HCID 66860039, compound → HCID 46864434, compound

HRID 1803278Notes

Reaction equation

HRID 1803278 reaction equation
[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18](=[O:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([Mg]Br)=[CH:30][CH:29]=1.C1COCC1>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:24]=[C:17]4[C:18]([C:31]5[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=5)([OH:23])[CH2:19][CH2:20][CH2:21][CH2:22][N:16]4[N:15]=3)=[CH:9][C:8]=2[O:25][CH3:26])[CH:6]=1

Participants

4

Reactant 2

HCID 66860039HCID 66860039, compoundHCID 178420690HCID 178420690, compound2×

Product 1

HCID 46864434HCID 46864434, compoundYield 9.7%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a suspension of 2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenylamino)-7,8-dihydro-5H-[1,2,4]triazolo[1,5-a]azepin-9(6H)-one (28 mg, 0.075 mmol) in THF (0.5 mL) was added (4-fluorophenyl)magnesium bromide/THF (0.188 mL, 0.188 mmol) at −20° C. under nitrogen. After warming from −20° C. to rt, the mixture was stirred for 16 h. An additional portion of (4-fluorophenyl)magnesium bromide/THF (0.225 mL, 0.225 mmol) was added. The rxn was stirred an additional 3 h at rt, then 4 h at 60° C. The reaction mixture was concentrated in vacuo. The crude residue was dissolved in dichloromethane (2 mL). The solution was washed with water (1 mL) and then loaded onto silica gel. The crude product was purified using silica gel column chromatography (0-80% EtOAc/hexanes). The fractions containing product were combined and concentrated. The residue was repurified using reverse phase preparatory HPLC (AcCN/water/ammonium acetate) to afford the titled compound (3.4 mg, 7.25 μmol, 9.7% yield). LC-MS (M+H)+=469.1. 1H NMR (500 MHz, chloroform-d) δ ppm 1.43-1.52 (m, 1 H) 1.82-1.95 (m, 2 H) 1.99-2.10 (m, 1 H) 2.11-2.21 (m, 1 H) 2.59 (ddd, J=14.34, 6.41, 2.14 Hz, 1 H) 3.85 (s, 3 H) 3.86-3.93 (m, 1 H) 4.43 (ddd, J=11.60, 2.90, 2.59 Hz, 1 H) 6.77 (s, 1 H) 6.95 (dd, J=8.39, 2.29 Hz, 1 H) 7.02-7.09 (m, 3 H) 7.09-7.17 (m, 3 H) 7.39 (d, J=2.14 Hz, 1 H) 7.53 (d, J=1.22 Hz, 1 H).

Workup

  1. temperatureAfter warming from −20° C. to rt
  2. stirringThe rxn was stirred an additional 3 h at rt
  3. custom4 h
  4. customat 60° C
  5. concentrationThe reaction mixture was concentrated in vacuo
  6. dissolutionThe crude residue was dissolved in dichloromethane (2 mL)
  7. washThe solution was washed with water (1 mL)
  8. customThe crude product was purified
  9. additionThe fractions containing product
  10. concentrationconcentrated
  11. customThe residue was repurified

Sources & evidence

ORD record
ord-93c93aa16567459cb36d59d79669c92a
Source dataset
uspto-grants-2013_01
Patent number
US08349880B2

Reaction notes

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