Trifluoroacetic acid → 4-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-5-oxo-7-(propan-2-yloxy)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carbonitrile

HRID 577559Notes

Reaction equation

HRID 577559 reaction equation
C([O:8][C:9]1[C:14]([CH2:15][N:16]2[C:22](=[O:23])[C:21]3[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27](Br)[C:20]=3[O:19][CH2:18][CH2:17]2)=[C:13]([CH3:34])[CH:12]=[C:11]([CH3:35])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:43][N:44](C)C(=O)C>O>[CH3:34][C:13]1[CH:12]=[C:11]([CH3:35])[NH:10][C:9](=[O:8])[C:14]=1[CH2:15][N:16]1[C:22](=[O:23])[C:21]2[C:24]([CH3:33])=[C:25]([O:29][CH:30]([CH3:32])[CH3:31])[CH:26]=[C:27]([C:43]#[N:44])[C:20]=2[O:19][CH2:18][CH2:17]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 31374DimethylacetamideHCID 867237854-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one

Product 1

HCID 867237864-[(4,6-Dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-6-methyl-5-oxo-7-(propan-2-yloxy)-2,3,4,5-tetrahydro-1,4-benzoxazepine-9-carbonitrileYield 19%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Conditions

Temperature
120 °C

Procedure

To a solution of 4-((2-(benzyloxy)-4,6-dimethylpyridin-3-yl)methyl)-9-bromo-7-isopropoxy-6-methyl-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (116 g, 98 mg, 0.18 mmol) in N,N-dimethylacetamide (2 mL) was added cuprous cyanide (50 mg, 0.55 mmol). The reaction mixture was heated at 120° C. in a sealed tube for 20 hours, cooled to room temperature then additional cuprous cyanide (25 mg, 0.26 mmol) was added and the reaction was heated at 150° C. in a sealed tube for 5 hours. The reaction was cooled to room temperature, diluted with water (5 mL) and extracted with methyl tert-butyl ether (2×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate and concentrated under vacuum. The crude residue was taken up in dichloromethane (0.5 mL) and trifluoroacetic acid (0.5 mL, 2 mmol) and stirred at room temperature overnight then concentrated under vacuum. The residue was purified by reverse phase HPLC to provide the title compound (Example 116, 13 mg, 19% yield). 1H NMR (700 MHz, DMSO-d6) δ 7.47 (s, 1H), 5.93 (br. s., 1H), 4.58-4.69 (m, 3H), 4.12 (br. s., 2H), 2.19 (d, J=12.91 Hz, 6H), 2.14 (s, 3H), 1.26 (d, J=6.02 Hz, 6H): MS 396 [M+H].

Workup

  1. temperaturecooled to room temperature
  2. temperaturethe reaction was heated at 150° C. in a sealed tube for 5 hours
  3. temperatureThe reaction was cooled to room temperature
  4. extractionextracted with methyl tert-butyl ether (2×5 mL)
  5. washThe combined organic layers were washed with brine (5 mL)
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated under vacuum
  8. concentrationthen concentrated under vacuum
  9. customThe residue was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-a5ede1a6b6974befa8fa8fd70a73f209
Source dataset
uspto-grants-2015_05
Patent number
US09040515B2

Reaction notes

Loading…