2-Acetylamino-5-bromo-3-methylpyridine → HCID 67195457, compound

HRID 547900Notes

Reaction equation

HRID 547900 reaction equation
Br[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([NH:8]C(=O)C)=[N:6][CH:7]=1.[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[CH:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:12])[CH:3]=2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]

Participants

7

Reactant 4

HCID 9019482-Acetylamino-5-bromo-3-methylpyridineHCID 12682914-Amino-1-Boc-piperidineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl2×HCID 178418922HCID 178418922, compound

Product 1

HCID 67195457HCID 67195457, compoundYield 45%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

To a degassed solution of N-(5-bromo-3-methyl-pyridin-2-yl)-acetamide (4.92 g, 21.48 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.16 g, 25.77 mmol, 1.2 equiv; commercially available) in toluene (40 mL) was added KOtert-Bu (6.03 g, 53.69 mmol, 2.5 equiv), dicyclohexyl-(2′,4′,6′-triisopropyl-biphenyl-2-yl)-phosphane (0.21 g, 0.43 mmol, 0.02 equiv; X-Phos ligand [CAS RN 564483-18-7]; commercially available from Strem Chemicals, USA) and tris(dibenzylideneacetone)dipalladium(0) (1.78 g, 1.72 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 ethyl acetate/triethylamine (10:0→4:1) and then recrystallized from ethyl acetate/heptane to provide 2.96 g (45%) of the title compound in 70% purity according to 1H NMR. 1H NMR (250 MHz, DMSO): δ 1.03-1.28 (m, 2H), 1.39 (s, 9H), 1.82 (dd, J=12.3 Hz, J=3.9 Hz, 2H), 1.98 (s, 3H), 2.72-2.98 (m, 2H), 3.11-3.29 (m, 1H), 3.84 (d, J=13.4 Hz, 2H), 4.52 (d, J=8.7 Hz, 1H), 5.60 (br s, 2H), 6.73 (d, J=2.3 Hz, 1H), 7.29 (d, J=2.7 Hz, 1H). MS (ESI): 307.2 [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 ethyl acetate/triethylamine (10:0→4:1)
  6. customrecrystallized from ethyl acetate/heptane

Sources & evidence

ORD record
ord-5c01b5b7e6f04172bf0cf2dcb37908fa
Source dataset
uspto-grants-2011_05
Patent number
US07939661B2

Reaction notes

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