Indanone inhibitors of acetylcholinesterase WO 2010077730 A2...........DONEPEZIL

EXAMPLE 1

2-(l-Benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan-l-one

(donepezil)

Step 1

[00106] 2-(l-Benzyl-piperidin-4-ylmethylene)- ,6-dimethoxy-indan-l-one: At about 0 ⁰ C and under an atmosphere of argon, a solution of n-butyllithium in hexane (2.5 M, 3.7 mL, 1.12 equiv.) was added dropwise to a solution of diisopropylamine (930 mg, 9.19 mmol, 1.12 equiv.) in tetrahydrofuran (10 mL). The resulting solution was stirred at about 0 ⁰C for about 10 minutes. After cooling the solution to about -78 ⁰C, a solution of 5,6-dimethoxyindan-l-one (1.58 g, 8.22 mmol, 1.00 equiv.) and hexamethylphosphoramide (1.47 g, 8.20 mmol, 1.00 equiv.) in tetrahydrofuran (10 mL) was added dropwise. The solution was stirred at about -78 ⁰C for about 15 minutes, and then a solution of l-benzyl-piperidine-4-carbaldehyde (1 g, 4.92 mmol, 0.60 equiv.) in tetrahydrofuran (10 mL) was added. After warming the solution to ambient temperature, the solution was stirred at ambient temperature for about 2 hours and then an aqueous solution of ammonium chloride (1%) was added. The resulting precipitant was collected by filtration, and then dried in an oven in vacuo to afford the tittle product as a solid (2 g), which was used in the next step without further purification. LC-MS: m/z = 378 (MH)⁺.

Step 2

[00107] 2-(l-Benzyl-piperidin-4-ylmethyl)-5,6-dimethoxy-indan-l-one (donepezil): Under an atmosphere of hydrogen (1 atm), a mixture of 2-(l-benzyl- piperidin-4-ylmethylene)-5,6-dimethoxy-indan-l-one (800 mg, 2.12 mmol, 1.00 equiv.), 10% palladium on carbon (0.2 g), and tetrahydrofuran (20 mL) was stirred at ambient temperature for about 16 hours. The mixture was filtered, and the resulting filtrate was concentrated in vacuo. The resulting crude residue was purified by silica gel column chromatography (dichloromethane / methanol (100 : 2)) to give a semi- pure product (390 mg), which was further purified by re-crystallization from a mixture of solvents (hexane / ethyl acetate (5:1), 5 mL) to afford the title product as an off-white solid (300 mg, yield = 37%). 

LC-MS: m/z = 380 (MH)⁺; 

¹H NMR (300 MHz, CHCl₃) δ: 7.25-7.38 (m, 5H), 7.19 (s, IH), 6.87 (s, IH), 3.98 (s, 3H), 3.92 (s, 3H), 3.54 (s, 2H), 3.21-3.30 (q, IH), 2.92-2.96 (m, 2H), 2.72-2.75 (m, 2H), 1.47- 2.05(m, 9H).