Synthetic method of daclatasvir

A synthesis method and technology of daclatasvir, which can be applied in the field of medicine and chemical industry, can solve the problems of high price and the like

Inactive Publication Date: 2017-12-22
ANHUI YELLEN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The drug is a highly effective inhibitor of hepatitis C virus NS5A, but due to its high price, many patients cannot afford the high cost

Method used

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  • Synthetic method of daclatasvir
  • Synthetic method of daclatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] A preparation method of daclatasvir. Including the following steps:

[0026] 1-1 Synthesis of intermediate N-4: Add 600g of acetonitrile, 70g of bis(2-bromoacetyl)biphenyl, 23.5g of tert-butoxycarbonyl-L-proline, and 15.8g of triethylamine into a 1000ml three-neck flask, Stir the reaction at room temperature for 5 h, filter and evaporate the filtrate to dryness at 65°C to obtain intermediate N-4.

[0027] 1-2 Synthesis of intermediate N-3: Add 600 g of toluene and 32 g of ammonium acetate to 1-1, raise the temperature to 55° C. and stir for 18 hours, and a solid precipitates out. The solid obtained by filtration was dried at 70°C until the water content was less than 1.0%, to obtain intermediate N-3.

[0028] 1-3 Synthesis of intermediate N-2: Take the dried solid N-3, add 200g of toluene, 400g of methanol and 75g of 31% hydrochloric acid, heat up to 50°C for hydrolysis reaction for 10h, cool down to 20°C for 3h to crystallize, and filter to obtain The solid was vacu...

Embodiment 2

[0032] Example 1 was repeated, with the difference that 20 g of tert-butoxycarbonyl-L-proline was added in 1-1, and 102.3 g of daclatasvir was finally obtained, with a yield of 78.3%.

Embodiment 3

[0034] Repeat Example 1, the difference is that 30 g of MOC-L-valine was added in 1-4, and finally 100.7 g of daclatasvir was obtained, with a yield of 77.2%.

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Abstract

The invention discloses a synthetic method of daclatasvir. The method adopts bis(2-bromoacetyl) biphenyl and t-butyloxycarboryl-L-proline as initial raw materials, the initial raw materials are separately synthesized into a midbody N-4, N-3, N-2 and N-1 in four steps, and finally a product daclatasvir is produced. The synthetic method of the invention has the advantages of short production process, high product yield, low cost, easiness in acquiring raw materials and suitability for industrialized mass production.

Description

technical field [0001] The invention relates to a synthesis method of a high-efficiency hepatitis C virus inhibitor daclatasvir, which belongs to the field of medicine and chemical industry. Background technique [0002] Daclatasvir, English name daclatasir, also known as N,N'-[[1,1'-biphenyl]-4,4'-diyl bis[1H-imidazole-5,2-diyl-(2S) -2,1-Pyrrolidinediyl[(1S)-1-(1-methylethyl)-2-oxo-2,1-ethanediyl]]]biscarbamic acid C,C'-di Methyl ester, the molecular formula is C 40 h 50 N 8 o 6 , molecular weight 738.875, CAS registration number 1009119-64-5, pale yellow solid. [0003] Daclatavir was developed by Bristol-Myers Squibb and was approved in Europe on August 22, 2014. On July 24, 2015, Daclatasvir was approved by the US Food and Drug Administration for the treatment of hepatitis C genotype 3 infection. [0004] Daclatasvir is the first drug to have shown safety and efficacy in the treatment of genotype 3 HCV infection without the need for co-administration of interferon...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 顾世海
Owner ANHUI YELLEN PHARMA
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