Trifluoroacetic acid → HCID 78079921, compound

HRID 1423856Notes

Reaction equation

HRID 1423856 reaction equation
Br[C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1.[CH3:30][Zn]C.C(O)(C(F)(F)F)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:30][C:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH:12]3[CH2:27][CH2:26][CH2:25][C:14]4([O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:15]4)[CH2:13]3)[C:6]=2[CH:5]=[C:4]([C:28]#[N:29])[CH:3]=1

Participants

6

Reactant 3

HCID 6422Trifluoroacetic acidHCID 71116092HCID 71116092, compoundHCID 178477796HCID 178477796, compound2×

Product 1

HCID 78079921HCID 78079921, compoundYield 40.7%

Reagents, catalysts & solvents 2

HCID 178418397HCID 178418397, compoundCatalystHCID 8028TetrahydrofuranSolvent

Procedure

4-bromo-1-((3-neopentyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (0.100 g, 0.218 mmol) was dissolved in THF (1.00 mL) and treated with tetrakis(triphenylphosphine)palladium(0) (0.503 g, 0.044 mmol) followed by dimethylzinc (1.09 mL, 2.18 mmol). Addition of the dimethylzinc resulted in an exotherm with gas evolution and a color change from brownish-yellow to bright yellow. The reaction mixture was purged with nitrogen and capped. The reaction was allowed to stir at rt for 18 h. The reaction mixture turned dark brown over the course of the reaction. The reaction was quenched with sat. aq. ammonium chloride solution and diluted with EtOAc. The layers were separated, and the organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 15 min run; 50 mL/min elution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 35-69% solvent A) to afford the title compound (0.035 g, 31% yield) as the TFA salt. 1H NMR (400 MHz, DMSO-d6) δ 8.55 (br. s., 1H), 8.19 (s, 1H), 7.44 (s, 1H), 4.21 (d, J=7.03 Hz, 2H), 3.31 (dd, J=8.78, 18.57 Hz, 2H), 2.85 (s, 2H), 2.56 (s, 3H), 2.06-2.21 (m, 1H), 1.81 (d, J=11.04 Hz, 1H), 1.73 (d, J=13.80 Hz, 1H), 1.40-1.58 (m, 4H), 1.25-1.35 (m, 1H), 0.95-1.08 (m, 1H), 0.83 (s, 9H). MS (m/z) 395.2 (M+H+).

Workup

  1. customresulted in an exotherm with gas evolution
  2. customThe reaction mixture was purged with nitrogen
  3. customcapped
  4. customThe reaction mixture turned dark brown over the course of the reaction
  5. customThe reaction was quenched with sat. aq. ammonium chloride solution
  6. additiondiluted with EtOAc
  7. customThe layers were separated
  8. washthe organics were washed with brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude product was purified by reverse-phase HPLC (Sunfire Prep C18 column (30×150 mm); 15 min run; 50 mL/min elution; Solvent A: MeCN/0.1% TFA, Solvent B: water/0.1% TFA, gradient: 35-69% solvent A)

Sources & evidence

ORD record
ord-e143a7a7b4dd408a9c460831af35eceb
Source dataset
uspto-grants-2015_01
Patent number
US08927585B2

Reaction notes

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