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Preparation method of key intermediate of anti-hepatitis C drug ledipasvir

An intermediate and key technology, applied in the field of preparation of 1--2-chloroethyl ketone, can solve the problems of long reaction route, expensive raw materials, low yield, etc., and achieve the effect of mild reaction conditions and low price

Inactive Publication Date: 2019-04-26
IANGSU COLLEGE OF ENG & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The same raw materials of this scheme are more expensive, the reaction route is longer, and the yield is not high

Method used

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  • Preparation method of key intermediate of anti-hepatitis C drug ledipasvir
  • Preparation method of key intermediate of anti-hepatitis C drug ledipasvir
  • Preparation method of key intermediate of anti-hepatitis C drug ledipasvir

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0053]Synthesis (2) of embodiment 1,2-iodo-5-bromobenzoic acid

[0054] Take 2-amino-5-bromobenzoic acid (2.14g, 10mmol), NaNO 2 (0.828g, 12mmol) and NaOH (0.55g, 11mmol) were dissolved in 40ml of water, under stirring, cooled in an ice bath to 0°C, and 12ml of 6mol / L hydrochloric acid solution was added dropwise, and the drop was completed in 2h. After the hydrochloric acid was added dropwise, the reaction system continued to react at 0°C for 1h, then the reaction system was heated to 35-40°C, and the solution of KI [(KI 2.5g, 15mmol), H2SO4 (0.6ml) and water (5ml) was slowly added ], 20min to finish adding. Then the temperature of the reaction system was raised to 90° C. for 1 h. After the reaction, the reaction system was slowly cooled to room temperature, and a large amount of solid precipitated out, which was filtered and washed with water to obtain a yellow crude product. The crude product was recrystallized from 50% ethanol solution to obtain 2.87 g of a light yellow...

Embodiment 2

[0056] Synthesis (3) of embodiment 2,2-iodo-5-bromobenzoic acid methyl ester

[0057] Take 2-iodo-5-bromobenzoic acid (3.25g, 10mmol), dissolve it in 30ml of dichloromethane, add thionyl chloride (1.8g, 15mmol), 3 drops of DMF, stir at room temperature for 3h, after the reaction, reduce Remove the solvent and excess thionyl chloride under pressure, add 30ml of dichloromethane to the residue to dissolve, slowly add 20ml of methanol under ice bath, after the addition, the reaction system is warmed up to room temperature and continue to stir for 1h, after the reaction is over, under ice bath, Add 40ml of saturated aqueous sodium carbonate solution, stir for 5min, separate the liquids, wash the filtrate until neutral, dry the organic layer over anhydrous magnesium sulfate, filter, and concentrate the filtrate under reduced pressure. %. M.p.45-47°C.

[0058] 1 HNMR (400MHz, CDCl 3 ): δ7.95(s, 1H), 7.86(d, J=8Hz, 1H), 7.31(d, J=8Hz, 1H), 3.96(s, 3H); 13 C NMR (100MHz, CDCl 3 )...

Embodiment 3

[0059] The synthesis (4) of embodiment 3,5-bromo-2-phenylbenzoic acid methyl ester

[0060] Take Pd(PPh3)2Cl2 (70mg, 0.1mmol), phenylboronic acid (1.28g, 10.5mmol), sodium carbonate (2.12g, 20mmol), water 30ml and THF 30ml. Under the protection of argon, the reaction system was stirred at room temperature for 5 min, and then methyl 4-bromo-2-iodobenzoate (3.39 g, 10 mmol) was added. Then the temperature of the reaction system was raised to 80° C. for 8 h. After the reaction, the reaction system was slowly cooled to room temperature, extracted with dichloromethane (50ml*3), the organic phases were combined, washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate recovered the solvent under reduced pressure, and the residue was obtained by column chromatography. Color liquid 2.44g, yield 86%.

[0061] 1 H NMR (400MHz, CDCl 3 ): δ7.99(d, J=2.0Hz, 1H), 7.67(dd, J=8.4, 2.0Hz, 1H), 7.44–7.38(m, 3H), 7.31–7.28(m, 3H), 3.67( s,3H); 13...

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Abstract

The invention provides a preparation method of a key intermediate 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone. The method comprises the steps as follows: 2-amino-5-bromobenzoic acid is taken as a raw material, and subjected to diazotization, iodination,synthesis of 5-bromo-2-iodobenzoic acid, methylation, coupling reaction with phenylboronic acid, ester hydrolysis, acyl chlorination,intramolecular Friedel-Crafts alkylation, carbonyl reduction, iodization, fluorination and final reaction with 2-chloro-N-methoxy-N-methylacetamide to prepare the target product. The process adopts easily available starting raw materials, is low in price and free of hazardous process and has mild reaction conditions..

Description

technical field [0001] The present invention relates to a preparation method of the key intermediate of the anti-hepatitis C drug ledipasvir, that is, the preparation of 1-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-2-chloroethanone method. Background technique [0002] Ledipasvir (ledipasvir), chemical name: N-[(2S)-1-[(6S)-6-[5-[9,9-difluoro-7-[2-[(1S,2S,4R )-3-[(2S)-2-(Methoxycarbonylamino)-3-methylbutyryl]-3-azabicyclo[2.2.1]-2-heptyl]-3H-benzimidazole- 5-yl]-2-fluorenyl]-1H-2-imidazolyl]-5-azaspirane[2.4]-5-heptyl]-3-methyl-1-oxo-2-butyl]amino Methyl formate, developed by Gilead Sciences, is combined with Sovaldi (common name: Sofosbuvir), another blockbuster anti-hepatitis C product of the company. ), approved by the U.S. FDA on October 10, 2014, and approved by the European Union on November 21 of the same year. It is an all-oral, once-a-day tablet for the treatment of genotype 1 hepatitis C infection. Harvoni can be used alone or in combination with other oral agents ...

Claims

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Application Information

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IPC IPC(8): C07C45/45C07C49/813
CPCC07C17/12C07C17/354C07C45/455C07C51/09C07C51/363C07C67/08C07C67/343C07C2603/18C07C49/813C07C63/70C07C69/76C07C63/72C07C49/697C07C25/22
Inventor 冯成亮姚文瑾严宾
Owner IANGSU COLLEGE OF ENG & TECH
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