Ethylenediamine → (+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

HRID 2173912Notes

Reaction equation

HRID 2173912 reaction equation
[C:1]([C:3]1[CH:43]=[CH:42][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([C:10]([C:13]3[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][C:19]([CH3:26])=[C:18]4[C:14]=3[CH:15]=[CH:16][N:17]4C(OC(C)(C)C)=O)([OH:12])[CH3:11])=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(OC(F)F)=CC(C)=C4C=3C=CN4C(OC(C)(C)C)=O)(O)C)N(COCC[Si](C)(C)C)C=2C=1)#N.C(N)CN.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:25][CH:23]([F:24])[O:22][C:21]1[C:13]([C:10]([C:8]2[NH:7][C:6]3[CH:42]=[CH:43][C:3]([C:1]#[N:2])=[CH:4][C:5]=3[N:9]=2)([OH:12])[CH3:11])=[C:14]2[C:18](=[C:19]([CH3:26])[CH:20]=1)[NH:17][CH:16]=[CH:15]2

Participants

6

Reactant 4

HCID 3301EthylenediamineHCID 2724141Tetrabutylammonium FluorideHCID 86701450HCID 86701450, compoundHCID 86701451HCID 86701451, compound

Product 1

HCID 178429112(+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
60 °C

Procedure

To a solution of a mixture of (±)-tert-butyl 4-(1-(5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-(1-(6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-5-(difluoromethoxy)-7-methyl-1H-indole-1-carboxylate (310 mg, 0.504 mmol) in THF (5 mL) at room temperature, ethylenediamine (0.34 mL, 5.04 mmol) was added followed by TBAF (1M in THF, 5.04 mL, 5.04 mmol) and the reaction was stirred at 60° C. After 2 days the reaction was cooled to room temperature, quenched with sat. aq. WWI and extracted with EtOAc. The organic layers were combined, dried over MgSO4, filtered and concentrated. The resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes) to provide the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.51 (s, 1H) 11.12 (br. s., 1H) 8.06 (m) 7.81 (m) 7.65-7.74 (m) 7.46-7.56 (m) 7.29 (t, J=2.78 Hz, 1H) 6.72 (br. s., 1H) 6.68 (s, 1H) 6.65 (t, J=75.8 Hz, 1H) 6.22 (s, 1H) 2.45 (s, 3H) 2.09 (s, 3H). HRMS calcd. for C20H16F2N4O2 (M+H)+ 383.1314. found 383.1321.

Workup

  1. temperatureAfter 2 days the reaction was cooled to room temperature
  2. customquenched with sat. aq. WWI
  3. extractionextracted with EtOAc
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe resulting residue was purified by flash chromatography (0-100% EtOAc in heptanes)

Sources & evidence

ORD record
ord-2e5e4de2f9c24626a023028408b59196
Source dataset
uspto-grants-2015_06
Patent number
US09056874B2

Reaction notes

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