Acetic Acid → 4-(6-Acetylamino-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

HRID 547898Notes

Reaction equation

HRID 547898 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(O)(=O)C.ClC(Cl)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[Na+].[Cl-]>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][CH:22]([NH:1][C:2]2[CH:7]=[N:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]

Participants

7

Reactant 5

HCID 176Acetic AcidHCID 63651,1-DichloroethaneHCID 735900tert-Butyl 4-oxopiperidine-1-carboxylateHCID 27352192-Acetamido-5-aminopyridineHCID 5049666Sodium triacetoxyborohydride

Product 1

HCID 671965384-(6-Acetylamino-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl esterYield 20%

Reagents, catalysts & solvents 1

HCID 5234Sodium ChlorideSolvent

Procedure

A mixture of N-(5-amino-pyridin-2-yl)-acetamide (2.05 g, 13.55 mmol, 1.0 equiv; commercially available) and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (2.70 g, 13.55 mmol, 1.0 equiv; commercially available) in conc. acetic acid (0.78 mL, 0.81 g, 13.55 mmol, 1.0 equiv) and dichloroethane (50 mL) was stirred at rt for 4 h. Sodium triacetoxyborohydride (3.45 g, 16.26 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 (50:1→12:1). Recrystallization from diethylether provided 0.91 g (20%) of the title compound in 90% purity according to 1H NMR. 1H NMR (400 MHz, DMSO): δ 1.12-1.28 (m, 2H), 1.40 (s, 9H), 1.86 (d, J=12.3 Hz, 2H), 2.00 (s, 3H), 2.90 (br s, 2H), 3.39 (d, J=9.1 Hz, 1H), 3.86 (d, J=12.8 Hz, 2H), 5.48 (d, J=8.4 Hz, 1H), 7.00 (d, J=8.9 Hz, 1H), 7.69 (d, J=2.7 Hz, 1H), 7.77 (d, J=8.9 Hz, 1H), 10.01 (s, 1H). MS (ESI): 335.3 [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 (50:1→12:1)
  7. customRecrystallization from diethylether

Sources & evidence

ORD record
ord-e966624812244bc987a0cc62dccf1090
Source dataset
uspto-grants-2011_05
Patent number
US07939661B2

Reaction notes

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