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Novel preparation method for novel anti-hepatitis C drug-daklinza

A daclatasvir and anti-hepatitis C technology, which is applied in the field of preparation of the new anti-hepatitis C drug daclatasvir, can solve the problems of multiple synthesis steps and high economic costs, and achieve the effects of easy-to-obtain raw materials, strong applicability, and simple operation

Inactive Publication Date: 2016-06-01
SUZHOU BUYUE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The above methods have their own advantages, but they all have the defects of many synthesis steps and high economic cost, so it is necessary to explore a new synthesis route of daclatasvir with few steps and low cost

Method used

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  • Novel preparation method for novel anti-hepatitis C drug-daklinza
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  • Novel preparation method for novel anti-hepatitis C drug-daklinza

Examples

Experimental program
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Effect test

Embodiment 1

[0026] Example 1 , Synthesis of ester (14)

[0027] Add 4,4'-bis(2-chloroacetyl)biphenyl (14 g, 45 mmol) and N-(methoxycarbonyl)-L-valyl-L-proline (25.7 g, 94.5 mmol) and Acetonitrile (140mL) was put in a 250mL there-necked flask, stirred until it was fully dissolved and cooled to 10°C, and diisopropylethylamine DIPEA (12.2g, 94.5mmol) was added dropwise at 10-30°C, after the addition was complete, the Stir at 40-45 degrees for 4-7 hours, the reaction is complete, the reaction solution is concentrated under reduced pressure, and replaced with toluene solution (140mL), washed twice with saturated aqueous sodium chloride solution (70mL), and the toluene is concentrated to obtain an oily foamy solid (33.7g , yield 95%).

Embodiment 2

[0028] Example 2 , the synthesis of ester (14)

[0029] Add 4,4'-bis(2-chloroacetyl)biphenyl (14 g, 45 mmol) and N-(methoxycarbonyl)-L-valyl-L-proline (25.7 g, 94.5 mmol) and Acetonitrile (140mL) was added to a 250mL three-necked flask, and diisopropylethylamine DIPEA (12.2 g, 94.5 mmol) was added dropwise at 10-15 degrees. After the addition was complete, it was stirred at 10-15 degrees for 30-36 hours, After the reaction was complete, the reaction solution was concentrated under reduced pressure and replaced with toluene solution (140 mL), washed twice with saturated chloride (70 mL), and the toluene was concentrated to obtain an oily foamy solid (32.9 g, yield 92.7%).

Embodiment 3

[0030] Example 3 , the synthesis of ester (14)

[0031] Add 4,4'-bis(2-chloroacetyl)biphenyl (14 g, 45 mmol) and N-(methoxycarbonyl)-L-valyl-L-proline (25.7 g, 94.5 mmol) and Acetonitrile (140mL) was added to a 250mL three-necked flask, and diisopropylethylamine DIPEA (12.2 g, 94.5 mmol) was added dropwise at 20-25 degrees. After the addition was complete, it was stirred at 20-25 degrees for 16-20 hours, After the reaction was complete, the reaction solution was concentrated under reduced pressure and replaced with toluene solution (140 mL), washed twice with saturated chloride (70 mL), and the toluene was concentrated to obtain an oily foamy solid (33.1 g, yield 93.2%).

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Abstract

The invention provides a novel preparation method for a novel anti-hepatitis C drug-daklinza. The method comprises the steps of performing condensation on 4,4'-bis(2-chloracetyl)biphenyl as a raw material and N-(methoxycarbonyl)-L-valyl-L-proline at first and then performing ring-closing on a condensation product and ammonium acetate to obtain daklinza. The method has the advantages of cheap raw materials, few reaction steps, relatively short synthetic cycle and wide applicability.

Description

technical field [0001] The invention belongs to the field of chemical medicines, and in particular relates to a new preparation method of a new anti-hepatitis C drug daclatasvir. Background technique [0002] Daclatasvir (DAKLINZA) is Bristol-Myers Squibb's latest drug for the treatment of hepatitis C. It is a hepatitis C virus (HCV) NS5A inhibitor suitable for use with Sofosbuvir for chronic HCV genotype 3 infection treat. [0003] WO2008021927, WO2009020825, WO2009020828, WO2012048421, US20090068140 and US20100158862 have reported the synthesis method of daclatasvir. So far, there are three synthesis methods of the drug, and the synthesis routes are as follows: Figure 1 to Figure 3 shown. Method 1, using p-bromoacetyl bromide as the starting material, first condensing with Boc proline, then closing the ring with ammonium acetate, and then preparing a boronate ester for coupling, finally removing Boc protection, and reacting with Moc-L -Condensation of valine to obtain d...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D207/16
CPCC07D403/14C07D207/16
Inventor 冯志勇周盛峰宋斌杨凯华陈龙
Owner SUZHOU BUYUE PHARMA CO LTD
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