Trifluoroacetic acid → HCID 58110042, compound

HRID 1803314Notes

Reaction equation

HRID 1803314 reaction equation
[CH2:1]([Mg]Br)[CH3:2].FC(F)(F)C(O)=O.[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31](=[O:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1.C(O)(C(F)(F)F)=O>C1COCC1.[Cu]I>[Cl:12][C:13]1[N:14]=[CH:15][N:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:42]=[C:28]4[CH:29]([C:35]5[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=5)[CH2:30][C:31]([CH2:1][CH3:2])([OH:34])[CH2:32][CH2:33][N:27]4[N:26]=3)=[CH:20][C:19]=2[O:43][CH3:44])[CH:17]=1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 66860172HCID 66860172, compoundHCID 178418443HCID 178418443, compound

Product 1

HCID 58110042HCID 58110042, compoundYield 13.4%

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 (8.16 mg, 0.043 mmol) in THF (1 mL), and cooled to 0° C. A solution of ethylmagnesium bromide (0.714 mL, 2.142 mmol, 3 M in Et2O) was added dropwise to the stirred solution and stirred for 20 min. To this was added 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-9-(4-fluorophenyl)-8,9-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-7(6H)-one (100 mg, 0.214 mmol, from example 137) in THF (1 mL) and the reaction was stirred at 0° C. for an additional 2 h and then slowly warmed to rt and stirred for 16 h. The reaction mixture was quenched slowly with saturated ammonium chloride, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were then washed with brine (100 mL), dried over sodium sulfate and concentrated in vacuo. The crude product was purified using reverse phase preparatory HPLC (MeOH/water/trifluoroacetic acid) to afford the titled compound (14.2 mg, 10% yield) as a TFA salt. LC-MS (M+H)+ 497.2. 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.14 (1 H, br. s.), 7.45-7.97 (2 H, m), 7.05-7.20 (6 H, m), 4.63-4.77 (2 H, m), 4.36-4.49 (1 H, m), 3.88 (3 H, s), 1.88-2.35 (4 H, m), 1.71 (2 H, q, J=7.4 Hz), 1.24-1.51 (1 H, m), 1.03 (3 H, t, J=7.5 Hz).

Workup

  1. stirringthe reaction was stirred at 0° C. for an additional 2 h
  2. temperatureslowly warmed to rt
  3. stirringstirred for 16 h
  4. customThe reaction mixture was quenched slowly with saturated ammonium chloride
  5. extractionthe aqueous layer was extracted with EtOAc (×3)
  6. washThe combined organic layers were then washed with brine (100 mL)
  7. dry with materialdried over sodium sulfate
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified

Sources & evidence

ORD record
ord-b1e32f1928394aef9e59183af2c85d3f
Source dataset
uspto-grants-2013_01
Patent number
US08349880B2

Reaction notes

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