Preparation method of velpatasvir intermediate

A technology of velpatasvir and intermediates, which is applied in the field of preparation of velpatasvir intermediates, can solve the problems of long route, high cost, expensive starting raw materials, etc., and achieves the effects of high yield and high purity

Inactive Publication Date: 2018-01-26
安徽省诚联医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The starting material of this route is expensive, the route is long, and the cost is high

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Synthesis of 2-Methylacetanilide (I)

[0031] Take 107g of o-methylaniline, dissolve it in 200ml of ethyl acetate, add 102g of acetic anhydride dropwise under ice bath, and finish dropping in 30 minutes. After the dropwise addition, continue the reaction for 30 minutes. The layer was dried over anhydrous magnesium sulfate, filtered, and ethyl acetate was recovered from the filtrate under reduced pressure to obtain a brown solid. Petroleum ether: ethyl acetate = 1:1 and recrystallized to obtain 148 g of colorless needle crystals, with a yield of 99%.

[0032] The specific chemical reaction formula is:

[0033]

Embodiment 2

[0035] Preparation of 3-methyl-4-acetamidoacetophenone (II)

[0036] Take 149g of o-methylacetanilide, dissolve it in 400ml of ethyl acetate, add 102g of acetic anhydride, under ice bath, add 140g of anhydrous aluminum trichloride in batches, add 1h, after adding, react at room temperature for 1h, react After the end, the reaction system was slowly added to 300 ml of 3mol / L ice-dilute hydrochloric acid, separated, the organic layer was washed with water until neutral, the organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate recovered the solvent under reduced pressure to obtain a dark solid, petroleum Ether: ethyl acetate = 2:1 and recrystallized to obtain 151 g of an orange-yellow solid, with a yield of 79%.

[0037] The specific chemical reaction formula is:

[0038]

Embodiment 3

[0040] Preparation of 3-methyl-4-aminoacetophenone (III)

[0041] Take 191 g of 3-methyl-4-acetylaminoacetophenone, dissolve it in 300 ml of methanol, add 300 ml of 3mol / L dilute hydrochloric acid, and reflux for 6 hours. After the reaction, adjust the pH to 8-9 with sodium bicarbonate, and filter , the filter cake was washed with water until neutral, and dried to obtain 136 g of pale yellow needle crystals, with a yield of 91%.

[0042] The specific chemical reaction formula is:

[0043]

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Abstract

The invention provides a preparation method of a velpatasvir intermediate. According to the preparation method, ortho-toluidine is taken as an initial raw material, amino acetylation protection, Friedel-Crafts acylation, deamination protection, diazotization, and bromination are adopted so as to obtain 3-bromomethyl-4-bromoacetophenone; and alkylation with 7-hydroxy-1-tetralone, intramolecular coupling, and bromination are adopted so as to obtain 9-bromo-3-(2-bromoacetyl)-10, 11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one. The yield and the purity of the velpatasvir intermediate preparedvia the preparation method are high, cost is low, and large size production is convenient to realize.

Description

technical field [0001] The invention belongs to the technical field of velpatasvir preparation, 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 million 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. [0003] 9-Bromo-3-(2-bromoacetyl)-10,11-dihydro-5H-benzo[d]naphtho[2,3-b]pyran-8(9H)-one as vepata Wei's key intermediate, its synthetic scheme mainly contains the following three synthetic methods: Scheme 1, u...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/78
Inventor 刘辉
Owner 安徽省诚联医药科技有限公司
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