Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1) → N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide

Participants

Reaction Steps

To a solution of (6,7-difluoro-1H-benzimidazol-1-yl)acetic acid (250 mg, 1.18 mmol) prepared according to scheme 2, 2-[4-(1-aminoethyl)-3-methylphenyl]-2-methylpropanenitrile (202 mg 1.18 mmol) prepared according to scheme 15 and DMAP (285 mg, 2.35 mmol) stirred in anhydrous DMF (4.0 mL) is added HATU (448 mg, 1.18 mmol) after 18 hours of stirring, the mixture is diluted with 1N NaOH (40.0 mL) and then extracted 4 times with EtOAc (4×40.0 mL). The organic phases are combined and dried over MgSO4. The mixture is filtered and concentrated. The product is purified on a preparative LCMS system equipped with a Synergi Polar (4u) 21.2×50 mm column, mobile phase: A=water (ammonium carbonate buffer 0.01 M), B=MeCN using a short 40 to 60% B 10 min. gradient high pH method. The pure fractions are combined then extracted with ethyl acetate which is separated dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to provide the expected product N-{1-[4-(1-cyano-1-methylethyl)-2-methylphenyl]ethyl}-2-(6,7-difluoro-1H-benzimidazol-1-yl)acetamide (350 mg, 75%) as a white solid. 1H NMR (400 MHz, METHANOL-D4) d ppm 1.44 (d, J=6.84 Hz, 3H) 1.66 (s, 6H) 2.36 (s, 3H) 5.06 (d, J=16.99 Hz, 1H) 5.11 (d, J=16.99 Hz, 1H) 5.20 (q, J=7.03 Hz, 1H) 7.14 (ddd, J=11.38, 8.84, 7.52 Hz, 1H) 7.26 (d, J=2.15 Hz, 1H) 7.32 (dd, J=6.05, 2.15 Hz, 1H) 7.37-7.43 (m, 2H) 8.09 (s, 1H). MS [M+H], calcd: 397.2. found: 397.3. The enantiomers are separated on a chiral OD column, using methanol and CO2 as the mobile phase.

Provenance & Evidence