About

Nicole’s research focuses on reaction engineering under flow conditions and the development of batch-flow hybrid approaches for the synthesis of pharmaceuticals and pharmaceutical intermediates. During her masters degree Nicole developed a batch-flow hybrid synthesis of the antipsychotic clozapine which showed superior performance with regards to overall yield and processing time when benchmarked against the reported batch syntheis and she developed a flow approach for perfoming selective reductions of ketones in the presence of aldehydes. Highlights from Nicole’s PhD research involved the development of a bespoke gas-liquid reactor for performing ozonolysis reactions with on-the-fly degassing, the development of a laser mediated photochemical reactor and the co-development with Lorinda van Wyk of a green fully automated synthesis of the antidepressant bupropion.

Thesis

Engineering reaction chemistry with flow technology: a discussion on method development and multistep organic synthesis.

Dissertation

Continuous flow synthesis of the antipsychotic Clozapine

Publications


7. Design and testing of an ozonolysis reactor module with on-the-fly ozone degassing under flow conditions

Nicole.C. Neyt, C. Johan van der Westhuizen, Jenny-Lee Panayides and Darren L. Riley, 2022, https://doi.org/10.1039/D1RE00554E

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Ozonolysis is an attractive, efficient, and green means of introducing oxygen containing functionalities using only oxygen and electricity. Unfortunately, safety issues associated with the accumulation of dissolved ozone and potentially explosive ozonides coupled with an oxygen rich reaction atmosphere have limited its integration into large scale process reactions. Herein we report on the development and testing of a prototype flow-based ozonolysis reactor which allows on-the-fly removal of ozone and oxygen negating the need for a downstream degassing step and allowing the continuous processing of intermediate ozonides in a safe manner. The approach lends itself to being able to telescope directly into downstream reactions without concern for the effect of residual ozone and minimises contact between the oxygen rich ozone atmosphere and the reaction mixture. The prototype was shown to remove between 98.5 and 99.7% of residual ozone-oxygen on-the-fly and its performance was demonstrated through the ozonolysis of several alkenes to afford a range of oxygen containing functional groups in good to high yields.

6. Application of reactor engineering concepts in continuous flow chemistry: a review

Nicole C. Neyt and Darren L. Riley, Reaction Chemistry and Engineering, 2021, 6, 1295-1326

The adoption of flow technology for the manufacture of chemical entities, and in particular pharmaceuticals, has seen rapid growth over the past two decades with the technology now blurring the lines between chemistry and chemical engineering. Current indications point to a future in which flow chemistry and related technologies will be a major player in modern chemical manufacturing and the 4th industrial revolution. In this review we highlight the application of new reactor configurations and designs in the context of either bespoke or commercial flow apparatus specifically related to microwave chemistry, photochemical transformations, electrochemical promoted reactions and multi-phasic reactions. In addition, we look at how 3D printing in reactor design and computer-aided automation is growing within the field and finally describe how innovative solutions are being developed to tackle challenging down-stream processing operations.

5. Mild and selective reductions of aldehydes utilising sodium dithionite under flow conditions.

N.C. Neyt, D.L. Riley Beilstein Journal of Organic Chemistry 2018, 14, 1529-1536

We recently reported a novel hybrid batch–flow synthesis of the antipsychotic drug clozapine in which the reduction of a nitroaryl group is described under flow conditions using sodium dithionite. We now report the expansion of this method to include the reduction of aldehydes. The method developed affords yields which are comparable to those under batch conditions, has a reduced reaction time and improved space-time productivity. Furthermore, the approach allows the selective reduction of aldehydes in the presence of ketones and has been demonstrated as a continuous process.


4. Approaches for performing reductions under continous flow conditions. 

D. L. Riley, N.C. Neyt. Synthesis2018, 50 (14), 2707-2720

A concise overview of approaches to perform reductions of various functionalities including aldehydes, ketones, esters, imines, nitriles, nitro groups, alkenes and alkynes under continuous-flow conditions are highlighted and discussed in this short review.


3. Batch-flow hybrid synthesis of the anti-psychotic clozapine. 

N.C. Neyt, D. L. Riley. Reaction Chemistry and Engineering, 2018, 3, 17-24.

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The development of batch–flow hybrid processes is becoming an attractive prospect through which chemists can make use of the best aspects of both technologies. We have reported the implementation of an on-the-fly purification by trituration which can also be utilised to perform solvent swaps. We have demonstrated this concept through the synthesis of the antipsychotic clozapine. In addition, we report a novel means of performing a reduction of an aryl nitro group under flow conditions and an overall improved process route for the total synthesis of clozapine.

2. Utilising flow technology to synthesise neurological active pharmaceutical ingredients.

N.C.Neyt, D.L. Riley Suid-Afrikaanse Tydskrif vir Natuurwetenskap en Tegnologie, 2017, 35(1), a1413.

1. Thermochemical processing of a South African ultrafine coal fly ash using ammonium sulphate as extracting agent for aluminium extraction.

Frédéric J. Doucet, Sameera Mohamed, Nicole Neyt, Barbara A. Castleman, Elizabet M. van der Merwe, Hydrometallurgy, 2016, 166, 174-184.

Conferences

2015 – SWAAK Conference (Bloemfontein) “Gebruik van vloei tegnologie vir die sintese van neurologiese aktiewe farmaseutiese bestanddele” Poster Prize

2016 – Frank Warren (Rhodes University) “Utilizing flow technology to synthesize Clozapine”

2017 – Young Chemists Symposium (Tshwane University of Technology) “Integrating batch and flow techniques to synthesize the antipsychotic clozapine” 2nd Prize Presentation

2018 – Flow Chemistry Europe (Cambridgeshire, UK) “Trituration under batch-flow hybrid conditions: A total synthesis of the anti-psychotic clozapine”.  2nd Prize Poster Presentation

2018 – RSC Twitter Poster Conference “Trituration under batch-flow hybrid conditions: A total synthesis of the anti-psychotic clozapine”. 1st Prize Engineering Category 

2019 – IUPAC 2019 (Paris, France) “Enabling flow technology: Methods, materials and multistep organic synthesis”

2022 – RSC Twitter Poster Conference “Design and testing of an ozonolysis reactor module with on-the-fly ozone degassing under flow conditions”. 1st Prize Engineering Category 

Posters