The Synthesis of GV143253A: A Case Study for the Use of Analytical and Statistical Tools to Elucidate the Reaction Mechanism and to Optimize the Process

Abstract

GV143253A 1 is a broad-spectrum injectable β-lactam belonging to the class of trinem antibiotics. This article describes the work which enabled a detailed process understanding via several analytical techniques and the subsequent optimization of a key intermediate. By means of a combined application of 31 P NMR spectroscopy and MS spectrometry, the main impurities have been identified and the reaction mechanisms clarified. Moreover, a design of experiments (DoE) approach was applied which substantially improved the overall yield.

A Brief Introduction to Chemical Reaction Optimization

“…DoE has been used extensively in the optimization of chemical processes, particularly in pharmaceutical and fine chemical settings. DoE is often used for studies relating to enhancing the yield − and purity − of particular products but is also used for drug formulations − and delivery, − analytical method development, − and more. − This is because there are numerous and undisputed benefits to the use of DoE for experimental parameter screening and optimization, especially when compared with traditional human intuition-guided experimentation. With the rise of user-friendly software packages and the increased awareness of the chemical community, there has been a large uptake of this statistical method in recent years, although the technique itself has been around since the mid-20th century .…”

Design of Experiments (DoE) and Process Optimization. A Review of Recent Publications

“…GSK workers optimized an acylation and cyclization in the synthesis of GV143253A, a broad-spectrum antibiotic . Initially the acylation of the β-lactam nitrogen of intermediate 34 with FmOCOCOCl proceeded in only 45–50% yield (Scheme ).…”

“…GSK workers optimized an acylation and cyclization in the synthesis of GV143253A, a broad-spectrum antibiotic. 31 The Process Chemistry team from Teva employed DoE to optimize several continuous variables in the synthesis of 41 (Scheme 4), a derivative of delanzomid (CEP-18770), a peptide boronic acid under investigation as a proteasome inhibitor for the treatment of multiple myeloma. 32 Several DoEs using Design Expert were performed to optimize the operating range of each variable of the acylations to yield 39 and 40 and transesterification in the three step process.…”

Self-optimising processes and real-time-optimisation of organic syntheses in a microreactor system using Nelder–Mead and design of experiments

“…15,17 Design of experiments is mainly used in the optimisation of batch processes, identifying optimal parameters for organic syntheses in lab contexts. [37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56] In continuous flow, design of experiments is used less frequently. [57][58][59][60][61][62][63][64][65][66][67][68][69][70] In these rare applications, design of experiments is predominantly combined with offline analysis.…”