First total synthesis of 3a-hydroxy-1,1-dimethyl-5-((N-methylsulfamoyl)methyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium 2,2,2-trifluoroacetate by mimicking the oxidative degradation pathway of sumatriptan ☆ Author links open overlay panel Pradip K. Sasmal a ,
Ganesh Ramachandran a ,
Ying Zhang b ,
Zhong Liu b Show more
Highlights
• Forced degradation studies were performed on sumatriptan autoinjector product Zembrace under different stress conditions.
• The primary impurity in the drug product formed due to oxidative degradation of Zembrace.
• To support toxicological studies and drug safety of Zembrace, degradation compound 3 was synthesized for the first time.
• This synthesis was achieved by oxidative cyclization of indole moiety followed by N-quarternization as key steps.
• Compound 3 was extensively characterized by 1D and 2D NMR spectroscopy including COSY and HSQC.
Abstract The expiry date of any medicine is decided based on the time span during which the drug product maintains its quality and is safe as well as effective. The levels of various impurities present in any drug product are considered safe based on various toxicological studies in preclinical species and safety parameters monitoring during clinical studies. The shelf life of US FDA approved sumatriptan auto-injector product ZEMBRACE SymTouch was extended till 36 months after toxicological qualification of the degradation compound 3a-hydroxy-1,1-dimethyl-5-((N-methylsulfamoyl)methyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-1-ium 2,2,2-trifluoroacetate. The first total synthesis of this degradation product by mimicking the oxidative degradation pathway of sumatriptan is described herein. © 2021 Elsevier Science. All rights reserved.
Keywords Sumatriptan
Zembrace
Degradation
Oxidative cyclization
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© 2021 The Authors. Published by Elsevier B.V.