Methanol → (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate

HRID 218379Notes

Reaction equation

HRID 218379 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([CH:22]=1)[C:7]([C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[O:8].C1(C)C=CC=CC=1.CO>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:23])=[C:6]([C@H:7]([OH:8])[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:10]2)[CH:22]=1

Participants

6

Reactant 3

HCID 887MethanolHCID 1140TolueneHCID 58011513(R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate

Product 1

HCID 58011489(R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylateYield 29.4%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-15 °C

Procedure

To a solution of (R)-tert-butyl 3-(5-fluoro-2-methylbenzoyl)piperidine-1-carboxylate (10.5 g, 0.0336 mol) in anhydrous THF (150 mL) at −15° C. under nitrogen was added dropwise a solution of 1 M R-CBS-oxazaborolidine in toluene (3 mL, 3 mmol, 0.09 eq). After stirring for 1 hr at −15° C., a solution of 10 M BH3 in THF (17 mL, 0.0336 mol, 1 eq) was added dropwise. After addition, the reaction mixture was stirred for 2 hr at −15° C. Methanol (80 mL) was added dropwise carefully at −15° C. The solvent was removed under reduced pressure, the residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15) to provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1). The mixture was dissolved in a minimum volume of EtOAc, the solvent was removed on the rotary evaporator until crystals appeared. The solution was cooled to rt and stood for 1-2 h. To the solution was added hexane and then filtered, the crystals were washed with cool hexane and re-crystallized an additional two times to afford the pure isomer (R)-tert-butyl 3-((R)-(5-fluoro-2-methylphenyl)(hydroxy)methyl)piperidine-1-carboxylate (3.2 g, ee≧99%). 1H NMR (CDCl3) δ 7.1 (m, 2H), 6.85 (m, 1H), 4.7 (m, 1H), 2.3 (s, 3H), 1.45 (s, 9H), 1.25 (m, 4H).

Workup

  1. additionAfter addition
  2. stirringthe reaction mixture was stirred for 2 hr at −15° C
  3. customThe solvent was removed under reduced pressure
  4. customthe residue was purified by column chromatography on silica gel eluting with AcOEt/hexane (1:30→1:15)
  5. customto provide the light yellow oil (95 g, HPLC≧70%, ratio≧3:1)
  6. customthe solvent was removed on the rotary evaporator until crystals
  7. temperatureThe solution was cooled to rt
  8. waitstood for 1-2 h
  9. additionTo the solution was added hexane
  10. filtrationfiltered
  11. washthe crystals were washed with cool hexane
  12. customre-crystallized an additional two times

Sources & evidence

ORD record
ord-5f54b72c9dbe47ca975bf28b6b35cf87
Source dataset
uspto-grants-2012_06
Patent number
US08198453B2

Reaction notes

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