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Novel synthesis method of hepatitis drug velpatasvir

A synthesis method and velpatasvir technology are applied in the field of new method synthesis of a new hepatitis C virus drug velpatasvir and a series of intermediates thereof, which can solve the problems of increasing the pressure of subsequent reaction purification, high cost and low efficiency.

Active Publication Date: 2016-07-06
山东科巢生物制药有限公司
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Problems solved by technology

[0005] WO2015191437 reported the synthesis route of intermediate 1 as the starting material, which still needs to go through 6 steps of reaction, and the efficiency is not high. Although several intermediates are not separated and continuously injected, the accumulated impurities greatly increase the purification pressure of the subsequent reaction. To obtain The cost of velpatasvir with high purity is very high

Method used

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  • Novel synthesis method of hepatitis drug velpatasvir
  • Novel synthesis method of hepatitis drug velpatasvir
  • Novel synthesis method of hepatitis drug velpatasvir

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045]

[0046] Add compound 31 (45.01g, 100mmol), compound 3 (35.04, 100mmol), N,N-dimethylformamide (225mL) into the three-necked flask, stir well, add potassium carbonate (27.64g, 200mmol), and react at room temperature 6 -8 hours. Add water (450mL) and ethyl acetate (450mL) after the reaction, separate the layers, extract the aqueous layer once with ethyl acetate (225mL), combine the organic phases and wash with water (225mL) twice, dry over anhydrous sodium sulfate, filter, and concentrate Most of the ethyl acetate was removed, petroleum ether (450 mL) was added to make a slurry, filtered, and vacuum-dried to obtain intermediate 4 (56.13 g, yield 78%). MS(ESI)m / z719[M+H] + , 1 HNMR(CDCl3,400MHz)7.95-7.80(m,2H),7.75-7.65(m,2H),7.50-7.40(m,2H),7.40-7.25(m,4H),6.20-5.90(m,1H) ,5.55-5.45(m,2H),5.34-5.22(m,1H),5.16(s,2H),4.77-4.50(m,2H),3.85-3.77(m,1H),3.65-3.61(m, 3H), 3.40-3.15(m, 6H), 2.98-2.88(m, 2H), 2.65-2.45(m, 3H), 1.98-1.83(m, 2H).

Embodiment 2

[0048]

[0049]Add compound 4 (35.98g, 50mmol) in the three-necked flask, compound 5 (15.03g, 52.5mmol), N,N-dimethylformamide (180mL), stir well and add cesium carbonate (32.58g, 100mmol), heat React at 50°C for 4-6 hours, cool to room temperature after the reaction, add saturated ammonium chloride (360mL), ethyl acetate (360mL), separate the layers, extract the water layer with ethyl acetate (180mL) once more, combine the organic phases and wash with water (180mL) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (360mL) for slurry, filtered, and vacuum-dried to give intermediate 6 (34.69g, yield 75%). MS(ESI)m / z925[M+H] + , 1 HNMR(CDCl3,400MHz)8.00-7.60(m,4H),7.58(s,1H),7.47-7.25(m,5H),6.25-5.95(m,1H),5.63-5.45(m,3H),5.30 -5.22(m,2H),5.16(s,2H),4.75-4.55(m,2H),4.35-4.15(m,1H),3.86-3.77(m,1H),3.72-3.58(m,6H) ,3.40-3.05(m,7H),2.91(m,1H),2.62-1.80(m,10H),1.45-1.35(m,3H),1.05-0.80(m,6H).

Embodiment 3

[0051]

[0052] Add compound 4 (35.98g, 50mmol) in the three-necked flask, compound 9 (12.04g, 52.5mmol), N,N-dimethylformamide (180mL), stir well and add cesium carbonate (32.58g, 100mmol), heat React at 50°C for 4-6 hours, cool to room temperature after the reaction, add saturated ammonium chloride (360mL), ethyl acetate (360mL), separate the layers, extract the water layer with ethyl acetate (180mL) once more, combine the organic phases and wash with water (180mL) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (360mL) for slurry, filtered, and vacuum-dried to give intermediate 10 (31.96g, yield 72%). MS(ESI)m / z868[M+H] + , 1 HNMR(CDCl3,400MHz)δ7.98-7.80(m,2H),7.98-7.59(m,3H),7.44(d,J=7.6Hz,2H),7.37-7.27(m,3H),6.24-5.90 (m,1H),5.65-5.45(m,3H),5.28-5.21(m,1H),5.17(s,2H),4.76-4.63(m,1H),3.90-3.70(m,1H),4.52 -4.30(m,1H),4.11-3.90(m,1H),3.85-3.77(m,1H),3.70-3.60(m,3H),3.40-3.10(m,7H),2.95-2.87(m...

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Abstract

The invention provides a novel synthesis method of hepatitis drug velpatasvir.Two intermediate compounds including a compound 4 and a compound III are utilized to synthesize the velpatasvir, the structures of the two compounds are as shown in the following formulas, wherein PG radical is t-butyloxycarboryl (Boc), carboxybenzyl (Cbz), acetyl, benzoyl or (S)-2-methoxyl acyl carbonyl amino-3-methyl-butyryl group (Moc-L-Valyl).

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a new synthesis method of velpatasvir, a new hepatitis C virus drug, and a series of intermediates thereof. Background technique [0002] Hepatitis C virus infection seriously endangers human health and is one of the main causes of post-transfusion hepatitis. At present, the infection rate of hepatitis C in the world is 3%. From this, it is estimated that about 170 million to 200 million people are infected with hepatitis C virus (HCV), and about 3.5 million people are newly infected every year. At present, research on NS5A as an antiviral target has become a hot spot in the field of anti-HCV. Velpatasvir (CAS: 1377049-84-7), as a new NS5A hepatitis C specific drug developed by Gilead, has broad market prospects. [0003] The synthesis method disclosed in PCT patent WO2012068234 starts from intermediate 2 and obtains the final product through 7 steps. T...

Claims

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Application Information

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IPC IPC(8): C07K5/065C07D491/052
CPCC07D491/052C07K5/06017
Inventor 郑旭春张一平吴怡华
Owner 山东科巢生物制药有限公司
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