Novel method for preparing lopinavir

A new method and compound technology, applied in the field of medicine, can solve the problems of adding activated ester reaction steps, complicated operation and post-processing, unsuitable for industrial production, etc., and achieve the effect of fewer synthesis steps.

Active Publication Date: 2020-04-17
厦门蔚嘉制药有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0010] Although the product quality and yield of method 3 are acceptable, the step of activated ester reaction is increased, and the operation and post-treatment are cumbersome. Considering the cost, it is not suitable for industrial production;

Method used

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  • Novel method for preparing lopinavir
  • Novel method for preparing lopinavir
  • Novel method for preparing lopinavir

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Experimental program
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Embodiment 1

[0055]

Embodiment 1-1a

[0056] The preparation method of embodiment 1-1a formula (IIa)

[0057]

[0058] Disperse 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 150ml of dichloromethane to form a suspension, add 17.8g of CDI (0.11mol) solid to the reaction solution in batches at room temperature at 25°C, add After completion, stir at 25° C. for 2 h. After the reaction is complete, concentrate under reduced pressure to remove dichloromethane, and the concentrate obtained is the compound represented by formula (IIa).

Embodiment 1-1b

[0060] Add 25.3 g of the compound represented by formula (IIa) and 59.5 g (0.1 mol) THP to 150 ml of dichloromethane at 25°C, and continue stirring at 25°C for 8 h until the reaction is complete. Quench the reaction with 2g (0.02mol) N,N-dimethyl-1,3-propanediamine, continue to stir at room temperature for 2h, and use 5% citric acid solution 100ml, 5% sodium bicarbonate solution 100ml, 50ml Washed with water 3 times, the organic phase was concentrated under vacuum, the concentration temperature did not exceed 50°C, to obtain 60.3g (96% yield) of lopinavir.

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Abstract

The invention relates to a novel method for preparing lopinavir (I), a condensation reaction of a compound shown in a formula (II) and a compound shown in a formula (III) is carried out at room temperature under mild condensation reaction conditions, and heating or cooling is not needed; the preparation method does not need special chemical reagents, the special chemical reagents are solvents andreagents commonly used in laboratories, the total yield is higher than 85%, preferably higher than 90%, in some embodiments, the yield reaches 96%, and the preparation method is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a new method for preparing lopinavir. Background technique [0002] Lopinavir, chemical name: (2S)-N-[(2R,4S,5S)-5-[[2-(2,6-Dimethylphenoxy)acetyl]amino]-4-hydroxy -1,6-diphenyl-hex-2-yl]-3-methyl-2-(2-oxo-1,3-diazacyclohex-1-yl)butanamide, its structure is as follows Shown: [0003] [0004] Lopinavir is an HIV-1 and HIV-2 protease inhibitor, which can be combined with low-dose ritonavir to improve its pharmacokinetic properties. Approved by the Food and Drug Administration for marketing, it has reliable curative effect, few side effects, and is less affected by food. It is currently used as a first-line or second-line treatment drug against human immunodeficiency virus, and plays an important role in the antiviral treatment of HIV patients who have failed initial treatment due to drug resistance. ; [0005] Lopinavir has 4 chiral centers. The synthetic routes reported i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/10C07D233/60C07D207/46C07D209/48C07D209/76
CPCC07D207/46C07D209/48C07D209/76C07D233/60C07D239/10
Inventor 侯鹏翼贝洛夫·叶夫根尼
Owner 厦门蔚嘉制药有限公司
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