Method for preparing Daclatasvir

A compound and alcohol solvent technology, which is applied in the synthesis field of daclatasvir, can solve the problems of production personnel's personal health threat, non-recyclable, high toxicity of acetonitrile, etc.

Active Publication Date: 2016-12-07
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] And the method for synthesizing daclatasvir in CN 101558059A has adopted acetonitrile as reaction solvent, and acetonitrile is highly toxic and cannot be recycled, so it will cause serious pollution to the environment and pose a serious threat to the personal health of production personnel

Method used

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  • Method for preparing Daclatasvir
  • Method for preparing Daclatasvir
  • Method for preparing Daclatasvir

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preparation example Construction

[0021] The method for preparing daclatasvir compound provided by the present invention, the method uses compound 1 and compound 2 as reaction materials,

[0022]

[0023] With the participation of activators and alkaline reagents, ECA was used as a reaction catalyst, and the synthesis reaction was carried out in alcoholic solvents.

[0024] In some embodiments, the alcoholic solvent may be methanol, ethanol, isopropanol, propanol, butanol, isobutanol or ethanol-water mixture.

[0025] In other embodiments, the activator may be EDC.

[0026] In other embodiments, the alkaline reagent can be DIPEA, triethylamine, N-methylmorpholine, sodium hydroxide, potassium carbonate, sodium carbonate or potassium hydroxide.

[0027] In some embodiments, first add alcohol solvent to the reaction vessel, then control the temperature of the reaction solvent at -10°C to 35°C, add compound 1, compound 2, ECA, activator and alkaline reagent; The temperature of the reaction system is 15°C-45°C...

specific Embodiment approach

[0037] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting examples are further disclosed below to further describe the present invention in detail.

[0038] The reagents used in the present invention can be purchased from the market or can be prepared by the methods described in the present invention.

Embodiment 1

[0040]

[0041] Add 450mL ethanol and DIPEA (142.8g, 1.105mol) to the reaction flask at room temperature, and add compound 2 (150.0g, 0.263mol), compound 1 (106.0g, 0.605mol), ECA (15.0 g, 0.106 mol), EDC (116.0 g, 0.605 mol). After adding the materials, control the temperature at 35°C and react for 2h to 4h. Use thin-layer chromatography to detect the complete reaction of the raw materials. Add the reaction liquid dropwise to 2250mL water. After the dropwise addition, control the temperature at 10°C to 30°C and stir for 1h, then filter to obtain daclatasvir , 212.6g was obtained after drying, and the yield was 99.5%.

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Abstract

The invention provides a method for preparing Daclatasvir. According to the method disclosed by the invention, N-(methoxycarbonyl)-L-valine and 5,5'-(4,4'-biphenylyl)di(2-((2S)-2- pyrrolidinyl)-1hydrogen-imidazole)tetrahydrochloride are used as reaction materials, under the participation of an activating agent namely 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride and an alkaline reagent, ethyl cyanoglyoxylate-2-oxime is used as a reaction catalyst, and a reaction is performed in an alcohol solvent. The method for preparing the Daclatasvir provided by the invention is simple and convenient to operate, economic and cheap, environmental-friendly, safe, high in recovery rate and suitable for industrialized production.

Description

technical field [0001] The invention relates to the field of medicine and chemical industry, in particular to a synthetic method for preparing daclatasvir. Background technique [0002] Daclatasvir, the chemical name is ((1S)-1-(((2S)-2-(5-(4'-(2-((2S)-1-((2S)-2-((A Oxycarbonyl)amino)-3-methylbutyryl)-2-pyrrolidinyl)-1H-imidazol-5-yl)-4-biphenyl)-1H-imidazol-2-yl)-1-pyrrolidinyl Base) carbonyl) -2-methylpropyl) methyl carbamate, its structure is as follows: [0003] [0004] Daclatasvir has been disclosed in CN 101558059A, which belongs to an NS5A inhibitor and is mainly used for treating hepatitis C infection. [0005] Disclosed in the prior art CN 101558059A is a method for preparing daclatasvir compounds, the method is by sequentially adding 100mL acetonitrile (ACN), 13.69g ( 89.4mmol, 2.5 molar equivalents) hydroxybenzotriazole hydrate (HOBt), 15.07g (86mmol, 2.4 molar equivalents) N-(methoxycarbonyl)-L-valine (compound 1), 16.46g ( 85.9 mmol, 2.4 molar equivalent...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
Inventor 寇景平林碧悦程三平陈辉吴舒铭
Owner SUNSHINE LAKE PHARM CO LTD
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