One-pot preparation of lopinavir

A carboxyl activator and condensation reaction technology, applied in the field of medicine, can solve the problems of cumbersome operation and post-processing, increase the reaction steps of activated ester, not suitable for industrial production, etc., and achieve the effect of saving process and fewer synthesis steps.

Active Publication Date: 2021-05-25
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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  • One-pot preparation of lopinavir
  • One-pot preparation of lopinavir
  • One-pot preparation of lopinavir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053]

Embodiment 1-1

[0055] 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 stirring at 25°C for 2h, 59.5g (0.1mol) THP was added to the reaction solution, and stirring was continued at 25°C for 8h until the reaction was 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.

Embodiment 1-2

[0057] Dissolve 21.6g (0.12mol) of 2,6-dimethylphenoxyacetic acid in 60ml of DMF to form a solution, add 17.8g (0.11mol) of CDI in batches at 25°C, and stir at room temperature for 1h. Add 59.5 g (0.1 mol) THP to the reaction solution at 25°C, and continue to stir at room temperature for 8 h until the reaction is complete. The reaction solution was quenched with 2g (0.02mol) N,N-dimethyl-1,3-propanediamine, continued to stir at room temperature for 2h, added 200ml of 5% citric acid to the reaction solution, cooled to 5°C, and stirred for 2h Crystallize, filter, wash the filter cake with 5% citric acid solution, 5% sodium bicarbonate solution and water, and dry the filter cake under vacuum at 50° C. to obtain 58.4 g (93% yield) of lopinavir.

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Abstract

One-pot preparation of lopinavir (I), which is performed by 2,6-dimethylphenoxyacetic acid, a carboxyl activator, and a compound represented by formula (III) in an organic solvent to carry out a condensation reaction. Condensation reaction conditions are mild, in It can be carried out at room temperature without heating or cooling; the preparation method does not require special chemical reagents, and all are solvents and reagents commonly used in laboratories, and the total yield is higher than 85%, preferably higher than 90%, and in some embodiments, the yield Up to 96%, especially suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a one-pot 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 report...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/10
CPCC07B2200/07C07D239/10
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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