Preparation method of velpatasvir intermediate

A technology for velpatasvir and intermediates, which is applied in the field of preparation of velpatasvir intermediates, can solve the problems of unfavorable industrial production, low total yield, long route, etc., and achieve cheap and easy-to-obtain starting materials and excellent reaction conditions Gentle, high-yield effect

Inactive Publication Date: 2017-12-22
PHARMA SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0008] But this route raw material is difficult to obtain, and price is expensive, and route is long, and total yield is low, is also unfavorable for industrialized production

Method used

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  • Preparation method of velpatasvir intermediate
  • Preparation method of velpatasvir intermediate
  • Preparation method of velpatasvir intermediate

Examples

Experimental program
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Effect test

Embodiment 1

[0052] Add the compound 4-bromoacetophenone (100g, 0.503mol) of formula I and 500ml 1,2-dichloroethane into a 1L three-necked flask, stir to dissolve, and add anhydrous aluminum chloride (254.8 g, 1.911mol), control the temperature not to exceed 45°C, cool down to 20-25°C after adding, slowly add paraformaldehyde (68g, 0.755mol) in batches, control the temperature to not exceed 45°C, after the addition is completed, rise to React at 45±2°C for 16-24h, monitor the reaction by HPLC, when the conversion rate of product II reaches 60-65%, lower the reaction temperature to ≤10°C, transfer to a 3L three-necked flask, add 1L of water dropwise to quench the reaction, Control the temperature to ≤35°C, stir and separate the layers, extract the water layer once with 200ml 1,2-dichloroethane, combine the organic phases, wash once with water, dry over anhydrous sodium sulfate, filter, concentrate, and use a mixed solvent of toluene and petroleum ether After beating, 62.2 g of off-white sol...

Embodiment 2

[0054] Add the compound 4-bromoacetophenone (100g, 0.503mol) and 500ml of dichloromethane into a 1L three-necked flask, stir to dissolve, and add anhydrous aluminum chloride (268.3g, 2.012mol) in batches under nitrogen protection. ), control the temperature not to exceed 40°C, and then lower the temperature to 20-25°C after adding, slowly add paraformaldehyde (90.6g, 1.006mol) in batches, control the temperature not to exceed 40°C, and rise to 40± React at 2°C for 16-24h, monitor the reaction by HPLC, when the conversion rate of product II reaches 60-65%, lower the reaction temperature to ≤10°C, transfer to a 3L three-necked flask, add 1L water dropwise to quench the reaction, control the temperature ≤ Stir and separate at 35°C, extract the water layer once more with 200m methylene chloride, combine the organic phases, wash once with water, dry over anhydrous sodium sulfate, filter, concentrate, and beat with a mixed solvent of toluene and petroleum ether to obtain 58.3g off-wh...

Embodiment 3

[0056] Add the compound 4-bromoacetophenone (100g, 0.503mol) and 500ml chloroform into a 1L three-necked flask, stir to dissolve, and add anhydrous aluminum chloride (201.3g, 1.509mol) in batches under nitrogen protection, Control the temperature not to exceed 50°C, and then lower the temperature to 20-25°C after adding, slowly add paraformaldehyde (45.4g, 0.503mol) in batches, control the temperature not to exceed 50°C, and rise to 50±2°C after the addition is complete React for 16-24 hours, monitor the reaction by HPLC, when the conversion rate of product II reaches 60-65%, lower the reaction temperature to ≤10°C, transfer to a 3L three-necked flask, add 1L of water dropwise to quench the reaction, and control the temperature to ≤35°C , stirred and separated, the aqueous layer was extracted once with 200ml chloroform, the organic phases were combined, washed once with water, dried over anhydrous sodium sulfate, filtered, concentrated, and beaten with a mixed solvent of toluen...

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Abstract

The invention discloses a preparation method of velpatasvir intermediate, namely [9-bromine-3-(2-bromoacetyl)-10,11-dihydro-5H-bibenzo(c,g) chromene-8(9h)-one]. The structure of the intermediate corresponds to a formula VI as shown in the description. The method comprises the steps of by taking a compound, namely 4-bromoacetophenone as raw materials, carrying out chloromethylation, condensation, cyclization and bromination, and finally obtaining the velpatasvir intermediate of the formula VI. According to the method, the starting raw materials are cheap and easily available, the reaction conditions are mild, the rout is short, the yield is high and the preparation method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a preparation method of a velpatasvir intermediate. Background technique [0002] Hepatitis C virus (HCV) infection seriously endangers human health and is one of the main causes of post-transfusion hepatitis. Currently, the worldwide hepatitis C infection rate is 3%. It is estimated that about 170 to 200 million people are infected with hepatitis C virus, and about 3.5 million people are newly infected every year. At present, research on NS5A as an antiviral target has become a hot spot in the field of anti-HCV. Velpatasvir (CAS: 1377049-84-7), as a new NS5A hepatitis C specific drug developed by Gilead, has broad market prospects. 9-Bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-dibenzo(c,g)chromen-8(9h)-one is an important intermediate in the synthesis of velpatasvir . [0003] The current patent document WO2015191437A1 discloses two synthetic methods. The...

Claims

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Application Information

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IPC IPC(8): C07D311/78
CPCC07D311/78
Inventor 彭少平庄银枪穆成磊
Owner PHARMA SHANGHAI
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