Diisopropylethylamine → N-[2-(1,1-Difluoroethyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]acetamide

HRID 1435543Notes

Reaction equation

CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:25][C:26]1[CH:27]=[C:28]([NH:40][C:41](=[O:43])[CH3:42])[CH:29]=[CH:30][C:31]=1[NH:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.[F:44][C:45]([F:50])([CH3:49])[C:46](O)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[F:44][C:45]([C:49]1[N:32]([CH2:33][CH:34]2[CH2:35][CH2:36][O:37][CH2:38][CH2:39]2)[C:31]2[CH:30]=[CH:29][C:28]([NH:40][C:41](=[O:43])[CH3:42])=[CH:27][C:26]=2[N:25]=1)([F:50])[CH3:46]

Participants

Conditions

Temperature: 80 °C

Procedure

HATU (1.58 g, 4.17 mmol) and N-{3-amino-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (1.00 g, 3.79 mmol) were added to a solution of 2,2-difluoropropanoic acid (0.43 g, 3.98 mmol) and DIPEA (0.80 mL, 4.55 mmol) in DMF (100 mL) at ambient temperature. The reaction mixture was stirred overnight and the solvent was concentrated. The intermediate was heated to 80° C. for 3 h in glacial AcOH (100 mL), and the solvent was concentrated. The crude product was recovered in DCM (300 mL), washed with saturated NaHCO3 solution (3×100 mL), brine and dried over anhydrous MgSO4. The solvent was concentrated and the product was purified by normal-phase MPLC using MeOH 5% and Acetone 10% in DCM to provide the title compound as a white solid. Yield: 1.07 g (83%); MS (ESI) (M+H)+=338.2.

Workup

concentrationthe solvent was concentrated
concentrationthe solvent was concentrated
customThe crude product was recovered in DCM (300 mL)
washwashed with saturated NaHCO3 solution (3×100 mL), brine
dry with materialdried over anhydrous MgSO4
concentrationThe solvent was concentrated
customthe product was purified by normal-phase

Sources & evidence

ORD record: ord-a8bc8d4f180b46e3804b75a17c05ea3b
Source dataset: uspto-grants-2009_11
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07615642B2

Reaction notes

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