Hydrochloric Acid → Hydrochloric Acid

Participants

Reaction Steps

To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.

Provenance & Evidence