2,2,4-Trimethylpentane → Orvepitant maleate

Participants

Reaction Conditions

Reaction Steps

IPA solution (total of 70 ml) containing (2R,4S)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide (10.01 g) and (2R,4 R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4-[(8aS)-6-oxohexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl]-1-piperidinecarboxamide (4.27 g) was diluted with IPA (23.8 ml). Maleic acid (2.85 g) in IPA (21 ml) was added, was washed in with IPA (2.8 ml) and was seeded with orvepitant maleate A (10 mg). The slurry was stirred for 1 hour. Isooctane (95 ml) was added dropwise over 15 minutes and the slurry was stirred for a further 1 hour. The mixture was cooled to 7-10° C. and was filtered, washed with a 1:1 mixture of IPA and isooctane and was dried in vacuo at about 50° C. Yield 10.88 g. 2.0 g of this was dissolved in IPA (20 ml), was heated to give a clear colourless solution, allowed to cool to about 50° C., seeded (10 mg of example 3 Form 1) and was then allowed to cool. This gave a very thick unstirrable slurry which was reheated to give a solution. Isooctane (20 ml) was added at 60° C., cooled to about 50° C. and was reseeded (10 mg example 3 Form 1). The hazy solution was stirred overnight at about 50° C. and was allowed to cool to about 20° C. After 5 hours, the solid was collected by vacuum filtration, was washed with a mixture of 1:1 of IPA and iso-octane (2×2 ml, 2×1 ml) and was dried in vacuum at 50° C. Yield 1.546 g.

Provenance & Evidence