[F:1][C:2]1([F:17])[C:7](O)(O)[CH2:6][CH2:5][N:4]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3]1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[C:13]([O:12][C:10]([N:4]1[CH2:5][CH2:6][CH:7]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:2]([F:17])([F:1])[CH2:3]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
A mixture of tert-butyl 3,3-difluoro-4,4-dihydroxypiperidine-1-carboxylate (1 g, 3.36 mmol), and benzylamine (539 mg, 550 μL, 5.03 mmol) in dry toluene (70 mL) was heated to reflux with dean stark apparatus for 12 hours. Further benzyl amine (20 μL, 185 μmol) was added and heated to reflux with dean stark apparatus for another 12 hours. About 50 mL of toluene were distilled off, the residue was cooled to 55° C., ethanol (35 mL) and NaBH4 (508 mg, 13.4 mmol) were added and the reaction mixture stirred at 55° C. for 2 hours. Further NaBH4 (508 mg, 13.4 mmol) was added and stirred for another hour. Further NaBH4 (508 mg, 13.4 mmol) was added. After 2 hours the reaction mixture was concentrated, then 2 N Na2CO3 solution was added and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over Na2SO4 and the solvents were evaporated. The residue was purified by flash chromatography (70 g, 0% to 100% EtOAc in hexanes). The title compound was obtained as colorless oil (875 mg, 80%).
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