Tetramethyltin → 2,4,5-Trimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide

HRID 222805Notes

Reaction equation

HRID 222805 reaction equation
[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20](Br)[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.[CH3:32]N(C)P(N(C)C)(N(C)C)=O.C[Sn](C)(C)C>[CH2-]C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Pd+2]>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([CH3:32])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 11661TetramethyltinHCID 12679HexamethylphosphoramideHCID 532387715-Bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide

Product 1

HCID 532394472,4,5-Trimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amideYield 31%

Reagents, catalysts & solvents 1

HCID 609723122784-59-4Catalyst

Conditions

Temperature
140 °C

Procedure

A mixture of 5-bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid (S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (2a, 20.0 mg, 0.0414 mmol) 07), hexamethylphosphoramide (0.500 mL, 2.87 mmol), tetramethyltin (22.8 uL, 0.166 mmol) and benzylbis(triphenylphosphine)palladium(II) chloride (1.44 mg, 0.00190 mmol) was heated at 140° C. under microwave irradiation for 90 min. It was partitioned between water (2 mL) and ethyl acetate (3×2 mL). The combined organic solution was washed with brine (1 mL), dried (MgSO4) and evaporated. The title compound (5.3 mg, yield 31%) was separated by flash chromatography on silica gel. LC-MS (m/z) 419.8 (MH+); tR=1.59 (method C).). 1H NMR (T=+70° C., 500 MHz, DMSO-d6, DMSO-d5=2.50 ppm): 1.72 (overlapping s, 3H, Me), 1.78 (overlapping s, 3H, Me), 1.74-1.84 (overlapping m, 4H), 1.88 (overlapping m, 1H), 1.99 (overlapping s, 3H, Me), 2.06 (overlapping br. m, 1H), 2.66 (m, 1H, CH of Cb), 4.93 (t, J=9.2 Hz, CH—N), 7.01 (dt, J(d)=2 Hz, J(t)=8.5 Hz, 1H), 7.11-7.20 (m, 4H), 7.34 (q (unresolved dt), J(d)=6.5 Hz, J(t)=7.7 Hz, 1H), 7.45 (t, J=7.4 Hz, 1H, para-H of Ph), 7.52 (br. t, 2H, two meta-H of Ph), 8.60 (br. d, J=8.3 Hz, 1H, NH).

Workup

  1. customIt was partitioned between water (2 mL) and ethyl acetate (3×2 mL)
  2. washThe combined organic solution was washed with brine (1 mL)
  3. dry with materialdried (MgSO4)
  4. customevaporated

Sources & evidence

ORD record
ord-7814e79f36974ebe8926651b7d4aa622
Source dataset
uspto-grants-2012_06
Patent number
US08207347B2

Reaction notes

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