Methanol → (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

HRID 451995Notes

Reaction equation

HRID 451995 reaction equation
C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:10]=[C:11]([CH:27]=[C:28]([F:30])[CH:29]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13].CO>C1COCC1.CCOC(C)=O>[Cl:8][C:9]1[CH:10]=[C:11]([C@H:12]([OH:13])[C@@H:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:15]2)[CH:27]=[C:28]([F:30])[CH:29]=1

Participants

6

Reactant 3

HCID 887MethanolHCID 1140TolueneHCID 58017408(R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate

Product 1

HCID 58017388(R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylateYield 37%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a solution of 1 M R-CBS-oxazaborolidine in toluene (11 mL, 11 mmol, 0.15 eq) and 10 M BH3 in THF (7.3 mL, 73 mmol, 1.0 eq) at −15° C. under nitrogen was added dropwise a solution of (R)-tert-butyl 3-(3-chloro-5-fluorobenzoyl)piperidine-1-carboxylate (25 g, 73 mmol) in anhydrous THF (50 mL). After addition, the reaction mixture was stirred for 1 hr at rt. Methanol (100 mL) was added dropwise carefully at 0° C. The solvent was removed under reduced pressure to provide the crude product. The crude product was dissolved in EtOAc until the alcohol was just dissolved (about 5 mL/1 g), the solvent was removed on the rotary evaporator until a few crystals appeared. To the above solution was added petroleum ether (about 300 mL) under stirring, which was allowed to stir at rt for 2 hr and then filtered, the crystals were washed with petroleum ether and re-crystallized a few more times to afford pure (R)-tert-butyl 3-((R)-(3-chloro-5-fluorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (9.2 g, 37%). 1H NMR (DMSO, 400 MHz): δ 7.44 (d, 1H), 7.38 (s, 1H), 7.30 (d, 1H), 4.48 (t, 1H), 4.20 (brs, 1H), 3.98 (d, 1H), 2.73 (s, 2H), 1.70 (s, 2H), 1.48 (s, 10H), 1.36-1.39 (m, 2H).

Workup

  1. additionAfter addition
  2. customThe solvent was removed under reduced pressure
  3. customto provide the crude product
  4. dissolutionwas just dissolved (about 5 mL/1 g)
  5. customthe solvent was removed on the rotary evaporator until a few crystals
  6. additionTo the above solution was added petroleum ether (about 300 mL)
  7. stirringunder stirring
  8. stirringto stir at rt for 2 hr
  9. filtrationfiltered
  10. washthe crystals were washed with petroleum ether
  11. customre-crystallized a few more times

Sources & evidence

ORD record
ord-0754e7a0b55a441ea504201282fb0a7f
Source dataset
uspto-grants-2013_07
Patent number
US08487108B2

Reaction notes

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