米拉贝隆原料药主要降解产物的鉴定研究

目的：对米拉贝隆主要降解产物的结构进行鉴定。方法：应用LC-MS对米拉贝隆4个主要降解产物进行了鉴定，色谱柱为COSMOSIL C₁₈-MS-II（250 mm×4.6 mm，5 μm），流动相为乙腈-0.1%三氟醋酸水溶液，梯度洗脱，流速1.0 mL·min^-1；利用高效液相色谱对4个降解产物进行了制备，并进一步利用核磁共振技术和旋光仪进行了结构确证。结果：4个主要降解产物分别为米拉贝隆的酰胺基水解物：2-氨基-4-噻唑乙酸、2-氨基-4-甲基噻唑、（R）-2-[（4-氨基苯基乙基）氨基]-1-苯基乙醇，以及1个肟衍生物：（Z）-苯甲醛肟。结论：本法为米拉贝隆生产及贮存条件的选择提供了科学依据。

Objective: To identify the structure of the main degradation products of mirabegron. Methods: LC-MS was adopted to analyze the structure of four main degradation products of mirabegron. HPLC was performed on a COSMOSIL C₁₈-MS-II(250 mm×4.6 mm, 5 μm) column, using gradient elution with acetonitrile-0.1% trifluoroacetic acid buffer as the mobile phase at a flow rate of 1.0 mL·min^-1. Four main degradation products were separated from mirabegron by HPLC, and their structures were further identified by NMR and polarimeter. Results: The four main degradation products were the acylamino group hydrolysates:2-amino-4-thiazoleacetic acid, 4-methylthiazol-2-amine,(R)-2-[(4-aminophenethyl)amino]-1-phenylethanol, and oximes of mirabegron:(Z)-benzaldehyde oxime. Conclusion: This method provides a scientific basis for selecting the conditions of mirabegron production and storage.

[1] 那彦群,叶章群,孙颖浩,等. 2014版中国泌尿外科疾病诊断治疗指南[M].北京:人民卫生出版社,2014:410 NA YQ,YE ZQ,SUN YH,et al. The 2014 Edition of the Diagnostic China Guidelines for the Treatment of Diseases in Department of Urology[M]. Beijing:People's Medical Publishing House,2014:410
[2] 沈周俊,张祥,邵远.膀胱过度活动症的治疗新进展[J].现代泌尿外科杂志,2014,19(10):640 SHEN ZJ,ZHANG X,SHAO Y. Treatment advances for overactive bladder[J]. J Mod Urol,2014,19(10):640
[3] 范鸣.膀胱过度活动症治疗药Mirabegron[J].药学进展,2012, 36(3):133 FAN M. Medicine for the treatment of overactive bladder syndrome Mirabegron[J]. Prog Pharm Sci,2012,36(3):133
[4] 章磊,谭支敏,焦慧荣,等.米拉贝隆有关物质的合成[J].中国医药工业杂志,2014,45(1):9 ZHANG L,TAN ZM,JIAO HR,et al. Synthesis of related substance of mirabegron[J]. Chin J Pharm,2014,45(1):9
[5] 唐启东,宫平.米拉贝隆(mirabegron)[J].中国药物化学杂志, 2012,22(6):544 TANG QD,GONG P. Mirabegron[J]. Chin J Med Chem,2012,22(6):544
[6] 李杨.米拉贝隆的合成及工艺优化[D].哈尔滨:黑龙江大学,2014 LI Y. Synthesis and Process Optimization of Mirabegron[D]. Harbin:Heilongjiang University,2014
[7] ZHOU F,ZHOU Y,ZHOU Q,et al. Liquid chromatographic separation and thermodynamic investigation of mirabegron enantiomers on a Chiralpak AY-H column[J]. Chromatogr Sci, 2015,53(8):1361
[8] TEIJLINGEN R,MEIJER J,TAKUSAGAWA S,et al. Development and validation of LC-MS/MS methods for the determination of mirabegron and its metabolites in human plasma and their application to a clinical pharmacokinetic study[J]. J Chromatogr B, 2012,887-888:102
[9] KRAUWINKEL W,van DIJK J,SCHADDELEE M,et al. Pharmacokinetic properties of mirabegron,a β3-adrenoceptor agonist:results from two phase I,randomized,multiple-dose studies in healthy young and elderly men and women[J]. Clin Ther,2012, 34(10):2144
[10] SETAMDIDEH D,KHEZRI B,ESMAEILZADEH S. Synthesis of oximes with NH 2OH. HCl/DOWEX(R)50WX4 system[J]. J Chin Chem Soc,2012,59:1119
[11] HANA B,DAVOOD S. An eco-friendly system for oximation of organic carbonyl compounds under microwave irradiation[J]. Orient J Chem,2014,30(2):699
[12] KELLY DR,BAKER SC,KING DS,et al. Studies of nitrile oxide cycloadditions and the phenolic oxidative coupling of vanillin aldoxime by Geobacillus sp. DDS012 from Italian rye grass silage[J]. Org Biomol Chem,2008,6(4):787