Cesium carbonate → Tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate

Participants

Reaction Conditions

Reaction Steps

To 4-[5-(3-amino-5-methylphenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one (Intermediate XX, 59 mg, 0.19 mmol) in a scintillation vial was added dioxane (0.97 ml), cesium carbonate (126 mg, 0.39 mmol), and tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate (67 mg, 0.21 mmol). The system was purged and flushed with argon (3×) before adding XantPhos (17 mg, 0.029 mmol) and palladium(II) acetate (5 mg, 0.021 mmol). The system was purged and flushed with argon (3×) before sealing the system and heating to 100° C. overnight. The reaction was cooled to room temperature, filtered through celite and diluted with water. The organic layer was separated, dried over sodium sulfate, and concentrated under reduced pressure. Purification via reverse phase chromatography (10-80% acetonitrile in water, linear gradient) provided tert-butyl 4-{[2-({3-methyl-5-[2-(3-oxo-1,4-diazepan-1-yl)-1,3-thiazol-5-yl]phenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate. This material was treated with 2 ml of 1:1 trifluoroacetic acid:dichloromethane solution for 1 hr. The reaction was concentrated to dryness and purified by reverse phase chromatography (5-60% acetonitrile in water) to provide 16 mg (0.027 mmol, 14% yield) of 4-[5-(3-methyl-5-{[4-(piperidin-4-yloxy)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-diazepan-2-one as the TFA salt. MS APCI: [M+H]+ m/z 480.2. 1H NMR (500 MHz, dmso) δ 9.70-9.49 (m, 1H), 8.72-8.37 (m, 2H), 8.34-8.08 (m, 1H), 7.70-7.61 (m, 1H), 7.61-7.54 (m, 1H), 7.54-7.47 (m, 1H), 7.41-7.33 (m, 1H), 6.96-6.91 (m, 1H), 6.41-6.13 (m, 1H), 5.42-5.15 (m, 1H), 4.17 (s, 2H), 3.96-3.65 (m, 2H), 3.36-3.14 (m, 2H), 3.14-2.93 (m, 2H), 2.27 (s, 3H), 2.22-2.07 (m, 2H), 2.01-1.84 (m, 2H), 1.84-1.63 (m, 2H), 1.21-1.01 (m, 2H). TFA salt proton was visible. rhSyk=+++.

Provenance & Evidence