SBIR-STTR Award

Light-driven chemistry (or photoredox catalysis) has made significant advances in the last decade for practical organic or drug synthesis. For example, light-induced reactions have enabled generation of radical intermediate R? for direct functionalization of biologically relevant heterocycles and cross-coupling reactions for important covalent bond formations. Therefore, photoredox catalysis offers tremendous potentials to access novel drug architectures not possible with conventional heat-driven processes, reduce drug synthesis steps, and improve process safety, all of which drastically reduce pharmaceutical manufacturing costs. These benefits have compelled drug companies to invest heavily in incorporating light-driven chemistry to their next generation of pharmaceutical manufacturing. From the public health’s perspective, light-driven chemistry has the potential to substantially lower the cost to access therapeutics to improve overall human health. Dihydrophenazine and phenoxazine organic photoredox catalyst (PC) products, a spin-off innovation from the Miyake lab, are key to enable this photoredox revolution in the pharmaceutical industry. Designed to possess advanced photophysical properties (highly reducing, charge transfer excited state, and redox reversibility), these organic PCs dominate any PCs (precious metals or other organic PCs) in the oxidative quenching applications, where an excited state reductant is required. Specifically, dihydrophenazine and phenoxazine PCs has been demonstrated as cost-effective replacement for precious metal iridium or ruthenium PCs in numerous radical-induced and cross-coupling reactions. In some cases, these organic PCs were shown superior than iridium or ruthenium PCs; for example, they were employed in lower catalyst loading and were used to discover novel chemistry. In this SBIR proposal, a number of technical hurdles associated with organic PCs commercialization will be resolved to de-risk and ensure long term competitiveness of the company. In Aim 1, optimization of synthetic routes was proposed for dihydrophenazine and phenoxazine synthesis to reduce production cost. In Aim 2, using the optimized synthetic routes, the organic PCs production will be scaled up from 10g/ week to 1kg/ week. In Aim 3, to validate the performance of the organic PCs in an industrially relevant environment, the organic PCs will be applied in kg-scale drug intermediate synthesis using a photoflow reactor. The completion of this project will advance the organic PC products from Technology Readiness Level (TRL) 4.5 to 6.

Public Health Relevance Statement:
PROJECT NARRATIVE Light-driven chemistry (or photoredox catalysis) has made significant advances in the last ten years for practical organic or drug synthesis. It offers promises to access novel drug architectures, reduce manufacturing steps, and improve process safety, all of which drastically reduce drug manufacturing costs. Organic photoredox catalysts, developed in this SBIR Phase I proposal, provide cost-effective and sustainable solutions to enable light-driven chemistry in pharmaceutical manufacturing and therefore will substantially lower the cost to access therapeutics to improve overall human health.

Project Terms:
Architecture; Biological; Businesses; Catalysis; catalyst; Charge; Chemistry; commercialization; cost; cost effective; Coupled; Coupling; covalent bond; design; Drug Industry; drug synthesis; Ensure; Environment; Generations; Health; Human; Image; improved; Industrialization; innovation; Investments; Iridium; Light; metal complex; Metals; next generation; novel; novel therapeutics; operation; Organic Synthesis; Oxidation-Reduction; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phenoxazine; Piperazines; Price; Problem Solving; Process; Production; Property; Public Health; Reaction; Readiness; Reducing Agents; research and development; Risk; Route; Ruthenium; Safety; scale up; Scheme; Small Business Innovation Research Grant; Technology; Therapeutic; Work

The underlying technology developed in this project is photoredox catalysis, an active research area with growing academic and industrial interest. The impact of photoredox catalysis is expected to exceed palladium catalysis, the Nobel-prize-winning chemistry that fueled the golden age of drug discovery. Photoredox catalysis uses light to activate chemical reactions, as opposed to heat in conventional processes. Unique single-electron radical chemistry is accessed through light absorption enabling new reactivities and unprecedented process efficiencies e.g. synthesis of drug candidates in fewer steps. Of additional industrial interest, it also permits the use of low-cost and structurally diverse raw materials in drug development and manufacturing that are otherwise unreactive in conventional processes. From a public health perspective, photoredox catalysis has the potential to substantially lower the cost of therapeutics and improve overall human health by enabling accelerated drug development and reduced drug manufacturing costs. Completing this NIH SBIR Phase II project will result in the commercialization of high performance organic photoredox catalyst (PC) products. PCs are the key enabler of photoredox catalysis. However, PCs predominantly used today are based on iridium and ruthenium, two rare and expensive precious metals that do not scale beyond R&D usage, posing serious cost and supply issues for industrial use. Organic PCs provide the solution. Made from abundant elements, they are sustainable and can easily scale to meet industrial demand. Notably, the organic PCs of interest here were designed by quantum simulations to possess critical properties resolving many limitations of earlier generations. In many applications, they were shown to match and in some cases exceed the performance of precious metal PCs. The organic PCs developed here provide the scalable solution for photoredox catalysis required for drug development and manufacturing. Specifically, this project integrates three main components pivotal to enabling industrial application of photoredox catalysis, namely i) organic PCs, ii) photochemical reactions, and iii) photoreactor technology. For organic PCs (Aims 1 and 2), a number of PC candidates will be synthesized with expanded ranges of reactivities capable of accommodating many industrial reaction conditions. For photochemical reactions (Aims 3 and 4), novel and medicinally important reactions (with extended substrate scope) with stated customer interest will be developed using various classes of organic PCs. Finally, for photoreactor integration (Aim 5), commercially available photoreactor designs and associated reaction conditions will be identified that maximize the performance of organic PCs.

Public Health Relevance Statement:
PROJECT NARRATIVE Photoredox catalysis, a subset of photochemistry, promises access to novel drug architectures via efficient synthetic routes, reduced drug development time, and improved process safety. In this NIH SBIR Phase II proposal, organic photoredox catalyst technology -- the key enabler of photoredox catalysis -- will be broadly developed. This project will increase the public’s access to life-enhancing and -saving therapeutics enabled by accelerated drug development and lower drug manufacturing costs.

Project Terms:
absorption; Age; Amines; aqueous; Architecture; Area; base; Benchmarking; Catalysis; catalyst; chemical reaction; Chemistry; commercialization; cost; cost effective; Coupling; design; Development; drug candidate; drug development; drug discovery; drug synthesis; Electrons; Elements; empowered; Generations; Health; Human; hydrophilicity; Hydrophobicity; improved; Industrialization; interest; Iridium; Life; Light; Measures; metal complex; Metals; Methods; Nobel Prize; novel; novel therapeutics; Oxidants; Palladium; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Phase; phenoxazine; Photochemistry; Process; Production; Property; Public Health; quantum; Reaction; Reducing Agents; Research; research and development; Route; Ruthenium; Safety; Savings; Scheme; Scientist; simulation; Small Business Innovation Research Grant; Solubility; Solvents; Structure; System; Technology; Therapeutic; Time; United States National Institutes of Health