A 5-step cGMP sequence for the preparation of an IL-17A inhibitor 1 was optimized and scaled up to deliver a total of 66 kg of the final drug substance 1 to support clinical and product development studies. Salt formation and polymorph screening identified a suitable polymorph of the hemiedisylate salt that provided desirable physical properties. Key impurities in the final drug substance were identified, and control strategies were developed and executed to control them to acceptable levels in the production batches.

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.

Amino acid pre-activation is a critical reaction step during solid phase peptide synthesis due in part to the formation of impurities such as isomer, N,N '-diisopropylcarbodiimide- adduct, single amino acid addition, and the generation of hazardous hydrogen cyanide side product. The conventional design of the experiment approach has been applied previously to elucidate the optimal pre-activation reaction conditions, but it is laborious and time-consuming amid numerous variables involved. In this work, we present a detailed mechanistic amino acid pre-activation kinetics model to correlate the input parameters with the output reaction conversion, isomer formation, and hydrogen cyanide generation response. The model is formulated using elementary mechanistic reaction steps and the kinetics parameters are fitted to literature data and goodness of fit is evaluated for the activation of other amino acids. Single-factor sensitivity analysis and multi-objective optimization are applied to understand the impact of process parameter ranges on impurity levels and the corresponding control strategies are recommended.

The hazard assessment of a telescoped Miyaura borylation and Suzuki coupling reaction employing bis(pinacolato)diboron (BisPin), used in the developmental synthesis of an intermediate for abemaciclib, led to the observation of hydrogen being generated. Quantitative headspace GC and solution B-11 NMR were used to show that the rapid decomposition of the excess BisPin from the borylation under the aqueous basic conditions of the Suzuki reaction was responsible for H-2 generation. The moles of H-2 observed were found equal to the BisPin excess, which is rationalized by mass balance and a stoichiometric reaction. The possible generation of the stoichiometric levels of H-2 should be considered in hazard assessments of this class of reaction. Kinetic and process modeling was used to minimize the risk upon scale-up, and results for commercial manufacturing batches are presented, which showed good agreement with the lab scale data. Furthermore, the hydrogen evolution potentials of other common borylating agents including bisboronic acid (BBA) and pinacol borane were demonstrated.

We have developed a continuous flow method to enable rapid scaleup of an enantioenriched benzodioxan intermediate. We propose that the reaction proceeds through an intramolecular SNAr cyclization. Interestingly, traditional SNAr conditions resulted in impurity formation. When the starting material 2 was treated with alkali base in polar aprotic solvents, an undesired product regioisomer was observed. The formation of this regioisomer impurity could be suppressed by using a less polar solvent, an organic base, and high temperature. By employing continuous flow technology, these high temperature conditions could be scaled up to produce 540 g of the desired intermediate. The continuous flow reactor allowed for rapid thermal equilibration, which minimized problematic product decomposition by reducing the time that the product was exposed to high temperature.

A practical synthesis of a D1 potentiator chiral tetrahydroisoquinoline has been accomplished employing diastereoselec-tive Pictet-Spengler methodology to access the required trans-stereochemistry. A dynamic kinetic resolution by crystal-lization gives high yields of a N-(phenylsulfonyl)alkyloxazolidinone that is converted to an acyl iminium ion when ex-posed to a variety of Lewis acids resulting in a highly diastereoselective Pictet-Spengler cyclization. An eight-step linear synthesis that starts with commercially available R-2-bromophenylalanine affords the chiral tetrahydroisoquinoline 1 in 54% overall yield.

Technology transfer of a small volume continuous (SVC) process and Current Good Manufacturing Practices (cGMP) manufacturing of merestinib are described. A hybrid batch-SVC campaign was completed at a contract manufacturing organization under cGMP. The decision process by which unit operations were selected for implementation in flow for the cGMP campaign is discussed. The hybrid process comprised a Suzuki–Miyaura cross-coupling reaction, a nitro-group hydrogenolysis, a continuous amide bond formation, and a continuous deprotection. A continuous crystallization using two mixed suspension, mixed product removal (MSMPR) crystallizers and a filtration with in situ dissolution were employed for purification between the two SVC steps. Impurity levels were monitored using both online process analytical technology (PAT) and offline measurements. The continuous processing steps operated uninterrupted for 18 days to yield the drug substance in solution at a throughput of 12.5 kg/day. Crystallization in batch mode afforded 183 kg of the drug substance in specification. Success of the campaign was attributed to robustness of the control strategy and to the multiyear partnership in continuous manufacturing between the development organization and the contract manufacturer. Key learnings are offered from the perspectives of both the development organization and the contract manufacturer.

Evolution of hydrogen cyanide (HCN) during amino acid activation using the reagent combination ethyl cyano(hydroxyimino)acetate (Oxyma)/diisopropylcarbodiimide (DIC) is observed under ambient conditions (20 degrees C) in N,N-dimethylformamide (DMF). Concentration versus time profiles obtained by 1H NMR spectroscopy in the presence and absence of amino acids indicate that HCN is formed upon addition of DIC to the reaction mixture and that HCN evolution continues to occur even after amino acid activation is complete when Oxyma and DIC are used in excess amounts relative to the amino acid. A mechanism for the reaction between Oxyma and DIC is proposed, and evidence for its validity was gathered by NMR spectroscopy.

Anin situmethod for determination of the overall volumetric mass transfer coefficients by direct observation and quantitation of dissolved gases that contain NMR active nuclei is presented.

Stilbenes are important and useful structural moieties, but methods for their preparation typically possess numerous inefficiencies. Presented here is a methodology for the two-step, one pot preparation of unsymmetrical stilbenes via sequential Heck reactions. The first Heck reaction with ethylene gas was analysed as a function of temperature and pressure for electronically differentiated naphthyl bromides and modelaided reaction optimization was utilized to define the system. In addition, reactNMR was utilized to determine ethylene solubility in common organic solvents useful for Heck reactions. Finally, an optimized sequential Heck reaction process was developed and applied to a range of substrates allowing for efficient preparation of unsymmetrical stilbenes, including the natural antioxidant, pterostilbene.

An efficient three-step synthesis of a series of fused bicyclic s-[1,2,4]triazolo[1,5-a]pyridines 1 was accomplished utilizing novel intermediates derived from inexpensive, commercially available hydrazides A and methyl coumalate B. A significant feature of this approach was the formation of a dihydrazide intermediate 2, bypassing the need for oxidative N-N bond formation in the 1,2,4-triazole synthesis. Further purification of the dihydrazides 2, beyond simple isolation, proved to be unnecessary owing to the impurity rejection afforded by the crystalline oxadiazolium salts 3. Additionally, the prepared oxadiazolium perchlorate salts showed excellent moisture stability, an unusual feature in compounds of this type.

A single-step method and a two-step method for the synthesis of aminopyrazoles from isoxazoles are presented and compared. Based on in situ NMR monitoring, both processes proceed through a ketonitrile. In the single-step process, hydrazine serves to both open the isoxazole to the unisolated ketonitrile intermediate and form the aminopyrazole. The two-step process involves ring opening of the isoxazole by deprotonation with hydroxide to generate the ketonitrile followed by the addition of acetic acid and hydrazine to form the aminopyrazole.

The design, development, and scale up of a continuous iridium-catalyzed homogeneous high pressure reductive amination reaction to produce 6, the penultimate intermediate in Lilly's CETP inhibitor evacetrapib, is described. The scope of this report involves initial batch chemistry screening at milligram scale through the development process leading to full-scale production in manufacturing under GMP conditions. Key aspects in this process include a description of drivers for developing a continuous process over existing well-defined batch approaches, manufacturing setup, and approaches toward key quality and regulatory questions such as batch definition, the use of process analytics, start up and shutdown waste, "in control" versus "at steady state", lot genealogy and deviation boundaries, fluctuations, and diverting. The fully developed continuous reaction operated for 24 days during a primary stability campaign and produced over 2 MT of the penultimate intermediate in 95% yield after batch workup, crystallization, and isolation.

Asymmetric hydroformylation (AHF) of 2-vinyl-6-methoxynaphthalene demonstrates important design characteristics of a vertical pipes-in-series plug flow reactor (PER). The regio- and enantioselectivity of the AHF reaction provide a chemical probe of gas liquid mixing in a flow reactor for comparison with well-stirred batch reactors. Results obtained with the flow reactor compare favorably to those obtained in batch. Thus, AHF provides an efficient, in-flow enantioselective synthesis of (S)-Naproxen.

A selective methodology for preparing highly substituted aminopyrazoles has been demonstrated. Starting with an acetophenol core, the corresponding substituted isoxazole is prepared in two steps. The isoxazole is transformed into a benzopyran. Alkylation of the aminobenzopyranone gives N-substituted aminobenzopyranone derivatives that react with substituted hydrazine to give aminopyrazoles. This versatile synthesis enables the preparation of highly substituted aminopyrazoles for use as key synthetic building blocks for biologically active molecules. In addition, this process represents the first amine alkylation of aminobenzopyranones.

A scalable, asymmetric synthesis of (3aS,6aS)-6a-(5-bromo-2-fluorophenyl)-1-((R)-1-phenylpropyl)tetrahydro-1H,3H-furo[3,4-c]isoxazole, a key intermediate in the synthesis of LY2886721, is reported. Highlights of the synthesis include the development of an asymmetric [3 + 2] intramolecular cycloaddition facilitated by trifluoroethanol, and the development of a new synthesis of (R)-N-(1-phenylpropyl)hydroxylamine tosylate which proceeds through a p-anisaldehyde imine and avoids the formation of toxic hydrogen cyanide gas as a byproduct. The synthesis proceeds over four steps and provides the product in 36% overall yield.

Galunisertib is a kinase inhibitor designed to selectively inhibit TGF-β signaling. Drug substance stress degradation studies performed during clinical development demonstrated two degradation products via oxidation of the nitrogen(s) of the pyridine moieties in the presence of dilute hydrogen peroxide. These “N-oxide” potential degradation products generated positive alerts for mutagenicity by in silico structure–activity relationship-based genotoxicity assessment, and both tested positive in the Ames bacterial mutagenicity test. These compounds were also identified as potential process impurities that could originate through the use of hydrogen peroxide, and this reagent was subsequently removed from the synthetic route. A toxicology limit of not more than 166 ppm (w/w relative to the drug substance) combined for the two N-oxides was assigned on the basis of clinical dosing. An LC–MS method was developed to test for the N-oxides with a limit of quantitation set at <10% of the toxicology limit in both the drug substance and the drug product tablets. Stability data demonstrated the absence of N-oxide formation under long-term and accelerated storage. On the basis of these results, the oxidative degradation pathway was shown to be inactive and nonrelevant for both the drug substance and the drug product.

This communication describes an in situ method for direct observation and quantitation of dissolved H2 at high pressure with concurrent monitoring and characterization of organic reactions. This capability also allows for direct measurement of k(L)a values and provides insight into reactions that was not previously attainable.

A mechanistic approach was undertaken to understand the oxygen sensitivity of a Pd-catalyzed amination reaction used in the synthesis of an active pharmaceutical ingredient. FlowNMR and dissolved oxygen probes were used as process analytical technology alongside kinetic and unit operation models to better characterize the oxidative deactivation pathways of the catalyst. Interplay between ligand excess, oxygen inertion, and additional degassing due to reflux were all found to contribute to reaction rate variability. This mechanistic approach allowed for appreciation and clear communication of the risks, development of protocols to mitigate those risks, and successful scale-up under rapid development timelines.