HCID 66858604, compound → HCID 58110061, compound

HRID 1803320Notes

Reaction equation

HRID 1803320 reaction equation
[CH3:1][Mg]Br.[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[CH:22]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH2:23][C:24](=[O:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1>C1COCC1.[Cu]I>[F:4][C:5]1[CH:6]=[C:7]([NH:17][C:18]2[N:35]=[C:21]3[C@@H:22]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[CH2:23][C@:24]([CH3:1])([OH:27])[CH2:25][CH2:26][N:20]3[N:19]=2)[CH:8]=[CH:9][C:10]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1

Participants

5

Reactant 2

HCID 66858604HCID 66858604, compoundHCID 178418573HCID 178418573, compound

Product 1

HCID 58110061HCID 58110061, compoundYield 7%

Reagents, catalysts & solvents 2

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A 25 mL round bottom flask was charged with copper (I) iodide (26.2 mg, 0.138 mmol) in THF (4 mL), and cooled to 0° C. A solution of methyl magnesium bromide (4.92 mL, 6.89 mmol) was added dropwise. The mixture was stirred for 20 min. To the solution of methyl cuprate was added 2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (300 mg, 0.689 mmol) in THF (1 mL). The mixture was stirred at 0° C. for 2 h. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc. The organic layer was sequentially washed with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford (7S,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (21 mg, 7% yield, Example 155, first to elute) and (7R,9R)-2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylamino)-9-(4-fluorophenyl)-7-methyl-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[1,5-a]azepin-7-ol (43.7 mg, 11% yield, Example 154). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.71 (1 H, br. s.), 8.55 (1 H, br. s.), 7.59-7.68 (2 H, m), 7.21-7.28 (2 H, m), 7.06-7.18 (3 H, m), 4.58-4.67 (2 H, m), 4.39 (1 H, ddd, J=14.8, 5.0, 2.4 Hz), 2.50 (3 H, s), 2.17-2.26 (1 H, m), 2.10-2.16 (1 H, m), 1.99-2.07 (1 H, m), 1.89-1.98 (1 H, m), 1.44 (3 H, s). Data for Example 153: LC-MS (M+H)+ 452.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.4 Hz), 7.58-7.69 (2 H, m), 7.21 (2 H, dd, J=8.5, 5.2 Hz), 7.16 (1 H, s), 7.07-7.13 (2 H, m), 7.03 (1 H, dd, J=8.9, 2.1 Hz), 4.54 (1 H, ddd, J=14.8, 8.4, 2.1 Hz), 4.22 (1 H, ddd, J=14.9, 8.8, 1.7 Hz), 4.03-4.11 (1 H, m), 2.51 (3 H, s), 2.42 (1 H, dd, J=14.0, 10.7 Hz), 2.02-2.17 (4 H, m), 1.51 (3 H, s).

Workup

  1. stirringThe mixture was stirred at 0° C. for 2 h
  2. customThe reaction mixture was quenched with saturated ammonium chloride
  3. additiondiluted with EtOAc
  4. washThe organic layer was sequentially washed with H2O (100 mL), aq sat. NaHCO3 solution (100 mL), and brine (100 mL)
  5. dry with materialThe organic layer was dried over sodium sulfate
  6. concentrationconcentrated in vacuo
  7. customThe crude product was purified

Sources & evidence

ORD record
ord-5ff4ac62844f4003905dee82f502fd8d
Source dataset
uspto-grants-2013_01
Patent number
US08349880B2

Reaction notes

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