Triethylamine → 4-{4-[4-(difluoromethyl)-2-fluorobenzoyl]piperazin-1-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile

Participants

Reaction Steps

4-(Difluoromethyl)-2-fluorobenzoic acid (10.1 mg, 0.0532 mmol) was dissolved in THF (0.39 mL). Triethylamine (29.7 uL, 0.213 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (16.2 mg, 0.0426 mmol) were added, followed by 4-piperazin-1-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]butanenitrile hydrochloride (21 mg, 0.035 mmol, prepared as in Example 12, step 2). The reaction was stirred for 30 minutes. Ethyl acetate and water were added, shaken, and layers separated. The organic layer was washed successively with water, 0.1N NaOH and brine, dried over sodium sulfate and concentrated. The residue was stirred in a 1:1 mixture of DCM:TFA for 1 hour, concentrated, then stirred in a solution of methanol (1 mL) containing ethylenediamine (0.2 mL) for one hour. Purification via preparative HPLC-MS (eluting with a gradient of MeCN/H2O containing 0.15% NH4OH) afforded product as the free base (7 mg, 39%). 1H NMR (300 MHz, d6-dmso): δ 12.06 (br s, 1H), 8.81 (s, 1H), 8.67 (s, 1H), 8.36 (s, 1H), 7.60 (d, 1H), 7.57-7.43 (m, 3H), 7.07 (t, 1H), 6.97 (d, 1H), 4.98 (tt, 1H), 3.63-3.55 (m, 2H), 3.25-3.18 (m, 2H), 3.317-3.10 (m, 2H), 2.91-2.77 (m, 2H), 2.66-2.26 (m, 4H); LCMS (M+H)+: 509.2.

Provenance & Evidence