Trifluoroacetic acid → HCID 54670231, compound

Participants

Reaction Conditions

Reaction Steps

(R)-BINAP (0.632 g, 1.015 mmol), diacetoxypalladium (0.053 g, 0.236 mmol) and toluene (10 mL) were combined and heated at 40° C. for 10 minutes. The reaction was removed from heat and 7-iodo-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridine and 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine as a 6:4 mixture of isomers (0.86 g, 2.355 mmol) suspended in toluene (15 mL), 2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-amine (0.557 g, 2.355 mmol), and sodium 2-methylpropan-2-olate (0.339 g, 3.53 mmol) were added. The reaction was sparged with nitrogen and heated at 100° C. over night. The reaction was cooled to room temperature and methanol (5 mL) was added. This solution was absorbed onto silica gel and chromatographed on silica gel eluting with a step gradient of ethyl acetate:hexanes (35-100%) to afford N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine as an orange foam (0.89 g, 79%). MS [M+H] found 474.4. To N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridin-7-amine and N-(2-(5-chloro-2-fluorophenyl)-6-methylpyridin-4-yl)-1-(4-methoxybenzyl)-1H-pyrazolo[4,3-b]pyridin-7-amine (0.89 g, 1.88 mmole) was added TFA (9.38 mL) and the mixture was stirred at 70° C. for 4 hours. The reaction was cooled to room temperature and concentrated to a dark amber residue. The residue was combined with dichloromethane (25 mL) followed by a saturated solution of Na2CO3 (25 mL) to give a solid. The solid was filtered, rinsed with dichloromethane and then water and then dissolved in ethyl acetate (600 mL), extracted with water and then saturated Na2CO3. The organic layer was separated, dried over sodium sulfate, and concentrated to give the title compound as a light yellow solid (0.46 g, 69%). A portion of this material (0.04 g) was purified with preparative using a Sunfire Prep 5 μm C18, 75×30 mm column HPLC eluting with a gradient of 15-25% acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA) to provide the title compound as a TFA salt. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.62 (s, 3H) 7.45-7.53 (m, 2H) 7.64 (br. s., 2H) 8.00 (d, J=4.04 Hz, 2H) 8.56 (d, J=6.06 Hz, 2H). MS [M+H] found 354.2.

Provenance & Evidence