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The present review article sheds light on the fabrication of heterogeneous metal oxide-supported nanostructure-based catalysts for boosting industrially significant oxidation processes.

The development of an efficient route for the synthesis of Canagliflozin is reported. The anhydroketopyranose intermediate was isolated as a novel intermediate, which was used to prepare Canagliflozin API in high purity.

Natural products have been included in our dietary supplements and have been shown to have numerous therapeutic properties. With the looming danger of many zoonotic agents and novel emerging pathogens mainly of viral origin, many researchers are launching various clinical trials, testing these compounds for their antiviral activity. The present work deals with some of the available natural compounds from the literature that have demonstrated activity in counteracting pathogen infections. Accordingly, we screened, using in silico methods, this subset of natural compounds for searching potential drug candidates able to interfere in the recognition of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and its target human angiotensin-converting enzyme 2 (hACE2) receptor, leading to the viral entry. Disrupting that recognition is crucial for slowing down the entrance of viral particles into host cells. The selected group of natural products was examined, and their interaction profiles against the host cell target protein ACE2 were studied at the atomic level. Based on different computer-based procedures including molecular docking, physicochemical property evaluation, and molecular dynamics, butein was identified as a potential hit molecule able to bind the hACE2 receptor. The results indicate that herbal compounds can be effective for providing possible therapeutics for treating and managing coronavirus disease 2019 (COVID-19) infection.

An alternate formal synthesis of Sitagliptin phosphate is disclosed from 2,4,5-trifluorobenzadehyde in 8 linear steps with an overall yield of 31%. The chiral β-amino acid moiety present in sitaglitpin is installed via an asymmetric hydrogenation followed by a stereoselective Hofmann rearrangement as the key steps. The key chiral intermediate Boc-amino acid 1 prepared by this novel route was further converted to Sitagliptin phosphate following the known literature protocol.

In the year 2019, the potent zoonotic virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began to rage globally, which resulted in the World Health Organization (WHO) declaring it as a pandemic on March 11th, 2020. Although extensive research is currently ongoing worldwide to understand the molecular mechanism and disease pathogenicity of SARS-CoV-2, there are still many nuances to elucidate. Therefore, developing an appropriate vaccine or therapeutic drug to combat coronavirus 2019 (COVID-19) is exceedingly challenging. Such scenarios require multifaceted approaches to identify suitable contenders for drugs against COVID-19. In this context, investigating natural compounds found in food, spices, and beverages can lead to the discovery of lead molecules that could be repurposed to treat COVID-19. Sixteen cucurbitacin analogues were investigated for activity against the SARS-CoV-2 main protease protein (Mpro), angiotensin-converting enzyme 2 (ACE2) binding receptor, nonstructural protein 12 (NSP12) RNA-dependent RNA polymerase (RdRp), NSP13 helicase, and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway using several relevant tools and simulated screening methods. All key proteins were found to bind efficiently only with cucurbitacin G 2-glucoside and cucurbitacin H with the lowest global energy. Further, the absorption, distribution, metabolism, and excretion (ADME) of all the cucurbitacins were analysed to explore their drug profiles. Cucurbitacin G 2-glucoside and H showed the best hits and all the analogues showed no adverse properties that would diminish their drug-likeness abilities. The encouraging results of the current study may lay the foundation for future research and development of effective measures and preventive medications against SARS-CoV-2., Graphical abstract Image 1

A simple, new and convenient metal free procedure for the synthesis of 5-substituted 1H-tetrazoles using various nitriles and sodium azide in the presence of urea and acetic acid with good to high yields is developed. The reaction plausibly proceeds through in situ formation of urea azide active complex without toxic and/or expensive metal catalysts.

Efforts toward a synthesis and process optimization of canagliflozin 1 are described. Canagliflozin synthesis was accomplished via purified open ring intermediate 12. The process was optimized by employing quality by design (QbD) methodologies, and a telescopic strategy was executed for the first three and last two steps in a total six-step sequence. Optimization of the Friedel–Craft acylation reaction followed by Lewis acid mediated reductive elimination, n-BuLi mediated C-arylation, and reductive demethoxylation was performed to develop a robust process. These steps were found to be critical; therefore, critical process parameters (CPPs) were identified by employing design of experiment (DoE) methodology. In addition, control strategies for dealing with impurities are described.

A novel reaction involving in situ redox conversion of glyoxylate esters to glycine is described. Simple starting materials and mild conditions for the synthesis of glycine derivatives probably indicate a pathway towards prebiotic chemistry. This proceeds analogous to Cannizzaro reaction involving ammonia therefore it can be termed as intramolecular Aza-Cannizzaro type reaction. This reaction is examined in detail with an aid of computational analysis to corroborate the proposed mechanism.

Inherent creativity in synthetic organic chemists is hallucinogenic and found to have potential to impact global healthcare industry incredibly by executing contemporary organometallic strategies to manufacture the products of varied interest. Application of organometallics in chemical industry has intensely perfected the manufacturing of the materials right from trade goods to very personalized medicines without generating significant amount of waste. In pursuit of drug development, two types of challenges are encountered. The first one is related to design of the molecules, and the second is related to the manufacturing of these at commercial scale. Contemporary organometallics in the context of drug development and process research have advanced the toolbox of enabling technologies for addressing these challenges posed during drug development.

Over decades dependency of humans on the drugs has become indispensable and irreplaceable. Thus, each year many new drugs are licensed. Nonetheless, drugs undergo rigorous testing and analysis to be available globally in economic price for the suitability of patients with different age and physiological conditions. The testing of drugs include phase I clinical trial using small group of 20–100 healthy volunteers for safety, pharmacology and efficacy; phase II clinical trial using 100–500 volunteer patients to optimize effective dose, dose interval, safety analysis and mode of delivery such as oral or intravenous; phase III clinical trial using 1000–5000 in a larger population of patients globally at different international places to collect sufficient safety and efficacy data for patenting and licencing. Moreover, thousands of drugs fail to achieve these objectives. Therefore, this mini-review intends to critically examine and assimilate the clinical applications of selected complex repurposed small drug molecules which are in different phase of trials for treating viral infection including complications due to COVID-19: (a) Remdesivir, (b) Galidesivir, (c) Favipiravir, (d) Baricitinib, and (e) Baloxavir., Graphical abstract Image 1

We envisioned a facile construction of diversified pyrazinoindoles by using 1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) as the solvent and catalyst, hence eliminating metal catalyzed routes for its development. The process is facilitated by HFIP that has emerged as a powerful tool for development of novel fused heterocycles. This cascade approach blends the asymmetric N-acylation with consecutive intramolecular cyclisation via Pictet-Spengler reaction as an efficient tool forming overall two stereogenic centers. Our approach deals with incorporation of l -amino acid on substituted indoles to provide the chiral N-acylated indole precursor followed by cyclisation to access pyrazinoindole derivatives in high enantiomeric excess up to >99% in good to excellent yields, which have great potential as molecular scaffolds in drug discovery. We have also described the mechanistic course of the reaction based on density functional theory.

A simple, highly effective and economical whole-cell mediated process was developed for the biocatalytic reduction of a ketone, intermediate in the synthesis of platelet inhibiting drug ticagrelor. Sixteen different microorganisms were screened for the bioreduction of 1-(3,4-difluorophenyl)-3-nitropropan-1-one (1) to (S)-1-(3,4-difluorophenyl)-3-nitropropan-1-ol (2). Growing as well as resting cells of Candida parapsilosis 104659 exhibited high conversion (>99.0%) and enantioselectivity (98.0%) for the S-enantiomer.

C-H activation in the synthesis of medicinally relevant molecules is reviewed. C-H activation is one of the most powerful components in the C-C or C-heteroatom bond formation tool box. This represents such an alternative which has provided the greener solutions to the organometallic/synthetic organic chemistry aiming to the synthesis of complex molecules. In recent years, there has been explosive growth in this area. In this review article we have presented effective methods of C-H activation employed in the synthesis of medicinally relevant molecules since 2010. C-H activation in the synthesis of medicinally relevant molecules is reviewed. C-H activation is one of the most powerful components in the C-C or C-heteroatom bond formation tool box. This represents such an alternative which has provided the greener solutions to the organometallic/synthetic organic chemistry aiming to the synthesis of complex molecules. In recent years, there is explosive growth in this area. In this review article we have presented effective methods of C-H activation employed in the synthesis of medicinally relevant molecules.

The development of a practical and scalable process for the asymmetric synthesis of sitagliptin is reported. Density functional theory calculations reveal that two noncovalent interactions are responsible for the high diastereoselection. The first is an intramolecular hydrogen bond between the enamide NH and the boryl mesylate S=O, consistent with MsOH being crucial for high selectivity. The second is a novel C–H···F interaction between the aryl C5-fluoride and the methyl of the mesylate ligand.

An investigation into the Kumada cross coupling reaction was conducted by developing a reliable, efficient procedure for the Grignard reagent and its subsequent cross coupling reaction. Safe Mg metal activation as well as a moisture-free system was created by using MeMgCl reagent and improved the efficiency of the Grignard reaction. The established coupling reaction was successfully demonstrated at the multikilogram (50 kg) scale, and the coupling product was purified by using an agitated thin film evaporator (ATFE) technique.

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Montelukast sodium is an orally active selective leukotriene receptor antagonist that inhibits the cysteinyl leukotriene (CysLT1) receptor. It was developed by Merck and Company and it is currently marketed under the brand name of Singulair®. Montelukast sodium (1) is one of the most prescribed allergy drugs for the treatment of asthma in the United States with sales of about $4.5 billion a year (before the expiry of its patent in 2012). Merck made significant efforts to develop a commercial manufacturing process of 1. Subsequently, other generic companies also worked towards developing non-infringing and cost-effective processes for 1. However, there is scope to improve the existing synthetic strategies and one of them is to replace hazardous reagents. Replacement of hazardous reagents would help in the management of life-cycle of the drug by simplifying process and thus lowering manufacturing cost.

Traditionally there are many transformations that employ hazardous reagents. Some of the transformations that afford important categories of organic building blocks useful for the synthesis of pharmaceutical intermediates and APIs cannot be performed due to the hazardous nature of reagents and conditions. Reactions whose reagents lead to the formation of highly reactive or highly exothermic intermediates typically are not suitable for implementation on a large scale because of the hazards that they pose. Efforts are ongoing in both industrial and academic settings to develop alternative approaches to help enable these transformations to be performed safely on a commercial scale. Examples include developing new forms of hazardous reagents that are stable and can readily be manipulated in the plant setting, within the scope of the transformation, changing the process landscape towards avoiding hazardous reagents, identifying new reaction conditions such as the use of flow chemistry that helps reduce the quantities of hazardous reagents and/or provide highly controlled conditions for energetic reactions and identifying entirely new routes that do not have these issues. While the selection of non-hazardous reagents and reaction conditions are critically determined by innate reactivity of the functional groups, solvents also play a pivotal role in determining the outcome of reaction and product. Therefore the selection of a solvent that does not pose health, safety and environmental challenges is extremely important. Understanding of the physicochemical characteristics of the solvents and other reaction components sets the stage for the selection of reaction attributes for a particular transformation.

Efforts toward the synthesis and process optimization of boceprevir 1 are described. Boceprevir synthesis was optimized by telescoping the first three steps and last two steps of the five-step process. Optimization of oxidation, which is one of the critical steps in the total synthesis, is discussed. A control strategy for the three impurities is described. A novel process for the synthesis of fragment A (2) has been developed, which is the key starting material for the synthesis of boceprevir.

Six potential process related impurities were detected during the impurity profile study of an antiarrhythmic drug substance, Dronedarone (1). Simple high performance liquid chromatography and liquid chromatography–mass spectrometry methods were used for the detection of these process impurities. Based on the synthesis and spectral data (MS, IR, 1H NMR, 13C NMR, and DEPT), the structures of these impurities were characterized as 5-amino-3-[4-(3-di-n-butylaminopropoxy)benzoyl]-2-n-butylbenzofuran (impurity I); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-N-(methylsulfonyl)methanesulfonamide (impurity II); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)-1-chloromethanesulfonamide (impurity III); N-{2-propyl-3-[4-(3-dibutylaminopropoxy)benzoyl]benzofuran-5-yl}methanesulfonamide (impurity IV); N-(2-butyl-3-(4-(3-(dibutylamino)propoxy)benzoyl)benzofuran-5-yl)formamide (impurity V); and (2-butyl-5-((3-(dibutylamino)propyl)amino)benzofuran-3-yl)(4-(3-(dibutylamino)propoxy)p...

Efficient and cost-effective synthesis of Zolmitriptan 1 employing Japp–Klingemann reaction and a new robust purification strategy is described.

An expeditious and practical method for the reduction of amides to amines is reported. The method consists of activation of amides with TMSCl followed by reduction with LiAlH 4 . Various amides/lactams including hindered amides and secondary amides gave the corresponding amines in good to excellent yields. This novel protocol has a wide substrate scope and shows good functional group tolerance with high stereoretention.

A novel synthesis of naproxen utilizing nitroaldol, 1,4-addition and Nef reaction is demonstrated where the desired S -enantiomer is achieved by resolution. Further to this first enantioselective 1,4-addition of Grignard reagent to nitroolefin is demonstrated to synthesize derivatives of naproxen.

An improved process is developed for the preparation of citalopram diol, 2 which involves two consecutive Grignard reactions in situ followed by an efficient and simple workup process with improved overall yield. Process development efforts for conversion of 2 into citalopram, 1, and a control strategy for impurities are discussed. The present work addresses the challenges associated with the process development and scale-up of citalopram such as handling of unstable intermediates, control of various potential impurities, and process safety to achieve an economic and scalable process.

Efficient methods have been developed for the synthesis of three active pharmaceutical ingredients (APIs) carbamazepine (Tegretol®) 1, oxcarbazepine (Trileptal®) 2, and eslicarbazepine acetate (Exalief®) 3 by employing enantioselective reduction and carboxamidation reaction.

Multiple sclerosis (MS) often results in chronic inflammatory and autoimmune disorders, and recent developments in understanding the disease pathogenesis has lead to newer therapeutic options for the treatment of the disease. The development of small molecule drugs with improved efficacy, better tolerability, and oral administration has received a new impetus with the discovery of newer classes of drugs. In this review, we have summarized the hitherto known synthetic strategies of fingolimod, laquinimod, cladribine, and teriflunomide reported in the literature which are the key small molecules and the first oral drug candidates for MS in various stages of clinical development or have been launched in the market.

An improved, practical, and scalable process for the manufacture of antineoplastic drug, 5-azacytidine (1), is described. A thorough understanding of the reaction parameters and stability of the reaction intermediates led us to the development of a robust process. The challenges in the isolation and systematic approach used to streamline the process into a very robust and practical manufacturing process are described.

Novel and robust crystallization approach based on solid solution formation was developed for the purification of finasteride. This is an unprecedented approach that describes the use of pure finasteride 1 to purify different lots of finasteride 1 (impure) contaminated with dihydrofinasteride 2.

An efficient process for the preparation of 1-(2-methoxyphenoxy)-2,3-epoxypropane, a key intermediate for the synthesis of ranolazine is described.

Stereocontrolled synthesis of trans-β-carboline derivatives by employing amidation strategy is presented.