Acetic Acid → Trifluoroacetic acid

Participants

Reaction Steps

N-[(5-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (40 mg, 0.059 mmol) and 1,1-dimethylethyl (1S,4S)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (11.68 mg, 0.059 mmol) were dissolved in 1,2-dichloroethane (DCE) (1 mL) in a 1 dram vial and acetic acid (3.71 μL, 0.065 mmol) was added. The mixture was stirred for 30 min and then MP-Triacetoxyborohydride (126 mg, 0.294 mmol) was added. The mixture was stirred overnight. The mixture was filtered through glass fibre filter paper and washed 2× with 0.3 mL of DCE. Trifluoroacetic acid (0.18 mL, 2.336 mmol) was added and the mixture stirred at room temperature overnight. The reaction mixture was concentrated and taken up in 1.1 mL of DMSO and purified on a Gilson HPLC eluting at 20 mL/min with a linear gradient running from 10% CH3CN/H2O (0.1% TFA) to 90% CH3CN/H2O (0.1% TFA). The desired fractions were concentrated to give the desired product as a TFA salt. This was converted to the free base by taking up the residue in EtOAc (30 mL) and 2.5 N NaOH (5 mL). The organic phase was washed with 2.5 N NaOH (3×5 mL) and then with brine (2×5 mL). The organic phase was dried over anhydrous Na2SO4, filtered and dried under 50° C. to give N-({5-chloro-3′-[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-ylmethyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (25.8 mg, 57.5%) as a white solid. LC-MS m/z 762 (M+H)+; mp 130-133° C.

Provenance & Evidence