2-Methyl-3-butyn-2-ol → 9-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

HRID 575096Notes

Reaction equation

HRID 575096 reaction equation
Br[C:2]1[C:3]([F:30])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[N:19]([CH2:24][C:25]([F:28])([F:27])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:29]=1.[CH3:31][C:32]([OH:36])([C:34]#[CH:35])[CH3:33]>C(NC(C)C)(C)C.CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:30][C:3]1[C:2]([C:35]#[C:34][C:32]([OH:36])([CH3:33])[CH3:31])=[CH:29][C:6]2[C:7]3[N:8]([C:12]([C:18]4[N:19]([CH2:24][C:25]([F:27])([F:28])[F:26])[N:20]=[C:21]([CH3:23])[N:22]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=3)[CH2:9][CH2:10][O:11][C:5]=2[CH:4]=1

Participants

8

Reactant 2

HCID 82582-Methyl-3-butyn-2-olHCID 8669312810-Bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide

Product 1

HCID 866931279-fluoro-10-(3-hydroxy-3-methylbut-1-ynyl)-3-(3-methyl-1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide

Reagents, catalysts & solvents 5

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 178418476HCID 178418476, compoundCatalystHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 7912DiisopropylamineSolvent

Conditions

Temperature
85 °C

Procedure

The title compound was prepared similarly according to Procedure E. To a solution of 10-bromo-9-fluoro-3-[5-methyl-2-(2,2,2-trifluoroethyl)-1,2,4-triazol-3-yl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (200 mg, 0.41 mmol), PdCl2(PPh3)2 (0.05 equiv., 14.5 mg, 0.02 mmol) and copper (I) iodide (0.05 equiv., 4.0 mg, 0.02 mmol) in diisopropylamine (1.1 mL, 2.6 mL/mmol) and DMF (0.53 mL, 1.3 mL/mmol) was added 2-methyl-3-butyn-2-ol (2.0 equiv., 0.08 mL, 0.82 mmol). The reaction was heated to 85° C. for 30 minutes. The reaction mixture was cooled to room temperature, diluted with methylene chloride and filtered over celite. The crude was purified by reverse-phase HPLC to afford 73 mg (36.3% yield) of a fluffy white solid. 1H NMR (400 MHz, DMSO) δ 8.66 (d, J=8.5 Hz, 1H), 7.99 (br s, 1H), 7.48 (br s, 1H), 7.05 (d, J=10.5 Hz, 1H), 5.53 (s, 1H), 5.12-4.96 (m, 2H), 4.56-4.47 (m, 2H), 4.30-3.98 (m, 2H), 2.37 (s, 3H), 1.50 (s, 6H). M+H=493.2.

Workup

  1. temperatureThe reaction mixture was cooled to room temperature
  2. filtrationfiltered over celite
  3. customThe crude was purified by reverse-phase HPLC

Sources & evidence

ORD record
ord-3e3914a52a904526980f7fae502de9a5
Source dataset
uspto-grants-2015_05
Patent number
US09034866B2

Reaction notes

Loading…