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目的为加强对皮质类激素卤倍他索丙酸酯原料药的质量控制,首次合成了卤倍他索丙酸酯的3个杂质。方法以卤倍他索丙酸酯及二氟拉松为起始原料,经过水解反应制得21-氯代-6α,9-二氟-11β,17-二羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮(杂质Ⅰ);以二氟拉松为起始原料,经过磺化反应、氯代反应及酯化反应得到21-氯代-6α,9-二氟-17-羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮-11-丙酸酯(杂质Ⅱ);以二氟拉松为起始原料,通过酯化反应生成6α,9-二氟-11β-羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮-17-丙酸酯-21-乙酸酯(杂质Ⅲ)。结果与结论合成的3种杂质的结构经~1H-NMR、HPLC-MS确证与美国药典中杂质结构一致,可以作为卤倍他索丙酸酯原料药质量控制的杂质对照品。
OBJECTIVE To improve the quality control of corticosteroid halobetasol propionate, three impurities of haloxapril hydrochloride were synthesized for the first time. Methods Haloperidol propionate and difluprase were used as starting materials to prepare 21-chloro-6α, 9-difluoro-11β, 17-dihydroxy-16β-methyl- 1,4-diene-3,20-dione (impurity I); using difluralin as a starting material, sulfonation, chlorination and esterification give 21-chloro-6α, Difluoro-17-hydroxy-16β-methylpregna-1,4-diene-3,20-dione-11- propionate (impurity II); using difluralin as starting material, The formation of 6α, 9-difluoro-11β-hydroxy-16β-methylpregna-1,4-diene-3,20-dion-17-propionate-21-acetate (impurity III) . RESULTS AND CONCLUSIONS The structures of the three impurities synthesized by ~ 1H-NMR and HPLC-MS confirmed that they were consistent with the impurities in the US Pharmacopoeia and could be used as reference substance for the quality control of halopexol propionate.