tert-butyl N-[(piperidin-3-yl)methyl]carbamate → 1,1-Dimethylethyl N-[(3R)-3-piperidinylmethyl]carbamate

HRID 2079375Notes

Reaction equation

HRID 2079375 reaction equation
[NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:2]1.C(C(C(O)=O)(O)C(C(=O)C1C=CC(OC)=CC=1)(O)C(O)=O)(=O)C1C=CC(OC)=CC=1>CCO>[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:13])([CH3:12])[CH3:14])[CH2:2]1

Participants

4

Reactant 2

HCID 2756030tert-butyl N-[(piperidin-3-yl)methyl]carbamateHCID 18464701HCID 18464701, compound

Product 1

HCID 15018481,1-Dimethylethyl N-[(3R)-3-piperidinylmethyl]carbamateYield 25.3%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent

Procedure

To a solution of tert-butyl piperidin-3-ylmethylcarbamate (162 g, 0.758 mol) in EtOH was added (+)-dianisoyltartaric acid (316 g, 0.756 mol). The suspension was heated until clear and allowed to cool to room temperature overnight. The precipitated salt was recrystallized three times from EtOH. The salt was washed with EtOH (2×200 mL) and air-dried. Residual solvent was removed in vacuo. The salt was taken up in tert-butyl methyl ether and 10% aq. NaOH. The organic layer was separated, and the aqueous layer was extracted with tert-butyl methyl ether (3×200 mL). More product was extracted after addition of 30% aq. NaOH to the aqueous layer. The combined organic layers were washed with water and saturated aqueous NaCl solution, dried over Na2SO4, and concentrated to give (R)-tert-butyl piperidin-3-ylmethylcarbamate as a white crystalline solid (41.3 g, 0.192 mol, 25%). For ee determinations, samples of the salt were taken up in CH2Cl2 and 1 N aq. NaOH. The organic layer was washed with water, dried over Na2SO4, and filtered. A drop of 1-naphthyl isocyanate was added, and after 15 minutes a drop of morpholine was added to quench excess isocyanate. Volatiles were evaporated after another 15 minutes. The sample was dissolved in EtOH for chiral HPLC (Chiralcel OD-H; heptane/EtOH/Et2NH 90/10/0.2; 0.5 mL/min; Rt (R): 46 min, Rt (S): 57 min, Rt (N-(naphthalen-1-yl)morpholine-4-carboxamide): 64 min.

Workup

  1. temperatureThe suspension was heated until clear and
  2. customThe precipitated salt was recrystallized three times from EtOH
  3. washThe salt was washed with EtOH (2×200 mL)
  4. customair-dried
  5. customResidual solvent was removed in vacuo
  6. customThe organic layer was separated
  7. extractionthe aqueous layer was extracted with tert-butyl methyl ether (3×200 mL)
  8. extractionMore product was extracted
  9. additionafter addition of 30% aq. NaOH to the aqueous layer
  10. washThe combined organic layers were washed with water and saturated aqueous NaCl solution
  11. dry with materialdried over Na2SO4
  12. concentrationconcentrated

Sources & evidence

ORD record
ord-d27abec2ee754a73815268e5fa3a569a
Source dataset
uspto-grants-2011_04
Patent number
US07928107B2

Reaction notes

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