(1-benzylpiperidin-4-yl)methanol

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: 1,1-carbonyldiimidazole (0.8 g., 0.005 mol) was added to a solution of 4-amino-5-chloro-2-methoxy-benzoic acid (1 g, 5 mmol) in THF (20 ml) and the reaction mixture was stirred at room temperature for about 30 minutes. The solvent was evaporated and the residue was taken up in H2O and extracted into ethyl acetate (3×20 ml). The organic phases were collected, dried and evaporated to dryness. The obtained solid residue was dissolved in THF (10 ml) and dropped into a solution of 1-benzylpiperidin-4-yl-methanol [J. Med. Chem. (1992), 35, 4344], (1 g, 5 mmol) in THF (10 ml) and butyllithium (1.6 M in hexane; 3 ml), maintained at 0° C. The reaction mixture was further stirred at room temperature for 1 hour. The solvent was evaporated and the residue was taken up into H2O and extracted into ethyl acetate. The organic extracts were dried and evaporated to give the desired product as a pale yellow oil, (1.63 g). The solvent was evaporated extracted into ethyl acetate (3×20 ml) The organic phases were collected dried evaporated to dryness The obtained solid residue was dissolved in THF (10 ml) maintained at 0° C The reaction mixture was further stirred at room temperature for 1 hour The solvent was evaporated extracted into ethyl acetate The organic extracts were dried evaporated

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

Procedure: Indole-3-carboxylic acid was converted to its acid chloride and then reacted with 1-benzyl-4-piperidinemethanol (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88%) The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1)

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

Procedure: Indole-3-carboxylic acid was converted to its acid chloride and then reacted with 1-benzyl-4-piperidinemethanol (D7) using the method given in Example 1a. The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1) to afford (1-benzyl-4-piperidyl)methyl indole-3-carboxylate as a yellow oil (88%) The resulting orange oil was chromatographed on silica gel eluting with chloroform/ethanol (9:1)

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: A suspension of sodium hydride (60% dispersion in oil, 0.76 g, 19 mmol) in anhydrous tetrahydrofuran (38 mL) was stirred at room temperature under a nitrogen atmosphere. A solution of 1-benzyl-4-hydroxymethyl piperidine (3.82 g, 18.6 mmol) was added dropwise. After the addition was completed, the reaction mixture was stirred for 2 h. 4-Fluorobenzyl bromide (2.4 mL, 19 mmol) was added dropwise, then the reaction mixture was stirred for 72 h. Water (50 mL) was added and the resulting mixture was extracted three times with ethyl acetate. Drying over magnesium sulfate, filtration and concentration in vacuo gave an oil. Vacuum distillation (170° C. (Kugelrohr oven), 1.0 Torr) gave a colorless oil (3.45 g, 59% yield): 'H-NMR: 7.34-6.98 (m, 9H), 4.46 (s, 2H), 3.50 (s, 2H), 2.93-2.87 (m, 2H), 2.02-1.59 (m, 5H), 1.39-125 HR-MS Calcd.: 313.1478; Found: 313.1479; (m, 2H); Anal. Calcd.: for C20H24FNO: C,76.65, H,7.72, N,4.47; Found: C,77.27, H,7.69, N,4.45. After the addition the reaction mixture was stirred for 2 h the reaction mixture was stirred for 72 h the resulting mixture was extracted three times with ethyl acetate Drying over magnesium sulfate, filtration and concentration in vacuo gave an oil Vacuum distillation (170° C. (Kugelrohr oven), 1.0 Torr)