反应详情

tert-Butyl 4-((1-(6-chloro-3-methyl-2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (26 mg, 0.040 mmol) was dissolved in trifluoroacetic acid (40% in dichloromethane, 1 mL) and stirred at room temperature for 1 h. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was flushed with several volumes of methanol which were discarded. The crude piperidine was eluted with 2M ammonia in methanol and concentrated. The crude product was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) followed quickly by sodium cyanoborohydride (5.0 mg, 0.08 mmol). To this was added two small drops of acetic acid over 5 minutes. The reaction was concentrated and the residue taken up in ethyl acetate, washed with saturated sodium bicarbonate, then brine, dried over magnesium sulfate, and concentrated. The crude product was dissolved in ethanol (10 mL) and heated at reflux overnight. The reaction was concentrated and purified by preparative HPLC (28% B isocratic method, TFA/ACN) to give 10.3 mg (47%). 1H-NMR (CD3OD, 500 MHz) δ 7.44 (m, 1.5H), 7.35 (m, 0.5H), 7.14 (m, 1.5H), 7.06 (m, 0.5H), 6.90-7.20 (m, 1H), 6.78 (d, J=2.1 Hz, 0.6H), 6.68 (m, 0.3H), 4.99 (m, 1H), 3.35-3.52 (m, 5H), 3.30 (d, J=9.2 Hz, 1H), 2.55-3.00 (m, 6H), 2.05 (m, 2H), 1.30-1.50 (m, 3H). Mass spec.: 432.1 (MH)+.

1. concentrationThe reaction was concentrated
2. customThe cartridge was flushed with several volumes of methanol which
3. washThe crude piperidine was eluted with 2M ammonia in methanol
4. concentrationconcentrated
5. dissolutionThe crude product was dissolved in acetonitrile (1 mL)
6. additiontreated with formalin (50 μL)
7. concentrationThe reaction was concentrated
8. washwashed with saturated sodium bicarbonate
9. dry with materialbrine, dried over magnesium sulfate
10. concentrationconcentrated
11. dissolutionThe crude product was dissolved in ethanol (10 mL)
12. temperatureheated
13. temperatureat reflux overnight
14. concentrationThe reaction was concentrated
15. custompurified by preparative HPLC (28% B isocratic method, TFA/ACN)
16. customto give 10.3 mg (47%)