventor 高军龙高飞飞宁向阳王焕挺朱敏亮
Owner ZHEJIANG XIANFENG TECH
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