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Daclatasvir synthetic method

A synthesis method and technology of daclatasvir, applied in the field of synthesis of daclatasvir, can solve the problems of complicated operation, harsh reaction conditions, long process route and the like, and achieve the effects of simple synthesis process, short synthesis period and low cost

Inactive Publication Date: 2016-12-28
SICHUAN TONGSHENG BIOTECH
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  • Abstract
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Problems solved by technology

Its defect is obvious, is not conducive to industrialized production
[0008] The current existing processes, whether using 4-bromoacetophenone or 4,4'-diacetylbiphenyl as raw materials, all have disadvantages such as long process routes, complicated operations, harsh reaction conditions, and the use of metal catalysts. factor
These unfavorable factors directly affect the quality and cost of raw materials

Method used

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preparation example Construction

[0033] This synthetic method comprises the following steps:

[0034] Step a: Use 4,4'-bis(2-haloacetyl)biphenyl as raw material, and N-(methoxycarbonyl)-L-valine-L-proline (Moc-Val-Pro) The esterification reaction takes place in the presence of an organic solvent and a base to obtain intermediate B.

[0035] In a preferred embodiment of the present invention, the above-mentioned 4,4'-bis(2-haloacetyl)biphenyl is prepared from 4,4'-diacetylbiphenyl through a halogenation reaction. The price of 4,4'-diacetylbiphenyl is cheap and easy to obtain. The preparation of 4,4'-bis(2-haloacetyl)biphenyl through the halogenation reaction can greatly reduce the raw material of daclatasvir The cost of drug production.

[0036] In a preferred embodiment of the present invention, the halogen atom in the above halogenation reaction is Cl, Br or I, and the halogen atom is preferably Br. Further, when carrying out the bromination reaction, the brominated reagent used is selected from bromine, ...

Embodiment 1

[0054] Synthesis and purification of embodiment 1 intermediate B

[0055] 10kg of 4,4'-bis(2-bromoacetyl)biphenyl was suspended in 78kg of acetonitrile, and 17.2kg of Moc-Val-Pro and 8.15kg of N,N-diisopropylethylamine ( DIPEA), keep the temperature at 20-25 degrees for 24 hours.

[0056] After the completion of the reaction was monitored by HPLC, 40 kg of water and 30 kg of ethyl acetate were added to the reaction solution. Stir and separate the organic phase. Then wash the organic phase once with 30-40 kg of 6mol / L hydrochloric acid, then wash the organic phase once with 25 kg of 10% sodium carbonate solution, and then wash the organic phase once with 10% NaCl solution. Finally, the organic phase was dried with 10 kg of anhydrous sulfuric acid, and the solvent was removed after filtration to obtain 19.25 kg of a white solid. The yield of intermediate B was 98%, and its purity was 98.5% as detected by HPLC.

[0057] Intermediate B 1 H NMR (400MHz, DMSO-d 6 ): δ8.10(d, J...

Embodiment 2

[0058] Synthesis and purification of embodiment 2 free base C

[0059] 335kg of xylene, 19.5kg of intermediate B and 38.5kg of ammonium acetate were mixed in a reaction kettle with a water separation device, so that the pH of the reaction solution was between 4-5. Subsequently, under the protection of nitrogen, it was heated to 100° C. to allow the reaction solution to reflux. When the reaction was carried out, the water produced by the reaction was continuously removed by a water separator, and the reaction was carried out for 3 hours, and the Karl Fischer value of the reaction solution was detected to be controlled within 0.05%.

[0060] After the completion of the reaction was monitored by HPLC, after the temperature of the reaction solution was lowered to 30-35° C., 500 kg of 10% sodium bicarbonate solution and 300 kg of ethyl acetate were slowly added to the reactor, stirred and mixed, and the organic phase was separated. Then, adjust the pH of the organic phase to 3-4 w...

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Abstract

The invention provides a daclatasvir synthetic method. The method comprises the following steps: taking 4,4'-di(2-halogenated acetyl)biphenyl as a raw material, performing an esterification reaction with N-(methoxycarbonyl)-L-valine-L-proline in an organic solvent under alkali existence to obtain an intermediate B; then performing a dehydrating-cyclizing reaction on the intermediate B and ammonium acetate in an xylene solution at the temperature of 100-120 DEG C to obtain free alkali C; and reacting the free alkali C and HCl to obtain a daclatasvir crude product; and finally re-crystallizing the daclatasvir crude product to obtain daclatasvir. The synthetic method has the advantages of simple synthesis route, convenient operation and simple purifying, the purity of daclatasvir obtained by the synthesis reaction is high, the yield is large, quality of the daclatasvir bulk drug is greatly increased, production cost is reduced, and the method is suitable for large industrial production.

Description

technical field [0001] The invention relates to the field of chemical medicines, in particular to a synthesis method of daclatasvir. Background technique [0002] Hepatitis C is the abbreviation of hepatitis C virus, which is an infectious disease caused by hepatitis C virus (HCV) inflammation and necrosis of the liver, which is extremely harmful to human health and life. Daclatasvir (Daclatasvir) is an anti-HCV drug developed by Bristol-Myers Squibb. The drug combined with Sofosbuvir (Sofosbuvir) in the treatment of genotype 3 hepatitis C patients without liver cirrhosis has a cure rate of 97%. . Its structure is as follows: [0003] [0004] At present, the methods for synthesizing daclatasvir mainly include: [0005] Method 1, patent WO2009020825 reports such as figure 2 Synthetic method. The method is through six steps of bromination, esterification, ring formation, deprotection, peptide bond formation, and finally salt formation and purification. According to th...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCC07D403/14
Inventor 燕青谢海陈纹锐白顺强张丽
Owner SICHUAN TONGSHENG BIOTECH
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