4-Methyl-1,5,6,7-tetrahydro-2H-cyclopenta[b]-pyridin-2-one synthesis

Yield:-

Reaction Conditions:

with ammonium acetate at 20; for 17.5 h;Heating / reflux;

Steps:

33

A mixture of cyclopentanone (55.0 g), ethyl acetoacetate (85.1 g), and AcONH₄ (50.4 g) was stirred at reflux for 9.5 h and stirred at ambient temperature for 8 h. The precipitate was collected by filtration, washed with water and hexane, and dried at 80 ⁰C to give a white solid (17.7 g). A mixture of the above solid (4.00 g) in POCl₃ (3.00 mL) and N,N-dimethylaniline (3.73 g) was stirred at reflux for 2 h. After cooling, the mixture was poured into EtOAc and cold water and the organic layer was separated. The aqueous layer was extracted with EtOAc twice. The combined organic layer was dried over MgSO₄, filtered, and concentrated under reduced pressure to give 2-chloro-4-methyl-6,7~ dihydro-5H-cyclopenta[6]pyridine including N,N-dimethylaniline (1.95 g) as a brown oil. A mixture of the above oil (650 mg), N-(c/s-4-aminocyclohexyl)-3-chloro-4-fluorobenzamide obtained in step A of example 1 (1.26 g), and BuOH (1 mL) was heated in a microwave synthesizer at 230 ⁰C for 30 min. The mixture was poured into saturated aqueous NaHCO₃ and the aqueous layer was extracted with CHCl₃ three times. The combined organic layer was dried over MgSO₄, filtrated, concentrated under reduced pressure, and purified by medium-pressure liquid chromatography (NH-silica gel, 40% to 50% EtOAc in.hexane and silica gel, 3% to 10% MeOH in CHCl₃). To a solution of the above purified material in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (10 mL). The mixture was stirred at ambient temperature for 4 h. The precipitate was collected by filtration, washed with Et₂O, and dried at 80 ⁰C under reduced pressure to give 3-chloro-4-fluoro-N-{c-4-[(4-methyl-6,7- dihydro-5H-cyclopenta[b]pyridin-2-yl)amino]cyclohexyl}benzamide hydrochloride (30.0 mg) as a white solid. EPO ¹H NMR (300 MHz, CDCl₃, δ): 1.66-2.06 (m, 8H), 2.14-2.28 (m, 2H), 2.32 (s, 3H), 2.79 (t, J= 7.4 Hz, 2H), 3.09 (t, J= 7.6 Hz, 2H), 3.72-3.83 (m, IH), 4.05-4.20 (m, IH), 6.34 (s, IH), 6.66-6.79 (m, IH), 7.18 (t, J= 8.6 Hz, IH), 7.67-7.77 (m, IH), 7.95 (dd, J= 7.1, 1.9 Hz, IH), 8.50-8.61 (m, IH); ESI MS m/z 402 [M (free)⁺+l, 100%].

References:

WO2006/35967,2006,A1 Location in patent:Page/Page column 79-80