TERT-BUTYL 4-(3-HYDROXYPROPYL)TETRAHYDRO-1(2H)-PYRIDINECARBOXYLATE

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: 1.63 g (6.83 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 50 ml of ethanol, treated with 350 mg of PtO2.H2O and hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated to give 1.65 g (99%) of 4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 244 (MH1, 1Cl). The reaction was filtered evaporated

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

Procedure: 1.63 g (6.83 mmol) of 4-(3-Hydroxy-prop-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester was dissolved in 50 ml of ethanol, treated with 350 mg of PtO2.H2O and hydrogenated (1 atm) for 7 h. The reaction was filtered and evaporated to give 1.65 g (99%) of 4-(3-Hydroxy-propyl)-piperidine-1-carboxylic acid tert-butyl ester, MS: 244 (MH1, 1Cl). The reaction was filtered evaporated

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

Procedure: To a tetrahydrofuran (110 mL) solution of 10.7 g of tert-butyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate was added 19.0 g of carbon tetrabromide under cooling with water, to which 15.0 g of triphenylphosphine was then added over a period of 13 minutes. This mixture was stirred at room temperature for 2 hours and 30 minutes and allowed to stand for 13 hours. To the reaction mixture were added water, ethyl acetate, and a saturated sodium chloride aqueous solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to provide 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate as colorless oily form. was then added over a period of 13 minutes to stand for 13 hours The organic layer was separated washed with a saturated sodium chloride aqueous solution dried with anhydrous magnesium sulfate by distilling off the solvent under reduced pressure The resultant residue was purified

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A solution of 6 g of di(tert-butyl)carbonate in 20 ml of dioxan was introduced into a solution of 3.2 g of 3-(4-piperidinyl)propanol in 50 ml of dioxan containing 25 ml of a 2N aqueous solution of sodium hydroxide, cooled at 0° C. The mixture was allowed to react for 16 hours at room temperature. The solution was then evaporated and the residue was extracted with ethylether. The organic layer was washed with a 10% solution of KHSO4 and then dried over MgSO4. to react for 16 hours at room temperature The solution was then evaporated the residue was extracted with ethylether The organic layer was washed with a 10% solution of KHSO4 dried over MgSO4

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

Procedure: Methanesulfonyl chloride (2.7 ml) was dropwise added to a methylene chloride (200 ml) solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) at 0° C., followed by stirring overnight at room temperature. The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v)) to obtain tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g). The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v))

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

Procedure: Methanesulfonyl chloride (2.7 ml) was dropwise added to a methylene chloride (200 ml) solution of tert-butyl 4-(3-hydroxypropyl)piperidine-1-carboxylate (8.00 g) and TEA (4.8 ml) at 0° C., followed by stirring overnight at room temperature. The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine, then dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v)) to obtain tert-butyl 4-{3-[(methylsulfonyl)oxy]propyl}piperidine-1-carboxylate (10.1 g). The reaction liquid was washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine dried over anhydrous magnesium sulfate the solvent was evaporated The residue was purified by silica gel column chromatography (eluent: EtOAc:hexane=1:3 (v/v))

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

Procedure: Using benzhydrol and 1-(tert-butoxycarbonyl)-4-piperidinepropanol, the procedure of Reference Example 23 was otherwise repeated to provide the title compound. Yield 90%.