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A kind of industrialized production method of high-purity darunavir intermediate

A technology of darunavir and production method, applied in the field of darunavir intermediates, can solve the problems of low product yield, low raw material reduction efficiency, and obtaining quality target products, etc.

Active Publication Date: 2021-06-15
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention is mainly aimed at the current production process of (3R,3AS,6AR)-hydroxyhexahydrofuro[2,3-β]furylsuccinimide-based carbonate, intermediate production process, The raw material reduction efficiency is not high, the reaction time is long, and the production process is unstable; The product yield is not high, and the target product with high quality cannot be obtained. A high-purity (3R,3AS,6AR)-hydroxyhexahydrofuro[2,3-β]furylsuccinyl Industrial production method of iminocarbonate

Method used

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  • A kind of industrialized production method of high-purity darunavir intermediate
  • A kind of industrialized production method of high-purity darunavir intermediate
  • A kind of industrialized production method of high-purity darunavir intermediate

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] (1) Under the protection of nitrogen, put 600kg tetrahydrofuran into a clean and dry 2000L reactor, and 100kg racketone (molar weight 158.06, molar number 633mol);

[0028] (2) Control the temperature of the reactor <25°C, add 28.7kg of sodium borohydride (mole weight 37.83, mole number 759mol) in batches, add anhydrous lithium chloride 5.4kg (mole weight 42.39, mole number 127mol) in batches, slowly Warming up to reflux reaction;

[0029] (3) After the reaction of the central control raw material is completed, the temperature of the reactor is lowered to below 10°C, and 175kg of concentrated hydrochloric acid is added dropwise to the reactor, and the pH is adjusted to 1-3. After the addition is completed, the reaction is kept for 2 hours; Neutralize the reaction pH to 6-7 with sodium carbonate;

[0030] (4) centrifugation, concentrated to obtain 80kg furan alcohol, GC>95%;

[0031] (5) Under nitrogen protection, drop 800kg dichloromethane into clean, dry 2000L reacto...

Embodiment 2

[0036] (1) Under the protection of nitrogen, put 400kg of acetone and 100kg of racketone into a clean, dry 2000L reactor (molar weight 158.06, molar number 633mol);

[0037] (2) Control the temperature of the reactor <25°C, add 28.8 kg of lithium aluminum hydride (37.95 moles, 759 mol moles) in batches; add 8.4 kg aluminum chloride (133.3 moles, 63.3 moles moles) in batches, and slowly raise the temperature to reflux reaction;

[0038] (3) After the reaction of the central control raw materials is completed, the temperature of the reactor is lowered to below 10°C, and 175kg of concentrated hydrochloric acid is added dropwise to the reactor, and the pH is adjusted to 1-3. After the addition, the temperature is kept for 2 hours. After the incubation, neutralize the reaction pH to 6-7 with sodium carbonate;

[0039] (4) centrifugal, concentration obtains 75.5kg furan alcohol, GC﹥95%;

[0040] (5) Under nitrogen protection, drop 378kg toluene into a clean, dry 2000L reactor, 75....

Embodiment 3

[0045] (1) Under the protection of nitrogen, put 700kg of 2-methyltetrahydrofuran into a clean and dry 2000L reactor, and 100kg of racketone (molar weight 158.06, molar number 633mol);

[0046] (2) Control the temperature of the reactor <25°C, add 26.3kg of sodium borohydride (37.83 moles, 696mol moles) in batches, add 5.4kg anhydrous lithium chloride (42.39 moles, 127mol moles) in batches, and slowly Warming up to reflux reaction;

[0047] (3) After the reaction of the central control raw materials is completed, the temperature of the reactor is lowered to below 10°C, and 175kg of concentrated hydrochloric acid is added dropwise to the reactor, and the pH is adjusted to 1-3. After the addition, the temperature is kept for 2 hours. After the incubation, neutralize the reaction pH to 6-7 with sodium carbonate;

[0048] (4) centrifugation, concentrated to obtain 80kg furan alcohol, GC>95%;

[0049] (5) Under nitrogen protection, drop into 960kg acetonitrile, 80kg furan alcohol (...

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Abstract

The invention relates to the field of biochemical technology, in particular to an industrial production method of a darunavir intermediate (3R, 3aS, 6aR)-hydroxyhexahydrofuro[2,3-β]furylsuccinimidyl carbonate. Compared with the existing technology, the industrial production method of (3R, 3AS, 6AR)-hydroxyhexahydrofuro[2,3-β]furylsuccinimide-based carbonate provided by the present invention can efficiently and stably produce High-quality (3R,3AS,6AR)-hydroxyhexahydrofuro[2,3-β]furylsuccinimide carbonate was produced with a purity greater than 99% and an unknown single impurity less than 0.1%.

Description

technical field [0001] The invention relates to the field of biochemical technology, in particular to the industrialization of high-purity darunavir intermediate (3R, 3aS, 6aR)-hydroxyhexahydrofuro[2,3-β]furylsuccinimide carbonate production method. Background technique [0002] (3R,3aS,6aR)-Hydroxyhexahydrofuro[2,3-β]furylsuccinimidyl carbonate, CAS No.: 253265-97-3. [0003] Chemical Structure: [0004] [0005] (3R,3AS,6AR)-Hydroxyhexahydrofuro[2,3-β]furylsuccinimidyl carbonate is a key intermediate in the synthesis of darunavir. Darunavir was developed by Tibotec, a subsidiary of Johnson & Johnson in Iceland. It was approved for marketing by the FDA in June 2006 with priority approval. In 2017, the sales revenue of anti-AIDS drugs related to darunavir was US$1.821 billion. Since 2008, this series of drugs Total sales amounted to $13.394 billion. Darunavir is a new non-peptide antiretroviral protease inhibitor for AIDS treatment. It is currently the most bioavailab...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D493/04
CPCC07D493/04
Inventor 王玉琴詹玉进陈友海
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD
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