Key intermediate for preparing limaprost and application thereof
A reaction and compound technology, applied in the preparation of limaprost, the application in the preparation of limaprost, the key intermediate field of the preparation of limaprost, can solve the problem of low synthesis efficiency, difficult experimental operation, poor environmental protection, etc. question
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[0124] In the preparation process of the compound shown in formula IX, the inventors further found that the condition control of its preparation reaction is very important, and various impurities will be produced if the reduction condition is not properly controlled, for example, partially reduced impurity (IX-1), debenzyme impurity ( IX-2) and overreduced impurities (IX-3). Therefore, the control and optimization of the reducing conditions are crucial for the selective reduction to obtain the compound shown in formula IX.
[0125]
[0126] In a preferred embodiment, the reaction temperature of the selective reduction reaction is controlled at -40°C to -20°C. In a preferred embodiment, the reaction pressure of the selective reduction reaction is controlled at 0.1 to 1 atm H 2 . In a preferred embodiment, the selective reduction reaction is carried out in the non-polar solvent ethyl acetate. In a preferred embodiment, the selective reduction reaction is performed using 5%...
Embodiment 1
[0156] The preparation of compound shown in embodiment 1. formula III
[0157]
[0158] 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.
[0159] 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
[0160] The preparation of compound shown in embodiment 2. formula V
[0161]
[0162] 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 th...
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