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Preparation of velpatasvir and its derivatives

A technology of velpatasvir and derivatives, which is applied in the field of drug synthesis, and can solve the problems of difficult industrialization, many side effects, and high cost of velpatasvir

Active Publication Date: 2020-03-17
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Among them, the synthetic routes 1 and 3 need to carry out the ring-closing reaction of two imidazole rings at high temperature at one time. There are many by-products and a large amount of tar is produced. very difficult
There is a three-step palladium-catalyzed coupling reaction in the second reaction of the synthetic route, which makes the cost of preparing velpatasvir by this route very high, and there are many side reactions, and the later purification is quite difficult

Method used

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  • Preparation of velpatasvir and its derivatives
  • Preparation of velpatasvir and its derivatives
  • Preparation of velpatasvir and its derivatives

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0087] The preparation of formula 1 compound

[0088] The inventor realizes by following technical scheme (shown in route four):

[0089]

[0090] In the method of the present invention, the compound of formula 5 is prepared by condensation of the compound of formula 7 and the compound of formula 6 under alkaline conditions; the compound of formula 5 is subjected to ring closure reaction with ammonia or its derivatives at high temperature to prepare the compound of formula 4; the compound of formula 4 and Substituting reagents, carbonyl α-position substitution occurs, and the compound of formula 3 is obtained; the compound of formula 3 is condensed with compound 8 under alkaline conditions to obtain the compound of formula 2; the compound of formula 2 undergoes ring closure reaction with ammonia or its derivatives at high temperature , to prepare the compound of formula 1; the compound of formula 1 is oxidized or oxidized-deprotected to obtain VLP-1, and VLP-1 is condensed ...

Embodiment 1

[0127] Embodiment 1: synthetic compound 5a

[0128]

[0129] Add 3.7g of compound 7, 2.85g of compound 6a, 2.76g of potassium carbonate, and 55.5ml of dichloromethane into a 100ml reaction flask, heat to 30-35°C, stir for 16 hours, monitor the disappearance of the reaction material 7 by LC, add water to quench reaction. The reaction mixture was washed with water, dried over sodium sulfate, and concentrated to obtain compound 5a (5.68 g, purity 96.58%, yield 100%).

Embodiment 2

[0130] Embodiment 2: synthetic compound 5b

[0131]

[0132] Add 3.7g of compound 7, 3.3g of compound 6b, 2.76g of potassium carbonate, and 55.5ml of dichloromethane into a 100ml reaction flask, heat to 30-35°C, stir for 16 hours, LC monitors that the reaction material 7 disappears, and add water to quench reaction. The reaction mixture was washed with water, dried over sodium sulfate, and concentrated to obtain compound 5b (5.45 g, yield 98%).

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Abstract

The present invention relates to a preparation method of velpatasvir and its derivatives, specifically, the present invention prepares velpatasvir and its derivatives through the intermediate compound shown in the following formula (the definition of each group is as in the specification mentioned). The method has few by-products and low cost, and is suitable for industrial production of velpatasvir.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular, the invention provides an intermediate of anti-hepatitis C drug velpatasvir (velpatasvir, GS-5816) and a preparation method thereof. Background technique [0002] Velpatasvir (GS-5816) is a new generation NS5A inhibitor developed by Gilead Sciences Co., Ltd. The combination of Velpatasvir and Sofosbuvir will be the first single-tablet oral regimen for the treatment of pan-genotype hepatitis C. efficient. Its structure is as follows: [0003] [0004] The compound shown in Formula 1 is an important intermediate for the preparation of velpatasvir (GS-5816). At present, the known preparation methods of the compound of Formula 1 are mainly the synthetic routes reported in WO2013075029, and the three routes are as follows: [0005] Route 1: [0006] [0007] Route two: [0008] [0009] Route three: [0010] [0011] Among them, the synthetic routes 1 and 3 need to carry o...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D405/14C07D491/052
CPCC07D405/14C07D491/052C07D405/12
Inventor 黄成军任毅李巍傅绍军
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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