Acetic Acid → (3R)-3-(3,5-Difluorophenyl)-3-methyl-1,4-diazaspiro[5,5]undecan-5-one
Reaction equation
[NH2:1][C:2]([C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=1)([CH3:15])[CH2:3][NH:4][C:5]1([C:11](OC)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.CC(O)=O.C([O-])(O)=O.[Na+]>>[F:23][C:18]1[CH:17]=[C:16]([C@@:2]2([CH3:15])[NH:1][C:11](=[O:12])[C:5]3([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]3)[NH:4][CH2:3]2)[CH:21]=[C:20]([F:22])[CH:19]=1Participants
4
Procedure
A solution of methyl 1-{[2-amino-2-(3,5-difluorophenyl)propyl]amino}cyclohexanecarboxylate from Step F (205 mg, 0.628 mmol), and AcOH (0.36 mL, 6.28 mmol) in xylenes (5 mL) was heated at 80° C. for 3 h, allowed to cool, then poured into saturated aqueous NaHCO3 (5 mL). The resulting mixture was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of EtOAc:MeOH—100:0 to 92:8, to give the racemic product. The enantiomers were separated by HPLC, using a ChiralPak AD column and eluting with hexane:EtOH:Et2NH—40:60:0.1. The first major peak to elute was (3R)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one, the title compound, and the second major peak to elute was (3S)-3-(3,5-difluorophenyl)-3-methyl-1,4-diazaspiro[5.5]undecan-5-one. MS: m/z=295 (M+1).