Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

Gérardy, Romaric; Winter, Marc; Vizza, Alessandra; Monbaliu, Jean‐Christophe M.

doi:10.1039/c6re00184j

Cited by 34 publications

(34 citation statements)

References 46 publications

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“…Methylphenidate consumption, both medical and illegal, is rising at an alarming rate. We have recently demonstrated the continuous flow preparation of methylphenidate hydrochloride ( 246· HCl) according to two strategies relying on the generation and consumption of hazardous diazo compounds (Figure ) . The first strategy involved an intermolecular C–H carbene insertion.…”

Section: Perspectivesmentioning

confidence: 99%

“…Complex multistep continuous flow processes are now implemented at every stage of chemical production. Hazardous reagents or unstable intermediates are now routinely implemented in research or production facilities,, while balancing the safety concerns. Slow reactions that would take hours or days to complete otherwise can now be performed within minutes using superheated conditions.…”

Section: Perspectivesmentioning

confidence: 99%

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Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

et al. 2018

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This review intends to provide the reader with a clear and concise overview of how preparative continuous flow organic chemistry could potentially impact on current important societal challenges. These societal challenges include health/well‐being and sustainable development. Continuous flow chemistry has enabled significant advances for the manufacturing of pharmaceuticals, as well as for biomass valorization toward a biosourced chemical industry. Examples related to pharmaceutical production are herein focused on (a) the implementation of flow chemistry to reduce the occurrence of drug shortages, (b) continuous flow manufacturing of orphan drugs, (c) continuous flow preparation of active pharmaceuticals listed on the WHO list of essential medicines and (d) perspectives for the manufacturing of peptide‐based pharmaceuticals. Examples related to sustainable development are focused on the valorization of biosourced platform molecules. Besides positive impacts on societal challenges, this review also illustrates some of the potentially most threatening perspectives of continuous flow technology within the actual context of terrorism and drug abuse.

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Section: Perspectivesmentioning

confidence: 99%

Section: Perspectivesmentioning

confidence: 99%

Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

et al. 2018

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“…Continuous flow systems are often well adapted to the handling of reactive species. [74][75][76][77][78] Moody, Hayes and colleagues developed a continuous flow process for the direct generation of diazoesters through a Bamford-Stevens elimination starting from sulfonylhydrazones 74. The freshly generated and unstable diazo derivative 75 was next directly used for various carbene insertion reactions including a P-H insertion reaction towards α-phosphono carboxylates 77.…”

Section: Carbene Insertionmentioning

confidence: 99%

Continuous Flow Organophosphorus Chemistry

2020

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Organophosphorus derivatives are widespread compounds that chemists find from the bench to the plant, with numerous daily life applications. Besides their common utility for a wide range of notorious reactions such as the Wittig and Horner‐Wadsworth‐Emmons olefinations, the Arbuzov reaction, the Staudinger reaction, the Mitsunobu reaction as well as ligands for a large variety of organometallic complexes, organophosphorus compounds have also found numerous applications as active pharmaceutical ingredients and agrochemicals. Some organophosphorus derivatives are also infamously known as Chemical Warfare Agents. Within the context of generalized adoption of new process technologies in the Chemistry Toolbox, this review intends to give an update on the most recent and significant advances in continuous flow organophosphorus chemistry. Selected examples in methodology, total synthesis and for the preparation of industrially relevant targets are discussed for illustrating the assets of flow chemistry.

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“…Collins, Maguire and co‐workers reported this approach for the synthesis of α‐diazo‐β‐ketoesters and cyclic α‐diazo‐β‐keto sulfoxides . Monbaliu and co‐workers investigated the continuous‐flow synthesis of Boc‐protected Ritalin ( 38 ) in flow (Scheme ) starting from bench‐stable tetrabutyl ammonium azide ( 34 ) and tosyl chloride ( 35 ) for the flow synthesis of methyl 2‐phenyl acetate, which undergoes rhodium catalyzed C−H insertion reaction with Boc‐piperidine ( 37 ) to yield 38 …”

Section: Diazo Transfer Reactionsmentioning

confidence: 99%

“…[46] Monbaliu and co-workers investigated the continuous-flow synthesis of Boc-protected Ritalin (38)i nf low (Scheme 13) starting from bench-stable tetrabutyl ammonium azide (34)a nd tosylc hloride (35)f or the flow synthesis of methyl 2-phenyl acetate, whichu ndergoes rhodiumc atalyzed CÀHi nsertion reactionw ith Boc-piperidine (37)t oy ield 38. [47] In summary,t he Regitz diazotransfer reactionc an be applied to continuous-flow reactions using simple reactor designa nd phase separation modules. From ap ractical perspective, the usage of the latter is mandatory, as impurities andb y-products of the Regitz diazotransfer need to be removed from the reaction mixture to conductt he downstream transformations.…”

Section: Diazo Transfer Reactionsmentioning

confidence: 99%

The Generation of Diazo Compounds in Continuous‐Flow

Hock

Koenigs

2018

Chemistry A European J

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Toxic, cancerogenic and explosive-these attributes are typically associated with diazo compounds. Nonetheless, diazo compounds are nowadays a highly demanded class of reagents for organic synthesis, yet the concerns with regards to safe and scalable transformations of these compounds are still exceptionally high. Lately, the research area of the continuous-flow synthesis of diazo compounds attracted significant interest and a whole variety of protocols for their "on-demand" preparation have been realized to date. This concept article focuses on the recent developments using continuous-flow technologies to access diazo compounds; thus minimizing risks and hazards when working with this particular class of compounds. In this article we discuss these concepts and highlight different pre-requisites to access and to perform downstream functionalization reaction.

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Assessing inter- and intramolecular continuous-flow strategies towards methylphenidate (Ritalin) hydrochloride

Abstract: Development of a scalable continuous-flow process towards enriched threo-methylphenidate (Ritalin) hydrochloride.

Cited by 34 publications

References 46 publications

Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

Continuous Flow Organic Chemistry: Successes and Pitfalls at the Interface with Current Societal Challenges

Continuous Flow Organophosphorus Chemistry

The Generation of Diazo Compounds in Continuous‐Flow

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