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Reference：
[1] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
[2] Journal of the Society of Chemical Industry, London, 1940, vol. 59, p. 92,94
With n-butyllithium; diethylamine; In tetrahydrofuran; hexane; at -78 - 0℃; for 25h;
Diethylamine (1.4 ml) was dissolved in tetrahydrofuran (26 ml), and a solution (1.59 M, 42 ml) of n-butyllithium in hexane was added dropwise at -78C. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of 2-methylbenzoic acid (4.1 g) in tetrahydrofuran was added dropwise to the reaction solution. The mixture was stirred at 0C for 30 min and cooled to -78C. A solution (26 ml) of <strong>[161609-84-3]1-benzyloxycarbonyl-4-cyanopiperidine</strong> (7.2 g) in tetrahydrofuran was added dropwise to the reaction solution, and the mixture was stirred at -78C for one day. After the completion of the reaction, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, and the solvent was concentrated. The obtained residue was subjected to silica gel column chromatography. A chloroform:methanol=30:1 effluent fraction was concentrated, and diisopropyl ether was added to the precipitated crystals. The crystals were collected by filtration. Recrystallization from isopropanol gave 3-(1-benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) as white crystals. melting point: 179-181C. 3-(1-Benzyloxycarbonylpiperidin-4-yl)-2H-isoquinolin-1-one (1.2 g) was suspended in chloroform (10 ml), and a solution (5 ml) of hydrobromic acid in acetic acid was added dropwise. After the completion of the reaction, the solvent was concentrated, and acetone was added to the obtained residue. The precipitated crystals were collected by filtration to give 3-(piperidin-4-yl)-2H-isoquinolin-1-one hydrobromide (1.1 g). melting point: >270C.
General procedure: To a solution of 3a (1 g) in ethanol was added Pd/C (5%, 0.1 g) and the mixture was stirred for 24 hrs at room temperature in a hydrogen atmosphere under atmospheric pressure. Insoluble matters were removed using Celite, and the filtrate was concentrated in vacuo to give the desired product 4a (0.76 g) as a yellow solid. To a solution of carboxylic acid (1 equiv) in CH2Cl2 (15 mL) at 0 C was added DMAP (1 equiv) and EDCI (1 equiv). The reaction mixture was stirred at 0 C for 45 minutes. At this time 4a (1 equiv) was added and the mixture was warmed to room temperature and stirred overnight. The resulting mixture was concentrated in vacuo, partitioned between 1.0 M HCl (20 ml) and ethyl acetate (3×20 mL). The combined organic layers were washed with brine (2 × 15 ml), dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatograph using a mixture of petroleum ether/ethyl acetate (20 : 5, v/v) as eluent to afford the product as a white solid. To a solution of the obtained solid (1 equiv) in 2:3:1 THF/MeOH/H2O (18 ml) was added LiOH·H2O (1.5 equiv). After stirring at room temperature for 4 h, the volatiles were removed under reduced pressure. The residue was acidified with 1N hydrochloric acid solution, and then filtered and the filter cake was washed with 5 mL of water, dried in vacuum to afford a white powder. Recrystallization from 75% EtOH gave the desired compounds 2-17 as white solid.
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