Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients
Authors: Laraia Luca , Majumdar Nilanjana , Sudhakar Gangarajula , Swain Sharada Prasanna 
Published: June 2024

The development of efficient and sustainable synthetic processes for pharmaceuticals is a critical area of research, primarily driven by the pharmaceutical industry. However, fostering such research in academic institutions holds immense potential. The SYNTHESIS special issue on "Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)" highlighted recent advancements in this field. In this Thieme Cheminar chaired by Prof. Laha (Guest Editor “Synthetic Development of Key Intermediates and Active Pharmaceutical Ingredients (APIs)” collection) our speakers will share discuss their recent results in this field.

Chair:
* Prof. Joydev Kumar Laha (National Institute of Pharmaceutical Education and Research, India)

Our speakers:
* Dr. Luca Laraia (Technical University of Denmark): Next-generation strategies for the synthesis of functional, natural product inspired compounds.
* Dr. Sharada Prasanna Swain (National Institute of Pharmaceutical Education and Research): Photocatalyzed Continuous-flow synthesis of Pharmaceuticals.
* Dr. Gangarajula Sudhakar (CSIR- Indian Institute of Chemical Technology): The role of synthetic steps order in developing key intermediates and active pharmaceutical ingredients.
* Dr. Nilanjana Majumdar (CSIR-Central Drug Research Institute): Unactivated Carboxylic Acids in Catalytic Asymmetric Ring Opening Reactions.

Next-generation strategies for the synthesis of functional, natural product inspired compounds

Natural products and their derivatives have been the source of bioactive compounds and therapeutics for centuries; however, isolation and synthetic feasibility challenges hamper their development and use. Chemists have sought to address this by developing strategies to rapidly access larger numbers of natural product-inspired compounds, including diversity- and biology-oriented synthesis (DOS and BIOS), complexity-to-diversity (CtD) and pseudo-natural products (PNPs). In this lecture I will highlight our group’s work on combining all of the synthetic strategies above to address specific biological challenges, including the development of selective inhibitors of sterol transport proteins (STPs) and G-protein coupled receptors (GPCRs), as well as the development of new photochemical methods to access diverse scaffolds from cheap, abundant natural products.

Unactivated Carboxylic Acids in Catalytic Asymmetric Ring Opening Reactions

Carboxylic acids are considered as feedstock chemicals as they are widely available, highly stable and inexpensive. They can be excellent choice of substrates in catalytic asymmetric reactions but can be quite challenging as well. Free carboxylic acids are generally not compatible for various transformations, e.g. they can be difficult substrates for nucleophilic or electrophilic reactions. Here, efficient and convenient use of free carboxylic acid substrates will be illustrated in catalytic asymmetric ring opening reactions for the preparation of important class of products that may act as useful chiral synthons.

The role of synthetic steps order in developing key intermediates and active pharmaceutical ingredients

The development of synthetic strategies tailored to specific target requirements
often differs significantly between academic research and process chemistry. In process chemistry,
the emphasis is typically on using known, reliable, and readily available raw materials to ensure
commercial viability, rather than employing complex reactions or specialized reagents. A consistent
focus in pharmaceutical large-scale manufacturing involves avoiding costly and hazardous reagents
and reaction conditions, enhancing yields, and reducing waste generation. In some instances, minor
modifications to the process can yield significant benefits, such as improved environmental impact,
cost reduction, more efficient use of raw materials, and increased energy efficiency and step
economy. In line with these objectives, our research has led to the development of a novel and more
efficient synthetic route for an advanced intermediate of Ledipasvir. This process involves late-stage
cyclopropanation and fluorination. Additionally, we have devised a telescopic synthesis for Gliflozin
Aglycone, which includes ortho-lithiation of 1,4-dihalobenzene followed by reaction with
corresponding aldehydes and subsequent reduction of the resulting diaryl methanol intermediate.
These innovative laboratory-scale syntheses are currently being evaluated for potential scale-up
processes, reflecting our commitment to optimizing pharmaceutical manufacturing through strategic,
incremental improvements.

Photocatalyzed Continuous-flow synthesis of Pharmaceuticals

Flow chemistry helps in safe handling of hazardous reagents, high temp. reactions, and scalable synthesis of photocatalyzed reactions. Boron containing compounds are building blocks for Suzuki coupling reactions and drug molecules such as Tavaborole, (antifungal), Crisaborole (antifungal), Bortezomib (anticancer) etc. A scalable metal-free method for synthesis of boron compounds has been developed in a flow reactor. This method is suitable for for synthesis of drug molecules such as Tavaborole, Crisbrooke and other boron compounds.