An Integrated Continuous‐Flow Synthesis of a Key Oxazolidine Intermediate to Noroxymorphone from Naturally Occurring Opioids

Mata, Alejandro; Cantillo, David; Kappe, C. Oliver

doi:10.1002/ejoc.201700811

Cited by 19 publications

(23 citation statements)

References 35 publications

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“…Kappea nd co-workers presented a telescoped procedure for the direct preparation of an advancedi ntermediate for noroxymorphone from the naturally occurring oripavine 65 under continuous-flow conditions. [22] This process included three steps:C 14 hydroxylation,h ydrogenation, and aerobic oxidation. In the first step, the continuousflow systemm inimized the risk of small amounts of hazardous materials (produced and consumed in situ) that could accumulate in the reactor.T he hydrogenation of 14-hydroxymorphinone 66 with over 95 %c onversion efficiency wasp erformed under continuous-flow conditions by using Pd/C as the catalyst at 60 8Ca nd 60 bar H 2 pressure (Figure 20).…”

Section: Multi-step Continuous-flow Synthesis Using Supported Synthetmentioning

confidence: 99%

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

Jiao

Nie

et al. 2021

Chemistry A European J

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Continuous‐flow multi‐step synthesis takes the advantages of microchannel flow chemistry and may transform the conventional multi‐step organic synthesis by using integrated synthetic systems. To realize the goal, however, innovative chemical methods and techniques are urgently required to meet the significant remaining challenges. In the past few years, by using green reactions, telescoped chemical design, and/or novel in‐line separation techniques, major and rapid advancement has been made in this direction. This minireview summarizes the most recent reports (2017–2020) on continuous‐flow synthesis of functional molecules. Notably, several complex active pharmaceutical ingredients (APIs) have been prepared by the continuous‐flow approach. Key technologies to the successes and remaining challenges are discussed. These results exemplified the feasibility of using modern continuous‐flow chemistry for complex synthetic targets, and bode well for the future development of integrated, automated artificial synthetic systems.

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Section: Multi-step Continuous-flow Synthesis Using Supported Synthetmentioning

confidence: 99%

Multi‐Step Continuous‐Flow Organic Synthesis: Opportunities and Challenges

Jiao

Nie

et al. 2021

Chemistry A European J

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“…In view of our group’s interest in the synthesis of opioid-derived APIs, 27 a telescoped continuous process toward a noroxymorphone precursor ( 4 ) was established that comprised the C14 hydroxylation of naturally occurring oripavine ( 2 ) employing HCO 3 H as the key step. 28 Performic acid was generated in situ from formic acid (HCO 2 H) and 30% aqueous hydrogen peroxide (H 2 O 2 ) which then rapidly oxidized the diene moiety of oripavine at 100 °C to provide 14-hydroxymorphinone ( 3 ) and the corresponding N -oxide ( Scheme 8 ). A subsequent continuous solvent switch, hydrogenation in a packed-bed hydrogenator, and palladium catalyzed N -methyl oxidation furnished 1,3-oxazolidine derivative 4 .…”

Section: Chemical Generators For Hazardous Reagentsmentioning

confidence: 99%

The Concept of Chemical Generators: On-Site On-Demand Production of Hazardous Reagents in Continuous Flow

2020

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Conspectus In recent years, a steadily growing number of chemists, from both academia and industry, have dedicated their research to the development of continuous flow processes performed in milli- or microreactors. The common availability of continuous flow equipment at virtually all scales and affordable cost has additionally impacted this trend. Furthermore, regulatory agencies such as the United States Food and Drug Administration actively encourage continuous manufacturing of active pharmaceutical ingredients (APIs) with the vision of quality and productivity improvements. That is why the pharmaceutical industry is progressively implementing continuous flow technologies. As a result of the exceptional characteristics of continuous flow reactors such as small reactor volumes and remarkably fast heat and mass transfer, process conditions which need to be avoided in conventional batch syntheses can be safely employed. Thus, continuous operation is particularly advantageous for reactions at high temperatures/pressures (novel process windows) and for ultrafast, exothermic reactions (flash chemistry). In addition to conditions that are outside of the operation range of conventional stirred tank reactors, reagents possessing a high hazard potential and therefore not amenable to batch processing can be safely utilized (forbidden chemistry). Because of the small reactor volumes, risks in case of a failure are minimized. Such hazardous reagents often are low molecular weight compounds, leading generally to the most atom-, time-, and cost-efficient route toward the desired product. Ideally, they are generated from benign, readily available and cheap precursors within the closed environment of the flow reactor on-site on-demand. By doing so, the transport, storage, and handling of those compounds, which impose a certain safety risk especially on a large scale, are circumvented. This strategy also positively impacts the global supply chain dependency, which can be a severe issue, particularly in times of stricter safety regulations or an epidemic. The concept of the in situ production of a hazardous material is generally referred to as the “generator” of the material. Importantly, in an integrated flow process, multiple modules can be assembled consecutively, allowing not only an in-line purification/separation and quenching of the reagent, but also its downstream conversion to a nonhazardous product. For the past decade, research in our group has focused on the continuous generation of hazardous reagents using a range of reactor designs and experimental techniques, particularly toward the synthesis of APIs. In this Account, we therefore introduce chemical generator concepts that have been developed in our laboratories for the production of toxic, explosive, and short-lived reagents. We have defined three different classes of generators depending on the reactivity/stability of the reagents, featuring reagents such as Br 2 , HCN, peracids, diazomethane (CH ...

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“…Opiates: 2016 syntheses of new N-demethyl-N-substituted analogues (propyl, allyl) of 1-fluorocodeine and their 7,8-dihydro derivatives [ 1047 ]; Collison nebulizer as an ionization source for the MS analysis of opiates [ 1048 ]; comparison opiate recovery from acid hydrolysis and enzymatic hydrolysis followed by LC-MS/MS (toxicology focus) [ 1049 ]; synthesis of noroxymorphone from thebaine [ 1050 ]; synthesis of nororipavine and noroxymorphone via N- and O-demethylation of iron tricarbonyl complex of thebaine [ 1051 ]; 2017 investigation of the acid/base behavior of the opium alkaloid thebaine in LC-ESI-MS mobile phase by NMR spectroscopy [ 1052 ]; review of Piritramide [ 1053 ]; model studies toward the total synthesis of Thebaine by an intramolecular [4+2] cycloaddition [ 1054 ]; physico-chemical profiling of semisynthetic opioids characterized by combining pH-potentiometry and deductive methods [ 1055 ]; integrated continuous-flow synthesis of a key oxazolidine intermediate to noroxymorphone from naturally occurring Opioids (oripavine and thebaine) [ 1056 ]; a colorimetric sensor array based on unmodified gold nanoparticles (AuNPs) was developed for the detection and identification of multiple structurally similar opioids including morphine, codeine, oxycodone, noroxycodone, thebaine, tramadol and methadone in aqueous media [ 1057 ]; 2018 Opioids in expensive formulations are being favored over IR morphine both at the dispensing level and in their inclusion in national list of essential medications [ 1058 ]; isolation and determination of Opium Alkaloids by dispersive liquid-liquid microextraction based on solidification of floating organic drop and HPLC-UV detection [ 1059 ]; novel retro-ene reaction via a [4.4.3]propellane intermediate containing a quaternary ammonium linkage [ 1060 ]; review of drug interactions with new synthetic opioids [ 1061 ]; crystal structures of Thebaine 6-O-demethylase in complexes with 2-oxoglutarate and succinate [ 1062 ]; abuse-deterrent Opioids [ 1063 ]; effects of ketamine and norketamine on the attenuation of morphine and oxycodone tolerance [ 1064 ]; review of abuse-deterrent Opioid formulations [ 1065 ]; identification of novel Opioid interferences using High-Resolution Mass Spectrometry [ 1066 ]; changes in consumption of opioid analgesics in Israel 2009 to 2016 focusing on oxycodone and fentanyl formulations [ 1067 ]; trends and characteristics of oxycodone exposures reported to the US Poison Centers, 2011–2017 [ 1068 ]; spatial pattern analysis of 3,396 locations of oxycodone positivity in drivers involved in fatal traffic crashes from the Fatality Analysis Reporting System (FARS) [ 1069 ]; impact of the introduction of tamper-resistant controlled-release (CR) oxycodone in April 2014 in Austra...…”

Section: Routine and Improved Analyses Of Abused Substancesmentioning

confidence: 99%