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Novel method for synthesizing daclatasvir intermediate

A cyclization and compound technology, which is applied in the field of preparation of daclatasvir intermediates, can solve the problems of rising raw material costs, many steps, and poor safety

Inactive Publication Date: 2015-12-16
SHANGHAI FOREFRONT PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] This method has made great progress compared with the previous method, but compound 10 still needs to be prepared separately in this method, and there are many steps, resulting in an increase in the cost of raw materials; at the same time, more expensive and less safe liquid bromine is used, and labor protection is required. At the same time, install safety protection equipment and formulate safety plans

Method used

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  • Novel method for synthesizing daclatasvir intermediate
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  • Novel method for synthesizing daclatasvir intermediate

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preparation example Construction

[0064] Preparation of daclatasvir intermediate

[0065] The present invention provides a daclatasvir intermediate, the preparation method of the compound shown in formula 1,

[0066]

[0067] Described method comprises the following steps:

[0068] i) under the action of a catalyst, the compound of formula II reacts with the compound of formula III to obtain the compound of formula IV;

[0069]

[0070] and

[0071] The compound of formula I is prepared from the compound of formula IV; wherein, the preparation can be prepared by referring to existing methods in the art, or designed by those skilled in the art based on common knowledge in the art.

[0072] x 1 、X 2 Each is independently selected from the following group: Cl, Br, I.

[0073] More preferably, the method comprises the following steps:

[0074] i) under the action of a catalyst, the compound of formula II reacts with the compound of formula III to obtain the compound of formula IV;

[0075]

[0076] i...

Embodiment 1

[0134]

[0135] Add 21.7g (163.0mmol, 2.5eq) of aluminum trichloride and 80ml of dichloromethane into a 250ml four-neck flask, start stirring, and slowly add 10.0g of biphenyl (65.0mmol, 1.0eq) dropwise at 20-25°C and A mixed solution consisting of 20ml of dichloromethane was stirred for 30 minutes until most of the aluminum chloride was dissolved.

[0136] The reaction mixture was cooled to 0°C, and 22.0g (194.8mmol, 3.0eq) of chloroacetyl chloride was slowly added dropwise. After the dropwise addition was completed, it was kept at 0°C for 1 hour, then naturally warmed to room temperature, and continued to stir for 2 hours. TLC tracking showed that the raw material disappear.

[0137] The reaction solution was poured into 100ml of 10% ice water-hydrochloric acid mixture, stirred for 30 minutes, and the organic layer was separated. The organic phase was washed with water, 10% sodium bicarbonate solution, saturated brine, dried over anhydrous sodium sulfate, and concentrate...

Embodiment 2

[0140]

[0141] Put 30.0g (97.7mmol, 1.0eq) of IV-Cl, Cl and 62.2g (107.5mmol, 2.2eq) of compound 11 in 500ml of acetone, start stirring, heat to 50-55°C for 2h, TLC shows that the raw materials disappear, concentrate To dryness, add 300ml of water, extract 3 times with 200mlX3 toluene, combine the toluene layers, wash with 300ml of water, dry over anhydrous sodium sulfate, filter, and the obtained toluene solution is directly used in the next reaction.

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Abstract

The invention provides a novel method for synthesizing a daclatasvir intermediate, particularly a preparation method of a compound disclosed as Formula 1. The method uses biphenyl and halogen acyl bromide as initial raw materials, and avoids using high-cost reaction raw materials. Thus, the preparation method is simple and safe, and is suitable for industrial production.

Description

technical field [0001] The invention relates to the field of preparation of pharmaceutical intermediates, specifically, the invention provides a method for preparing a daclatasvir intermediate. Background technique [0002] Daclatasvir (Daclatasvir) is a hepatitis C treatment drug developed by BMSquibb, which has been marketed in the United States, Europe and Japan respectively. The clinical cure rate of hepatitis C in combination with Sofosbuvir (Sofosbuvir) can be greater than 90%. , has been included in the list of the most important essential therapeutic drugs by WHO, and has good therapeutic effects and market prospects. [0003] In the method for preparing Daclatasvir (Daclatasvir) known in the art at present, the compound of formula I is the most important and most economical intermediate, so in order to industrialize the production of Daclatasvir, this field needs a kind of compound that can efficiently synthesize A method for a compound of formula I. [0004] ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14C07C49/813C07C45/46
CPCC07D403/14C07C45/46C07C49/813
Inventor 黄成军任毅王琼李巍朱燕燕傅绍军魏哲文富刚
Owner SHANGHAI FOREFRONT PHARMA CO LTD
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