Methanol → HCID 67053419, compound

Participants

Reaction Steps

2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide (50.0 g, 93.5 wt. %) and 200 mL of anisole are charged to a reactor and agitation at ˜150 rpm initiated to obtain an off-white slurry. 100 mL of 85% aqueous H3PO4 was added and the reaction mixture heated to 100° C.±5° C. After 1.0 hour, the reaction was checked by HPLC after preparing a sample by adding a ˜0.1 mL reaction mixture aliquot to 10 mL of MeOH. If the area % of 2-((R)-4-((5-(ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluoro-N—((S)-1-(4-methoxyphenyl)ethyl)benzamide is <0.5%, proceed; if it is not, age another 30 minutes at 100° C.±5° C. and repeat the HPLC check. The reaction mixture was cooled to 65° C.-70° C. and 200.0 mL of water was added while maintaining the reaction mixture at 65° C.-70° C. A rough slurry was obtained and 150 mL of MEK was added while maintaining the reaction mixture at 65° C.-70° C. The reaction mixture became a smooth slurry, which was held at 65° C.-70° C. for 30 minutes, then ramped to 20° C.-25° C. over no less than 3 hours. The reaction mixture was then held at 20° C.-25° C. for 3 to 4 hours. The solid was filtered, washed with 150 mL of water and then 150 mL of a mixture of MEK/heptane (1:2 v/v), and transferred to a vacuum oven and dried at 65° C.-70° C. with a nitrogen sweep until KF<0.5%. (R)-2-(4-((5-(Ethylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl)methyl)-5,5,5-trifluoro-4-hydroxy-2-methylpentan-2-yl)-5-fluorobenzamide anisole solvate was obtained as a white-yellow solid (44.1 g, 92.1% yield, HPLC: 98.0 area % (220 nm)).

Provenance & Evidence