2-(1-Adamantyl)-4-bromoanisole

White Solid

To a stirred mixture of the product of Step A (0.5 g; 1.62 mmol) and KTo a suspension of sodium hydride (60percent in mineral oil, 0.402g, 10.1 mmol) in 11 mL of DMF, 2-(1-adamantyl)-4-bromophenol 1-(5-Bromo-2-methoxyphenyl)-adamantane [0145] [0146] Reagent grade concentrated H2S04 (11 mL) was added dropwise to a solution of 1- adamantol (30.25 g, 200 mmol) and 4-bromoanisole (37.21g, 200 mmol) in 130 mL of CH2Cl2. The light pink solution was stirred at ambient temperature for 20 hours. The solvent was decanted, water (100 mL) and hexane (100 mL) were added and the solid was filtered and washed with hexane and dried to give 31 g of the product as a white powder. The supernatant was diluted with hexane, washed with water and brine, dried over MgS04 and filtered thru a silica gel pad. The solvent was removed and the solid was recrystallized from hexane to yield 17 g of the product as a white powder. [0147] Yield: 65 g (75percent) ; white solid; Rf= 0.9 in 25percent EtOAc-hexane. Reagent grade concentrated HStep A. 2-(1-adamantyl)-4-bromoanisoleIn a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to separating funnel and the organic layer collected, which is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO DStep A. 2-(1-adamantyl)-4-bromoanisole; EXAMPLE 1In a 1 L flask equipped with a stirrer, a reflux condenser and a dropping funnel, a mixture of 50 g (0.33 M) 1-adamantanol, 68 g (45.5 mL, 0.36 M) 4-bromoanisole and 500 mL of methylene chloride is prepared. The mixture is stirred until dissolved and then 35 g (19 mL, 0.36 M) of sulfuric acid added during one hour. The reaction mixture is stirred for 4 hours, 200 mL of water added, stirred for another 10 min, transferred to a separating funnel and the organic layer collected. It is neutralized by two portions of 100 mL 10percent sodium carbonate solution. Methylene chloride is distilled off completely, the residue dissolved in 300 mL of ethyl acetate, filtered, concentrated to 200 mL and left to crystallize at about 0° C. for 16 h. The crystals are filtered off, washed by 50 mL of cold ethyl acetate and dried at 100° C. for one hour. 2-adamantyl-4-bromoanisole, 76 g (72percent) with m.p. 140-141° C. is obtained.NMR (500 MHz, DMSO DPreparation of 2-(l-adamantyl)-4-bromoanisole (IV): A mixture of 2-(l-adamantyl)-4-bromophenol (III) (50 g, 162 mmol) and potassium carbonate (33.7 g, 216 mmol) in acetone (250 ml) was stirred at room temperature. Then dimethylsulphate (20.16 ml, 240 mmol) was added drop wise for 15 min at room temperature. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with water, acidified with dilute HCl. The solid separated was filtered and washed with water. The solid was dissolved in dichloromethane (200 ml) and washed with water. The organic layer was dried over sodium sulphate, evaporated and the solid obtain was purified with ethyl acetate (200ml).[Yield: 30 g, 58 percent]; Preparation of 2-(l-adamantyl)-4-bromoanisole (IV): To a solution of 2-(l-adamantyl)-4-Bromophenol (III) (50 g, 162 mmol) in acetone 200 ml, Potassium carbonate (33.7 g, 216 mmol) was added and stirred at RT. Dimethyl sulphate (20.53 ml, 244 mmol) was added dropwise for 15 min at RT. The reaction mixture was then refluxed for 4 hrs.

Adapalene (A225000) impurity.