Batch–flow hybrid synthesis of the antipsychotic clozapine

Neyt, Nicole C.; Riley, Darren L.

doi:10.1039/c7re00146k

Cited by 20 publications

(15 citation statements)

References 34 publications

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“…Clozapine is an atypical antipsychotic included as an essential active pharmaceutical on a complementary list for treating psychotic disorders by WHO. Riley described a batch‐flow hybrid protocol toward antipsychotic drug clozapine ( 122 ) (Figure ) . The 4‐step classical batch synthesis of clozapine notably involves insoluble intermediates, solvents incompatibilities between subsequent steps, and poor molecular diversity, which would result in a tedious translation to fully continuous flow conditions.…”

Section: Continuous Flow Preparation Of Active Pharmaceuticalsmentioning

confidence: 99%

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: Continuous Flow Preparation Of Active Pharmaceuticalsmentioning

confidence: 99%

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

et al. 2018

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“…The batch-flow hybrid process for the synthesis of clozapine, using a Key Ullmann/Goldberg step as described by Neyt and Riley [45] . The batch-flow hybrid process for the synthesis of clozapine, using a Key Ullmann/Goldberg step as described by Neyt and Riley [45] .…”

Section: 4-dibenzodiazepinesmentioning

confidence: 99%

“…In 2018 Neyt and Riley [45] successfully developed a new process for the total synthesis of clozapine via a batch-flow hybrid process (Scheme 15). The key reaction in this pathway, was a copper catalysed C-N coupling step, that was conducted under batch conditions as unfortunately there were significant solubility issues that precluded the efficient translation to flow (the main problem was precipitation of the diarylamine leading to reactor fouling).…”

Section: 4-dibenzodiazepinesmentioning

confidence: 99%

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Metal‐Catalyzed Routes to Dibenzodiazepines (DBDAs) and Structural Analogues: Recent Advances

2018

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It is common knowledge that the use of transition metals as catalysts has greatly revolutionized various coupling procedures to access heterocyclic compounds of significant industrial interest. Dibenzodiazepines (DBDAs) are a particularly important group of heterocyclic compounds, with considerable pharmaceutical applications. In this review, we look at some of the catalytic methods that have been developed during the last 10 years for the synthesis of these targets. Palladium catalysts have been frequently used for these transformations, and particularly for the Buchwald–Hartwig reaction which has been a key reaction in a number of synthetic pathways. Copper has also been frequently used, including some other metals like iron and molybdenum, but to a lesser extent. In most cases, the examples chosen are for the synthesis of DBDAs with interesting medicinal properties and will be of interest to medicinal chemists. It should also be mentioned that due to the structural characteristics of these compounds the potential for diversification – principally for functional group incorporation – is immense. Emerging and facilitating technologies have also been employed for the synthesis of these molecules and are reviewed here.

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“…We recently published a batch–flow hybrid synthesis of the antipsychotic drug clozapine in which we demonstrated a flow-based reduction of a nitro group utilising sodium dithionite as a reductant [ 14 ]. We further hypothesized that the development of a flow protocol for the reduction of carbonyl groups would also be possible using sodium dithionite ( Scheme 1 ) [ 15 – 16 ].…”

Section: Introductionmentioning

confidence: 99%

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

Neyt

Riley

2018

Beilstein J. Org. Chem.

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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.

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Batch–flow hybrid synthesis of the antipsychotic clozapine

Abstract: 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.

Cited by 20 publications

References 34 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

Metal‐Catalyzed Routes to Dibenzodiazepines (DBDAs) and Structural Analogues: Recent Advances

Mild and selective reduction of aldehydes utilising sodium dithionite under flow conditions

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