Background and overview[1][2]
Prostaglandins are an important class of endogenous physiologically active substances. They are important mediators in various physiological processes and have high pharmacological activity. Clinically, prostaglandin drugs are mainly synthesized artificially. CoreyLactoneBenzoate is an important intermediate for the synthesis of prostaglandin drugs. Its molecular formula is C15H16O5 and its chemical name is 5-(benzoyloxy)hexahydro-4-(hydroxymethyl)-2H- Cyclopenta[b]furan-2-one generally includes (±) benzoyl cory lactone, (-) benzoyl cory lactone and (+) benzoyl cory lactone.
Preparation[1]
One-pot preparation of (+) benzoyl corylide
Add 5L pyridine into the reaction kettle with a filter element at the bottom, add 1kg (1eq) of (+) corelactone diol under stirring, add 1.62kg (1eq) triphenylmethane, and control the temperature at 10°C for 24 hours. To complete reaction, add 670ml (1eq) benzoyl chloride dropwise, control the temperature at 20°C and react for 6h until complete reaction; add 10L pure water to the reaction kettle and stir for 3h to obtain a suspension. Pour nitrogen into the reaction kettle and pass it through the bottom of the kettle. The filter element will be suspended and hydraulically filtered, then 5L of methanol will be added to the reaction kettle, heated to reflux for 2 hours, and the liquid will be filtered to obtain a solid powder; 10L of acetonitrile will be added to the reaction kettle, 14L of 1mol/L hydrochloric acid aqueous solution will be added dropwise, and the temperature will be controlled at 30°C for 12 hours. When the reaction is complete, cool the reaction system to 20°C, add saturated sodium bicarbonate aqueous solution to neutralize the reaction to pH=7; evaporate the solvent acetonitrile in the reaction kettle under reduced pressure, and obtain the crude product by pressure filtration; add 5L of isoenzyme into the reaction kettle. propyl ether, heated to reflux for 3 hours, filtered and dried to obtain 1.48Kg of product (+) benzoyl corylide, with a yield of 92.39% and a purity of 99.41%.
One-pot preparation of (-) benzoyl corylide
Add 6L pyridine to the reaction kettle with a filter element at the bottom, add 0.8kg (1eq) of (-) corelactone diol under stirring, add 1.55kg (1.2eq) triphenylmethane chloride, and control the temperature at 20°C React for 10 hours until complete reaction, add 590ml (1.1eq) benzoyl chloride dropwise, control the temperature at 30°C and react for 3 hours until complete reaction; add 24L pure water to the reaction kettle and stir for 1 hour to obtain a suspension, introduce nitrogen into the reaction kettle, and pass The filter element at the bottom of the kettle will be suspended and hydraulically filtered, then 8L of ethanol will be added to the reaction kettle, heated to reflux for 1 hour, and the liquid will be filtered to obtain a solid powder; 16L of tetrahydrofuran will be added to the reaction kettle, and 8L of 3mol/L hydrochloric acid aqueous solution will be added dropwise, and the temperature will be controlled at 45 °C for 4 hours until the reaction is complete, cool the reaction system to 10°C, add saturated sodium carbonate aqueous solution to neutralize the reaction to pH=7; evaporate the solvent tetrahydrofuran in the reaction kettle under reduced pressure, and press filtrate to obtain the crude product; add it to the reaction kettle 8L of diethyl ether, heated to reflux for 2 hours, filtered and dried to obtain 1.17Kg of product (-) benzoyl corylide, with a yield of 91.11% and a purity of 99.21%.
One-pot preparation of (±) benzoyl corylide
Add 5L pyridine into the reaction kettle with a filter element at the bottom, add 0.5Kg (±) corelactone diol (1eq) under stirring, add 0.89Kg (1.1eq) triphenylmethane chloride, and control the temperature at 30°C React for 6 hours until complete reaction. Add 352ml (1.05eq) benzoyl chloride dropwise. Control the temperature at 30°C and react for 1 hour until complete reaction. Add 5L pure water to the reaction kettle and stir for 1 hour to obtain a suspension. Pour nitrogen into the reaction kettle and pass The filter element at the bottom of the kettle will be suspended by hydraulic filtration, then add 5L of isopropyl alcohol to the reaction kettle, heat and reflux for 1 hour, filter the liquid to obtain solid powder; add 10L of tetrahydrofuran to the reaction kettle, and add 3.5L of 6mol/L hydrochloric acid aqueous solution dropwise. Control the temperature at 60°C and react for 1 hour until complete reaction. Cool the reaction system to 0°C, add saturated sodium bicarbonate aqueous solution to neutralize the reaction to pH=7; evaporate the solvent tetrahydrofuran in the reaction kettle under reduced pressure, and press filtrate to obtain the crude product; 12.5L n-propyl ether was added into the reaction kettle, heated to reflux for 1 hour, filtered and dried to obtain 0.72Kg of product (±) benzoyl corylide, with a yield of 90.15% and a purity of 99.33%.
Isomer analysis[2]
Instruments and conditions
Column: BCchiralAS-H (250×4.6mm, 5.0μm)
Mobile phase: n-hexane-isopropyl alcohol (90:10)
Column temperature: room temperature
Flow rate: 1.0mL/min
Sample concentration: 10μg/mL
Injection volume: 1μL
Detection wavelength: 210nm
Experimental steps
Precisely weigh 10 mg of (±)-benzoylcorylide into a 10 mL volumetric flask, dissolve and dilute to the mark with n-hexane-isopropyl alcohol (90:10), shake well, and use it as a test sample mother liquor. Precisely draw 100 μL of the test sample mother solution into a 10 mL volumetric flask, adjust the n-hexane-isopropyl alcohol (90:10) solution to the mark, and prepare (±)-benzoyl corylide with a concentration of 10 μg/mL. For the test solution, draw 1 μL of the test solution into the liquid chromatograph and record the chromatogram.
Experimental results: The separation degree of the two enantiomers: (+)-benzoylcorylide and (-)-benzoylcorylide is 1.7. Enantiomers can be completely separated.
Main reference materials
[1][Chinese invention] CN201711470138.8 One-pot method for preparing benzoyl corylide
[2][China invention, China invention authorization] CN201610574784.8 A method of separating benzoyl corylide enantiomers by HPLC analysisIsomers method
