Lactic Acid → HCID 66916938, compound

Participants

Reaction Conditions

Reaction Steps

(4-Bromophenyl)(piperidine-4-yl)methanone (1, 22 kg, 82.1 mol), 3-chlorophenyl boronic acid (14.1 kg, 1.1 equiv), aqueous potassium carbonate (35 kg, 3 equiv, in 66 L water), (Ph3)2PdCl2 (0.28 kg, 0.5% mol) were mixed in isopropanol (IPA, 264 L) in a 300-gallon reactor. The cloudy yellow mixture was heated to 75-85° C. until the reaction is complete. The batch was cooled to 45-55° C. and the aqueous layer was separated. The organic layer was filtered through a diatomaceous earth pad and vacuum concentrated to about 100 L to give a cloudy yellow solution, which was diluted with isopropyl acetate (IPAc, 176 L). The resulting mixture was washed with 1 N NaOH (18 L) and separated and the aqueous phase was extracted with IPAc (44 L). The combined organic layers were washed with 1 N NaOH (18 L), and then water (18 L) and transferred to a clean 300-gallon reactor followed by water (176 L) and 85% lactic acid (30 kg, 3.3 equiv). The batch was heated to 50-60° C. and stirred at this temperature for 2 h before separation. The aqueous phase containing the batch was transferred to a clean 100-gallon reactor followed by the addition of 25% (w/w) NaOH (about 44 L) while maintaining the temperature at 30-40° C. until the pH was between 10.5-11. The aqueous phase was then extracted with IPAc (2×88 L) and the resulting combined organic layers were filtered through an in-line filter into a clean 300-gallon reactor. IPAc (147 L) and IPA (20 L) were charged to the batch before being heated to 45-55° C. Aqueous 6 N hydrochloric acid (20 L) was then added via the drop tank while maintaining the batch temperature at ≦55° C. After 30 min, the heating was discontinued and the resulting slurry was cooled to 15-25° C. The batch was filtered and the filter cake washed with IPAc (2×31 L) and dried at 40-50° C. under vacuum to afford HCl salt Compound 2 (23.4 kg, 84% yield, >99% purity) as an off-white crystalline solid.

Provenance & Evidence