Sodium hydride → 1,1-Dimethylethyl 4-[(2,6-dichloro-4-pyrimidinyl)amino]-1-piperidinecarboxylate

HRID 2242968Notes

Reaction equation

HRID 2242968 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[C:20]([Cl:25])[N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:22]2[CH:21]=[C:20]([Cl:25])[N:19]=[C:18]([Cl:17])[N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 773782,4,6-TrichloropyrimidineHCID 12682914-Amino-1-Boc-piperidine

Product 1

HCID 866185411,1-Dimethylethyl 4-[(2,6-dichloro-4-pyrimidinyl)amino]-1-piperidinecarboxylateYield 57%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4,6-trichloro-pyrimidine (2.82 g, 15.4 mmol, 1.0 equiv; commercially available) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 3.1 g (57%) of the title compound. 1H NMR (400 MHz, DMSO): δ 1.24-1.33 (m, 2H), 1.40 (s, 9H), 1.78-1.85 (m, 2H), 2.86-2.96 (m, 2H), 3.49-3.97 (m, 3H), 6.47 (s, 1H). MS (ISP): 347.3 [M+H]+.

Workup

  1. additioncommercially available) was added
  2. stirringthe mixture stirred at rt for 48 h
  3. customThe solvent was removed under reduced pressure
  4. customthe crude reaction product
  5. extractionextracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL)
  6. dry with materialThe combined organic phases were dried over MgSO4
  7. concentrationconcentrated by evaporation under reduced pressure
  8. customthe crude material purified with silica column chromatography
  9. washeluting with a gradient of heptane/ethyl acetate

Sources & evidence

ORD record
ord-0578fe2a14fa46bf9e9079afc4dcf2f6
Source dataset
uspto-grants-2010_03
Patent number
US07674804B2

Reaction notes

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