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Method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine

A technology of propylthiopyrimidine and mercaptopyrimidine, which is applied in the field of preparation of 4.6-dichloro-5-amino-2-propylthiopyrimidine, can solve the problems of poor progress of chlorination reaction, large alkylation reaction system, and side effects. The problem of many products

Inactive Publication Date: 2013-09-11
四川铂瑞生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Progress has been made in reducing production costs and side reactions, but there are still problems such as large alkylation reaction system, too many by-products, poor progress of chlorination reaction, and low productivity.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0028] 1. Preparation of 4,6-dihydroxy-2-propylthiopyrimidine

[0029] Add 4,6-dihydroxy-2-mercaptopyrimidine in water, add 10% NaOH and methanol solution of bromopropane dropwise at 20-30°C, heat up to 30°C, react at constant temperature for 11 hours, then cool to room temperature, HCl Adjust pH=2, stir, filter, and dry to obtain 4,6-dihydroxy-2-propylthiopyrimidine, wherein the molar ratio of 4,6-dihydroxy-2-mercaptopyrimidine:bromopropane:NaOH=1:1.5: 2. The mass volume ratio bromopropane:methanol:water=1:1.5:8.

[0030] NaOH is used as an acid-binding agent, bromopropane is used as an alkylating agent, and the methanol solvent of bromohexane is added dropwise. The temperature is controlled from the consideration of the similar activity of the hydroxyl and mercapto groups in the reaction itself, and from the consideration of the feeding method and temperature. for the purpose of reducing by-products.

[0031] 2. Preparation of 4,6-dihydroxy-5-nitro-2-propylthiopyrimidine ...

example 2

[0041] 1. Preparation of 4,6-dihydroxy-2-propylthiopyrimidine

[0042] Add 4,6-dihydroxy-2-mercaptopyrimidine in water, add 10% NaOH and methanol solution of bromopropane dropwise at 30°C, raise the temperature to 40°C, react at constant temperature for 11-13h, then cool to room temperature, HCl Adjust pH=3, stir, filter, and dry to obtain 4,6-dihydroxy-2-propylthiopyrimidine, wherein the molar ratio of 4,6-dihydroxy-2-mercaptopyrimidine:bromopropane:NaOH=1:2.5: 3. The mass-volume ratio of bromopropane:methanol:water=1:4:12.

[0043] 2. Preparation of 4,6-dihydroxy-5-nitro-2-propylthiopyrimidine

[0044] Add glacial acetic acid and fuming nitric acid into the container, cool down to 4°C, then add 4,6-dihydroxy-2-propylthiopyrimidine in batches, and keep the temperature at 10°C; , and then slowly poured into ice water to stir and crystallize, filter and dry to obtain 4,6-dihydroxy-5-nitro-2-propylthiopyrimidine, in which the molar ratio of 4,6-dihydroxy-2-propylthiopyrimidine...

example 3

[0050] 1. Preparation of 4,6-dihydroxy-2-propylthiopyrimidine

[0051] Add 4,6-dihydroxy-2-mercaptopyrimidine in water, add 10% NaOH and methanol solution of bromopropane dropwise at 25°C, raise the temperature to 35°C, react at constant temperature for 12 hours, then cool to room temperature, and adjust the pH with HCl =2.5, stirred, filtered, and dried to obtain 4,6-dihydroxy-2-propylthiopyrimidine, wherein the molar ratio of 4,6-dihydroxy-2-mercaptopyrimidine:bromopropane:NaOH=1:2:2.5, The mass volume ratio bromopropane:methanol:water=1:3:10.

[0052] 2. Preparation of 4,6-dihydroxy-5-nitro-2-propylthiopyrimidine

[0053] Add glacial acetic acid and fuming nitric acid to the container, cool down to 1°C, then add 4,6-dihydroxy-2-propylthiopyrimidine in batches, the temperature is controlled at 3°C; After the end, slowly pour into ice water to stir and crystallize, filter and dry to obtain 4,6-dihydroxy-5-nitro-2-propylthiopyrimidine, in which the molar ratio of 4,6-dihydro...

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Abstract

The invention belongs to the field of pharmaceuticals, and particularly relates to a method for preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine. The method comprises a step of preparing 4,6-dihydroxy-2-(propylsulfanyl)pyrimidine, a step of preparing 4,6-dihydroxy-5-nitro-2-(propylsulfanyl)pyrimidine, a step of preparing 4,6-dichloro-5-nitro-2-(propylsulfanyl)pyrimidine, a step of preparing 4,6-dichloro-5-amino-2-(propylsulfanyl)pyrimidine, and the like. The method provided by the invention has advantages of low cost, small alkylation reaction system, few byproducts, high productivity, reduced feeding amount of solvent, changed chlorinated reagent, changed reducing agent, and the like. The method provided by the invention has a yield more than or equal to 64.9%, and product purity more than or equal to 99%.

Description

technical field [0001] The invention belongs to the field of pharmaceuticals, in particular to a preparation method of 4.6-dichloro-5-amino-2-propylthiopyrimidine. [0002] Background technique [0003] Ticagrelor is a new type of selective small molecule anticoagulant. The drug can reversibly act on the purine 2 receptor (purinoceptor 2, P2) subtype P2Y12 on vascular smooth muscle cells (VSMC), does not require metabolic activation, and has a significant effect on platelet aggregation induced by adenosine diphosphate (ADP). Inhibitory effect, and rapid onset after oral administration, can effectively improve the symptoms of patients with acute coronary heart disease. Among them, 4.6-dichloro-5-amino-2-propylthiopyrimidine is used as a key intermediate of ticagrelor. [0004] 4. The commonly used technical scheme in the preparation method of 6-dichloro-5-amino-2-propylthiopyrimidine is to use 4,6-dihydroxy-2-mercaptopyrimidine as raw material, carry out bromopropane alky...

Claims

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Application Information

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IPC IPC(8): C07D239/47
Inventor 唐川
Owner 四川铂瑞生物医药有限公司