Preparation method for novel NS5A inhibitor medicine

A technology for inhibitors and drugs, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of difficult solidification and purification of intermediates, long synthesis process routes, and complicated preparation processes, and achieves short process routes, simple preparation processes, The effect of high reaction yield

Inactive Publication Date: 2015-09-23
NANTONG CHANGYOO PHARMATECH CO LTD
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Problems solved by technology

[0007] In order to solve the existing problems in the preparation of ledipasvir, such as long synthetic process route, cumbersome preparation process, difficult solidification and purification treatment of intermediates, and yield of synthetic route, the present invention provides a new, short synthetic process route, intermediate Preparation method of ledipasvir with easy control of body weight and high reaction yield

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  • Preparation method for novel NS5A inhibitor medicine
  • Preparation method for novel NS5A inhibitor medicine
  • Preparation method for novel NS5A inhibitor medicine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] (1). Preparation of intermediate L1:

[0038] In the reaction flask, add 40g of (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate Acetate tert-butyl ester, 38.2g diboronic acid pinacol ester, 4g potassium propionate and 500mL isopropyl acetate, stir, cool down to 10-15°C, stir, add 2g tetrakistriphenylphosphopalladium, and then under nitrogen protection The temperature was raised to 60-65° C. for the reaction, and the reaction was monitored by TLC. After the reaction is complete, add 300mL of water, stir, let stand for liquid separation, extract the aqueous layer twice with 150mL isopropyl acetate, combine the organic phases, wash with 300mL saturated sodium chloride solution, dry over anhydrous sodium sulfate, filter with suction, and evaporate to dryness , to obtain 38.4g solid product, yield 85.6%.

[0039] Preparation of intermediate L2:

[0040] Add 35g of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone, 49g o...

Embodiment 2

[0050] (1). Preparation of intermediate L1:

[0051] In the reaction flask, add 50g of (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate Acetate tert-butyl ester, 48.7g biboronic acid pinacol ester, 5g potassium acetate and 800mL ethyl acetate, stir, cool down to 10-15°C, stir, add 3g palladium chloride, and then raise the temperature to 60-65°C under nitrogen protection The reaction was carried out at ℃, and the reaction was monitored by TLC. After completion of the reaction, add 500 mL of water, stir, let stand for liquid separation, extract the aqueous layer twice with 300 mL of ethyl acetate, combine the organic phases, wash with 300 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, suction filter, and evaporate to dryness. Obtained 48.7g of solid product, yield 86.5%.

[0052] Preparation of intermediate L2:

[0053] Add 43.8g of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone, 61.3g of (6S...

Embodiment 3

[0063] (1). Preparation of intermediate L1:

[0064] In the reaction flask, add 30g of (1R,3S,4S)-3-(6-bromo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate Acetate tert-butyl ester, 30.5g diboronic acid pinacol ester, 3g sodium propionate and 400mL DMF, stir, cool down to 10-15°C, stir, add 2g bistriphenylphosphine palladium dichloride, and then under nitrogen protection The temperature was raised to 60-65° C. for the reaction, and the reaction was monitored by TLC. After completion of the reaction, add 500 mL of water, stir, let stand for liquid separation, extract the aqueous layer three times with 200 mL of ethyl acetate, combine the organic phases, wash with 200 mL of saturated sodium chloride solution, dry over anhydrous sodium sulfate, suction filter, and evaporate to dryness to obtain 29.7g of solid product, yield 87.9%.

[0065] Preparation of intermediate L2:

[0066] Add 26.3g of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone, 36...

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Abstract

The invention discloses a preparation method for novel NS5A inhibitor medicine. The preparation method includes the steps that step1, (1R, 3S, 4S)-3-(6-bromine-1H-benzimidazole-2-base)-2- azabicyalo (2.2.1) heptane-2-carboxylic acid tert-butyl ester serves as raw materials and reacts with bis (pinacolato) diboron under the action of a metal catalyst to obtain an intermediate L1; 1-(7-bromine-9,9-difluoro-9H-fluorene-2-base)-2-phenacyl chloride and (6S)-5-azaspiro (2.4) heptane-5,6-dicarboxylic acid 5-benzyl ester react under the action of a base to obtain an intermediate L2; the intermediate L1 and the intermediate L2 react under the action of a metal catalyst to obtain an intermediate L3; the intermediate L3 and an amine reagent react in a cyclization mode to obtain an intermediate L4; a protecting group is removed from the intermediate L4 under the action of methanesulfonic acid, so that an intermediate L5 in a mesylate form is obtained; the intermediate L5 and MOC valine react under the action of a condensing agent to obtain a Ledipasvir finished product. The process route is short, the preparation technology is simple, the intermediates are easy to control, and the reaction yield is high.

Description

technical field [0001] The invention relates to a preparation method of an NS5A inhibitor drug, in particular to a preparation method of Radipavir. Background technique [0002] Reddy Pavel is one of the components of Gilead's anti-hepatitis C heavyweight product Harvoni's compound combination, an NS5A inhibitor inhibitor. Harvoni is an anti-HCV drug developed by Gilead in the United States. It is the first all-oral anti-HCV regimen approved for the treatment of genotype 1 hepatitis C infection that does not require combination of interferon or ribavirin. Harvoni can be used alone or in combination with other oral agents such as ribavirin. Harvoni has been granted "Priority Review" by the FDA and is also the seventh drug to receive "Breakthrough Drug" qualification. Ledi Pawei, Ledipasvir, an NS5A inhibitor inhibitor, the chemical structure is shown in formula 1, and the chemical name is: [0003] Methyl N -[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S,2S,4R)-3-[(2S)-2-(met...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/14
CPCY02P20/55C07D403/14
Inventor 李泽标胡海洋黄虎祁晓庆顾文超林燕峰
Owner NANTONG CHANGYOO PHARMATECH CO LTD
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