2-Acetamido-5-bromo-6-methylpyridine → 4-(6-Acetylamino-2-methyl-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

HRID 547902

Reaction equation

HRID 547902 reaction equation
Br[C:2]1[CH:3]=[CH:4][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[N:6][C:7]=1[CH3:8].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].O(C(C)(C)C)[K].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[N:6][C:5]([NH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

7

Reactant 4

HCID 9545892-Acetamido-5-bromo-6-methylpyridineHCID 12682914-Amino-1-Boc-piperidineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 178418922HCID 178418922, compound

Product 1

HCID 671946624-(6-Acetylamino-2-methyl-pyridin-3-ylamino)-piperidine-1-carboxylic acid tert-butyl esterYield 6%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a degassed solution of N-(5-bromo-6-methyl-pyridin-2-yl)-acetamide (4.16 g, 18.18 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.37 g, 21.81 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (5.10 g, 45.44 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.17 g, 0.36 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.51 g, 1.45 mmol, 0.08 equiv). The reaction mixture was stirred under nitrogen at 100° C. for 16 h, cooled to rt, filtered and the filtrate concentrated by evaporation under reduced pressure. The crude material was purified with silica column chromatography eluting with a gradient of dichloromethane/methanol (10:0→9:1) and then recrystallized from diethylether to provide 0.38 g (6%) of the title compound in 90% purity according to 1H NMR. 1H NMR (250 MHz, DMSO): δ 1.31 (d, J=9.2 Hz, 2H), 1.40 (s, 9H), 1.86 (d, J=11.4 Hz, 2H), 1.99 (s, 3H), 2.24 (s, 3H), 2.86 (br s, 2H), 3.41 (br s, 1H), 3.92 (d, J=14.0 Hz, 2H), 4.51 (d, J=8.1 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 9.98 (s, 1H). MS (ESI): 349.3 [M+H]+.

Workup

  1. temperaturecooled to rt
  2. filtrationfiltered
  3. concentrationthe filtrate concentrated by evaporation under reduced pressure
  4. customThe crude material was purified with silica column chromatography
  5. washeluting with a gradient of dichloromethane/methanol (10:0→9:1)
  6. customrecrystallized from diethylether

Sources & evidence

ORD record
ord-0b55820eed184f51a89212d187fb95bd
Source dataset
uspto-grants-2011_05
Patent number
US07939661B2

Linked notes

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