Handling Hydrogen Peroxide Oxidations on a Large Scale: Synthesis of 5-Bromo-2-nitropyridine

The development of a stereospecific synthesis of a IDO1-selective inhibitor is described. The synthetic strategy toward enabling early discovery efforts along with additional findings pertaining to process safety that limited scalability are outlined. A convergent approach that supported the synthesis of material suitable for early preclinical and/or good laboratory practice toxicology studies and avoided the formation of key high-energy intermediates is summarized.

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

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Process Safety Considerations for the Supply of a High-Energy Oxadiazole IDO1-Selective Inhibitor

Martinot

Ardolino

Chen

et al. 2019

“…Based on all the collected safety assessment data, the one-pot deoxytrifluoromethylation using BBDFA can be assigned to a criticality class 1 or 2 following the systematic approach developed by Gygax and Stoessel (Table ). For applications beyond preparative scale, it is recommended to further evaluate the reaction mixture by accelerating reaction calorimetry (ARC) to determine T D,24 and perform in-depth material compatibility evaluation.…”

Section: Resultsmentioning

confidence: 99%

BBDFA: A Practical Reagent for Trifluoromethylation of Allylic and Benzylic Alcohols on Preparative Scale

Han¹,

Alabanza²,

Kelly³

et al. 2019

We report a safe and readily prepared reagent [1,1′-biphenyl]-4-yl 2-bromo-2,2-difluoroacetate (BBDFA) for Cu-catalyzed trifluoromethylation of allylic or benzylic alcohols. An operationally simple and columnchromatography-free process to prepare BBDFA was developed and demonstrated on >100 g scale. Detailed reaction calorimetry and thermal analysis of the deoxytrifluoromethylation were performed using cinnamyl alcohol as a model substrate, demonstrating that the reactions could be safely implemented on preparative scale.

“…There are several illustrations available in the literature where pharmaceutical process safety groups successfully managed to avert catastrophic incidents by stopping dangerous chemistry from being scaled-up. , For example, potential safety hazards associated with the violent thermal decomposition of dimethyl sulfoxide in the presence of an acid were identified and mitigated prior to scale-up . Other examples include the use of continuous operation that was championed by their PSL staff to enable their respective companies to run potentially hazardous chemistry such as ozonolysis. − …”

Section: Introductionmentioning

confidence: 99%

Process Safety in the Pharmaceutical Industry—Part I: Thermal and Reaction Hazard Evaluation Processes and Techniques

Allian

Shah

Ferretti

et al. 2020

Process safety groups in the pharmaceutical industry are important components of active pharmaceutical ingredient (API) development through its life cycle from discovery to commercial scale. The pharmaceutical process safety laboratory staff conduct a series of tests to identify chemically unstable reagents, intermediates and solvents, and mixtures to ensure that the proposed operating conditions provide a sufficient safety margin from the onset of undesired and potentially catastrophic thermal decomposition. Across several pharmaceutical companies, the methods used for these assessments and how results and conclusions are made are widespread (vide infra). A working group was created with members from several pharmaceutical companies within the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ), with the goal of precompetitive collaboration and to understand each of the participating companies’ procedures and assessment regarding process safety. Each company was invited to provide input using a blind survey format. This was done in the interest of making this knowledge accessible for the participating companies and the wider community of other pharma and chemical companies and even academic institutions in the US and throughout the world. This article provides the results of this in-depth survey of the members of the IQ Consortium thermal hazard working group. General issues around different tools used to assess thermal hazard risk and questions regarding staffing and tech transfer of process safety data/information from development to manufacturing were addressed. A snapshot of how various assessment strategies are employed as a function of stage of development (early, mid, and late) is also presented.