ARQ 092 synthesis

Yield: 4.032 g

Reaction Conditions:

with hydrogenchloride in 1,4-dioxane;dichloromethane at 20; for 2.5 h;

Steps:

1.4 Step 4 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride
Step 4 3-(3-(4-(1-aminocyclobutyl)phenyl)-5-phenyl-3H-imidazo[4,5-b]pyridin-2-yl)pyridin-2-amine hydrochloride
To a solution of tert-butyl (1-(4-(2-(2-aminopyridin-3-yl)-5-phenyl-3H-imidazo[4,5-b]pyridin-3-yl)phenyl)cyclobutyl)carbamate (4.1 g) in dichloromethane (100 mL) was slowly added 4.0 M HCl in dioxane (20 mL). The reaction was allowed to stir at room temperature for 2.5 hours. Upon completion of the reaction, ether (50 mL) was added to the suspension and the solid was filtered to give product (4.032 g) as a white solid. ¹H NMR (DMSO-d₆) 400 MHz δ: 8.94 (s, 3H), 8.47 (bs, 1H) 8.38 (d, J=8.8 Hz, 1H), 8.19-8.15 (m, 1H), 8.10-8.03 (m, 3H), 7.93-7.88 (m, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.52-7.40 (m, 3H), 6.92 (t, J=7.6 Hz, 1H), 2.70-2.57 (m, 4H), 2.29-2.20 (m, 1H), 1.90-1.80 (m, 1H); LCMS: 433 [M+H]. Calc. for C₂₉H₂₇ON₇ 3.06 hydrochloric acid 0.01 dioxane 0.03 diethylether: C59.61, H5.28, N15.36. Found C59.62, H5.05, N15.36.

References:

Arqule, Inc.;Dransfield, Daniel T.;Eathiraj, Sudharshan;Lapierre, Jean-Marc;Schwartz, Brian;Yu, Yi US2016/67260, 2016, A1 Location in patent:Paragraph 0284