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Method for preparing NS5A inhibitor-Velpatasvir

An inhibitor and reagent technology, applied in the field of drug synthesis, can solve the problems of less than 50% total cure rate, unsuitable production and preparation, limited drug application, etc., and achieves the effects of enhanced operability, easy handling and purification, and simplified preparation route.

Active Publication Date: 2020-04-10
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The standard treatment regimen is pegylated interferon (Peg-IFN) combined with ribavirin (RBV), the overall cure rate is less than 50%, and sufficient doses must be adhered to for more than one year
[0004] However, the velpatasvir synthesis process in the prior art has defects such as complicated route, poor operability, and low yield, and is not suitable for large-scale production and preparation, which limits the application of this type of drug to a certain extent

Method used

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  • Method for preparing NS5A inhibitor-Velpatasvir
  • Method for preparing NS5A inhibitor-Velpatasvir
  • Method for preparing NS5A inhibitor-Velpatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] The synthetic route is as follows:

[0030]

[0031] Step 1, preparation of VP1:

[0032] At room temperature, add 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8 into a 1000mL reaction flask (9H)-Kone (VPM1) (20g, 45mmol, 1.0eq), (2S,4S)-1-(tert-butoxycarbonyl)-4-(methoxymethyl)-pyrrolidine-2-carboxylic acid ( VPM2) (11.6g, 46mmol, 1.02eq), cesium carbonate (29.3g, 90mmol, 2.0eq) and 300mL tetrahydrofuran were stirred, heated to 50-55°C for reaction, and monitored by TLC. When TLC showed that the reaction residue of raw material VPM2 was below 2%, it was lowered to 30-35° C., and then 100 mL of VPM3 in tetrahydrofuran (13.2 g, 46 mmol, 1.02 eq) was added dropwise. After dropping, the temperature was raised to 50-55°C for reaction, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, add 500mL of water and 500mL of ethyl acetate, stir, let stand for liquid separation, extract the aqueous layer wi...

Embodiment 2

[0042] The synthetic route is as follows:

[0043]

[0044] Step 1, preparation of VP1:

[0045] At room temperature, add 9-bromo-3-(2-chloroacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran-8 into a 1000mL reaction flask (9H)-Kone (VPM1) (30g, 74mmol, 1.0eq), (2S,4S)-1-(benzyloxycarbonyl)-4-(methoxymethyl)-pyrrolidine-2-carboxylic acid (VPM2 ) (22.9g, 78mmol, 1.05eq), potassium carbonate (30.6g, 222mmol, 3.0eq) and 400mL of acetonitrile, stirred, heated to 50-55°C for reaction, TLC monitored the reaction. When TLC showed that the reaction residue of the raw material VPM2 was below 2%, it was lowered to 30-35° C., and then 100 mL of VPM3 in acetonitrile (22.3 g, 78 mmol, 1.05 eq) was added dropwise. After dropping, the temperature was raised to 50-55°C for reaction, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, add 500mL of water and 600mL of ethyl acetate, stir, let stand for liquid separation, extract the aqueous la...

Embodiment 3

[0055] The synthetic route is as follows:

[0056]

[0057] Step 1, preparation of VP1:

[0058] At room temperature, in a 500mL reaction flask, 9-bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[D]naphtho[2,3-B]pyran -8(9H)-Kone (VPM1) (15g, 33mmol, 1.0eq), (2S,4S)-1-(benzoyl)-4-(methoxymethyl)-pyrrolidine-2-carboxylic acid (VPM2) (9.2g, 35mmol, 1.05eq), cesium carbonate (23.3g, 66mmol, 2.0eq) and 200mL tetrahydrofuran were stirred, heated to 50-55°C for reaction, and monitored by TLC. When TLC showed that the reaction residue of raw material VPM2 was below 2%, it was lowered to 30-35° C., and then 80 mL of VPM3 in tetrahydrofuran (10 g, 35 mmol, 1.05 eq) was added dropwise. After dropping, the temperature was raised to 50-55°C for reaction, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, add 300mL of water and 400mL of ethyl acetate, stir, let stand for liquid separation, extract the aqueous layer with ethyl acetate (150mL...

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Abstract

The invention discloses a method for preparing an NS5A inhibitor-Velpatasvir, wherein the method mainly comprises the five steps: 1) carrying out docking reaction on reaction initial raw materials VPM1, VPM2 and VPM3 under the catalytic action of alkali to prepare an intermediate VP1; 2) removing amino protecting groups from the intermediate VP1 by using a protecting group removing reagent to prepare an intermediate VP2; 3) carrying out cyclization on the intermediate VP2 and an amine compound to prepare an intermediate VP3; 4) carrying out a reaction on the intermediate VP3 with VPM4 under the action of a condensing agent to prepare an amide compound intermediate VP4; and 5) carrying out oxidation reaction on the intermediate VP4 under the action of an oxidizing agent to prepare Velpatasvir. The preparation process of Velpatasvir has the characteristics of simplified route, simple reaction conditions, enhanced operability and higher product yield, and is more suitable for large-scaleindustrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a method for preparing NS5A inhibitor-velpatasvir. Background technique [0002] There are 6 genotypes of HCV virus. The standard treatment regimen is pegylated interferon (Peg-IFN) combined with ribavirin (RBV). The overall cure rate is less than 50%, and sufficient doses must be adhered to for more than one year. Peg-IFN, which needs to be injected once a week, has disadvantages such as many adverse reactions, drug interactions, and poor patient compliance, which limit its clinical use. Therefore, direct antiviral drugs (DAAs) for the treatment of hepatitis C that can improve the cure rate, shorten the treatment time, and replace the use of Peg-IFN in an all-oral form continue to emerge. [0003] Epclusa is a new pan-genotypic hepatitis C drug developed by Gilead Sciences. It is a compound tablet composed of NS5B inhibitor sofosbuvir and NS5A inhibitor velpatasvir (VEL), and is ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/052
CPCC07D491/052Y02P20/55
Inventor 李泽标沈敏哲丁红萍潘婧邹林
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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