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One-pot preparation process of ns5a protein inhibitor-daclatasvir

A protein inhibitor, daclatasvir technology, applied in the field of drug synthesis, can solve the problems of high cost, a lot of industrial waste, cumbersome operation, etc., and achieve the effect of safety assurance and high product yield

Active Publication Date: 2022-04-12
NANTONG CHANGYOO PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Patent WO2009020825 reports the process route for preparing daclatasvir from acetylbiphenyl through bromination, substitution, cyclization and other multi-step reactions. The safety and operability of the route
[0004] Patent US20100158862 reports a process route for preparing daclatasvir using 4-bromophenylacetamide and Boc-proline as starting materials. The route steps are long and the operation is cumbersome, resulting in more industrial waste and high cost. Not suitable for large-scale industrial production applications

Method used

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  • One-pot preparation process of ns5a protein inhibitor-daclatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Step 1, preparation of DT1:

[0029] Add 4,4'-bis(2-chloroacetyl)biphenyl (DTM1) (15g, 49mmol, 1.0eq), L-proline (DTM2) (5.7g, 50mmol, 1.02eq) into a 1000mL reaction flask , Potassium carbonate (13.5g, 98mmol, 2.0eq) and 500mL tetrahydrofuran, stirred, heated up to 30-35°C for reaction, and monitored by TLC. When TLC showed that the raw material DTM1 reaction remained below 2%, it was lowered to 0-5°C, then EDCI (14.2g, 74mmol, 1.5eq) and HOBt (10g, 74mmol, 1.5eq) were added, stirred for 30 minutes, and then added (R )-2-[tert-butoxycarbonyl(methoxyformyl)amino]-3-methylbutanoic acid (DTM3) (13.8 g, 50 mmol, 1.02 eq). After the addition was completed, the temperature was raised to 20-25°C for reaction, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, add 400mL of water and 600mL of ethyl acetate, stir, let stand for liquid separation, extract the aqueous layer with ethyl acetate (200mL×3), combine the organic phases, and...

Embodiment 2

[0035] Step 1, preparation of DT1:

[0036] Add 4,4'-bis(2-bromoacetyl)biphenyl (DTM1) (15g, 38mmol, 1.0eq), L-proline (DTM2) (4.6g, 40mmol, 1.05eq) into a 1000mL reaction flask , N,N-diisopropylethylamine (15.5g, 120mmol, 3.0eq) and 400mL acetonitrile, stirred, heated to 30-35°C for reaction, and monitored by TLC. TLC showed that when the raw material DTM1 reaction remained below 2%, it was lowered to 0-5°C, then DCC (19.6g, 95mmol, 2.5eq) and HOBt (12.8g, 95mmol, 2.5eq) were added, stirred for 30 minutes, and then added ( R)-2-[Benzoyl(methoxyformyl)amino]-3-methylbutanoic acid (DTM3) (11.2 g, 40 mmol, 1.05 eq). After the addition was completed, the temperature was raised to 20-25°C for reaction, and the reaction was monitored by TLC. After the reaction is complete, cool to room temperature, add 300mL water and 500mL ethyl acetate, stir, let stand to separate the liquids, extract the aqueous layer with ethyl acetate (200mL×3), combine the organic phases, and wash with satu...

Embodiment 3

[0042] Step 1, preparation of DT1:

[0043] Add 4,4'-bis(2-chloroacetyl)biphenyl (DTM1) (20g, 65mmol, 1.0eq), L-proline (DTM2) (7.7g, 69mmol, 1.05eq) into a 1000mL reaction flask , cesium carbonate (42.4g, 130mmol, 2.0eq) and 600mL tetrahydrofuran, stirred, heated to 30-35°C for reaction, and monitored by TLC. When TLC showed that the raw material DTM1 reaction remained below 2%, it was lowered to 0-5°C, then CDI (21.1g, 130mmol, 2.0eq) and HOBt (17.6g, 130mmol, 2.0eq) were added, stirred for 30 minutes, and then added ( R)-2-(benzyloxycarbonyl (methoxyformyl)amino-3-methylbutanoic acid (DTM3) (20.7g, 67mmol, 1.03eq). After addition, the temperature was raised to 20-25°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 layer with ethyl acetate (200mL×3), combine the organic phases, and wash with saturated brine ...

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Abstract

The invention discloses a one-pot preparation process of NS5A protein inhibitor daclatasvir, which mainly includes three steps, 1) preparation of intermediate DT1: the reaction starting materials DTM1, DTM2 and DTM3 are mixed with an alkali reagent and a condensation agent 2) Preparation of intermediate DT2: cyclization of intermediate DT1 with an amine compound to obtain intermediate DT2; 3) Preparation of Daclatasvir: Intermediate DT2 was deaminated with a protecting group reagent The product Daclatasvir is prepared by removing the amino protecting group. Using the method to prepare daclatasvir has the characteristics of high product yield, simple and easy operation of the overall process, and no strong corrosive substances in the preparation material, the safety is effectively guaranteed, and it is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a one-pot preparation process of NS5A protein inhibitor-daclatasvir. Background technique [0002] Daclatasvir is a highly selective hepatitis C virus (HCV) NS5A protein inhibitor developed by Bristol-Myers Squibb, and its trade name is Daklinza. It was approved by the U.S. Food and Drug Administration (FDA) on July 24, 2015 to be used in combination with Sofosbuvir to treat hepatitis C virus genotype-3 infection. [0003] Patent WO2009020825 reports the process route for preparing daclatasvir from acetylbiphenyl through bromination, substitution, cyclization and other multi-step reactions. The safety and operability of the route are improved. [0004] Patent US20100158862 reports a process route for preparing daclatasvir using 4-bromophenylacetamide and Boc-proline as starting materials. The route steps are long and the operation is cumbersome, resulting in more industrial waste ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D403/14
CPCC07D403/14C07B2200/07Y02P20/55
Inventor 李泽标吴洪当马甜甜潘婧严军
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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