Preparation of key intermediate of lima prostaglandin and its application
A technology of reaction and reaction temperature, applied in the preparation of lima prostaglandin, the key intermediate for the preparation of lima prostaglandin, the field of preparation of lima prostaglandin, can solve the problem of low synthesis efficiency, poor environmental protection, and difficult experimental operation And other issues
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Embodiment 1
[0160] The preparation of compound shown in embodiment 1. formula III
[0161]
[0162] The compound shown in formula I (143.0g, 0.5mol) [synthesized formula (I) from (-)-coreylactone diol according to the general method] was dissolved in dichloromethane (1430.0ml), cooled to 0°C, stirred and added to Dess-Martin Reagent (255.0g, 0.6mol), react at -5 to 0°C until TLC detects that the reaction is complete, flush with Na 2 S 2 o 3 / NaHCO 3 (700g / 260g) in the aqueous solution (3000L), layering, the aqueous layer is extracted with dichloromethane, and the dichloromethane layer is combined, dried over anhydrous magnesium sulfate, filters, and the filtrate is concentrated to volume 1000.0ml to obtain the compound shown in formula II dichloromethane solution.
[0163] Dissolve the phosphate side chain (150.0g, 0.6mol) in dichloromethane (1500.0ml), cool down to 0°C, add dropwise 30% sodium hydroxide solution (87.0g, 0.65mol), and continue at 0 to 5 After stirring for 30 minut...
Embodiment 2
[0164] The preparation of compound shown in embodiment 2. formula V
[0165]
[0166]Under the protection of argon, add the compound shown by formula III (204.0g, 0.5mol) and THF (2000.0ml) into the reaction flask, stir to dissolve, cool down to -25°C, add (-)-DIPCl (1233.0g, 2.5mol) dropwise ) and THF (500.0ml), the dropwise addition process controls the temperature between -30--20°C. React until the reaction is complete as detected by TLC, control the dropwise addition of methanol (300.0ml) at -25°C to terminate the reaction, and concentrate under reduced pressure to dryness to obtain a residue. After the residue is dissolved in ethyl acetate, it is poured into a saturated aqueous ammonium chloride solution, and the layers are separated. The aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with water and brine successively, and the layers were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the...
Embodiment 3
[0167] The preparation of compound shown in embodiment 3. formula VII
[0168]
[0169] Under the protection of argon, the compound represented by formula V (104.8g, 0.2mol) was dissolved in anhydrous toluene (2000ml), cooled to -30°C, and 1mol / L diisobutylaluminum hydride (600.0ml, 0.6 mmol), keep the internal temperature <-25°C until the reaction is complete as detected by TLC. Add methanol (500ml) dropwise to destroy the reaction, raise the temperature to room temperature and stir for 2 hours after adding, add 50 g of diatomaceous earth, stir and filter, rinse the filter cake with toluene, and concentrate the filtrate under reduced pressure to obtain an oil, which is purified on a silica gel column to obtain the formula VI shows the compound.
[0170] Under the protection of argon, the BnO(CH 2 ) 3 PPh 3 + Br - (467.0g, 1.0mol) was dissolved in THF (1000ml) and cooled to 10°C. Add 0.5mol / L KHMDS toluene solution (3600ml, 1.8mol), stir at room temperature for 1 hou...
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