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Production method of Prednicarbate

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Production method of Prednicarbate : Prednicarbate takes prednisolone as raw material.

110g(0.305mo1) prednisolone was dissolved in 2.2l anhydrous dioxane, and 147ml(0.70mo1) tetraethyl carbonate and 12g p-toluenesulfonic acid were added. Stir or leave at 22℃ for 17h. The reaction solution was poured into 17L of water and neutralized with sodium bicarbonate. First, an oily substance is precipitated and crystallized after 1 ~ 24h. Filter and wash. In the presence of phosphorus pentoxide, in high vacuum drying to constant weight, 126.5 g compounds (Ⅰ), yield of 90%. With methylene chloride - ethanol - ether recrystallization, can be used for the analysis of compounds (Ⅰ), melting point 155 ℃.

125 g (0.27 mo1) compounds (Ⅰ) soluble in anhydrous acetic acid, 1.4 L under 18 ℃ and stir, add 10 ml of water. Place it at 18℃ for 5h and stir it with 18L water containing 1kg sodium chloride. Filter and collect sediment. Wash with water. In the presence of phosphorus pentoxide, high vacuum drying to constant weight, 72g crude products. Filtrate was reduced and concentrated, and then precipitated into solid. After drying, 36g was obtained. Both amounted to 108 g compounds (Ⅱ) of crude products, yield of 92.3%. The crude product can be used for the next step reaction after recrystallization with acid-free dichloromethane - ethanol. The standard products used for analysis can be obtained by silica gel chromatography and elution of anhydrous dichloromethane to obtain the best Prednicarbate with a melting point of 145℃.

From the compound (Ⅱ) there are two ways to get Prednicarbate.

Method for 8.5 g (0.158 mo1) compounds (Ⅱ) dissolved in 680 ml anhydrous pyridine, under 0 ℃ and stirring, 60 minutes, add 18.2 g (0.197 mo1) propionyl chloride. Stir at 0℃ for 30min and then at 20℃ for 2h. The reaction solution was poured into 18L water containing 1kg of sodium chloride. Filter and collect sediment, wash thoroughly with water. In the presence of phosphorus pentoxide, 63g prenica ester crude product was obtained by high vacuum drying to constant weight with 81.4% yield. The crude product was eluted with toluene - ethyl acetate by silica gel chromatography (200g). After concentration, 5.7g Prednicarbate was obtained by recrystallization with ethanol-ethyl ether. The yield was 57% and the melting point was 110 ~ 112℃. 4g this product was heated in 80ml isopropyl ether for 60min, filtered and dried to obtain crystallization with higher melting point at 183℃.

Methods 2:1. 05 kg (2.43 mo1) compounds (Ⅱ) of crude product soluble in 10 l anhydrous methylene chloride in 20 ℃ drop 0.336 I. (2.6mo1) propionic anhydride was added to 50g(0.41mo1) 4-dimethylaminopyridine. After stirring at 20℃ for 16h, the reaction solution was successively washed with water, sodium bicarbonate solution and water, and dried with anhydrous sodium sulfate. The solvent was removed by vacuum distillation, and the residue was similar to the above method. After chromatography, isopropyl ether was used for recrystallization to obtain 360g Prednicarbate crude product with a yield of 30.4% and a melting point of 110 ~ 112℃.