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Method for preparing Ledipasvir and intermediates of method for preparing Ledipasvir

A process method and a technology of chemical formula, applied in the field of pharmaceutical synthesis, to achieve the effects of easy purification operation process, high product quality and yield, and easy recrystallization

Inactive Publication Date: 2015-04-22
PHARMA SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, the known preparation process is not optimal for industrial production in terms of yield, operating conditions, amount of by-products

Method used

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  • Method for preparing Ledipasvir and intermediates of method for preparing Ledipasvir
  • Method for preparing Ledipasvir and intermediates of method for preparing Ledipasvir
  • Method for preparing Ledipasvir and intermediates of method for preparing Ledipasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0064] (6S)-6-[2-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-2-oxoethyl]-5-tert-butyl-1,1-dibromo- Preparation of 5-azaspiro[2.4]heptane-5,6-dicarboxylate (4):

[0065]

[0066] Compound 2 (200 mg, 0.5 mmol) and compound 3 (180 mg, 0.5 mmol) were dissolved in acetone (5 mL), and sodium bicarbonate (130 mg, 1.5 mmol) was added. The reaction was stirred at 60°C overnight. Filter and concentrate the filtrate. The obtained concentrate was dissolved in ethyl acetate (20 mL), washed with water (15 mL) and saturated brine (15 mL), dried over sodium sulfate, and filtered. The filtrate was concentrated. The crude product was recrystallized from ethyl acetate and n-hexane (volume ratio 1:10 to 1:1) to obtain target compound 4. Yield: 280 mg (77%, 90:10 diastereomers). MS(M+1): 722. 1 H-NMR (400MHz, CDCl 3 ),δ8.15-8.03(m,2H),7.82(s,1H), 7.68(d,J=7.6Hz,1H), 7.54(d,J=7.2Hz,1H), 5.64(d,J= 16.4Hz,0.5H), 5.52(d,J=16.4Hz,0.5H), 5.32(d,J=16.4Hz,0.5H), 5.19(d,J=16.4Hz,0.5H), 4.80(d, J=7.6Hz,0.5H)...

Embodiment 2

[0068] (6S)-tert-butyl-1,1-dibromo-6-[5-(7-bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl)- Preparation of 5-azaspiro[2.4]heptane-5-carboxylate (5):

[0069]

[0070] Compound 4 (1.65 g, 2.3 mmol) was dissolved in toluene (17 mL), and ammonium acetate (1.06 g, 13.75 mmol) was added. The reaction mixture was heated to 90°C and reacted overnight for about 16 hours. TLC showed that compound 4 was completely converted. Cool to room temperature, add ethyl acetate (50 mL) to dilute, and wash with water (50 mL) and saturated brine (50 mL) respectively. Dry with anhydrous sodium sulfate and filter. The filtrate was concentrated. The obtained crude product was recrystallized with ethyl acetate and n-hexane (volume ratio 1:10 to 1:1) to obtain the target compound 5. Yield: 1.2 g (75%, 90:10 diastereomers). MS(M+1): 702. 1 H-NMR (400MHz, CDCl 3 ),δ10.47(br.1H),7.97(s,1H),7.90(d,J=8Hz,1H),7.75(s,1H),7.59(d,J=8Hz,1H),7.53(d ,J=8Hz,1H),7.42(d,J=8Hz,1H),7.32(s,1H), 5.25(d,J=8.8Hz,1H...

Embodiment 3

[0072] (1R,3S,4S)-tert-butyl-3-(6-(7-(2-((6S)-1,1-dibromo-5-(tert-butoxycarbonyl)-5-azaspiro[ 2.4)Heptane-6-yl)-1H-imidazol-5-yl)-9,9-difluoro-9H-fluoren-2-yl)-1H-benzimidazol-2-yl)-2-aza Preparation of bicyclo[2.2.1]heptane-2-carboxylate (7):

[0073]

[0074] Compound 5 (1.5g, 2.14mmol), compound 6 (1.14g, 2.57mmol), bis(di-tert-butylphenylphosphine) palladium dichloride (118mg, 0.19mmol) were dissolved in 15mL of isopropyl acetate , 1M aqueous potassium phosphate solution (7.5 mL) was added. The reaction system was replaced with nitrogen and heated to 75-80°C for 2 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (50 mL×2). The organic layers were combined, washed with saturated brine (50 mL), and dried over sodium sulfate. Filter and concentrate the filtrate. The crude product was recrystallized with ethyl acetate and n-hexane (volume ratio 1:10 to 1:1) to obtain target compound 7. Yield: 1.15 g (57.5%, 90:10 diastereomers). M...

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Abstract

The invention relates to a new preparing method of hepatitis c medicine Ledipasvir (I) and new intermediates used in the preparing method. The chemical formula of the Ledipasvir (I) is shown in the specification.

Description

Technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to a preparation method of Ledipavir and an intermediate used in the preparation method. Background technique [0002] Ledipasvir, English name: Ledipasvir, chemical name: Methyl-N-[(2S)-1-[(6S)-6-[5-[9,9-Difluoro-7-[2-[(1S ,2S,4R)-3-[(2S)-2-(methoxyc arbonylamino)-3-methylbutanoyl]-3-azabicyclo[2.2.1]heptan-2-yl]-3H-benzimidaz ol-5-yl]fluoren -2-yl]-1H-imidazol-2-yl]-5-azaspiro[2.4]heptan-5-yl]-3-methyl-1-ox obutan-2-yl]carbamate, the chemical structure is as in (I) Show. [0003] [0004] Radipavir is a hepatitis C virus NS5A protein inhibitor developed by Gilead Sciences for the treatment of hepatitis C. Phase III clinical testing was completed on February 10, 2014. Its cure rate is close to 100%. impressive. [0005] WO2013184702A discloses a preparation process of Ledipavir, as follows: [0006] [0007] However, in terms of yield, operating conditions, and the amount of by-p...

Claims

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Application Information

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IPC IPC(8): C07D403/14C07D209/54C07D403/04
CPCY02P20/55C07D403/14C07D209/54C07D403/04
Inventor 李因强林友刚蔡振伟
Owner PHARMA SHANGHAI
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