Dinos Paul Santafianos

Discovery of a new stable polymorph of 4-(3-ethynylphenylamino)-6,7-bis(2-methoxyethoxy)quinazolinium methanesulfonate using near-infrared spectroscopy to monitor form change kinetics

Polymorphism is an important property of crystalline organic molecules, particularly when used to develop medicines. Discovery of all the polymorphs in a series is often difficult. This paper highlights the use of near-infrared spectroscopy to monitor the kinetics of form changes of polymorphs and solvates (hydrates). In the case of mesylate salt 5, this led to the discovery of a new preferred form. Identification and confirmation of unique polymorph crystal states are determined using X-ray powder diffraction patterns. This complements and confirms the kinetic change observed in the near-infrared. The technique is generally applicable to the study of two-phase solid–liquid crystal slurries under isothermal conditions.

Solving impurity/degradation problems: Case studies

Publisher Summary The chapter presents case studies related to solving impurity/degradation problems. The chapter presents guidance for isolating and identifying process-related impurities and degradation products from pharmaceutical drug candidates using actual case studies. Impurity and degradant structure elucidation is a collaborative effort involving the analytical chemist, process chemist and/or formulator, as well as the degradation, mass spectrometry, and nuclear magnetic resonance (NMR) experts. The process described in this chapter uses a designed approach for the impurity and/or degradant identification, which focuses on efficiency so that the success of data collection is maximized and project time lines are met. There are a number of activities other than collecting experimental data, even though the experiments are central to the process. Some of these key activities include collecting project background information prior to pursuing experimental work, asking the right questions, and meeting with project analysts and structure elucidation experts. The activities associated with the overall process are captured in the process flowchart presented. One of the most important aspects of the project that determines approach is where the pharmaceutical drug candidate is in the drug development time line. NMR spectroscopy is used as a complementary technique to liquid chromatography/mass spectrometry (LC/MS). The chapter presents several case studies related to scaled-up oxidative degradation and isolation using solid-phase extraction and preparative high-performance liquid chromatography (HPLC), scaled-up oxidative degradation, preparative HPLC, and characterization by LC/MS and NMR, scaled-up light degradation and LC/MS and NMR characterization, and others.

Synthesis of trovafloxacin using various (1α,5α,6α)-3-azabicyclo[3.1.0]hexane derivatives

Trovafloxacin, a novel broad spectrum antibacterial, contains the unusual (1α,5α,6α)-3-azabicyclo[3.1.0]hexane ring system. The prototype of the industrial synthesis of this ring system and possible mechanistic pathways to exclusive formation of the exo or 6α-nitro derivative 4 are described, which leads to the key 6α-nitro-3-azabicyclo[3.1.0]hexane intermediate 10. The synthesis of 6α-amino-3-azabicyclo[3.1.0]hexane 16 and useful protected exo 6-amino derivatives 15 and 17 follows from 10. These can be coupled with the 7-chloronaphthyridone 18 to yield protected trovafloxacin compounds 20–22 in good yield. The ethyl ester of trovafloxacin 21 can also be accessed from the product of coupling 19, derived from 18 and the exo 6-nitro-3-azabicyclo[3.1.0]hexane compound 12. Removal of protecting groups from 20–22 with methanesulfonic acid yields trovafloxacin mesylate from which trovafloxacin zwitterion 1 can be liberated with base treatment. Zwitterion 1 can also be prepared directly from 16 tosylate salt and naphthyridone-2-carboxylic acid 26.

An unusual carbon–carbon bond scission reaction with molecular oxygen under mild conditions; formation of piperidines from 1-azabicyclo[2.2.2]octanes

Molecular oxygen reacts with 2-(1-phenylethyl)- and 2-benzhydryl-3-alkylimino-1-azabicyclo[2.2.2]octanes 1–7 in neutral solution at room temperature to form 1-acylpiperidine-4-carboxylic acid N-alkylamides 8–14. During the transformation two new carbonyl bonds are formed and a carbon–carbon bond is cleaved. The transformation is quite general provided the 2-substituent of the imine is of sufficient steric bulk, such as the 2-(1-phenylethyl) or 2-benzhydryl groups. No reaction is observed in the absence of a 2-substituent, as in the case of imine 15.