Match-Making Reactors to Chemistry: A Continuous Manufacturing-Enabled Sequence to a Key Benzoxazole Pharmaceutical Intermediate

The focus of this study was to develop a chemical reaction sequence toward a key benzoxazole building block, required for clinical manufacturing of a lead candidate in the respiratory disease area. The chemistry consisted of initial low-temperature reactions with an organometallic reagent to generate the benzoxazole core, and was followed by noncryogenic transformations toward a sulfonamide substituent. With particular interest in continuous-flow manufacturing we attempted to integrate the entire sequence on lab scale. Subsequent in-depth process research, supported by PAT and calorimetry studies, revealed the critical parameters of each step, leading to a more rational attribution of mode of operation: flow, batch, or semibatch. Two bench-scale cascades of continuously stirred tank reactors (CSTRs) were constructed to meet the challenge of high exothermicity and solids formation and were key to smoothly upscaling the chemistry to deliver 17 kg of benzoxazole in superior yield, quality, and robustness

Organic photocatalysis for the radical couplings of boronic acid derivatives in batch and flow.

We report an acridium-based organic photocatalyst as an efficient replacement for iridium-based photocatalysts to oxidise boronic acid derivatives by a single electron process. Furthermore, we applied the developed catalytic system to the synthesis of four active pharmaceutical ingredients (APIs). A straightforward scale up approach using continuous flow photoreactors is also reported affording gram an hour throughput

Top 200 Drugs by Worldwide Sales 2016

The poster series of the Top 200 Drugs by Worldwide Sales by G. Sedelmeier and J. Sedelmeier has now been updated with an overview of the top selling drugs in 2016. QuintilesIMS collected sales numbers in 59 countries for all companies

WHO Listed Small Molecule Kinase Inhibitors 2001-2017

The World Health Organization (WHO) publishes quarterly reports listing Internationally recognized Non-proprietary Names (INNs) for substances that are to be marketed as a pharmaceutical. Each INN is also globally recognized as the unique generic name of a drug. The INN contains a specific suffix that defines what compound class the drug belongs to. This poster depicts the chemical structures, biological targets, most advanced indications and associated pharmaceutical companies of small molecule drug compounds with the “-nib” suffix which refers to kinase inhibitors. Kinases comprise one of the largest families of proteins encoded by the human genome. Furthermore, they are one of the most sought-after targets in current pharmaceutical research. Kinases catalyze the transfer of the γ-phosphate group of ATP onto a protein substrate. This phosphate transfer mediates signal transductions which in turn regulate an array of cellular processes, including proliferation, survival, apoptosis and metabolism. Consequently, cancer is a common indication for which kinase inhibitors are developed. Thirty-seven kinase inhibitors have received FDA approval for the treatment of malignancies, with twenty-six approvals occurring in the last 6 years

Evolution of Small Molecule Kinase Drugs

The development of small molecule kinase drugs is a rapidly evolving field and represents one of the most important research areas within oncology. This innovation letter provides an overview and analysis of approved kinase drugs according to their WHO registration (INN) dates, primary biological targets, selectivity and structural similarities. It also discusses new trends in kinase drug discovery programs such as new kinase targets, novel mechanisms of action and diverse indications

Flash Chemistry on Multigram-Scale: Continuous Flow Synthesis of Boronic Acids within a Second

The benefits and limitations of a simple continuous flow setup for handling and performing of organolithium chemistry on multigram-scale is described. The developed metalation platform allows for the performance of organolithium chemistry on mulitgram scale mimicking the concept of flash chemistry. This setup embodies a valuable complement to existing methodologies as it combines the benefits of Flash Chemistry (chemical synthesis on a timescale of <1 s) with remarkable throughput while mitigating the risk of blockages

Continuous Flow as an Enabling Technology: A Fast and Versatile Entry to Functionalized Glyoxal Derivatives

Organometallic chemistry is a remarkable opportunity for continuous processing and has been applied to demonstrated effect in the industrial landscape. We herein report two complementary strategies employing organolithium chemistry for the synthesis of glyoxal derivatives. Micro-mixer technology allows for the generation of unstable organometallic intermediates and their instantaneous in-line quench with esters as electrophiles. Selective mono-addition was observed via putative stabilized tetrahedral intermediates. Advantages offered by flow chemistry technologies facilitate a direct and efficient access to masked 1,2-dicarbonyl compounds while mitigating undesired by-product formation. These two approaches enable the production of advanced and valuable synthetic building blocks for heterocyclic chemistry with throughputs of grams per minute

Visible Light Activation of Boronic Esters Enables Efficient Photoredox C(sp2)–C(sp3) Cross-Couplings in Flow

We report herein a new method for the photoredox activation of boronic esters. Using these reagents, an efficient and high throughput continuous flow process was developed to perform a dual iridium and nickel catalysed C(sp2)–C(sp3) coupling by circumventing solubility issues associated with potassium trifluoroborate salts. Formation of an adduct with a pyridine-derived Lewis base was found to be essential for the photoredox activation of the boronic esters. Based on these results we were able to develop a further simplified visible light mediated C(sp2)–C(sp3) coupling method using boronic esters and cyano heteroarenes under continuous flow conditions