Ethanol → Tert-butyl 4-(3,3-difluoropyrrolidin-1-YL)piperidine-1-carboxylate

HRID 645474Notes

Reaction equation

HRID 645474 reaction equation
Cl.[F:2][C:3]1([F:8])[CH2:7][CH2:6][NH:5][CH2:4]1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(O)C.[BH3-]C#N.[Na+]>C1COCC1.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([N:5]2[CH2:6][CH2:7][C:3]([F:8])([F:2])[CH2:4]2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]

Participants

7

Reactant 4

HCID 702EthanolHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5003444Sodium cyanoborohydrideHCID 249034823,3-Difluoropyrrolidine hydrochloride

Product 1

HCID 53419023Tert-butyl 4-(3,3-difluoropyrrolidin-1-YL)piperidine-1-carboxylate

Reagents, catalysts & solvents 2

HCID 178460666HCID 178460666, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 3,3-difluoro-pyrrolidine hydrochloride (2.02 mmol), 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.02 mmol) and Ti(OiPr)4 (2.42 mmol) in THF is stirred at room temperature for 1 h. To the resulting mixture are added ethanol (3 mL) and NaBH3CN (1.21 mmol). After stirring for 17 h, the reaction is quenched by the addition of sat. aq. NaHCO3 and the resulting precipitate is filtered out. After the filtrate is diluted with AcOEt, the mixture is washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography to give 4-(3,3-difluoro-pyrrolidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester; 1H NMR (CDCl)3 δ: 1.34-1.52 (2H, m), 1.45 (9H, s), 1.79 (2H, bd), 2.19-2.33 (3H, m), 2.78 (2H, dd), 2.83 (2H, dd), 2.95 (2H, dd), 4.00 (2H, bs).

Workup

  1. stirringAfter stirring for 17 h
  2. customthe reaction is quenched by the addition of sat. aq. NaHCO3
  3. filtrationthe resulting precipitate is filtered out
  4. additionAfter the filtrate is diluted with AcOEt
  5. washthe mixture is washed with brine
  6. dry with materialdried over MgSO4
  7. concentrationconcentrated in vacuo
  8. customThe residue is purified by silica gel column chromatography

Sources & evidence

ORD record
ord-7e2648ac1c024b558a58fa40ce064eee
Source dataset
uspto-grants-2010_04
Patent number
US07704996B2

Reaction notes

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