合成路线1

The intermediate piperidine (XXIX) has been prepared by an alternative procedure. N-Boc-3-(4-Piperidinyl)propionic acid (XXX) is converted to the mixed anhydride (XXXI), which is further reacted with N,O-dimethylhydroxylamine producing the Weinreb amide (XXXII). Condensation of (XXXII) with 4-fluorophenylmagnesium bromide (XXII) leads to ketone (XXXIII). Acidic cleavage of the N-Boc group of (XXXIII), followed by treatment of the resultant piperidine (XXXIV) with benzyl chloroformate leads to the Cbz-protected analogue (XXXV). Difluorination of ketone (XXXV) is carried out by the method of Katzenellenbogen, consisting of formation of dithioketal (XXXVI), which is then reacted with 1,3-dibromo-5,5-dimethylhydantoin (DBDMH) in the presence of HF-pyridine to afford the gem-difluoro compound (XXXVII), accompanied by an unseparable by-product. A new protecting group switch is required in order to achieve complete purification of (XXXVII), which is thus converted into the N-Boc derivative (XXVIII). Acidic cleavage of (XXVIII) as above leads to the piperidine (XXIX).