Sodium triacetoxyborohydride → 4-((3-Bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)-1-methylpiperidine

tert-Butyl 4-((3-bromo-5-(trifluoromethyl)benzyloxy)methyl)-4-(2,4-difluorophenyl)piperidine-1-carboxylate (200 mg, 0.35 mmol) was dissolved in methanol (5 mL). Hydrochloric acid (gas) was bubbled through for 20 seconds, then removed. The reaction was allowed to stir for 20 min and the solvent evaporated. The resulting solid was dissolved in dichloromethane (2 mL) and treated with formaldehyde (37 wt. % solution in water, 1.5 mL) at 0° C. After 20 min the reaction was treated with sodium triacetoxyborohydride (297 mg, 1.4 mmol). The reaction was stirred at 0° C. for 30 min and at room temperature for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol. The solvents were evaporated to afford 142 mg (85%). Mass Spec: 478.07 (MH)+. LC tr=1.885 min (Phenomenex-Luna 4.6×50 mm S10, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA Gradient Time=2 min, Flow rate=4 mL/min).

1. customHydrochloric acid (gas) was bubbled through for 20 seconds
2. customremoved
3. customthe solvent evaporated
4. dissolutionThe resulting solid was dissolved in dichloromethane (2 mL)
5. additiontreated with formaldehyde (37 wt. % solution in water, 1.5 mL) at 0° C
6. stirringThe reaction was stirred at 0° C. for 30 min and at room temperature for 1 h
7. customThe solvent was removed in vacuo
8. washAfter washing the column with several volumes of methanol
9. washthe product was eluted
10. washby washing the column with 2 M ammonia in methanol
11. customThe solvents were evaporated
12. customto afford 142 mg (85%)

ORD record

ord-bc3e67ca5bc342ebb5655eb3ac39df03

Source dataset

uspto-grants-2013_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08383821B2