Acetic Acid → Tert-butyl 4-[(pyridin-3-yl)amino]piperidine-1-carboxylate

HRID 547893Notes

Reaction equation

HRID 547893 reaction equation
[NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:10])[CH3:9].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:16]1)=[O:14])([CH3:11])([CH3:9])[CH3:10]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 63651,1-DichloroethaneHCID 100093-AminopyridineHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 22499486Tert-butyl 4-[(pyridin-3-yl)amino]piperidine-1-carboxylateYield 47%

Reagents, catalysts & solvents 1

HCID 5234Sodium ChlorideSolvent

Procedure

A mixture of 3-aminopyridine (2.60 g, 27.60 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (5.50 g, 27.60 mmol, 1.0 equiv; commercially available) in conc. acetic acid (1.57 mL, 1.66 g, 27.60 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (7.02 g, 33.12 mmol, 1.2 equiv) was added in one portion and the reaction mixture stirred for an additional time period of 16 h. To the reaction mixture was added a sat. solution of NaCl (2×50 mL) and the crude extracted with ethyl acetate (3×100 mL). The combined organic phases were washed over a sat. solution of Na2CO3 (50 mL), dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→4:1) to yield 3.60 g (47%) of the title compound in 90% purity according to 1H NMR. 1H NMR (360 MHz, CDCl3): δ 1.28-1.41 (m, 2H), 1.47 (s, 9H), 2.04 (dd, J=12.8 Hz, J=2.6 Hz, 2H), 2.93 (t, J=12.3 Hz, 2H), 3.44 (br s, 1H), 3.58 (br s, 1H), 4.07 (d, J=10.7 Hz, 2H), 6.83-6.91 (m, 1H), 7.08 (dd, J=8.2 Hz, J=4.5 Hz, 1H), 7.96 (d, J=3.6 Hz, 1H), 8.02 (d, J=2.5 Hz, 1H). MS (ESI): 278.5 [M+H]+.

Workup

  1. extractionthe crude extracted with ethyl acetate (3×100 mL)
  2. washThe combined organic phases were washed over a sat. solution of Na2CO3 (50 mL)
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated by evaporation under reduced pressure
  5. customthe crude material purified with silica column chromatography
  6. washeluting with a gradient of dichloromethane/methanol (10:0→4:1)

Sources & evidence

ORD record
ord-9ac7dad730b543148ba186ab7a8a766f
Source dataset
uspto-grants-2011_05
Patent number
US07939661B2

Reaction notes

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