2-(4-Bromophenyl)-2-methylpropanenitrile

45 g (1100 mmol) of sodium hydride (a 60percent dispersion in a mineral oil) was added in divided portions to a solution of 100 g (510 mmol) of 4-bromophenylacetonitrile in 1500 ml of N, N-dimethylformamide at 0° C. in an argon stream with stirring. A solution of 4-Bromophenylacetonitrile (10.0 g, 51.0 mmol) in tetrahydrofuran (200 mL) was added slowly to a suspension of sodium hydride (60percent in mineral oil, 6.0 g, 153 mmol) in tetrahydrofuran (400 mL) at room temperature over 30 minutes. (Reference Example 1) Step 1:4A. To a solution of (4-bromo-phenyl)-acetonitrile (1 g, 5.10 mmol) in DMF (10 mL) is added sodium hydride (0.408 g, 10.20 mmol, 60percent in mineral oil) at 0 °C. Thereaction mixture is stirred at 0 °C for 15 minutes and then methyl iodide (0.69 mL, 11.22 mmol) is added at 0 °C. The reaction mixture is stirred at room temperature forovernight. The reaction mixture is quenched with aqueous ammonium chloride solution (5 mL) and extracted with EtOAc (2x20 mL). The combined organic extracts arewashed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and evaporated. The crude material is purified over silica gel column chromatography(combiflash) eluting with 5-10percent EtOAc in hexanes to give an off white solid (0.9 g, 78percent). 1H NMR (400 MHz, CDC13) i5 7.51 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 1.77 (s, 3H).To a solution of (4-bromo-phenyl)-acetonitrile (1 g, 5.10 mmol) in DMF (10 mL) is added sodium hydride (0.408 g, 10.20 mmol, 60percent in mineral oil) at 0° C. A solution of (4-bromophenyl)acetonitrile (Method 1; 2.1 g, 0.010 mol) in DMSO (20 ml) was treated with sodium hydride (60percent, 1.3 g, 0.032 mol, 3 eq). Methyl iodide (2.0 ml, 0.032 mol, 3.0 equiv) was then added dropwise at 0 °C. The reaction mixture was stirred at 25 °C for 12 h. The reaction mixture was then quenched with water and extracted with EtOAc. The combined organics were dried with NaCl(sat) and then NaStep a) intermediate 20 Methyl iodide was added to a solution of 2-(4-bromophenyl)acetonitrile (1.5 g, 2.5 m mol) in dry THF (20 mL) at 0 °C, stirred for 10 min and then added to a solution of NaH (1.2 g, 5.1 mmol) in dry THF (80 mL) at 0 °C. The reaction mixture was slowly brought to rt and stirred for 4 h. The reaction mixture was poured into crushed ice and extracted with EtOAc (2x), the combined organics were washed with HTo a solution of KHMDS (50 g) in THF (300 mL) cooled to 0° C. there is added slowly a solution of commercial (4-bromophenyl)acetonitrile (16 g, 81 mmoles) in THF (90 mL), the temperature being maintained below 3° C. The mixture is stirred for 40 minutes at 0° C., and then methyl iodide (11.7 mL) is added in the course of 50 minutes at a temperature below 8° C. The mixture is stirred at ambient temperature for 20 hours and then poured carefully into ice-water (1.5 L). The aqueous phase is extracted with Et(Referential Example 1) A mixture of intermediate 3 (300 mg, 0.877 mmol, TFA salt), A solution of the intermediate obtained above (5 g, 22 mmoles) and of KOH (2.4 g) in a mixture of ethanol (25 mL) and water (7.5 mL) is heated at reflux for 20 hours. The reaction mixture is concentrated in vacuo, and the residue is taken up with ethyl ether (100 mL) and water (60 mL). The aqueous phase (free of organic solvent) is cooled to 10 C. and then acidified with a 37% HCl solution. The precipitate that forms is collected on a frit and dried in vacuo. Intermediate 599 (5.3 g) is obtained in the form of a white solid. 1H NMR (400 MHz, CDCl3): delta 9.00-8.00 (1H), 7.75 (d, 2H), 7.25 (d, 2H), 1.60 (s, 6H) IR (cm-1): 3347-2235, 1697

Molecular Weight:224.10
XLogP3:3.2
Hydrogen Bond Acceptor Count:1
Rotatable Bond Count:1
Exact Mass:222.99966
Monoisotopic Mass:222.99966
Topological Polar Surface Area:23.8
Heavy Atom Count:12
Complexity:193
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes