Synthetic method for Velpatasvir intermediate

A synthetic method, the technology of velpatasvir, is applied in the field of synthesis of the key core structure of the new hepatitis C virus drug velpatasvir and its series of intermediates, which can solve the problem that trimethylsilylacetylene is expensive and unsuitable for scale-up Production, low boiling point, etc.

Active Publication Date: 2016-06-29
HANGZHOU CHEMINSPIRE TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this route has few steps, the coupling yield is extremely low, only 33%. In addition, trimethylsilylacetylene is expensive and has a low boiling point. It is extremely inconvenient to use, store and transport in large quantities, and is not suitable for large-scale production.
Because the chlorine on the aromatic ring of intermediate 1 is relatively stable, the participating coupling reaction requires the use of special ligands, and the requirements for the reaction conditions are relatively harsh, and the yield is low, and the process scale-up cost is high

Method used

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  • Synthetic method for Velpatasvir intermediate
  • Synthetic method for Velpatasvir intermediate
  • Synthetic method for Velpatasvir intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049]

[0050]Add compound 6 (28.44g, 100mmol), 6-bromo-7-hydroxytetralone (24.11g, 100mmol), N,N-dimethylformamide (284mL) into the three-necked flask, stir well and add potassium carbonate ( 27.64g, 200mmol), react at room temperature for 4-6 hours, add water (284mL), ethyl acetate (284mL) after the reaction, separate the layers, extract the water layer with ethyl acetate (142mL) once more, combine the organic phases and wash with water (142mL ) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (284mL) for slurry, filtered, and vacuum-dried to give Intermediate 7 (41.79g, yield 94%).

[0051] 1 HNMR (400MHz, CDCl 3 )δ7.72(d, J=2.4Hz, 1H), 7.57(s, 1H), 7.52(s, 1H), 7.49(d, J=8.4Hz, 1H), 7.17(dd, J=8.4, 2.8 Hz,1H),5.13(s,2H),2.90(t,J=6.0Hz,2H),2.67-2.61(m,2H),2.16-2.09(m,2H)

Embodiment 2

[0053]

[0054] Add compound 7 (44.45g, 100mmol) in the there-necked flask, palladium acetate (0.92g, 3mmol), XantPhos (1.68g, 3mmol), pinacol biborate (26.66g, 105mmol), potassium carbonate (41.46g, 300mmol) and N,N-dimethylacetamide (222mL), stir to dissolve, then switch to nitrogen under vacuum, heat to 60°C for 3-4 hours, add deoxygenated water (111mL) to continue the reaction at 80°C for 4-6 hours after the reaction , cooled, the mixture was added with water (111mL), then extracted 3 times with isopropyl acetate (111mL), the combined organic phases were washed 2 times with water (222mL), dried over sodium sulfate, separated by column chromatography, and concentrated to give Intermediate 1 (17.94 g, 63%). 1 HNMR (400MHz, CDCl 3 )δ7.77(d, J=8.4Hz, 1H), 7.60(s, 1H), 7.53(s, 1H), 7.35(d, J=8.4Hz, 1H), 7.17(s, 1H), 5.06( s, 2H), 3.04-2.80 (m, 2H), 2.75-2.50 (m, 2H), 2.27-2.00 (m, 2H).

Embodiment 3

[0056]

[0057] Add compound 8 (29.20g, 100mmol), 6-bromo-7-hydroxytetralone (24.11g, 100mmol) and N,N-dimethylformamide (290mL) into a three-necked flask, stir well and add potassium carbonate ( 27.64g, 200mmol), react at room temperature for 4-6 hours, add water (290mL), ethyl acetate (290mL) after the reaction, separate the layers, extract the aqueous layer with ethyl acetate (145mL) once, combine the organic phases and wash with water (145mL ) twice, dried over anhydrous sodium sulfate, filtered, concentrated to remove most of the ethyl acetate, added petroleum ether (290mL) for slurry, filtered, and vacuum-dried to obtain intermediate 9 (40.22g, yield 89%). 1 HNMR (400MHz, CDCl 3 )δ7.88(d,J=2.4Hz,1H),7.75-7.65(m,3H),7.20-7.10(m,1H),5.17(s,2H),3.05-2.75(m,2H),2.70 -2.50(m,5H),2.15-1.95(m,2H)

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Abstract

The invention provides two synthetic methods for a Velpatasvir key intermediate 3 and further provides a new compound I and a new compound I3 for preparing the intermediate 3. Please see the structures of the three compounds in description.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to the synthesis method of the key core structure of the new hepatitis C virus drug velpatasvir and its series of intermediates. 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 (Velpatasvir), as a new type of NS5A hepatitis C specific drug developed by Gilead, has broad market prospects. [0003] [0004] Velpatasvir can basically be synthesized from the three parent ring molecules shown as starting mater...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D311/78C07C45/61C07C49/755C07C45/64C07C49/84C07C67/31C07C69/76C07C259/10
CPCC07C45/61C07C45/64C07C49/755C07C49/84C07C67/31C07C69/76C07C259/10C07D311/78
Inventor 郑旭春张一平吴怡华
Owner HANGZHOU CHEMINSPIRE TECH CO LTD
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