Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral

Gustafsson, T.; Pontén, Fritiof; Seeberger, Peter H.

doi:10.1039/b719603b

Cited by 98 publications

(49 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…AlMe 3 -mediated amide formations in batches with conventional heating typically require reaction times between 4 and 16 h, whereas both microwave and microreactor operation were completed within 2 min. The latter was applied for the synthesis of rimonabant and efaproxiral [123]. Rimonabant is an anti-obesity drug, which acts as a central cannabinoid receptor antagonist and has been synthesized in gram quantities with 49 % overall yield, Scheme 32.…”

Section: Trimethylaluminium Mediated Amide Bond Formationmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

View full text Add to dashboard Cite

Driven by the economics of scale, the size of reaction vessels as the major processing apparatus of the chemical industry has became bigger and bigger [1,2]. Consequently, the efforts for ensuring mixing and heat transfer have also increased, as these are scale dependent. This has brought vessel operation to (partly severe) technical limits, especially when controlling harsh conditions, e.g., due to large heat releases. Accordingly, processing at a very large scale has resulted in taming of the chemistry involved in order to slow it down to a technically controllable level. Therefore, reaction paths that already turned out too aggressive at the laboratory scale are automatically excluded for later scale-up, which constitutes a common everyday confinement in exploiting chemical transformations. Organic chemists are barely conscious that even the small-scale laboratory protocols in their textbooks contain many slow, disciplined chemical reactions. Operations such as adding a reactant drop by drop in a large diluted solvent volume have become second nature, but are not intrinsic to the good engineering of chemical reactions. These are intrinsic to the chemical apparatus used in the past. In contrast, today's process intensification [3][4][5][6][7][8][9][10][11][12] and the new flow-chemistry reactors on the micro-and milli-scale allow such limitations to be overcome, and thus, enable a complete, ab-initio type rethinking of the processes themselves. In this way, space-time yields and the productivity of the reactor can be increased by orders of magnitude and other dramatic performance step changes can be achieved. A hand-in-hand design of the reactors and process re-thinking is required to enable chemistry rather than subduing chemistry around the reactor [40]. This often leads to making use of process conditions far from conventional practice, under harsh environments, a procedure named here as Novel Process Windows. Starting Point: Novel Process WindowsIntensify Rather than OptimizeThe aim of the following introductory remarks, and the paper as whole, is to make sensible -while everyone in the field would agree that microstructured reactors and micro-process technology [3-12] form a major direction within process intensification -that the exploitation of such innovation can still profit considerably by joining both concepts. It is frequently thought that the use of a microstructured reactor automatically and implicitly results in process intensification; simply because this is a major direction within process intensification and since the latter is also concerned with apparatus developments. This is only partly true and actually ignores significant chances for process breakthrough. In many investigations, the use of a microstructured reactor is still more concerned with process optimization, which is involves a slight to moderate improvement of processes using classical paths, in particular with the same or similar chemical and processing protocol. Often, the most radical and innovative step is the

show abstract

Section: Trimethylaluminium Mediated Amide Bond Formationmentioning

confidence: 99%

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

2009

View full text Add to dashboard Cite

show abstract

“…Furthermore, the overall reaction apparatus was simplified in flow reducing the number of unit operations from 21 to 14 mainly due to simplification in the downstream steps such as pharmaceutical formulation, mixing and granulation. Gustafsson et al 26 showed feasibility of flow synthesis for a wide range of amides using highly reactive trimethylaluminium agent. Liu and Jensen 27 combined heterogeneous oxidation, gas-liquid separation and oxidation amination for the synthesis of amides from amines and alcohols.…”

Section: Introductionmentioning

confidence: 99%

Direct amide synthesis over core–shell TiO₂@NiFe₂O₄ catalysts in a continuous flow radiofrequency-heated reactor

et al. 2016

View full text Add to dashboard Cite

A note on versions:The version presented here may differ from the published version or, version of record, if you wish to cite this item you are advised to consult the publisher's version. Please see the 'permanent WRAP url' above for details on accessing the published version and note that access may require a subscription. AbstractCore-shell composite magnetic catalysts TiO2@NiFe2O4 with a titania loading of 9-32 wt. % have been synthesised by sol-gel method for direct amide synthesis in a radiofrequency (RF)-heated continuous flow reactor. The catalyst calcination temperature was optimised in the range of 350-500 ºC and the highest activity was observed for the catalyst calcined at 500 ºC due to conversion of titania into catalytically active anatase phase. No reaction between the magnetic core and the titania shell was observed up to the calcination temperature of 1000 ºC and no sintering of titania shell was observed after calcination at 500 ºC. The comparison of direct amide synthesis in a continuous flow fixed bed reactor under conventional and RF heating demonstrated that the RF heating mode increased the apparent reaction rate by 60 % and decreased the deactivation rate due to a better temperature uniformity. The titania weight normalised reaction rate in the RF-heated reactor was constant for titania loadings above 17 wt. %, while it decreased by a factor of 3 at lower titania loadings because of interactions between the ferrite core on the thin layer of the catalyst. The catalyst deactivation study showed that the deactivation rate could be accurately described by a first order kinetics and that the main reason of deactivation was coking. The catalyst regeneration via calcination at 400 ºC resulted in the catalyst sintering, while a treatment with a hydrogen peroxide solution at 90 ºC fully recovered catalytic activity.

show abstract

“…The synthesis of Rimonabant, an antiobesity drug acting as a central cannabinoid receptor antagonist, has been attempted in a three-step process. As a key step in the synthesis, a tetra-substituted pyrazole core was obtained via cyclocondensation reaction of 1,3-diketoester and 2,4-dichlorophenylhydrazineÁHCl at 125 C for 16 min in 80% yield (Scheme 20) [36].…”

Section: Five-membered Ring Heterocycles With Two Heteroatomsmentioning

confidence: 99%

Continuous‐flow syntheses of heterocycles

Glasnov

Kappe

2010

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral

Abstract: A safe, functional-group-tolerant and high-throughput version of the trimethylaluminium mediated amide bond formation reaction has been developed in a microreactor system; rimonabant and efaproxiral were prepared to illustrate the utility of the method.

Cited by 98 publications

References 24 publications

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Direct amide synthesis over core–shell TiO₂@NiFe₂O₄ catalysts in a continuous flow radiofrequency-heated reactor

Continuous‐flow syntheses of heterocycles

Contact Info

Product

Resources

About

Trimethylaluminium mediated amide bond formation in a continuous flow microreactor as key to the synthesis of rimonabant and efaproxiral

Abstract: A safe, functional-group-tolerant and high-throughput version of the trimethylaluminium mediated amide bond formation reaction has been developed in a microreactor system; rimonabant and efaproxiral were prepared to illustrate the utility of the method.

Cited by 98 publications

References 24 publications

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Novel Process Windows – Gate to Maximizing Process Intensification via Flow Chemistry

Direct amide synthesis over core–shell TiO2@NiFe2O4 catalysts in a continuous flow radiofrequency-heated reactor

Continuous‐flow syntheses of heterocycles

Contact Info

Product

Resources

About

Direct amide synthesis over core–shell TiO₂@NiFe₂O₄ catalysts in a continuous flow radiofrequency-heated reactor