反应详情

4-piperidin-4yl-benzoic acid (110 mg, 0.54 mmol, reference example 109) was added to paraformaldehyde (180 mg, 6 mmol) in MeOH (10 mL) and NaCNBH3 (120 mg, 1.94 mmol). The reaction was stirred at room temperature for 4 days, at which time HPLC shows no remaining starting material. The solution was acidified to pH 2 with concentrated HCl, evaporated, dissolved in water (20 mL), and extracted with ether (3×20 mL). Then the solution was brought to pH 12 with KOH pellets, extracted with dichloromethane (3×20 mL) and finally brought to pH5 with acetic acid. The mixture was lyophilized and the solid was extracted with MeOH (3×15 mL). The combined methanol extracts were evaporated and the residue chromatographed (reverse-phase HPLC, C18 column, 10-100% CH3CN/water) to yield, after lyophilization, 72 mg of the desired product (61%). 1H NMR (CD3OD): δ 7.98 (d, 2H), 7.38 (d, 2H), 3.60 (m, 2H), 3.18 (t, 2H), 2.94 (s, 3H), 2.85-2.95 (m, 2H), 2.08-2.18 (m, 2H), 1.90-2.02 (m, 2H). MS (ion spray) m/z 220 (M+H+). >98% pure by analytical HPLC.

1. customevaporated
2. dissolutiondissolved in water (20 mL)
3. extractionextracted with ether (3×20 mL)
4. extractionextracted with dichloromethane (3×20 mL)
5. extractionthe solid was extracted with MeOH (3×15 mL)
6. customThe combined methanol extracts were evaporated
7. customthe residue chromatographed (reverse-phase HPLC, C18 column, 10-100% CH3CN/water)
8. customto yield