Ethanol → Ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate

Temperature

90 °C

In toluene (50 ml) is dissolved S-isomer-rich 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid (3.6 g), and ethanol (10 ml) and p-toluenesulfonic acid (0.2 g) are added to the solution, followed by agitating at 90° C. for 1.5 hours. The mixture is diluted with ethyl acetate (100 ml), washed with saturated sodium hydrogen-carbonate solution (100 ml) and water (100 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give S-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate (3.7 g) as an oil. This product (1.0 g) is dissolved in pyridine (5 ml), and methanesulfonyl chloride (0.4 ml) is added dropwise to the solution with stirring over the period of 5 minutes under ice-cooling. After stirring is continued for 15 minutes under ice-cooling, water (3 ml) is added to the mixture, followed by stirring for 30 minutes. Ethyl acetate (150 ml) is added to the mixture, and the resulting mixture is washed with 1N hydrochloric acid (50 ml×2), saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml). The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give S-isomer-rich 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate [1.2 g: [α]D -16.6° (in methanol)] as a pale yellow oil. This product (1.2 g) and cesium propionate [prepared from cesium carbonate (0.47 g) and propionic acid (0.32 g)] are added to N,N-dimethylformamide (30 ml), and the mixture is stirred at 90° C. for 1 hour. After cooling, ethyl acetate (150 ml) is added to the mixture, and the mixture is washed with 0.1N hydrochloric acid (50 ml×2), sodium hydrogencarbonate solution (50 ml) and water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily product is purified by silica gel column chromatography (hexane-ethyl acetate=3:1) to give R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-propionyloxyhexanoate (1.07 g) as a colorless oil. This product (1.05 g) is dissolved in ethanol (10 ml), and 1N aqueous sodium hydroxide solution (10 ml) is added dropwise to the solution over the period of 5 minutes, followed by agitating for 30 minutes. The mixture is made acidic with conc. hydrochloric acid and extracted with ethyl acetate (100 ml). The ethyl acetate layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich 6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoic acid as an oily product. This product is dissolved in toluene (30 ml), and ethanol (5 ml) and p-toluenesulfonic acid (0.1 g) are added to the solution, followed by stirring at 90° C. for 1.5 hours. Ethyl acetate (150 ml) is added to the mixture, and the resulting mixture is washed with saturated sodium hydrogencarbonate solution (50 ml) and water (50 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)- 2-hydroxyhexanoate (0.84 g) as a colorless oil. This product (0.3 g) is dissolved in pyridine (3 ml), and methanesulfonyl chloride (0.15 ml) is added dropwise to the solution with stirring under ice-cooling over the period of 2 minutes. The mixture is stirred for 1 hour under ice-cooling, and ethyl acetate (70 ml) is added to the mixture. The resulting mixture is washed with 1N hydrochloric acid (30 ml×2), saturated sodium hydrogencarbonate solution (30 ml) and water (30 ml). The ethyl acetate layer is dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give R-isomer-rich ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-methanesulfonyloxyhexanoate [0.35 g: [α]D +16.6° (in methanol)] as a colorless oil.

1. additionare added to the solution
2. washwashed with saturated sodium hydrogen-carbonate solution (100 ml) and water (100 ml)
3. dry with materialdried over anhydrous magnesium sulfate
4. concentrationconcentrated under reduced pressure

ORD record

ord-59f4df480c784b679d2a6473bf4bab51

Source dataset

uspto-grants-1988_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04739066