2-Methoxyquinoline → 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-(2-methoxy-3-quinolinyl)piperidin-4-ol

Temperature

-72 °C

To a cooled solution (-72° C.) or t-butyllithium (1.7M in pentane, limiting reagent, 1.90 mL, 3.19 mmol) in tetrahydrofuran (24 mL) under nitrogen was added several drops of diisopropylamine (catalytic amount). This was followed by 2-methoxyquinoline (0.69 mL, 4.39 mmol, 1.38 eq). The reaction was stirred at -72° C. for 1 h, warmed to 0° C. and stirred at this temperature for 3 h. After recooling to -72 ° C., a solution of 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (1.00 g, 3.30 mmol, 1.03 eq) in tetrahydrofuran (3.0 mL) was added dropwise to the lithioquinoline solution. The reaction was stirred at room temperature for 18 h and quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×200 mL), dried with anhydrous sodium sulfate and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (100 mL; eluent: 25% ethyl acetate in hexane) to obtain 1.00 g (66%) of the title compound as a white solid. TLC analysis (Rf 0.19, 25% ethyl acetate in hexane). 1H NMR (CDCl3, 250 MHz) 7.89 (s, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.59 (dd, J=6.8, 7.3 Hz, 1H), 7.38 (dd, J=7.4, 7.5 Hz, 1H), 7.23 (m, 4H), 6.93 (m, 4H), 4.27 (s, 1H), 4.16 (s, 3H), 3.80 (s, 1H), 3.49 (s, 2H), 2.87 (m, 4H), 2.63 (s, 2H), 2.09 (m, 4H) MS (CI, CH4) m/z 463 (M+1,100), 491 (M+29,19), 445 (23). The free base was dissolved in methylene chloride, treated with ethereal HCl, and the hydrochloride salt was precipitated with ether dilution. The solid was filtered, rinsed with fresh diethyl ether and dried in vacuo (50° C., 10 pascal, 18 h) to yield a white solid, mp 213°-217° C. (dec).

1. temperaturewarmed to 0° C.
2. stirringstirred at this temperature for 3 h
3. customAfter recooling to -72 ° C.
4. stirringThe reaction was stirred at room temperature for 18 h
5. customquenched with water (10 mL)
6. extractionThe aqueous phase was extracted with ethyl acetate (200 mL)
7. extractionThe organic extract
8. washwas washed with water (2×200 mL)
9. dry with materialdried with anhydrous sodium sulfate
10. customThe reaction mixture was purified by flash chromatography over silica gel (100 mL; eluent: 25% ethyl acetate in hexane)

ORD record

ord-b257343b7ee0466eb111468455dc3c63

Source dataset

uspto-grants-1996_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05512575