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Example 1

A mixture of the chloride (25 g, 168 mmol), the amine (40 g, 168 mmol), Pd(OAc)2 (1.5 g, 6.72 mmol), (+-) BINAP (4.18 g, 6.72 mmol), and Cs2CO3 (76.7 g, 235.2 mmol) in toluene (800 mL) was stirred at 90 C under N2 for 23 h. The mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was concentrated in vacuo and purified by flash chromatography (EtOAc/petroleum ether, 1:5) to provide the product as a red solid. [22.4 g, 37%]

[Patent Reference: WO2010016005, page 91, (11.3 MB)]

Example 2

A 2 mL microwave vial under N2 was charged with the SM (13 mg, 0.023 mmol), t-butyl carbamate (5 mg, 0.043 mmol), dry powdered Cs2CO3 (15 mg, 0.046 mmol), Xanthphos (4 mg, 0.007 mmol), and Pd2(dba)3 (4 mg, 0.004 mmol). Dry THF (1.5 mL) was then added and the mixture was irradiated in a microwave reactor at 140 C for 45 min, after which time the mixture was diluted with EtOAc (30 mL) and filtered through celite. The solution was washed with brine (10 mL), dried (Na2SO4), and concentrated in vacuo. The residue was then dissolved in DCM (10 mL), treated with TFA (1 mL), and stirred at RT overnight. The resulting mixture was concentrated in vacuo and partitioned between sat aq NaHCO3 (10 mL) and DCM (40 mL). The layers were separated and the org layer was washed with brine (10 mL), dried (Na2SO4), concentrated, and purified by silica gel chromatography (0-50% EtOAc/cyclohexane) to provide 4 mg of the product as a free-base. The free-base (4 mg) was dissolved in MeOH (2 mL) and treated with a 0.49M HCl solution in MeOH (0.5 mL). The mixture was stirred at RT for 5 min and concentrated in vacuo to provide the HCl salt of the product as a pale brown solid. [4 mg, 38%]

[Patent Reference: WO2012112946, page 187, (11.2 MB)]

Example 3

To a solution of the amine (2.81 g, 10 mmol) in dioxane (45 mL) were added the chloride (2.57 g, 9.55 mmol, XantPhos (231 mg, 0.40 mmol), and t-BuONa (1.44 g, 15 mmol). Argon was bubbled through the mixture for 10 min. Pd2(dba)3 (183 mg, 0.20 mmol) was added, and argon was again bubbled through the mixture for 5 min. The reaction mixture was stirred at 100 C for 3 h, after which time it was cooled to 40 C and diluted with DCM (90 mL) and treated with Si-triamine (functionalized silica gel) overnight at RT. Celite (6 g) was added and the mixture was filtered and the solid phase rinsed with DCM (100 mL). The filtrate was concentrated to 25 mL and diluted with 1:1 EtOAc/hexane (20 mL). The resulting slurry was stirred at RT 5 h, filtered, and the filter cake washed with 1:1 EtOAc/hexane (20 mL). The solids were air dried for several hours to provide the product as an off-white solid. [4.90 g, 100%]

[Patent Reference: WO2012129344, page 126, (7.3 MB)]