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Method for synthesizing 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride

A technology of hydroxypyrimidine hydrochloride and synthesis method, which is applied in the field of synthesis of 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride, which can solve the problems of high catalyst price, cumbersome post-treatment, long reaction time, etc. problem, achieve the effect of reducing production cost, complete reaction and short reaction time

Inactive Publication Date: 2015-04-08
SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Method (1) takes a long time to react, post-processing is cumbersome, and a large amount of waste water is produced. At the same time, there are certain safety risks in the production and transportation of hydrosulfite, and the cost is relatively high; method (2) uses palladium-carbon catalyst, although the reaction Thorough, high product purity, less waste water, but due to the high price of the catalyst, its application in large-scale production is limited

Method used

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  • Method for synthesizing 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride
  • Method for synthesizing 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride
  • Method for synthesizing 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride

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Experimental program
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Embodiment 1

[0029] 1), put 298.7g of 28% sodium methoxide solution and 76.4g of guanidine hydrochloride into a four-necked bottle, stir and heat up to 50°C, add 114.4g of dimethyl malonate dropwise, keep the temperature at 50°C during the dropping process, drop After the addition, keep the reaction at 50°C for 3 hours. After the reaction was completed, methanol was recovered by distillation under reduced pressure. After the recovery, 400 g of water was added, and then concentrated hydrochloric acid was added to adjust the pH to 3-4. A total of 165 g of hydrochloric acid was removed, and the intermediate product was obtained by suction filtration and drying to obtain 98.2 g of the intermediate product.

[0030] 2), add intermediate product I98.2g and water 320g in the reactor, then add 30% sodium hydroxide aqueous solution 208g, stir and heat up to 40 ℃, add sodium nitrite 63.5g, then start to drop concentrated hydrochloric acid to adjust to pH = 2-3, after 1 hour, the dropwise addition wa...

Embodiment 2

[0034] 1), put 373.3g of 28% sodium methoxide solution and 76.4g of guanidine hydrochloride into a four-necked bottle, stir and heat up to 40°C, add 124.8g of dimethyl malonate dropwise, keep the temperature at 40°C during the dropping process, drop After the addition, keep the reaction at 40°C for 5 hours. After the reaction, methanol was distilled under reduced pressure to recover methanol. After the recovery, 400 g of water was added, and then glacial acetic acid was added to adjust the pH to pH=4-5. A total of 125 g of deglacial acetic acid was used, cooled to room temperature, suction filtered, and dried to obtain an intermediate product I98.8 g.

[0035] 2), add intermediate product I98.8g and water 350g in the reactor, then add 195g of 30% aqueous sodium hydroxide solution, stir and heat up to 50°C, add sodium nitrite 66.2g, then start to drop concentrated hydrochloric acid to adjust to pH = 2-3, after 1.5 hours, the dropwise addition was completed, kept stirring at 60°...

Embodiment 3

[0039] 1), put 448.0g of 28% sodium methoxide solution and 76.4g of guanidine hydrochloride into a four-necked bottle, stir and heat up to 45°C, add 135.2g of dimethyl malonate dropwise, keep the temperature at 45°C during the dropwise addition, drop After the addition, keep the reaction at 45°C for 4 hours. After the reaction, methanol was distilled under reduced pressure to recover methanol. After the recovery, 400 g of water was added, and then glacial acetic acid was added to adjust the pH to pH=4-5. A total of 126 g of deglacial acetic acid was used, cooled to room temperature, suction filtered, and dried to obtain an intermediate product I99.3 g.

[0040]2), add intermediate product I99.3g and water 380g in the reactor, add 30% sodium hydroxide aqueous solution 198g again, stir and heat up to 50 ℃, add sodium nitrite 69.0g, then start to drop concentrated hydrochloric acid to adjust to pH= 2-3, after 1.5 hours, the dropwise addition was completed, kept stirring at 60°C f...

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Abstract

The invention discloses a method for synthesizing 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride. According to the method, dimethyl malonate and guanidine hydrochloride serving as raw materials are subjected to cyclization, nitrosation, reduction and salt-forming reactions to obtain a product, the total yield is 75 percent, and the product purity is 99.0 percent. The method can be used for simplifying operation, reducing cost, increasing reaction yield, reducing energy consumption and reducing emission of the 'three wastes', and is suitable for industrial production.

Description

technical field [0001] The invention relates to a synthesis method of an abacavir intermediate, in particular to a synthesis method of 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride. Background technique [0002] The chemical name of abacavir is (1S,4R)-cis-4-(2-amino-6-cyclopropylamino-9-H-purin-9-yl)-2-cyclopentene-1-methanol, which belongs to Nucleoside reverse transcriptase inhibitors, the inhibition of HIV-1 replication is to prevent the replication of viral DNA double strands by simulating nucleic acids. For viruses, they lack the necessary chemical structure and cannot connect to the subsequent nucleic acids. Clinically proven It has a strong inhibitory effect on HIV replication. Abacavir is mainly synthesized from two key intermediates: 2-amino-4,6-dichloro-5-formylaminopyrimidine and (1S,4R)-cis-4-acetylamino-2-cyclopentene- 1-methanol. [0003] The synthesis of 2-amino-4,6-dichloro-5-formylaminopyrimidine is based on 2,5-diamino-4,6-dihydroxypyrimidine hydroc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/545
CPCC07D239/545
Inventor 曾淼余志强徐剑锋朱家可卫海浩
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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