Mehtyl 6-[3-(1-adamanty)-4-methoxy phenyl]-2-naphthoate

Chemical Properties

White to Off-White Solid

Uses

Adapalene intermediate

Synthesis

General procedure for the preparation of methyl 6-[3-(1-adamantyl)-4-methoxyphenyl]-2-naphthalenecarboxylate (V): magnesium scraps (1.26 g, 51.85 mmol) were mixed with THF (10 mL) under nitrogen protection and stirred at room temperature. 2-(1-adamantyl)-4-bromoanisole (IV) (1.4 g, 4.36 mmol) and 1,2-dibromoethane (0.56 mL) were added, and the reaction mixture was subsequently heated to 40 °C to initiate the reaction. Then a solution of 2-(1-adamantyl)-4-bromoanisole (12.6 g, 39.25 mmol) in THF (40 mL) was slowly added dropwise under reflux conditions for 30 min. A solution of purified zinc chloride (8.4 g, 61 mmol) in THF (30 mL) was added slowly dropwise at reflux temperature over 15 minutes. After the reaction mixture was refluxed for 1 h, methyl 6-bromo-2-naphthalenecarboxylate (8.0 g, 30 mmol) was added and stirred for 10 min, followed by the addition of NiCl2ZDPPE catalyst (0.21 g). The mixture was continued to be stirred at the same temperature for 2 h. The residue was subsequently concentrated. The residue was treated with dichloromethane (100 mL) and 1N HCl (100 mL), and the dichloromethane layer was washed sequentially with 10% EDTA disodium salt solution and water, dried with anhydrous sodium sulfate, and distilled to give the crude product. The crude product was stirred in ethyl acetate (140 mL) at 70 °C for 1 h, cooled to 15 °C and kept for 1 h. The solid was collected by filtration and dried. [Yield: 9.45 g, 50% yield].

References

[1] Organic Process Research and Development, 2006, vol. 10, # 2, p. 285 - 288
[2] Patent: WO2007/125542, 2007, A2. Location in patent: Page/Page column 16
[3] Journal of Medicinal Chemistry, 1995, vol. 38, # 26, p. 4993 - 5006