8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole

Synthesis

GENERAL STEPS: To a stirred solution of 4-bromophenylhydrazine hydrochloride (5.0 g, 22.36 mmol) in ethanol (100 mL) was added piperidin-4-one hydrochloride (1.316 g, 8.5984 mmol) and the mixture was heated to reflux. Reflux was maintained for 4 hours, then cooled to room temperature and dry hydrogen chloride gas was passed through the reaction mixture for 1 hour. The mixture was then heated to reflux again and held for 2 hours. After completion of the reaction, the ethanol was distilled under vacuum and the residue was dissolved in water. The aqueous layer was neutralized with 2N sodium hydroxide solution and extracted in dichloromethane (2 x 100 mL). The pH of the aqueous layer was then adjusted to 12.0 with 2N sodium hydroxide solution and the product was extracted with ethyl acetate. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated in vacuum. The crude solid was washed with ethyl ether (50 mL) to afford 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.2 g, 39.3%) with 98.82% purity. HPLC: 1HNMR (200 MHz, DMSO-d6) δ: 2.7 (t, 2H, CH2), 3.0 (t, 2H, CH2), 3.8 (d, 2H, CH2), 7.05 (d, 1H, Ar-H), 7.2 (d, 1H, Ar-H), 7.45 (s, 1H, Ar-H), 10.97 (bs, 1H. NH). m/e = 251 (M + H). a solution of 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (250 mg, 0.991 mmol) in anhydrous DMF (10 mL) at room temperature was added Example 7 (258 mg, 1.194 mmol) and potassium carbonate (204 mg, 1.401 mmol). The reaction mixture was stirred at 100 °C for 6 hours. Upon completion, the reaction mixture was diluted with water and the compound was extracted with EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography to give Example 33 (80 mg, 21%). HPLC: (RT = 17.39 min). 1H NMR (200 MHz, CDCl3) ppm: 8.88 (s, 2H), 7.95 (bs, 1H), 7.65-7.15 (m, 3H), 5.05 (s, 2H), 4.35 (m, 2H), 3.88 (s, 3H), 2.93 (t, 2H, J = 5.4Hz); m/e = 387 (M + 1).

References

[1] Patent: WO2006/88949, 2006, A1. Location in patent: Page/Page column 113; 114
[2] Journal of Medicinal Chemistry, 2013, vol. 56, # 24, p. 10183 - 10187