(1-butylpiperidin-4-yl)methanol

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

Procedure: 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methanol (D6) using the method of Example 1a to afford (1-n butyl -4-piperidyl)methyl 5-fluoroindole-3-carboxylate as an orange oil (30%), following flash chromatography on silica gel eluting with 10% ethanol/chloroform.

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

Procedure: 1-Butyl-4-piperidinylmethanol (0.500 g 2.12 mmol) was dissolved in dry THF (3 ml) and treated with methyllithium (1.5M solution in diethyl ether) 2.16 ml, 2.33 mmol) with stirring under nitrogen. After 10 minutes, N-chlorocarbonyl-1,2,3,4,4a,9a-hexahydrocarbazole (0.630 g, 2.68 mmol) (Ref: WO 89/09217) in dry THF (5 ml) was added dropwise with stirring. After 48 hours, the reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica-gel chromatography, eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3 to give the title compound as a clear, colourless oil, which was converted to the oxalate salt, nap 187°-189° C. with stirring After 48 hours the reaction mixture was filtered the filtrate evaporated under reduced pressure The residue was purified by silica-gel chromatography eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3

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

Procedure: 1-Butyl-4-piperidinylmethanol (0.500 g 2.12 mmol) was dissolved in dry THF (3 ml) and treated with methyllithium (1.5M solution in diethyl ether) 2.16 ml, 2.33 mmol) with stirring under nitrogen. After 10 minutes, N-chlorocarbonyl-1,2,3,4,4a,9a-hexahydrocarbazole (0.630 g, 2.68 mmol) (Ref: WO 89/09217) in dry THF (5 ml) was added dropwise with stirring. After 48 hours, the reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica-gel chromatography, eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3 to give the title compound as a clear, colourless oil, which was converted to the oxalate salt, nap 187°-189° C. with stirring After 48 hours the reaction mixture was filtered the filtrate evaporated under reduced pressure The residue was purified by silica-gel chromatography eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3

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

Procedure: A stirred solution of (1-butyl-4-piperidinyl)methanol (125 mg, 0.72 mmole) in dry THF (5 ml) at 5° C. under argon was treated with 1.5M methyllithium in ether (0.35 ml, 0.50 mmole). After 10 minutes, a solution of ethyl 3,4-dihydro-2H-pyrano[2,3-b]indolizine-10-carboxylate (55 mg, 0.22 mmole) in dry THF (5 ml) was added and the mixture heated under reflux for 3 h. The mixture was then allowed to cool and concentrated in vacuo. The residue was treated with 10% Na2CO3 solution (10 ml) and extracted with ethyl acetate (2×40 ml). The combined extracts were dried (Na2SO4) and concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform to afford the title compound as a pale pink oil (65 mg, 78%). the mixture heated under reflux for 3 h to cool concentrated in vacuo The residue was treated with 10% Na2CO3 solution (10 ml) extracted with ethyl acetate (2×40 ml) The combined extracts were dried (Na2SO4) concentrated in vacuo to leave a yellow oil, which was chromatographed on silica gel eluting with 3% methanol/chloroform

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

Procedure: A mixture of ethyl isonipecotate (102 g, 0.65 mole) and 1-bromobutane (72 ml, 0.67 mole) in ethanol (1.2 L) was treated with anhydrous potassium carbonate (180 g, 1.3 mole) and heated under reflux for 2 h. The mixture was allowed to cool an then filtered through kieselguhr. The filtrate was concentrated in vacuo to leave a yellow oil, which was dissolved in ether (300 ml) and added dropwise over 20 minutes to a stirred suspension of lithium aluminium hydride (50 g, 1.3 mole) in ether (500 ml) at 0° C. under nitrogen. The mixture was stirred at room temperature for 18 h, then cooled to 0° C. and treated with water (50 ml), 10% NaOH solution (50 ml) and water (150 ml). The mixture was filtered through keiselguhr and the filtrate concentrated under vacuum to leave a pale yellow oil, which was distilled to afford the title compound as a colourless oil (88.5 g, 80%) bp 102°-108° C. at 0.1 mm Hg. heated under reflux for 2 h to cool an then filtered through kieselguhr The filtrate was concentrated in vacuo to leave a yellow oil, which cooled to 0° C. The mixture was filtered through keiselguhr the filtrate concentrated under vacuum to leave a pale yellow oil, which was distilled

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

Procedure: A suspension of lithium aluminum hydride (1.39 g) in THF (100 ml) was ice-cooled, to which was added dropwise a solution of a mixture (4.15 g) of ethyl 1-n-butylisonipecotate and 1-n-butylisonipecotic acid obtained in Preparation Example 19 in THF (100 ml) over a period of 15 minutes with stirring. The mixture was stirred under ice-cooling for 10 minutes, and then at room temperature for 30 minutes. To the reaction solution were successively added water (2 ml), a 15% aqueous solution of sodium hydroxide (2 ml), water (6 ml) and anhydrous magnesium sulfate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure to give the title compound (3.84 g). This compound was used for the subsequent reaction without purification. cooled, to which The mixture was stirred under ice- cooling for 10 minutes The reaction solution was filtered off with Celite the solvent was distilled off under reduced pressure

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

Procedure: A suspension of lithium aluminum hydride (1.39 g) in THF (100 ml) was ice-cooled, to which was added dropwise a solution of a mixture (4.15 g) of ethyl 1-n-butylisonipecotate and 1-n-butylisonipecotic acid obtained in Preparation Example 19 in THF (100 ml) over a period of 15 minutes with stirring. The mixture was stirred under ice-cooling for 10 minutes, and then at room temperature for 30 minutes. To the reaction solution were successively added water (2 ml), a 15% aqueous solution of sodium hydroxide (2 ml), water (6 ml) and anhydrous magnesium sulfate, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was filtered off with Celite, and the solvent was distilled off under reduced pressure to give the title compound (3.84 g). This compound was used for the subsequent reaction without purification. cooled, to which The mixture was stirred under ice- cooling for 10 minutes The reaction solution was filtered off with Celite the solvent was distilled off under reduced pressure

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

Procedure: 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methanol (D6) using the method of Example 1a to afford (1-n butyl -4-piperidyl)methyl 5-fluoroindole-3-carboxylate as an orange oil (30%), following flash chromatography on silica gel eluting with 10% ethanol/chloroform.

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

Procedure: 5-Fluoroindole-3-carboxylic acid chloride was reacted with (1-n butyl-4-piperidyl)methanol (D6) using the method of Example 1a to afford (1-n butyl -4-piperidyl)methyl 5-fluoroindole-3-carboxylate as an orange oil (30%), following flash chromatography on silica gel eluting with 10% ethanol/chloroform.

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

Procedure: 1-Butyl-4-piperidinylmethanol (0.500 g 2.12 mmol) was dissolved in dry THF (3 ml) and treated with methyllithium (1.5M solution in diethyl ether) 2.16 ml, 2.33 mmol) with stirring under nitrogen. After 10 minutes, N-chlorocarbonyl-1,2,3,4,4a,9a-hexahydrocarbazole (0.630 g, 2.68 mmol) (Ref: WO 89/09217) in dry THF (5 ml) was added dropwise with stirring. After 48 hours, the reaction mixture was filtered and the filtrate evaporated under reduced pressure. The residue was purified by silica-gel chromatography, eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3 to give the title compound as a clear, colourless oil, which was converted to the oxalate salt, nap 187°-189° C. with stirring After 48 hours the reaction mixture was filtered the filtrate evaporated under reduced pressure The residue was purified by silica-gel chromatography eluting with 2% MeOH/CHCl3 -3%MeOH/CHCl3