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Preparation of key intermediates of ledipasvir

A Chinese-style and systematic technology, applied in organic chemistry and other directions, can solve problems such as affecting the quality of finished drugs, difficult to remove disubstituted impurities, and unstable compounds.

Active Publication Date: 2017-10-10
WISDOM PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

First of all, 4-bromo-1,2-phenylenediamine is very unstable due to its aromatic ring diamine structure, and is easily oxidized by oxygen in the air during production, packaging, transportation, and feeding, thereby bringing a large amount of impurities into the follow-up reaction, which is why 4-bromo-1,2-phenylenediamine is not easy to commercially purchase in large quantities; secondly, because 4-bromo-1,2-phenylenediamine contains two exposed amino groups, Therefore, in the condensation reaction process, disubstituted impurities (VII) will be produced, and the disubstituted impurities are not easy to remove in the post-treatment process, and will directly participate in the next step reaction, thus affecting the quality of the finished drug

Method used

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  • Preparation of key intermediates of ledipasvir
  • Preparation of key intermediates of ledipasvir
  • Preparation of key intermediates of ledipasvir

Examples

Experimental program
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Effect test

Embodiment 1

[0025] Preparation of compound (X) (X = Br): Add IV (10.0g, 0.041mol, 1.0eq) and anhydrous CH to a clean four-neck flask 2 Cl 2 (50 mL), turn on magnetic stirring (nitrogen protection). Add DMAP (20mg, 0.16mmol) and 4-bromo-2-nitroaniline (9.8g, 0.045mol), stir well after adding, add hydroxybenzotriazole (HOBT) (6.1g, 0.045mol) and 1- Ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC .HCl) (8.6 g, 0.045 mol). Stir evenly after the addition, cool the reaction system to 5°C, then slowly add triethylamine (TEA) (10.4g, 0.10mol), and keep the reaction temperature not higher than 10°C during the dropwise addition. After the dropwise addition, the reaction solution was stirred at room temperature for 20 h. After the reaction was completed, the reaction solution was added with H 2 The reaction was quenched with O (50 mL) and the organic phase was separated. CH for aqueous phase 2 Cl 2 (3×40 mL) for extraction; the organic phases were combined, washed with 1M HCl (...

Embodiment 2

[0027] Preparation of compound (X) (X = Cl): add anhydrous CH to a 250mL three-neck flask 2 Cl 2 (90 mL), methyl chloroformate (7.5 g, 0.079 mol) and IV (18.0 g, 0.075 mol, 1.0 eq). After the addition, stir until it dissolves. Slowly cool the system down to 0°C, then slowly add diisopropylethylamine (DIPEA, 10.7g, 0.083mol), and keep the system temperature below 5°C during the dropwise addition. After the dropwise addition, slowly add 4-chloro-2-nitroaniline (14.2g, 0.083mol) in CH 2 Cl 2 (90mL) solution, keep the temperature of the system not exceeding 10°C during the dropwise addition, and it takes 1h. After the dropwise addition, the system was naturally raised to room temperature and stirred for 3 h. Add H2O (100mL) to the reaction system to quench the reaction, let stand to separate the organic phase, and the aqueous phase with CH 2 Cl 2 (3 x 90 mL) extraction. The organic phases were combined and washed with 1M HCl (100 mL) and then with saturated brine, and th...

Embodiment 3

[0029] Preparation of compound (XI) (X = Br): Add DMF (60mL), 5-bromo-2-nitroaniline (8.4g, 0.039mol), IV (8.5g, 0.035mol, 1.0eq) and N-methylmorpholine (7.8g, 0.078mol). After the reaction system was cooled to 0°C with ice-brine, 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 14.6g, 0.038mol ). Subsequently, the reaction was naturally raised to room temperature for 3 h. After the reaction system was concentrated under reduced pressure, the residue was added to H 2 O (50mL) and CH 2 Cl 2 (50mL). Separate the organic phase and use CH for the aqueous phase 2 Cl 2 (3 x 50 mL) extraction. The organic phases were combined and washed with 1M HCl (30 mL) and then with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to dryness under pressure at 40°C, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, then 2 / 1) to o...

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Abstract

The invention relates to a preparation method of a ledipasvir key intermediate, and concretely relates to a preparation method of t-butyl (1R,3S,4S)-3-(5-halo-1H-benzimidazolyl-2-yl)-2-azabicyclo[2. 2. 1]heptane-carboxylate. The method has the advantages of low price and massive commercial purchasing of a raw material, and complete avoiding of generation of disubstituted impurities.

Description

technical field [0001] The present invention relates to the key intermediate of ledipasvir (1R,3S,4S)-3-(5-halo-1H-benzimidazol-2-yl)-2-azabicyclo[2.2.1]heptane- A new method for the preparation of tert-butyl 2-carboxylate. Background technique [0002] At present, the global drug market is showing huge business opportunities, which can be seen from the market performance of recently launched new drugs. The vitality of this field has also stimulated the enthusiasm of enterprises for the research and development of new drugs and the process optimization of new drug intermediates. Ledipasvir, formerly known as GS-5885, is an NS5A protease inhibitor developed by Gilead Sciences. After the completion of phase III clinical trials of ledidevir, the tablet of the fixed-dose combination of ledipasvir / sofosbuvir for the treatment of genotype I hepatitis C was included in the United States Pharmacopoeia on February 10, 2014. On October 10, 2014, the combination product ledidevir / so...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D209/52C07D403/04
CPCC07D209/52C07D403/04
Inventor 邱小龙王东辉邓贤明游正伟江中兴黄鑫胡林邹平
Owner WISDOM PHARM CO LTD
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