4-(bromomethyl)-2-methylbenzonitrile

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the suspension of potassium carbonate (2.16 g, 15.7 mmol) in THF at room temperature was added imidazole (4.27 g, 62.8 mmol). The mixture was stirred at room temperature for 10 minutes then 4-(bromomethyl)-2-methylbenzonitrile (CAS 1001055-64-6) (6.6 g, 31.4 mmol) was added and refluxed for 24 hours. The mixture was then cooled to room temperature. Potassium carbonate was filtered off. The filtrate was concentrated and residue was redissolved in dichloromethane. The dichloromethane phase was washed with water (three times) and then HCl (three times). To the combined HCl phase was added sodium carbonate (solid) and extracted with ethyl acetate. Ethyl acetate phase was washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography (10% methanol/ethyl acetate) gave 4-((1H-imidazol-1-yl)methyl)-2-methylbenzonitrile (3.59 g, 58%) as a white solid. refluxed for 24 hours The mixture was then cooled to room temperature Potassium carbonate was filtered off The filtrate was concentrated residue was redissolved in dichloromethane The dichloromethane phase was washed with water (three times) To the combined HCl phase was added sodium carbonate (solid) extracted with ethyl acetate Ethyl acetate phase was washed with water and brine dried over sodium sulfate concentrated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To the suspension of potassium carbonate (2.16 g,15.7 mmol) in THF at room temperature was added imidazole (4.27 g, 62.8 mmol). The mixture was stirred at room temperature for 10 minutes then 4-(bromomethyl)-2-methylbenzonitrile (CAS 1001055-64-6) (6.6 g, 31.4 mmol) was added and refluxed for 24 hours. The mixture was then cooled to room temperature. Potassium carbonate was filtered off. The filtrate was concentrated and residue was redissolved in dichloromethane. The dichloromethane phase was washed with water (three times) and then HCl (three times). To the combined HCl phase was added sodium carbonate (solid) and extracted with ethyl acetate. Ethyl acetate phase was washed with water and brine, dried over sodium sulfate and concentrated. Column chromatography (10% methanol/ethyl acetate) gave 4-((1H-imidazol-1-yl)methyl)-2-methylbenzonitrile (3.59 g, 58%) as a white solid. refluxed for 24 hours The mixture was then cooled to room temperature Potassium carbonate was filtered off The filtrate was concentrated residue was redissolved in dichloromethane The dichloromethane phase was washed with water (three times) To the combined HCl phase was added sodium carbonate (solid) extracted with ethyl acetate Ethyl acetate phase was washed with water and brine dried over sodium sulfate concentrated

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of tert-butyl (3R,4 S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from Example 1/Step 2 in DMF (0.05 M) was added methyl 4-(bromomethyl)benzonitrile (1.6 eq.) and cesium carbonate (1.3 eq.). The reaction was heated to 80° C. and stirred for 16 h. After cooling to rt, the reaction was diluted with ether and quenched with water. The aqueous layer was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 5% EtOQc in Hex→100% EtOAc) to afford the title compound as a oil After cooling to rt quenched with water The aqueous layer was extracted with ether The combined organic extracts were washed with water, brine dried over MgSO4 concentrated in vacuo The crude product was purified by flash column chromatography (SiO2, 5% EtOQc in Hex→100% EtOAc)