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The preparation method of obetasvir

A technology for obettavir and preparation steps, which is applied in the field of preparation of a hepatitis C drug obettavir, can solve the problems of expensive chiral catalysts and chiral ligands, unfavorable industrialization and the like, and achieves the goal of promoting development and raw materials Easy to obtain, simple process effect

Active Publication Date: 2018-09-04
铜陵王燕堂生物科技有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existing preparation technology requires multi-step synthesis, and involves relatively expensive chiral catalysts and chiral ligands, which is not conducive to its industrialization

Method used

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  • The preparation method of obetasvir
  • The preparation method of obetasvir
  • The preparation method of obetasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] Under nitrogen atmosphere, add (1R,3S,6S)-1-phenyl-3-(1-benzotriazolyl)-1H,6H-naphtho[1,2-e]pyrrole into a dry reaction flask Cyclo[2,1-b][1,3]oxazine (A) (4.2g, 10mmol) and 80mL of dry tetrahydrofuran were cooled to -10°C, and 4-nitrophenylmagnesium bromide (2.1 g, 40mmol) in tetrahydrofuran solution 20mL. The reaction was stirred at this temperature for 2-3 hours. The temperature was raised to 35-40° C., and the stirring reaction was continued for 3-4 hours. TLC detected that the reaction was complete. The reaction was quenched with 25 mL of saturated ammonium chloride, extracted three times with dichloromethane, the organic phases were combined, washed successively with 5% by mass sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration, the residue was recrystallized from ethanol to obtain off-white solid (R)-1-[α-(2S,5S)-bis(4-nitrophenyl)pyrrolidinyl)benzyl]-2-naphthol ( II) 4.6g, yield 84.4%, FAB-MS m / z: 54...

Embodiment 2

[0047] Add (R)-1-[α-(2S,5S)-bis(4-nitrophenyl)pyrrolidinyl)benzyl]-2-naphthol (II) (4.0g, 7.34mmol ), ceric ammonium nitrate (10.0g, 18.3mmol) and acetonitrile / water (volume ratio 2 / 1) mixed solvent 120mL, stirred at room temperature for 5-7 hours, TLC detection reaction ended. After filtering, the filtrate was adjusted to pH 8-9 with 10% sodium bicarbonate solution by mass percentage, extracted three times with dichloromethane, combined the organic phases, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure, and recrystallize the residue with ethyl acetate / n-hexane (volume ratio 1 / 1) to obtain 2.0 g of yellow solid (2S, 5S)-bis(4-nitrophenyl)pyrrolidine (III). Yield 87.0%, EI-MS m / z: 314[M+H] + .

Embodiment 3

[0049] Under a nitrogen atmosphere, (2S, 5S)-bis(4-nitrophenyl)pyrrolidine(III) (1.6g, 5mmol), palladium acetate (28mg, 0.125mmol), tert-butyl Potassium alkoxide (0.84g, 7.5mmol) and dimethyl sulfoxide 25mL, stirred at room temperature for 30 minutes, added 4-tert-butylbromobenzene (1.17g, 5.5mmol), raised the temperature to 120°C, kept the temperature for 10- After 12 hours, TLC checked that the reaction was complete. Cool down, filter, add 50 mL of dichloromethane to the filtrate, wash the organic phase three times with water, dry over anhydrous sodium sulfate, and concentrate to obtain light yellow solid (2S,5S)-1-(4-tert-butylphenyl)-2,5 - Bis(4-nitrophenyl)pyrrolidine (IV) 1.7g, yield 76.4%, EI-MSm / z: 446[M+H] + .

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Abstract

The invention discloses a preparation method of Ombitasvir. The method includes the steps of conducting a substitute open-loop reaction through chiral shift reagent (1R,3S,6S)-1-phenyl-3-(1-benzotriazolyl)-1H, 6H-naphtho[1,2-e]pyrrole[2,1-b][1,3]oxazine and Grignard reagent 4-nitrophenyl magnesium halide to obtain (R)-1-[alpha-(2S,5S)-bi(4-nitrophenyl)pyrrolidyl)benzyl]-2-naphthol, making the midbody subjected to a debenzylation reaction, a condensation reaction with bromo-4-tert-butylbenzene, and a nitroreduction reaction to obtain a midbody (2S,5S)-1-(4-tert-butylphenyl)-2,5-bi(4-aminophenyl)pyrrolidine, and making (2S,5S)-1-(4-tert-butylphenyl)-2,5-bi(4-aminophenyl)pyrrolidine subjected to an amidation reaction with side chains to prepare Ombitasvir. The preparation method is simple in process, economical, environmentally friendly and suitable for industrial production, and raw materials are easy to obtain.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of obetasvir, a drug for treating hepatitis C. Background technique [0002] Ombitasvir (ABT-267) is a small molecule NS5A inhibitor developed by AbbVie located in Chicago, Northern Illinois, USA, for the treatment of hepatitis C (HCV). In December 2014, the U.S. FDA approved AbbVie to treat chronic hepatitis C virus (HCV) genotype by fixed dose Ombitasvir / Paritaprevir / Ritonavir (25mg / 150mg / 100mg, once a day) and Dasabuvir (250mg, twice a day) 1 Infected patients, including those with cirrhosis. Since there is no standard Chinese name for Ombitasvir, the applicant transliterated it as "Ombitasvir". [0003] The chemical name of Ombitasvir (Ombitasvir, I) is: {[(2S,5S)-1-(4-tert-butylphenyl)pyrrolidine-2,5-diyl]bis[benzene-4,1 -Diylcarbamoyl-(2S)-pyrrolidine-2,1-diyl((2S)-3...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/062C07K1/06C07K1/00
Inventor 许学农
Owner 铜陵王燕堂生物科技有限公司
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