Reaction Steps
3-(Piperidin-4-ylmethoxy)-benzoic acid methyl ester. Prepared as described in Example 28, Step 2, on a 39.0 mmol scale. The crude product was diluted with in 1 N NaOH and extracted with diethyl ether. The organic layer was washed with brine, dried over Na2CO3, and concentrated to give the desired product as an oil that crystallized on standing (7.14 g, 73%). MS: exact mass calcd for C14H19NO3, 249.1; m/z found, 250.4 [M+H]+. 1H NMR (MeOH-d4): 7.66 (d, J=6.8, 1H), 7.60 (s, 1H), 7.45 (m, 1H), 7.22 (d, J=7.3, 1H), 4.98 (s, 1H), 3.98 (s, 3H), 3.92 (d, J=4.6, 2H), 3.18 (d, J=11.4, 2H), 2.72 (t, J=12.0, 2H), 2.02 (br s, 1H), 1.92 (d, J=12.4, 2H), 1.44 (m, 2H). Step 3. 3-(1-Isopropyl-piperidin-4-ylmethoxy)-benzoic acid methyl ester. A mixture of 3-(piperidin-4-ylmethoxy)-benzoic acid methyl ester (6.82 g, 27.4 mmol), acetone (40 mL), acetic acid (1.6 mL, 27.4 mmol), and NaB(OAc)3H (18.4 g, 86.8 mmol) in THF (110 mL) was stirred for 4.5 h. The mixture was diluted with CH2Cl2, washed with 1 N NaOH and brine, dried (Na2CO3), and concentrated to give the crude product. Chromatographic purification (EtOAc/hexanes) yielded the desired product as a pale yellow oil (6.43 g, 81%). MS: exact mass calcd for C17H25NO3, 291.2; m/z found, 292.5 [M+H]+. 1H NMR (MeOH-d4): 7.55 (dd, J=1.0, 7.7, 1H), 7.49 (m, 1H), 7.33 (m, 1H), 7.12 (m, 1H), 3.87 (s, 3H), 3.82 (d, J=6.2, 2H), 2.91 (d, J=11.6, 2H), 2.69 (heptet, J=6.6, 1H), 2.18 (m, 2H), 1.83 (d, J=13.2, 2H), 1.77 (m, 1H), 1.40 (m, 2H), 1.05 (d, J=6.6, 6H). Step 4. 4-[3-(4,5-Dihydro-3H-pyrrol-2-yl)-phenoxymethyl]-1-isopropyl-piperidine. Prepared as described in Example 1, Step 4, on a 21.8 mmol scale, to give 4.92 g (75%) of the desired product as a colorless oil after column chromatography (NH3 in MeOH/CH2Cl2). A small sample was purified by reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass calcd for C19H28N2O, 300.2; m/z found, 301.5 [M+H]+. 1H NMR (MeOH-d4): 7.63 (m, 2H), 7.57 (m, 1H), 7.39 (m, 1H), 4.24 (t, J=7.8, 2H), 4.0 (d, J=5.8, 2H), 3.64 (m, 2H), 3.52 (m, 3H), 3.10 (m, 2H), 2.42 (quintet, J=7.9, 2H), 2.17 (m, 3H), 1.76 (m, 2H), 1.37 (m, 6H). Step 5. 1-Isopropyl-4-(3-pyrrolidin-2-yl-phenoxymethyl)-piperidine. Prepared as described in Example 1, Step 5, on a 20.4 mmol scale, to give 5.79 g (99%) of the desired product as a colorless oil after column chromatography (NH3 in MeOH/CH2Cl2). A small sample was purified by reverse-phase HPLC to give a clear film (TFA salt). MS: exact mass calcd for C19H30N2O, 302.2; m/z found, 303.5 [M+H]+. 1H NMR (MeOH-d4, TFA salt): 7.36 (m, 1H), 7.06 (m, 2H), 6.98 (m, 1H), 4.93 (s, 5H), 4.59 (m, 1H), 3.92 (d, J=5.5, 2H), 3.40 (m, 5H), 3.08 (m, 2H), 2.47 (m, 1H), 2.18 (m, 6H), 1.71 (m, 2H), 1.37 (m, 6H). Step 6. 2-{2-[3-(1-Isopropyl-piperidin-4-ylmethoxy)-phenyl]-pyrrolidin-1-yl}-1-(4-methoxy-phenyl)-ethanone. Prepared as described in Example 8, Step 1, on a 3.31 mmol scale, to give 1.04 g (70%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C27H36N2O3, 450.3; m/z found, 451.5 [M+H]+. 1H NMR (MeOH-d4): 7.84 (m, 2H), 7.20 (m, 1H), 7.01 (d, J=1.5, 1H), 6.96 (d, J=7.5, 1H), 6.92 (m, 2H), 6.81 (m, 1H), 4.89 (s, 1H), 3.96 (d, J=16.6, 1H), 3.86 (m, 5H), 3.46 (m, 3H), 3.29 (m, 3H), 2.80 (t, J=12.3, 2H), 2.33 (m, 1H), 2.18 (m, 1H), 2.02 (m, 4H), 1.87 (m, 1H), 1.75 (m, 1H), 1.64 (m, 2H), 1.28 (d, J=6.7, 6H). Step 7. 9-(1-Isopropyl-piperidin-4-ylmethoxy)-6-(4-methoxy-phenyl)-2,3-dihydro-1H-pyrrolo[2,1-a]isoquinolinylium salt. Prepared as described in Example 17, Step 2, on a 2.05 mmol scale, to give 740 mg (77%) of crude product. MS: exact mass calcd for C28H35N2O2+, 431.3; m/z found, 431.5 [M]+. Step 8. Prepared as described in Example 17, Step 3, on a 1.58 mmol scale to give 102.3 mg (12%) of the desired product as the TFA salt. MS: exact mass calcd for C28H38N2O2, 434.3; m/z found, 435.6 [M+H]+. 1H NMR (MeOH-d4): 7.15 (d, J=8.6, 2H), 6.93 (d, J=8.8, 2H), 6.85 (d, J=2.3, 1H), 6.76 (m, 1H), 6.70 (d, J=8.7, 1H), 4.85 (m, 1H), 4.34 (m, 1H), 3.88 (m, 3H), 3.78 (s, 3H), 3.53 (m, 4H), 3.38 (m, 2H), 3.06 (t, J=11.8, 2H), 2.81 (m, 1H), 2.25 (m, 3H), 2.11 (d, J=12.2, 3H), 1.72 (m, 2H), 1.35 (d, J=6.7, 6H).
