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Synthetic method for 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, can solve the problem of high catalyst price, long reaction time, cumbersome post-processing, etc. problem, to achieve the effect of high purity, short reaction time, and complete reaction

Inactive Publication Date: 2015-10-14
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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  • Synthetic method for 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride
  • Synthetic method for 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride
  • Synthetic method for 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride

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Experimental program
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Embodiment 1

[0023] 1), put 298.7g of 28-30% (mass fraction) 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, during the dropwise addition Keep the temperature at 50°C, and keep the reaction at 50°C for 3 hours after the dropwise addition. After the reaction was completed, the methanol was recovered by distillation under reduced pressure, and 400 g of water was added after the recovery, and then 30-35% hydrochloric acid was added to adjust the pH to 3-4, and 165 g of hydrochloric acid was removed in total, and the intermediate product I was obtained after cooling down to room temperature, suction filtration, and drying. 98.2 g of 2-amino-4,6-dihydroxypyrimidine.

[0024] 2), add intermediate product I98.2g and water 320g in the reactor, then add 30% (mass fraction) sodium hydroxide aqueous solution 208g, stir and heat up to 40 ℃, add sodium nitrite 63.5g, then start to drop 30- 35%...

Embodiment 2

[0028] 1), 373.3g of 28-30% (mass fraction) sodium methoxide solution and 76.4g of guanidine hydrochloride were dropped into a four-necked bottle, stirred and heated to 40°C, and 124.8g of dimethyl malonate was added dropwise. The temperature was 40° C., and the temperature was kept at 40° C. for 5 hours after the dropwise addition was completed. After the reaction was completed, methanol was recovered by distillation under reduced pressure, and 400 g of water was added after the recovery, and then glacial acetic acid was added to adjust the pH to pH=4-5, and 125 g of deglacial acetic acid was shared, and the intermediate product I, 2- Amino-4,6-dihydroxypyrimidine 98.8g.

[0029] 2), add the intermediate product I, 98.8g of 2-amino-4,6-dihydroxypyrimidine and 350g of water into the reactor, then add 195g of 30% (mass fraction) sodium hydroxide aqueous solution, stir and heat up to 50°C, add Sodium nitrite 66.2g, then start to add 30-35% (mass fraction) hydrochloric acid drop...

Embodiment 3

[0033]1), put 448.0g of 28-30% (mass fraction) 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, and keep The temperature was 45°C, and the reaction was kept at 45°C for 4 hours after the dropwise addition. After the reaction was completed, methanol was recovered by distillation under reduced pressure, and 400 g of water was added after the recovery, and then glacial acetic acid was added to adjust the pH to pH=4-5, and 126 g of deglacial acetic acid was shared, and the intermediate product I, 2- Amino-4,6-dihydroxypyrimidine 99.3 g.

[0034] 2), add the intermediate product I, 99.3g of 2-amino-4,6-dihydroxypyrimidine and 380g of water into the reactor, then add 198g of 30% (mass fraction) sodium hydroxide aqueous solution, stir and heat up to 50°C, add Sodium nitrite 69.0g, then start to add 30-35% (mass fraction) hydrochloric acid dropwise to adjust to pH = 2-3, after...

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Abstract

The invention discloses a synthetic method for 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride. The synthetic method comprises the following steps: adding guanidine hydrochloride into a sodium methylate solution with a concentration of 28 to 30%, carrying out heating and stirring and adding dimethyl malonate drop by drop; after completion of heat preservation, successively carrying out pressure-reduced distillation, addition of water for dissolving, addition of acid for adjustment of a pH value, cooling, pumping filtration, drying and the like to prepare an intermediate product; and subjecting the primarily prepared intermediate product, a Raney nickel catalyst and the like to continuous conversion so as to prepare 2,5-diamino-4,6-dihydroxypyrimidine hydrochloride. According to the invention, total yield reaches 75% and product purity is up to 99.0%; and the synthetic method provided by the invention can simplify operation, reduce cost and improve reaction yield and is more applicable to 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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IPC IPC(8): C07D239/545
CPCC07D239/545
Inventor 余志强徐剑锋曾淼程晓文张庆战朱燕阮孟华
Owner SUZHOU KAIYUAN MINSHENG SCI & TECH CORP
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