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Synthesis method of dolutegravir core intermediate

A synthesis method and technology of dolutegravir, applied in the field of synthesis of dolutegravir core intermediates, can solve the problems of rising product impurity content, unfavorable industrial production, and high boiling point of mineral oil, and achieve improved product purity and yield, The effect of simplifying the post-reaction treatment process and reducing the three wastes

Active Publication Date: 2022-04-15
JIANGSU YUXIANG CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This route can effectively suppress the occurrence of by-products of ester hydrolysis because the reaction temperature is low, but the sodium hydride used contains 40% mineral oil, which has a relatively high boiling point and is not easy to remove, causing the product impurity content to rise, and the final reaction It is still necessary to distill the product under reduced pressure at high temperature and high vacuum, and these two routes are not conducive to industrial production

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] 201×7 strong basic styrene-based anion exchange resin is fully activated before use, and then fully soaked and replaced by methanol, then it can be used.

[0025] 1) In the reactor, first drop in 200kg of methanol. Under stirring, then add strong basic anion exchange resin 100kg. Finally, 10 kg of raw material 4-chloroacetoacetate methyl ester was added.

[0026] 2) heat up to reflux, and react for 8 hours.

[0027] 3) During the reflux process, the rising steam enters the intermediate tank after condensation, and 100kg of 3A molecular sieve is put into the intermediate tank. After passing through the intermediate tank, the condensate flows back into the reactor.

[0028] 4) After the reaction finishes, cool down to room temperature. The reaction liquid was filtered out from the reaction kettle.

[0029] 5) The reaction solution is rectified, and the methanol is returned to the reactor to participate in the next batch of reactions; finally, a colorless liquid ethyl...

Embodiment 2

[0031] 201×7 strong basic styrene-based anion exchange resin is fully activated before use, and then fully soaked and replaced by methanol, then it can be used.

[0032] 1) In the reactor, first drop in methanol 1000kg. Under stirring, then add strong basic anion exchange resin 300kg. Finally, 10 kg of raw material 4-chloroacetoacetate methyl ester was added.

[0033] 2) heat up to reflux, and react for 4 hours.

[0034] 3) During the reflux process, the rising steam enters the intermediate tank after condensation, and 100kg of 3A molecular sieve is put into the intermediate tank. After passing through the intermediate tank, the condensate flows back into the reactor.

[0035] 4) After the reaction finishes, cool down to room temperature. The reaction liquid was filtered out from the reaction kettle.

[0036] 5) The reaction solution is rectified, and the methanol is returned to the reactor to participate in the next batch of reactions; finally, a colorless liquid ethyl 4...

Embodiment 3

[0038] 201×7 strong basic styrene-based anion exchange resin is fully activated before use, and then fully soaked and replaced by methanol, then it can be used.

[0039] 1) In the reactor, first drop in methanol 600kg. Under stirring, then add strong basic anion exchange resin 200kg. Finally, 10 kg of raw material 4-chloroacetoacetate methyl ester was added.

[0040] 2) heat up to reflux, and react for 6 hours.

[0041] 3) During the reflux process, the rising steam enters the intermediate tank after condensation, and 100kg of 3A molecular sieve is put into the intermediate tank. After passing through the intermediate tank, the condensate flows back into the reactor.

[0042] 4) After the reaction finishes, cool down to room temperature. The reaction liquid was filtered out from the reaction kettle.

[0043] 5) The reaction solution is rectified, and the methanol is returned to the reactor to participate in the next batch of reactions; finally, a colorless liquid ethyl 4-...

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Abstract

The invention discloses a synthesis method of a dolutegravir core intermediate. Comprising the following steps: firstly adding methanol into a reaction kettle, stirring, then adding strongly basic anion exchange resin, finally adding a raw material methyl 4-chloroacetoacetate, heating to reflux, reacting for 4-8 hours and the like. The reaction post-treatment process is greatly simplified, the process is simple, few three wastes are generated, and the cost is low. According to the method, the yield of the ethyl 4-methoxy acetoacetate is greater than 98%, and the content of the ethyl 4-methoxy acetoacetate is greater than 99%.

Description

technical field [0001] The invention relates to the technical field of chemical engineering, in particular to a method for synthesizing a dolutegravir core intermediate. Background technique [0002] AIDS (acquired immunodeficiency syndrome, acquiredimmuno-deficiency syndrome, AIDS) is a very threatening malignant infectious disease, so far there is no preventive and therapeutic vaccine and completely curative drugs. [0003] Dolutegravir is a safe and highly effective anti-HIV drug developed by GlaxoSmithKline, a subsidiary of the United States, with a high genetic barrier and good drug metabolism properties. In August 2013, the oral tablet with its sodium salt (dolutegravir sodium) as the only active ingredient was approved by the US FDA for marketing, and the trade name was Tivicay[12]. It was approved by the European Medicines Agency in January 2014. In March 2014, it was approved by PMDA of Japan. In December 2015, it obtained the China Import Registration Certificat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C67/31C07C69/716B01J31/08
Inventor 张治国徐官根李思远王金程红伟程云涛
Owner JIANGSU YUXIANG CHEM
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