4-(2-methoxyphenyl)piperidine

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a mixture of 4-(2-methoxyphenyl)piperidine (0.951 g, 4.97 mmol) and (3S,7aR)-7a-cyclopropyl-3-phenyl-2,3-dihydropyrrolo[2,1-b]oxazol-5(7aH)-one (preparation #24) (1.0 g, 4.1 mmol) was added water (0.8 mL, 44 mmol). After about 5 minutes, DCM (5 mL) was added. All the solids dissolved. The reaction mixture was stirred at room temperature for about 16 hours. Purification on a Biotage silica gel column eluting with DCM/EtOAc (1:0 to 1:1) afforded (3S,7R,7aR)-7a-cyclopropyl-7-(4-(2-methoxyphenyl)piperidin-1-yl)-3-phenyltetrahydropyrrolo[2,1-b]oxazol-5(6H)-one (1.29 g, 2.98 mmol) as a white solid. RP-HPLC (Table 1, Method a) Rt 2.14 min; m/z: (M+H)+ 433. All the solids dissolved Purification on a Biotage silica gel column eluting with DCM/EtOAc (1:0 to 1:1)

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-t-Butoxycarbonyl-4-(2-methoxyphenyl)piperidine (120 mg, 0.41 mmol) was dissolved in methylene chloride (2 ml). Thereto was added trifluoroacetic acid (2 ml) and the resulting solution was stirred at a room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 82 mg of the aforementioned compound of interest (0.43 mmol, 104% in yield). The solvent was evaporated under a reduced pressure the thus obtained residue was mixed with ethyl acetate This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order the solvent was evaporated under a reduced pressure to obtain

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-t-Butoxycarbonyl-4-(2-methoxyphenyl)piperidine (120 mg, 0.41 mmol) was dissolved in methylene chloride (2 ml). Thereto was added trifluoroacetic acid (2 ml) and the resulting solution was stirred at a room temperature for 1 hour. The solvent was evaporated under a reduced pressure, and the thus obtained residue was mixed with ethyl acetate. This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order, and then the solvent was evaporated under a reduced pressure to obtain 82 mg of the aforementioned compound of interest (0.43 mmol, 104% in yield). The solvent was evaporated under a reduced pressure the thus obtained residue was mixed with ethyl acetate This was washed with 1 N sodium hydroxide aqueous solution and saturated brine in that order the solvent was evaporated under a reduced pressure to obtain

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.368 g) was coupled to 4-(2-methoxyphenyl)piperidine (0.177 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.424 g); mp 150°-160° C.; MS: m/z=508(M+1); NMR(CD3SOCD3): 1.93-2.08 (m,4), 2.75 (m,1), 3.07 (s,3), 3.39 (m,5), 3.67-3.71 (m,32), 4.87 (d,1, J=3.7), 6.77-6.80 (m,3), 6.97-7.07 (m,3), 7.31 (m,1), 7.50 (m,2), 7.67 (m,1), 7.94 (d,1, J=7.7). Analysis for C29H29Cl2N2O2.1.5 HCl.0.5 H2O: Calculated: C, 60.88; H, 5.55, N, 4.90; Found: C, 61.09; H, 5.64; N, 4.73. The reaction product was not purified by chromatography

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.368 g) was coupled to 4-(2-methoxyphenyl)piperidine (0.203 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in Example 8 to afford the desired title compound (0.469 g); mp 175°-182° C.; MS: m/z=523(M+1); NMR(CD3SOCD3): 1.83-1.90 (m,3), 2.05-2.13 (m,2), 2.80 m(1), 3.07 (s,3), 3.57 (m,2), 3.8 (s,3), 4.89 (d,1, J=3.7), 6.7 (dd,1, J=8.4, 2), 7.0 (m,3), 7.12-7.6 (m,6), 7.94 (d,1, J=7.5). Analysis for C30H32Cl2N2O2.1.0 HCl.1.5 H2O: Calculated: C, 61.39; H, 6.18, N, 4.77; Found: C, 61.33; H, 6.12; N, 4.99. The reaction product was not purified by chromatography