Suzuki reaction

To a solution of [(R)-5-(3-bromo-5-trifluoromethyl-benzenesulfonylamino)-5,6,7,8- tetrahydro-naphthalen-1-yloxy]-acetic acid tert-butyl ester (100 mg, 0.177 mmol) in N,N-dimethylformamide (1 ml) in a Biotage microwave vial were successively added tetrakis(triphenylphosphine)palladium(0) (21 mg, 0.0177 mmol), potassium tert-butoxide (40 mg, 0.35 mmol) and isopropenyl boronic acid pinacol ester (0.05 ml, 0.27 mmol). The resulting mixture was heated in a microwave at 130 °C for 15 minutes. After being cooled to room temperature, the reaction mixture was partitioned between 0.1 N hydrochloric acid and dichloromethane. The organic phase was extracted with water. The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (RediSep® Flash column from Teledyne Isco, Inc., 230-400 mesh, 0-10% methanol in dichloromethane) gave [(R)-5-(3- isopropenyl-5-thfluoromethyl-benzenesulfonylamino)-5,6,7,8-tetrahydro-naphthalen- 1-yloxy]-acetic acid te/t-butyl ester (50 mg, 54%). 


Patent reference: WO2010018112 (Roche)

.To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (140 mg, 0.593 mmol) in ethanol (10 mL), (6-bromo-2-nitro-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester (151 mg, 0.455 mmol), Pd(PPh3)2Cl2 (42 mg, 0.059 mmol) and Et3N (127 μL, 0.909 mmol) were added. The reaction mixture was stirred at 100°C for 30 minutes in a microwave reactor. Volatiles were removed under reduced pressure. The residue was diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ethyl acetate in hexane. Evaporation of solvent gave title compound 8 (170 mg) as a pale yellow solid.


Patent reference: WO2010024769 (Astrazeneca)

A mixture of 2-bromo-4,5-dimethoxybenzaldehyde (0.368 g, 1.5 mmol), pyridin- 3-ylboronic acid (0.246 g, 2.0 mmol), Pd(PPh3)4 (0.173 g, 0.150 mmol), and cesium carbonate (0.977 g, 3 mmol) were suspended in dioxane (4 mL) and water (1 mL). The mixture was heated to 140°C in a microwave for 1 h. The reaction vessel was allowed to cool to ambient temperature, diluted with ethyl acetate (~ 25 mL), filtered through a bed of Celite, and cone, in vacuo to afford the aldehyde which was purified via SiO2 chromatography (40 g) using ethyl acetate / hexanes (5:1) as eluent to afford the title compound as a white solid (0.340 g, 93 %)


Patent reference: WO2010001169 (Astrazeneca)

2-chloro-8-methoxyquinazoline (1.0 eq), 2,6-difluorophenylboronic acid (1.5 eq), and DIEA ( 3 eq) was mixed with toluene and ethanol (1 :1, 0.5M) in a microwave vial. The reaction mixture was degassed by anhydrous N2 stream for 5 min followed by the addition of Pd(dppf)Cl2-DCM (0.1 eq). The reaction mixture was stirred at 130°C for 30min in microwave. Solvents were removed under reduced pressure. The crude product was purified by column (ethyl acetate : hexanes = 1 : 1) to give the mixture of starting material choride and desired product. The mixture was treated with IN HCl in 1,4-dioxane. Solvents were removed under reduced pressure. The residue was dissolved in ethyl acetate (150 mL), and washed with NaHCO3, brine, then dried over MgSO4, filtered, and evaporated under reduced pressure to give crude product, which was purified by column (ethyl acetate : hexanes = 1 : 1) to yield 2-(2,6-difluorophenyl)-8- methoxyquinazoline (46%).


Patent reference: WO2010026122 (Novartis)