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Abstract: Aril azides are popular reagents in the laboratory, but their explosive properties prevent their larger-scale application. The safety risk is even greater for N-heterocyclic azides, which are rarely studied. Flow chemistry can be an effective tool in the synthesis and utilization of dangerous and explosive chemicals. In small-diameter flow reactors, good heat and mass transfer prevent local hot spots and side reactions, and since only small amounts of hazardous chemicals are present at any time, the potential danger is reduced in the event of an accident. In this work, the safe syntheses of 9 different 2-azidopyridine, 2-azidopyrimidine and 2 azidoquinoxaline derivatives were successfully achieved within the continuous-flow system. In most cases, simple work-up resulted in pure products. In-line extractive work-up was also implemented, which allowed us to transform 2-azidopyridine in a subsequent Staudinger reaction in a connected flow reactor, without manual handling of the hazardous azide.

A three-step batch-flow hybrid process has been developed for an expeditious synthesis of the enynol key intermediate of antifungal terbinafine. This procedure involves consecutive organometallic steps without the necessity of any in-line purification: after a metalation by n-butyllithium, a selective addition of the lithium salt was elaborated followed by a Grignard reaction resulting in a high yield of 6,6-dimethylhept-1-en-4-yn-3-ol. Moreover, as an alternative to tetrahydrofuran, cyclopentyl methyl ether was used as solvent implementing a safe, sustainable, yet selective synthetic process. Even on a laboratory-scale, the optimized batch-flow hybrid process had a theoretical throughput of 41 g/h. Furthermore, the newly developed process provides an efficient synthesis route to the key-intermediate, while making acrolein obsolete, minimizing side-products, and enabling safe and convenient scale-up.

Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the antagonists of melanin concentrating hormone receptor 1 (MCHR1). The design, synthesis, and biological studies of novel MCHR1 antagonists based on benzofuro-pyridine and pyrazino-indole scaffold was performed. We confirmed that fine-tuning lipophilicity and basic pK

The systemic use of GABA

The dynamic progress in the multi-step continuous-flow synthesis of active pharmaceutical ingredients is part of the current industrial revolution. The recently implemented examples are the forerunners of safer and more sustainable pharmaceutical manufacturing. These systems utilize interconnected flow apparatuses, integrated with in-line work-up, purification and analysis. Challenging targets call for customized, flow-oriented designs to establish novel, telescoped continuous-flow sequences. In this review we focus on these efforts towards the development of uninterrupted continuous-flow systems.

A novel method for synthesis of tricyclic benzimidazole derivatives by using continuous flow reactor is reported. Disadvantages of the well-known batch methods have been avoided utilizing the flow chemistry technology. Beside the one pot reductive cyclization using H-Cube Pro®, the dehydration step was also optimized producing the desired lactam compounds. Then the acylation was optimized under microwave conditions and that reaction was also integrated into the flow system using an Asia heater module. This acylation dramatically reduced the reaction time under continuous-flow conditions, with a residence time of 30 min.

The N-protected cis-4-aminocyclohexanol derivatives have proven to be valuable intermediates in the syntheses of active pharmaceutical ingredients (APIs). A novel continuous flow process for hydrogenation of N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene cycloadducts to the corresponding cis-4-aminocyclohexanols has been reported using H-Cube Pro. A > 99% selectivity towards the desired product was obtained using Raney nickel catalyst cartridge. Under carefully selected hydrogenation parameters the reduction could stop at the also valuable 2-oxa-3-azabicyclo[2.2.2] octane intermediate, with a selectivity of >99%. The N-protected 2-oxa-3-azabicyclo[2.2.2]oct-5-ene producing nitroso hetero-Diels–Alder cycloaddition was also accomplished in a flow system using an Omnifit column packed with MnO2. The two flow reactions were successfully merged in a system, thus the product was obtained in a multistep flow synthesis without any isolation or purification steps. Compared with the previously reported batch processes, the present multistep procedure facilitates an efficient cis selective preparation of numerous synthetically valuable 4-aminocyclohexanol derivatives.

An uninterrupted, four-step continuous-flow sequence was developed for the preparation of the aryl piperazine-type serotonin receptor modulator drug, flibanserin. The unprecedented route was designed for efficient operation in flow, consisting of heterogeneously catalyzed reductive amination reactions, benzimidazolone formation using the protecting group as a building block, and biphasic flow deprotection integrated with in-line purification. Gas–liquid and liquid–liquid separations facilitate the coupling of the reaction steps and aid removal of excess reagents, which make the system capable of steady-state operation without manual interaction.

HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.

Recent advances in the field of continuous flow chemistry allow the multistep preparation of complex molecules such as APIs (Active Pharmaceutical Ingredients) in a telescoped manner. Numerous examples of laboratory-scale applications are described, which are pointing towards novel manufacturing processes of pharmaceutical compounds, in accordance with recent regulatory, economical and quality guidances. The chemical and technical knowledge gained during these studies is considerable; nevertheless, connecting several individual chemical transformations and the attached analytics and purification holds hidden traps. In this review, we summarize innovative solutions for these challenges, in order to benefit chemists aiming to exploit flow chemistry systems for the synthesis of biologically active molecules.

Flow chemistry proved to be a valuable technique to improve the discovery chemistry route to melanin-concentrating hormone receptor 1 (MCHr1) antagonists with 1H,2H,3H,4H,5H-[1,4]diazepino[1,7-a]indole scaffold. Novel, one-step heterogeneous catalytic hydrogenation for the synthesis of ethyl 2-(2,3-dihydro-1H-indol-2-yl) acetate was developed from ethyl 4-(2-nitrophenyl)-3-oxobutanoate to avoid commonly used reducing chemicals. The N-alkylation reaction of the indoline nitrogen was also optimised using a purpose-built flow reactor and design of experiments. Applying the optimal set of parameters allowed us to decrease almost ten-fold the excess of carcinogenic 1,2-dibromoethane. Additionally, nearly complete conversion was achieved in a fraction of the original reaction time (30 min vs. 4 days); therefore, the productivity (space time yield) of the flow reactor system is proved to be ca. 200 times more than the batch process.

Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.

A continuous-flow system consisting of two sequential microreactors was developed for the synthesis of nonsymmetrically substituted ureas starting from tert-butoxycarbonyl protected amines. Short reaction times could be achieved under mild conditions. In-line FT-IR analytical technique was used to monitor the reaction, including the formation of the isocyanate intermediate, thus allowing optimization of the reagent ratios. The mechanistic role of the applied base was also clarified. The setup was successfully utilized for the synthesis of several urea derivatives including the active pharmaceutical ingredient cariprazine.

To further proceed with our previous work, novel steroid-based histamine H

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes.

In this study, lipase-mediated dynamic kinetic resolution (DKR) of various benzylic amines (1a–g) is presented which is realized in a so far unprecedented fully continuous-flow system. The DKR process applying sol–gel immobilized lipase B from Candida antarctica as biocatalyst, palladium on 3-aminopropyl-functionalized silica as racemization catalyst, isopropyl 2-ethoxyacetate as acylating agent, ammonium formate as hydrogen and nitrogen sources, and 2-methyl-2-butanol as solvent under regulated pressure provided the desired products in moderate to good yields with excellent enantiomeric excesses.

In medicinal chemistry, the development of synthetic procedures for the access of new heterocyclic systems as potential scaffolds is elementary. Herein, we report our results on the formation of small drug-like heterocycles, utilizing flow chemistry. This approach enables the extension of the reaction parameter window, including high-pressure/high-temperature or hazardous chemistry. In our work, various novel condensed tricyclic benzothiazoles fused with furo- and thieno-rings were synthesized applying a multistep continuous-flow protocol. The process includes two ring closure steps and a nitro group reduction step. Batch and telescoped continuous-flow syntheses were also designed and performed.

Emerging from an HTS campaign, novel steroid-based histamine H

Today, the 'obesity pandemic' is one of the biggest health issues around the world. Melanin-concentrating hormone (MCH), a hypothalamic neuropeptide, is one of the most potent, central stimulators of feeding and it also attenuates energy expenditure. Inhibitions of the MCH receptor, the melanin-concentrating hormone receptor-1 (MCHR1), has attracted considerable attention as a potential anti-obesity drug, during the last decade. Now, there are a large number of MCHR1 antagonists, pharmacological tools and clinical drug candidates that can provide clues to develop new structures with high potency and good pharmacokinetic profile. The function of MCHR1 in energy homeostasis, obesity, metabolic syndrome, mood disorders and inflammatory bowel disease is discussed. Relevant clinical trials and patent background information of the MCHR1 antagonists over the last 4 years are also reviewed.

To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an ‘amine-to-amide’ modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.

A molecule with an indole skeleton, containing a latent acrylic ester function—acting as a diene—was produced from Nb-trityl-2-(hydroxy-methyl)-tryptamine and reacted with esters containing an aldehyde or aldehyde-equivalent structural unit, yielding 3-oxo-16,17-dihydro-Δ20-secodin-17-ol type intermediates from which dehydration, followed by [4+2]cycloaddition, furnished 3-oxovincadifformine and 3-oxominovincine. We also wished to apply the method to produce 15β-hydroxyvincadifformine, however, the appearance of a dimeric product with indole skeleton was observed instead of the expected cycloaddition.

The first syntheses of the alkaloids (−)-mehranine (3), (+)-voaphylline/conoflorine (4), (+)-Na-methylvoaphylline/hecubine (5), and (−)-lochnericine (2) were achieved by stereoselective epoxidation starting from (−)-tabersonine (1), through intermediates with the aspidospermane and quebrachamine skeleton.

The oxidation of (-)-tabersonine (1) with dimethyldioxirane (DMD) in neutral and acidic medium gave 16-hydroxytabersonine-N-oxide (3) and the didehydrovincamine isomers 4 and 5, respectively. (+)-14,15-Didehydro-quebrachamine (7) furnished the hydroxyindolenine 9, and the pentacyclic derivative 11. (+)-Quebrachamine (8) and DMD in neutral medium gave (7S,20S)-(+)-rhazidigenine (12) which was converted to (2R,7S,20S)-(+)-rhazidine (13b) with hydrochloric acid.

Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC. Donepezil—a highly CNS-penetrating Cholinesterase inhibitor—prevents the negative BOLD and cognitive deficits regardless whether the provoking agent is scopolamine or butylscopolamine. Interestingly, the non-BBB-penetrating Cholinesterase inhibitor neostigmine also prevents or substantially inhibits those cognitive and fMRI changes. Intact cerebral blood flow and optimal metabolism are crucial for the normal functioning of neurons and other cells in the brain. Drugs that are not BBB penetrating yet act on the CNS highlight the importance of unimpaired circulation, and point to the cerebral vasculature as a primary target for drug action in diseases where impaired circulation and consequently suboptimal energy metabolism are followed by upstream pathologic events.

The individual epimerization steps of vincadifformine (1), deethylvincadifformine isomers (2,3), their synthetic intermediates (4–13) as well as that of simpler compounds with D-secoaspidospermane skeleton (15–17) were studied a) in protic medium (boiling deuteroacetic acidic) and b) under reductive (with sodium borodeuteride in boiling acetic acid, or with sodium borohydride in boiling deuteroacetic acid) conditions.

A new series of quinolinyl- and phenantridinyl-acetamides were synthesizer and evaluated against bradykinin B1 receptor. In vitro metabolic stability data were reported for the key compounds.The analgesic effect of compound 20 from the phenantridine series was proved in-vivo.