Study On The Synthesis And The Quality Of Fluticasone Propionate

Fluticasone propionate is a synthetic trifluoro-replacing glucocorticoid. It was a highly selective glucocorticoid receptor agonist, and was applied in the clinical treatment of asthma, allergic rhinitis, chronic infarct pneumonia, and atopic dermatitis. This article introduced the pharmacological effects of fluticasone propionate in the treatment of rhinitis, asthma and chronic infarct pneumonia; pharmacokinetic properties of absorption, distribution, and elimination of fluticasone propionate; acute toxicity; and the main indication and efficacy of fluticasone propionate.The flumethasone was oxidated by H₅IO₆, then the oxidated product was acylated by propionate chloride, replaced by N,N-dimethylthiocarbamoyl chloride, and then treated with alcoholysis by methanol and then replace fluoromethyl with bromofluoromethane, the target product fluticasone propionate obtained. We optimized the reaction conditions in initial, the overall yield was 57% in terms of flumethasone. The structure of the product was confirmed by UV, MS, NMR and IR. The data obtained by the thermal analysis indicate that fluticasone propionate bears no crystal water and the melting point was consistent to reports.Then we studied the quality of fluticasone propionate. The physical character, such as its solubility, melting point, UV absorbtion spectrum, absorbtion percentage coefficient, were tested according to the part II of Ch.P(2005). The fluticasone propionate was soluble in DMSO and DMF, and the melting point was 278℃～280℃, the maximum absorption in methanol was 237 nm, the absorbtion percentage coefficient was 362.33. Chosen methanol-0.01 mol/L ammonium dihydrogen orthophosphate water solution (using phosphorylation to adjust pH to 3.5)-acetonitrile (50:35:15) as the mobile phase. The limited detection was also examined, and the data was 0.56 ng. The exclusive character of the relative substances were examined by the destruction experiments of high temperature, acid, base and oxidation, and the result showed that it worked well. The content was mensured by HPLC, through the examination of the linearity, the recur ratio and the stability, the concentration of fiuticasone propionate was linearity to the area of the peak in the range of 7～35μg/ml, the linearity regress formula was A=11587C-3296.3, and the relative constant is 1.000. The examination of stability showed that the sample was stable in 8h, and the RSD was 0.81%. Injecting the same sample five times continuous, the RSD was 0.57%, showed good reproducibility; the results showed that this method was accurate and convenient. Its relative substances content and the contents of three batches were met the requirement. Impact study of high temperature carried under 200℃, impact study of high humidity carried under 25℃and RH92.5%, impact study of light carried under 4000 1x±500 1x, inspection when 5th d and 10th d. The accelerated experiment carried under 40℃±2℃and RH 75%±5%, inspection when 1st,2nd,3rd,6th month; long-term experiment carried under 25℃±2℃and RH 60%±10%, inspection when 3rd,6th month. Experimental results of impact factors showed that the high-temperature, high humidity, and high light intensity made slight effect on the stability of fiuticasone propionate; and the results of accelerated experiment and long-term experiment showed that fiuticasone propionate changed insignificantly in six months.According to the results of the study on the quality of fiuticasone propionate, the draft of the quality standard of fiuticasone propionate was formulated.