AMG 193 is an MTA-cooperative PRMT5 inhibitor that has shown promising antitumor activity in the clinic. Despite a five-month development window from molecule identification to multi-kg manufacture of this small molecule drug substance, a robust process was developed, featuring multiple bio- and chemocatalytic steps. In particular, two wild-type enzymes were applied to the synthesis of key building blocks, including the formation of a chiral morpholine fragment, which was further improved through directed evolution. Additionally, a selective Ir-catalyzed C–H borylation, followed by a Pd-catalyzed Suzuki coupling and cyclization, was executed in a single pot, enabling rapid access to the naphthyridine core. Altogether, the development of this convergent synthesis has enabled a continued supply of AMG 193 for clinical studies.

The syntheses of therapeutically important μ-opioid receptor antagonists such as naloxone and naltrexone use noroxymorphone as a key late-stage intermediate, which is manufactured from the poppy-derived alkaloids oripavine or thebaine. However, it would be advantageous to instead use morphine as the starting material, which is cheaper and more abundant. In this paper, we describe the conversion of morphine into a dienol acetate required for installation of the C14 hydroxyl group of noroxymorphone. Our approach is more efficient than previously described approaches and uses a one-pot Albright–Goldman oxidation/dienol acetate formation sequence of an allylic alcohol as the key feature. This synthesis has been successfully applied on multikilogram scales. A brief investigation of the scope of the one-pot Albright–Goldman oxidation/dienol ester formation on other substrates is also described.

Although mechanochemical synthesis has gained widespread application, our understanding and enhancement of the control of the reaction need to be improved. In this work, we confirm that the mechanochemical reaction of the active pharmaceutical ingredient dantrolene is controlled by diffusion-controlled kinetics. On this basis, we demonstrate a novel approach to modulate mechanochemical reactivity through a diffusion enhancement strategy mediated by supramolecular interactions. The method employs a highly efficient spiral gas–solid two-phase flow technique, in which urea, an additive that can establish supramolecular interactions with 1-aminohydantoin hydrochloride, is introduced into the reaction system to substantially enhance diffusion, thus facilitating the efficient synthesis of dantrolene. Notably, in this diffusion enhancement process, the weakening of mechanical forces triggers the nucleation and growth of the active substrate to form structurally well-defined eutectic crystals that inhibit the reaction. This strategy reduces the mechanochemical reaction time of dantrolene and its analogs to less than 30 s. In addition, thiourea and acetamide, which are structurally similar to urea, promote the reaction, and their effects correlate with the number of supramolecular sites of action.

PF-07104091 (tegtociclib) is a cyclin-dependent kinase 2 (CDK2) selective inhibitor under investigation as an oncology treatment with breast cancer as the leading indication. In this report, we detail the development and optimization of a selective enzyme cascade-carbamate formation telescoped sequence for the synthesis of PF-07104091. The newly developed process enables exquisite stereochemical control and efficient processing, affording crude active pharmaceutical ingredient (API) in good yield and high purity while demonstrating reduced process mass intensity (PMI) and cycle time. This optimized highly efficient and sustainable process was demonstrated during pilot plant scale production of >450 kg of PF-07104091.

A variety of eye infections are caused by microorganisms such as bacteria, viruses, fungi, and parasites, and they have a significant impact on eyes in all ages of population worldwide ranging from inconvenience, visual impairment, blindness, and death. The objective of this review is to provide a brief overview of eye infectious diseases, with an emphasis on the importance of quinolone antibiotics in eye care. Gatifloxacin (1) and ofloxacin (2) are important anti-infectious agents widely used for the treatment of ocular infections. A literature review of various synthetic approaches for the preparation of gatifloxacin (1) and ofloxacin (2) drug substances is presented. In addition, the reported gatifloxacin (1) and ofloxacin (2) synthetic routes were assessed for their strengths and weaknesses from a process chemistry perspective. A comparative summary is provided based on drug substance batch size, quality, process and manufacturability, safety, and environmental considerations.

This paper describes the research and development of a practical and efficient process for manufacturing a soluble guanylate cyclase stimulator, 1. The newly developed process includes an efficient telescoped process consisting of four consecutive reactions: tetrazole formation, difluoromethylation of a tetrazole moiety, deprotection, and tert-butyldiphenylsilyl (TBDPS) protection. Although regioselectivity in difluoromethylation of the tetrazole moiety was moderate, the selective TBDPS protection gave the desired regioisomer exclusively. We addressed safety issues related to thermally unstable tetrazole compounds and developed a safe process based on the thermal analysis results in which operating temperatures were controlled and the dangerous compounds were not isolated. Notably, the need for chromatographic purifications was avoided for all synthetic steps. This highly efficient and safe process was successfully demonstrated on a pilot scale to yield 24.6 kg of 1 with high quality. Overall yield was improved from 35% by the medicinal chemistry route to 45%.

An enabling synthesis of tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine was developed starting from p-phenylenediacetic acid. The readily available p-phenylenediacetic acid was first converted in four steps to 1,4-dibromo-2,5-bis(2-bromoethyl)benzene, which was then subjected to Parham cyclization conditions. The mechanistic analysis of the Parham cyclization revealed that controlling the temperature and solvent environment was crucial. Process analytical technology (PAT) was used in the optimization of this intramolecular cyclization to identify the optimal temperature range for the halogen–metal exchange and intramolecular cyclization steps by means of a single kinetic experiment with increasing temperatures. A set of these small-scale experiments were conducted to fine-tune the reaction parameters and ensure scalability. Additionally, THF/n-hexane mixtures were utilized to balance solvent effects and solubility of the reactants, thereby minimizing competitive E2 elimination and affording the desired product in >60% assay yields. To complete the synthesis of tricyclo[6.2.0.03,6]deca-1,3(6),7-trien-2-amine, tricyclo[6.2.0.03,6]deca-1,3(6),7-triene was iodinated using N-iodosuccinimide and subsequently subjected to direct C–N coupling conditions.

The development of cost-effective and sustainable manufacturing processes is a growing priority in the pharmaceutical industry, with many companies turning to computational modeling to reduce reliance on experimental campaigns. Established simulation frameworks must however support in silico pharma R&D, especially for detailed process design and optimization. This paper introduces a robust but simple and flebible modeling framework for simulating and optimizing batch manufacturing processes, applying it to the production of AZD1775 HMS (a small-molecule intermediate required for the synthesis of the experimental anti-cancer drug Adavosertib). The entire design space is mapped using high-fidelity submodels for batch reactors and liquid–liquid extraction (LLE) units. The impact of solvent selection, reagent concentration, separation solvent ratio, operating temperature, and equipment size on process viability has also been evaluated, towards identification of a cost-optimal and environmentally friendly LLE solvent system (water–acetonitrile–toluene) and process conditions. Drug development can thus be streamlined by this systematic pathway for sustainable manufacturing, achieving economic and environmental goals simultaneously.

A scalable 8-step route for a key (S)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole intermediate for orforglipron was developed to support clinical trials. Highlights of process development results in this contribution include the following: (1) approximately 50% reduction of a key des-carbonyl impurity in the reductive removal of the Evans auxiliary by the introduction of MgCl2 as a chelating agent for the reduction with LiBH4, (2) a telescoped process for PTC alkylation with chloroacetonitrile and subsequent cyclopropyl ring formation with an asymmetric cyclic sulfate avoiding the problematic isolation of the alkylation product, and (3) significantly improved isolated yield and stereoselectivity of the cyclopropyl ring formation by replacing KHMDS with LiOt-Bu as the base for the reaction. The developed process was successfully scaled up to >400 kg scale for each step to deliver a high-quality product in an overall yield of 22%, demonstrating the robustness of the optimized process.