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PROCESS FOR THE PREPARATION OF VELPATASVIR INTERMEDIATE

IP.com Disclosure Number: IPCOM000248131D
Publication Date: 2016-Oct-28
Document File: 8 page(s) / 317K

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Abstract

This invention relates to a process for the preparation of velpatasvir intermediate

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PROCESS FOR THE PREPARATION OF VELPATASVIR INTERMEDIATE

Velpatasvir is chemically named as Methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2R)-2-[(methoxycarbonyl)amino]-2-phenylacetyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4’,3’:6,7]naphtha[1,2-d]imidazole-2-yl)-5-methyl pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate and is represented by the following chemical structure:

I 

The present disclosure provides a process for the preparation of compound of formula II, which is a key intermediate in the preparation of velpatasvir. The schematic representation of the process is as shown in scheme-I.

Scheme-I

Example 1: Preparation of Methyl (4R)-4-hydroxy-L-prolinate hydrochloride (IX)

Thionyl chloride (109 g) was added to stirred suspension of (4R)-4-hydroxy-L-proline (100 g) in methanol (400 mL) at 0°C, then heated to reflux temperature at 62 °C for 4 hours. After completion of reaction, the solvent was distilled under vacuum to get a residue and triturated with ethylacetate. The solid obtained was removed by filtration and washed with ethylacetate. The wet material was dried under vacuum to afford Methyl (4R)-4-hydroxy-L-prolinate hydrochloride (130 g). 

Example 2: Preparation of 1-tert-butyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1, 2-dicarboxylate (VIII)

Triethylamine (139 g) was added to stirred suspension of methyl (4R)-4-hydroxy-L-prolinate hydrochloride (100 g) in 300 mL of dichloromethane at 0°C and Boc anhydride was added at same temperature. The reaction mass was stirred for 4 hours at ambient temperature. After completion of reaction, 300 mL of water was added. The organic layer was washed with water 2X300 mL, distilled under vacuum to get a residue and was triturated with cyclohexane. The solid obtained was removed by filtration and washed with cyclohexane. The wet material was dried under vacuum to afford 1-tert-butyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1, 2-dicarboxylate (120 g).

Example 3: Preparation of 1-tert-butyl 2-methyl (2S, 4R)-4-{[(4-methylphenyl) sulfonyl] oxy} pyrrolidine-1, 2-dicarboxylate (VII)

Triethylamine (124 g) and 4-Dimethylaminopyridine (10 g) was added to a solution of 1-tert-butyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1, 2-dicarboxylate (100 g) in 500 mL of dichloromethane at 0°C and then stirred. p-toluenesulfonyl chloride (132 g) was added lot wise at same temperature, heated the reaction mixture to ambient temperature and stirred for 16 hours at ambient temperature. After completion of reaction, 500 mL of water was added. Separated the organic layer and washed with 1M NaOH solution 2X500 mL, then distilled the organic layer under vacuum to get a residue and was triturated with ethylacetate and hexane mixture. The solid obtained was removed by filtration and washed with hexane. The wet material was dried under vacuum to afford 1-tert-butyl 2-methyl (2S,4R)-4-{[(4-methylphenyl)sulfonyl]oxy}pyrrolidine-1,2-dicarboxylate (140 g).

Example 4: Preparation of 1-te...