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Stage #1: With oxalyl dichloride; dimethyl sulfoxide In dichloromethane at 0℃; for 0.166667h;
Stage #2: (1-Isopropyl-piperidin-4-yl)-methanol In dichloromethane at 0℃; for 2.25h;
Stage #3: With triethylamine In dichloromethane for 0.166667h;
134.2 Reference Example 134: 3-(1-Isopropylpiperidin-4-yl)acrylic acid hydrochloride
(1) Lithium aluminum hydride (1.10 g) is suspended in tetrahydrofuran (80 ml), and thereto is added a solution of ethyl 1-isopropylpiperidine-4-carboxylate (5.00 g) obtained in Reference Example 127 in tetrahydrofuran (30 ml) dropwise under ice-cooling. The reaction solution is stirred for 2 hours under the ice-cooling, and water (1.1 ml), 15 % aqueous sodium hydroxide solution (1.1 ml) and water (3.3 ml) are added dropwise successively and stirred for additional 10 minutes. To the resulting reaction solution is added potassium carbonate, and the mixture is stirred for 20 minutes, and then the insoluble materials are removed by filtration. The filtrate is concentrated under reduced pressure, and then the resulting residue is purified by NH-silica gel column chromatography (eluent: chloroform/ethyl acetate = 1/1) to give (1-isopropylpiperidin-4-yl)methanol (4.29 g). APCI-MS M/Z:158[M+H]+.(2) Oxalyl chloride (2.0 ml) is dissolved in dichloromethane (120 ml) and thereto is added dropwise a solution of dimethylsulfoxide (3.3 ml) in dichloromethane (15 ml) under dry ice-acetone cooling. After stirring for 10 minutes under ice-cooling, a solution of (1-isopropylpiperidin-4-yl)methanol (3.00 g) obtained in Reference Example 134(1) in dichloromethane (30 ml) is added dropwise over a period of 15 minutes. After addition, the reaction solution is stirred for 2 hours under ice-cooling, and thereto is added dropwise triethylamine (13.3 ml) over a period of 10 minutes. The reaction solution is stirred for one hour while it is warmed to room temperature, and then the solution is poured to saturated aqueous sodium hydrogen carbonate solution. The mixture is extracted with dichloromethane and evaporated to remove the solvent under reduced pressure. The aqueous layer is extracted with ethyl acetate, and the extract is combined with the residue obtained by removing solvent from the above dichloromethane-extract, washed with water and saturated brine and dried over sodium sulfate. The solvent is evaporated under reduced pressure to give the crude material, 1-isopropylpiperidine-4-carbaldehyde (1.96 g). APCI-MS M/Z:156[M+H]+.(3) Triethyl phosphonoacetate (7.96 g) is dissolved in tetrahydrofuran (50 ml) and thereto is added gradually 60 % sodium hydride in oil (1.45 g) under ice-cooling. After stirring for 20 minutes under ice-cooling, to the mixture is added 1-isopropylpiperidine-4-carbaldehyde (5.03 g) obtained in Reference Example 134(2) in tetrahydrofuran (25 ml). The reaction solution is stirred for 3 hours, diluted with diethyl ether, thereto is added water and the mixture is extracted with ethyl acetate. The organic layer is washed with water and saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate = 9/1) to give ethyl 3-(1-isopropylpiperidin-4-yl)acrylate (6.87 g). APCI-MS M/Z:226[M+H]+.(4) Ethyl 3-(1-isopropylpiperidin-4-yl)acrylate (1.01 g) obtained in Reference Example 134(3) is dissolved in ethanol (20 ml), thereto is added 2 N aqueous sodium hydroxide solution (4.5 ml) and the mixture is stirred at room temperature for 24 hours. To the reaction solution is added 2 N hydrochloric acid (9 ml), and the mixture is concentrated under reduced pressure, and then the resulting residue is lyophilized to give the title compound (1.43 g). APCI-MS M/Z:198[M+H]+.
272.D D.
D. 1-Isopropylpiperidine-4-carboxaldehyde A solution of 1-isopropylpiperidine-4-methanol (0.40 g, 2.5 mmol) and N-methylmorpholine (0.46 g, 3.8 mmol) in methylene chloride (20 mL) was treated with tetrapropylammonium perruthenate (0.089 g, 0.25 mmol). After 3 h, the mixture was concentrated and the residue purified by column chromatography (SiO2: 10% to 20% methanol:methylene chloride) affording 0.20 g (50%) of the title compound. 1NMR; FIA-MS, m/e 156 (m+).
With sodium bicarbonate; dimethyl sulfoxide; triethylamine In dichloromethane; water; ethyl acetate
R.2 Reference Example 2
Reference Example 2 Oxalyl chloride (3.15 ml) was dissolved in 30 ml of dichloromethane, a solution of 3.20 ml of dimethyl sulfoxide in 6 ml of dichloromethane was added thereto at-70ØC, the mixture was stirred for 15 minutes, a solution of 2.93 g of (1-isopropyl-4-piperidyl)methanol in 15 ml of dichloromethane was added thereto at -70ØC and the mixture was stirred for 1 hour. After 12.5 ml of triethylamine were added at -70ØC, the mixture was raised to room temperature, then water and a saturated aqueous solution of sodium hydrogen carbonate were added and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated in vacuo and ethyl acetate was added to the resulting residue. After removing the insoluble matter by filtration, the solvent was evaporated in vacuo to give 1.15 g of 1-isopropylpiperidine-4-carbaldehyde. This compound was used for the next reaction without purification.
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