Study On The Synthetic Process Of Dexamethasone Disodium Phosphate

Dexamethasone Disodium Phosphate, with the name 1,4-pregnadiene-9α-fluro-16α-methyl-11β,17a,21-triol-3,20-dione-21-phosphate disodium salt, belongs to adrenal cortical hormones, which is a commonly used pharmaceutical of great importance and is highly effective in the area of anti-inflammatory, anti-allergy and anti-rheumatism treatment. This paper reports the synthetic process starting from 8-DM Acetate. First a ring-opening reaction was carried out with the HF- pyridine reagent; then a hydrolysis reaction was conferred with the catalyst of Na2CO3; then with pyrophosphoryl chloride as the reagent, under low temperature dexamethasone phosphate was obtained; finally the neutralization reaction was carried out with NaOH-methanol solution. The products were identified by MS, 'H-NMR, DEPT NMR,13C-NMR, and IR, also the mechanisms of the reactions were briefly discussed.In this paper the optimized conditions of the process in which Dexamethasone Disodium Phosphate was obtained is reported. In the ring opening reaction:n(8-DM Acetate):n(HF): n(DMF)=1.0:93.3:44.1, reaction temperature of-5～0℃, reaction time of 1h, with the yield of 82.8% and the purity of 99.5% after recrystallization with H2O/Methanol solution; the hydrolysis reaction:n(Dexamethasone Acetate):n(Na2CO3):n(Methanol)= 1.0:0.4:214.7, reaction temperature of 25℃, reaction time of 10min, with the yield of 90.3% and the purity of 99.2%; the 21-esterification reaction:n(Dexamethasone):n(Pyrophosphoryl Chloride): n(THF)= 1.0:5.1:18.9, reaction temperature of-65～60℃, reaction time of 1h, with the yield of 89.0% and the purity of 98.7%; the neutralization reaction:n(Dexamethasone Phosphate):n(NaOH):n(Methanol)=1.0:2.12:169.0, reaction temperature of 25℃, reaction time of 1 h, with the yield of 97.5% and the purity of 99.1%。Another purify process with piperazine acetate was porposed and resulted in the overall yield of 85.3% and the purity of 99.7%.This paper also brief study of the crystallization process of the target product. Also this paper tried to grope for the crystal process of Dexamethasone Disodium Phosphate. The result shows that acetone performed better than ether in the crystallization yield, and the evaporation of the solvent helped to increase the yield as well, when acetone was added to the evaporated solution, the crystallization yield was 98.8% of high aggregation. The addition of Tween80 increased the separation and the crystal size of the product.