Synthesis
1. Dissolve 4-bromobenzoic acid (6.00 g, 29.8 mmol) in 80 mL of dichloromethane, add N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (6.30 g, 32.9 mmol), 4-(dimethylamino)pyridine (7.70 g, 63.0 mmol) and methylamine hydrochloride (2.23 g, 33.0 mmol). ). The mixture was stirred overnight, washed with 1.0 N hydrochloric acid, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by rapid chromatography on silica gel using hexane/ethyl acetate as eluent to afford 4-bromo-N-methylbenzamide (5.80 g, 90%) as a white solid.
2. 4-Bromo-N-methylbenzamide (4.00 g, 18.9 mmol) was dissolved in 10 mL of 1,4-dioxane, and bis(pinacolato)diboron (11.9 g, 46.8 mmol), potassium acetate (5.50 g, 56.1 mmol), and [1,1'-bis(diphenylphosphino)ferrocenyl]-dichloropalladium(II) (0.410 g, 0.560 mmol) were added. 0.560 mmol). The mixture was heated at 90 °C overnight, filtered and concentrated. The residue was purified by rapid chromatography on silica gel using hexane/ethyl acetate as eluent to afford N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.50 g, 91%) as a white solid.
3. N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide was reacted with ethyl 2-(4-bromophenyl)-2-methylpropanoate to form ethyl 2-methyl-2-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)propanoate as an off-white solid according to General Method F. The reaction was completed by the following method.
4. Ethyl 2-methyl-2-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)propanoate (1.00 g, 3.07 mmol) was dissolved in a solvent mixture of 4 mL of tetrahydrofuran, 8 mL of methanol, and 3 mL of water and solid sodium hydroxide (0.640 g, 16.0 mmol) was added. After stirring at room temperature overnight, the reaction mixture was concentrated and dissolved in water. It was acidified with 1 N hydrochloric acid to pH~6 and extracted with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to afford 2-methyl-2-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)propionic acid (0.950 g, 100%) as a white solid. The compound can be used directly in the next step of the reaction without further purification.
5. 2-Methyl-2-(4'-(methylcarbamoyl)-[1,1'-biphenyl]-4-yl)propionic acid was reacted with quinuclidinium cyclic-3-ol according to General Method I to afford 4-N-methylcarboxyamino phenylboronic acid pinacol ester as an off-white solid.
1H NMR (500 MHz, DMSO-d6) δ 8.47 (q, J = 4.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 2H), 7.74 (d, J = 6.5 Hz, 2H), 7.67-7.65 (m, 2H), 7.60 (s, 1H), 7.44 (d, J = 6.5 Hz, 2H), 4.43 ( m, 1H), 3.76 (m, 1H), 2.81-2.63 (m, 7H), 2.47-2.36 (m, 1H), 1.85 (m, 2H), 1.56-1.34 (m, 9H) ppm.
13C NMR (125 MHz, CD3OD) δ 170.4, 156.9, 149.1, 145.3, 139.2, 134.1, 128.8, 127.9, 126.7, 71.4, 56.1, 55.9, 48.0, 47.0, 30.0, 29.9, 27.0, 26.5, 24.6, 20.0 ppm.
Purity: 100% (214 and 254 nm) LCMS; retention time: 1.72 min; (M + H+) 422.3.
