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One-pot preparation technology of NS5A protein inhibitor daclatasvir

A protein inhibitor, daclatasvir technology, applied in the field of drug synthesis, can solve the problems of a lot of industrial waste, high cost, weakened route safety and operability, etc., to achieve high product yield and guaranteed safety. Effect

Active Publication Date: 2020-03-13
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 technology of NS5A protein inhibitor daclatasvir
  • One-pot preparation technology 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 of water and 500mL 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 ...

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 technology of an NS5A protein inhibitor daclatasvir. The technology mainly comprises the following three steps: 1) preparing an intermediate DT1: carryingout a butt reaction on reaction initial raw materials which are DTM1, DTM2 and DTM3 under the action of an alkali reagent and a condensing agent to prepare the intermediate DT1; 2) preparing an intermediate DT2: cyclizing the intermediate DT1 and an amine compound to prepare the intermediate DT2; and 3) preparing daclatasvir: removing an amino protecting group from the intermediate DT2 by using an amino protecting group removing reagent to prepare the product daclatasvir. The method for preparing daclatasvir has the characteristics of high product yield, simple and easy-to-operate overall process, no strong corrosive substances in the preparation materials, effectiveness in safety ensuring, and suitableness 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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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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