Patent ID: 8759542
Filing Date: 2014-06-24
Classification: C07D

Abstract:
1. A process for the preparation of (5R)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-L-prolinamide represented by Formula (A) which comprises: (a) reacting 1-(4-[2-fluorobenzyloxy]phenyl)-2-propen-1-one which is represented by Formula (B) with a compound of Formula (III) wherein R wherein the chiral ligand is selected in the group consisting of: (R)-1-[(S)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct; (S)-1-[(R)-2-(Diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine ethanol adduct; (R)-1-[(S)-2-Diphenylphosphinoferrocenyl]ethyldi-tert-butylphosphine; (S)-1-[(R)-2-Diphenylphosphinoferrocenyl]ethyldi-tert-butylphosphine; (R)-1-[(S)-2-Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine; (S)-1-[(R)-2-Dicyclohexylphosphino)ferrocenyl]ethyldicyclohexylphosphine; (R)-1-[(S)-2-Diphenylphosphino)-ferrocenyl]ethyl-di-3,5-xylylphosphine; (S)-1-[(R)-2-Diphenylphosphino)-ferrocenyl]ethyl-di-3,5-xylylphosphine; (R)-1-[(S)-2-Di-(3,5-bis(trifluoromethyl)phenyl)phosphino)-ferrocenyl]ethyldicyclohexylphosphine; (S)-1-[(R)-2-Di-(3,5-bis(trifluoromethyl)phenyl)phosphino)-ferrocenyl]ethyldicyclohexylphosphine; (R)-1-[(S)-2-Di-(4-methoxy-3,5-dimethylphenyl)phosphino)-ferrocenyl]ethyldicyclohexylphosphine; (S)-1-[(R)-2-Di-(4-methoxy-3,5-dimethylphenyl)phosphino)-ferrocenyl]ethyldicyclohexylphosphine; (R)-1-[(S)-2-Di-(3,5-bis(trifluoromethyl)phenyl)phosphino)-ferrocenyl]ethyldi-(3,5-xylyl)phosphine; (S)-1-[(R)-2-Di-(3,5-bis(trifluoromethyl)phenyl)phosphino)-ferrocenyl]ethyldi-(3,5-xylyl)phosphine; (R)-1-[(S)-2-Dicyclohexylphosphino)ferrocenyl]-ethyldi-tert-butylphosphine; (S)-1-[(R)-2-Dicyclohexylphosphino)ferrocenyl]-ethyldi-tert-butylphosphine; (R)-1-[(S)-2-Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine; (S)-1-[(R)-2-Di-(4-trifluoromethylphenyl)phosphino)ferrocenyl]ethyldi-tert-butylphosphine; (R)-1-[(S)-2-(Di-2-furylphosphino)-ferrocenyl]ethyldi-3,5-xylylphosphine; (S)-1-[(R)-2-(Di-2-furylphosphino)-ferrocenyl]ethyldi-3,5-xylylphosphine; (R)-4-Isopropyl-2-[(R)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline; (S)-4-Isopropyl-2-[(S)-2-(diphenylphosphino)ferrocen-1-yl]oxazoline; (S)-1-Diphenylphosphino-2-[(R)-[alpha]-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene; (R)-1-Diphenylphosphino-2-[(S)-[alpha]-(N,N-dimethylamino)-o-diphenylphosphinophenyl)methyl]ferrocene; (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; (S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; (R)-1-[(R)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]-ethyldiphenylphosphine; (S)-1-[(S)-2-(2′-Diphenylphosphinophenyl)ferrocenyl]ethyldiphenylphosphine; (S)-1-[(S)-2-{2′-Di(3,5-dimethyl-4-methoxyphenyl)phosphinophenyl}-ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; (R)-1-[(R)-2-{2′-Di(3,5-dimethyl-4-methoxyphenyl)phosphinophenyl}-ferrocenyl]ethyldi(bis-3,5-trifluoromethylphenyl)phosphine; ([alpha]R,[alpha]R)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(diphenylphosphino)ferrocene; ([alpha]S,[alpha]S)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis(diphenylphosphino)ferrocene; ([alpha]R,[alpha]R)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis(dicyclohexyl phosphino)-ferrocene; ([alpha]S,[alpha]S)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis(dicyclohexylphosphino)-ferrocene; ([alpha]R,[alpha]R)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis-Ni(bis-(3,5-trifluoromethyl)phenyl)-phosphino]ferrocene; ([alpha]S,[alpha]S)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis-[di(bis-(3,5-trifluoromethyl)phenyl)-phosphino]ferrocene; ([alpha]R,[alpha]R)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene; ([alpha]S,[alpha]S)-2,2′-Bis([alpha]-N,N-dimethylaminophenylmethyl)-(R,R)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene; Hydroquinidine(anthraquinone-1,4-diyl)diether; Hydroquinidine-2,5-diphenyl-4,6-pyrimidinediyl diether; (S)-(−)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl and (R)-(+)-2,2′-Bis(di-p-tolylphosphino)-1,1′-binaphthyl; (b) reacting a compound of Formula (C) in aqueous acidic media under conditions of time and temperature sufficient to produce the compound of Formula (D) after neutralization with an appropriate base (c) reacting a compound of Formula (D) with Pt/C under an atmosphere of hydrogen at elevated pressure in a suitable protic solvent at room temperature for a time sufficient to give a compound of formula (E) (d) reacting a compound of Formula (E) with a solution of NH