Hydrogen Peroxide → trans-Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate

HRID 1507206Notes

Reaction equation

HRID 1507206 reaction equation
[BH4-].[Na+].B(F)(F)F.CC[O:9]CC.[F:12][C:13]1[CH:14]=[C:15]([C:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH:22]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20].OO.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C.O.C(O)C>[F:12][C:13]1[CH:14]=[C:15]([C@@H:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][C@H:22]2[OH:9])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]

Participants

10

Reactant 5

HCID 784Hydrogen PeroxideHCID 8000Boron trifluoride etherateHCID 14798Sodium HydroxideHCID 4311764Sodium borohydrideHCID 66865349tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate

Product 1

HCID 95566615trans-Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylateYield 186.3%

Reagents, catalysts & solvents 4

HCID 702EthanolSolventHCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a suspension of NaBH4 (0.37 g, 9.8 mmol) in tetrahydrofuran (50 mL) was added BF3.OEt2 (1.3 mL, 10 mmol) at 0° C. The reaction mixture was warmed to rt for 1 h and then re-cooled to 0° C. Tert-butyl 4-(3-fluoro-4-methoxyphenyl)-5,6-dihydropyridine-1(2H)-carboxylate (1 g, 3.3 mmol) in tetrahydrofuran (10 mL) was then added. The resulting mixture was allowed to warm to rt over 2 h. It was then re-cooled to 0° C. and water (4 mL), ethanol (4 mL), 30% H2O2 (3 mL, 29.4 mmol) and a NaOH solution (4 mL, 3.25 mmol) were added sequentially and the final mixture was heated to 65° C. for 12 h. It was cooled to room temperature, and 50 mL water and 200 mL ethyl acetate were added. The layers were separated and the aqueous layer was twice extracted with 150 mL of ethyl acetate. The combined organic layers were washed with 1N HCl followed by brine. The organic layer was dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure to obtain 2 g of crude (±)-rel-(3S,4S)-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate as a brown gum. The crude compound was purified on a 40 g silica gel column eluting with 30% ethyl acetate in petroleum ether to obtain 450 mg of the pure product as a liquid. LCMS (Method P) RT 0.98 min, m/z 252 (M+H+−t-butyl), 270 (M+H+−t-butyl, —H2O); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.42 (s, 9H) 1.46-1.58 (m, 1H) 1.61-1.71 (m, 1H) 2.32-2.48 (m, 2H) 2.62-2.77 (m, 1H) 3.34-3.47 (m, 1H) 3.80 (s, 3H) 3.91-4.01 (m, 1H) 4.05-4.14 (m, 1H) 4.82 (s, 1H) 6.96-7.02 (m, 1H) 7.03-7.13 (m, 2H).

Workup

  1. temperaturere-cooled to 0° C
  2. temperatureto warm to rt over 2 h
  3. temperatureIt was then re-cooled to 0° C.
  4. temperatureIt was cooled to room temperature
  5. customThe layers were separated
  6. extractionthe aqueous layer was twice extracted with 150 mL of ethyl acetate
  7. washThe combined organic layers were washed with 1N HCl
  8. dry with materialThe organic layer was dried over anhydrous Na2SO4
  9. filtrationfiltered
  10. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-7962730503a84bd488dd2d57fcc1929d
Source dataset
uspto-grants-2015_12
Patent number
US09221796B2

Reaction notes

Loading…