Sodium Hydroxide → CI-1029

Participants

Reaction Conditions

Reaction Steps

(S)-N-(4-{2-[5-(2-tert-Butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-2-isopropyl-6-oxo-3,6-dihydro-2H-pyran-2-yl]ethyl}phenyl)acetamide (27b) (8.90 Kg, 16.4 mol correcting for HPLC purity of 96.8%), water (43 L) and cold ethyl alcohol (76 L) were added to a reactor under an inert atmosphere. Sodium hydroxide, 50% aqueous solution (31 Kg) and water (27 L) were added and the vessel sealed. The mixture was stirred and heated to 108° C. Stirring was continued at 108-112° C. for 2.5 hours. The mixture was cooled to 65° C. and the pH adjusted to 6.9 by addition of 23.7 Kg glacial acetic acid over 40 minutes while maintaining the batch temperature between 65 and 69° C. The solution was transferred to a second reactor containing 3 Kg ADP carbon. The first reactor was rinsed with ethyl alcohol (5 L) and the rinse transferred to the second reactor. The resulting mixture was stirred at 65-67° C. for 15 minutes and then filtered with the aid of Supercel Hyflo (5 Kg) into a still. The second reactor and the filter were rinsed with a solution of water (5 L) in ethyl alcohol (25 L) and the rinse combined with the product solution in the still which was then concentrated under vacuum at 40-46° C. to remove 18-20 L solvent. Seed crystals were added to the remaining solution in the still and the mixture stirred and cooled to 0° C. and filtered. The product was washed with water (40 L) and vacuum dried overnight at 61° C. to give (S)-6-[2-(4-aminophenyl)-ethyl]-3-(2-tert-butyl-4-hydroxymethyl-5-methylphenylsulfanyl)-4-hydroxy-6-isopropyl-5,6-dihydropyran-2-one (27) (7.00 Kg, 13.4 mol, 82% yield correcting for HPLC purity, ethanol and water content): mp: 140° C. (dec); Assay (HPLC): 99.2 area%; Chiral assay (HPLC): 99.7 area % (S) isomer; Ethanol (GC): 6.7 w/w %; Water (KF): 0.32 w/w %. This material is suitable for use in the preparation of pharmaceutically acceptable salts.

Provenance & Evidence