Hydrochloric Acid → 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-methylnicotinamide

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A mixture of ethyl 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]nicotinate (2-2, 150 mg, 0.40 mmol, 1 equiv) and aqueous sodium hydroxide solution (1N, 1.0 mL), 1.0 mmol, 2.5 equiv) in a mixture of t-BuOH (2 mL) and DME (2 mL) was heated at reflux for 1 hour. The reaction mixture was allowed to cool to 23° C., and then it was acidified with aqueous 1 N hydrogen chloride solution. The precipitate was filtered, washed with water, and air dried. Oxalyl chloride (150 TL, 1.7 mmol, 4.3 equiv) followed by a catalytic amount of DMF (4 TL) was then added to a suspension of the filtered solid in dichloromethane (10 mL), and the resulting mixture was stirred for 30 minutes, then concentrated. A suspension of one-tenth of this residue (approximately 15 mg, 0.040 mmol), methylamine hydrochloride (27 mg, 0.40 mmol, 10 equiv) and N,N-diisopropylethylamine (200 TL, 1.1 mmol, 30 equiv) in dichloromethane (3 mL) was stirred at 23° C. for 30 minutes. The reaction mixture was partitioned between half-saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol (3 mL) and filtered to give 5-[6-(4-methoxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-methylnicotinamide (2-3) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 9.49 (d, 1H, J=2.2 Hz), 9.45 (d, 1H, J=2.2 Hz), 9.12 (d, 1H, J=2.2 Hz), 8.91 (s, 1H), 8.88 (t, 1H, J=2.0 Hz), 8.83 (d, 1H, J=2.0 Hz), 8.66 (br m, 1H), 7.84 (d, 2H, J=8.8 Hz), 7.10 (d, 2H, J=8.8 Hz), 3.82 (s, 3H), 2.84 (d, 3H, J=4.4 Hz).

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