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目的对氯可托龙新戊酸酯及其原料药中有关物质进行分离及结构鉴定。方法采用制备高效液相色谱法对氯可托龙新戊酸酯中的杂质进行分离,并应用HPLC-ESI-MS、NMR、UV、IR法对氯可托龙新戊酸酯及其有关物质进行结构鉴定。结果氯可托龙新戊酸酯原料药中含有(6R,9R,16R)-9-氯-6β-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-21-新戊酸酯[(6R,9R,16R)-9-chloro-6β-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate,1]、(9R,16R)-9-氯-4-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-21-新戊酸酯[(9R,16R)-9-chloro-4-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate,2]和(9R,16R)-9-氯-6α-氟-11β,21-二羟基-16α-甲基-1,4-孕甾二烯-3,20-二酮-11,21-二新戊酸酯[(9R,16R)-9-chloro-6α-fluoro-11β,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-11,21-dipivalate,3]3种杂质。结论从氯可托龙新戊酸酯原料药中分离得到3个杂质,3个化合物均为首次发现。其中杂质1为6-H的差向异构体,杂质2为同分异构体,杂质3为11-OH与新戊酸酯化产物。结合合成过程分析,三者可能均为合成过程中的副产物。
OBJECTIVE To isolate and identify the related substances of clotriptyline pivalate and its raw drug. Methods The impurities in chloro-tolterodipropionate were separated by preparative high performance liquid chromatography (HPLC), and the effects of the content of chlorotocolicin pivalic acid and its related substances were analyzed by HPLC-ESI-MS, NMR, UV, IR Structural identification. Results The clomipramine pivalate drug substance contained (6R, 9R, 16R) -9-chloro-6β-fluoro-11β, 21-dihydroxy-16α-methyl-1,4-pregnadien- 3,20-dione-21-pivalate [(6R, 9R, 16R) -9-chloro-6β-fluoro-11β, 21-dihydroxy-16α-methylpregna-1,4-diene-3,20- dione-21-pivalate, 1], (9R, 16R) -9-chloro-4-fluoro-11β, 21- dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione 21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione-21-pivalate, And (9R, 16R) -9-chloro-6α-fluoro-11β, 21-dihydroxy-16α-methyl-1,4-pregnadiene-3,20-dione-11,21-dipentene The ester [(9R, 16R) -9-chloro-6α-fluoro-11β, 21-dihydroxy- 16α-methylpregna-1,4-diene-3,20-dione-11,21-dipivalate, . Conclusion Three impurities were isolated from clotriptyline p-valerate. Three compounds were found for the first time. Among them, impurity 1 is the 6-H epimer, impurity 2 is an isomer, and impurity 3 is 11-OH and a pivalic acid esterification product. Combined with the synthetic process analysis, the three may be by-products of the synthesis process.