A scalable synthetic route to the kinase inhibitor's core (R)-2-((4-(4-amino-2-fluorophenoxy)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl)amino)propan-1-ol targeting TAM and MET kinases is presented. A selective nucleophilic aromatic substitution (SNAr) reaction was developed as the key transformation along with a Cu-catalyzed C–N coupling reaction. This route comprises fewer steps (four steps) compared to the six-step sequence previously reported in the literature, delivering significantly improved overall yield.

A continuous flow protocol for the α-bromination of aldehydes with bromine is reported, demonstrating significantly improved reaction efficiency and superior mono/dibromination selectivity compared to conventional batch methods. A wide range of aldehydes, including both aryl-substituted and simple aliphatic aldehydes, exhibited excellent reactivity and selectivity under optimized flow conditions. Utilizing this α-bromination flow strategy, a two-step flow synthesis of 2-aminothiazoles, a core structural motif present in many biologically active molecules, was successfully developed, starting from aldehydes. Furthermore, by integrating the α-bromination, 2-aminothiazole formation, and subsequent condensation, a three-step flow process was established for the synthesis of a 2-aminothiazole-containing Hep3B inhibitor. This study highlights the potential of continuous flow chemistry in both bromination reactions and the downstream multistep synthesis of complex bioactive molecules.

Pyrimidin-4-ones and (3H)-quinazolin-4-ones are widely occurring heterocyclic motifs found in biologically active substances. This report presents a practical and scalable three-step, two-pot synthesis of 2-unsubstituted-3-alkyl/aryl derivatives of these heteroaromatics. During the mechanistic investigation of the hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU)-mediated coupling of 4-hydroxyquinazolines with amines, we found that the N-activated heterocycle underwent nucleophilic attack on the methine atom with subsequent ring opening and ring closing (ANRORC mechanism). Building on the new mechanistic insight, we designed and developed an efficient synthesis of 2-unsubstituted-3-substituted pyrimidin-4-ones through the condensation of β-aminoacrylates with dimethylformamide dimethylacetal (DMF-DMA), followed by cyclization with primary amines. The required β-aminoacrylates were easily obtained in a single step via ZnCl2-mediated decarboxylative Blaise–Reformatsky reaction of nitriles, which was extended to aliphatic substrates using an improved protocol. The methodology described herein is particularly suited to execution on a large scale as it requires no chromatography, utilizes no solvents of very high concern, and has been successfully demonstrated on the liter scale.

The pharmaceutical manufacturing sector is steadily transitioning from batch to continuous operations, as the drawbacks of batch operations and the advantages of continuous operations have increasingly provided compelling motivation for change. This study, which details the Step 2 synthesis of baloxavir marboxil (from S-033447 to S-033188), provides an example of how continuous manufacturing implementation can offer significant operational benefits. The process includes four unit operations (i.e., reaction to S-033188, crystallization and purification of S-033188, continuous rotary filtration of S-033188, and continuous wet milling and drying of S-033188). S-033188 was formed in a three-stage 500 mL CSTR cascade with a ReactIR in the third stage. The total residence time was 10.5 h, and the high-performance liquid chromatography (HPLC) area% of S-033188 and S-033447 in the third stage was 96.6 and 0.6%, respectively. The continuous crystallization of S-033188 was performed in a three-stage MSMPR system, and the crystallization yield was 97.1% with a 15-fold antisolvent addition. Focused beam reflectance measurement (FBRM) was located in the third stage to monitor the start-up and steady state during the run. A continuous rotary filter was used to process the S-033188 slurry, and it operated with a vacuum pressure of approximately −15 kPa and a cake height of 4 mm after reaching a steady state. Wet milling was applied to achieve the required quality attribute of S-033188 on particle size distribution (PSD), and heptane/ethyl acetate (50:1, v/v) was selected as the resuspension solvent. After wet milling, S-033188 was dried with a continuous drum dryer, resulting in desired Form I.

A scalable enzymatic process has been developed for the preparation of optically pure 3-bromo- or 3-methylsulfonyl-substituted l-phenylalanine (S)-1a–b, which serves as key intermediates in the synthesis of lifitegrast. This method utilizes enzymatic dynamic kinetic resolution (DKR) of the ethyl esters of racemic 3-bromo- or 3-methylsulfonyl-substituted dl-phenylalanine esters (rac-8a–b), catalyzed by the commercially available protease enzyme Alcalase. The reaction was carried out in a miniemulsion system that acts as a nanoreactor with high substrate loading (50% w/v). Notably, the process was completed within 24 h using less than 10% (w/w) of the enzyme. The desired optically pure (S)-isomer was obtained with >90% isolated yield and >99% enantiomeric excess (e.e.) under these conditions. Furthermore, the solvent system, along with the surfactant and enzyme, was successfully recycled, highlighting the sustainability and cost-efficiency of the process.

Extensive research efforts are dedicated to studying and understanding the dynamics of the crystallization of an active pharmaceutical ingredient (API), aiming to optimize product quality, yield, and robustness. In this study, we developed, tuned, and demonstrated a data-rich experimentation workflow that can be used to characterize and model the dynamic behavior of an antisolvent crystallization of an API. First, automated, parallel experiment technology and empirical models are used to describe the API solubility as a function of temperature and solvent composition. Next, an efficient protocol that leverages laboratory automation and process analytical technologies was used to generate an accurate chemometric model to quantify API supernatant concentration with in situ Fourier-transformed infrared spectroscopy. Using a 22 full-factorial design and data-rich experimentation, supernatant concentration profiles were obtained to characterize the impact of the crystallization temperature and antisolvent charge rate on the isolation procedure. These multivariate, time-series data profiles were subsequently modeled using dynamic response surface methodology (DRSM). This approach provided a comprehensive understanding of the sensitivity of the operating parameters on the crystallization process to enable rapid process development. The DRSM model successfully predicted the concentration dynamics based on antisolvent fraction, addition rate, and temperature for the training data set from the initial design of the experiment as well as a separate validation experiment. This study highlights how the combination of data-rich experimentation and process modeling can lead to valuable process knowledge for optimization and control strategies for crystallization in pharmaceutical manufacturing.

Brovana Inhalation Solution is a sterile, clear, colorless aqueous solution of the tartrate salt of arformoterol. Arformoterol, the R,R-enantiomer of formoterol, is a highly effective medication with improved pharmacodynamic properties, including increased receptor binding affinity and prolonged bronchodilation. This report describes the development of a robust, efficient, cost-effective, and commercially scalable process for the production of the targeted (R,R)-isomer of formoterol featuring a chiral resolution of inexpensive and readily available formoterol fumarate. This newly developed resolution process proved its efficacy by providing >99.90% chiral pure arformoterol with 74% overall yield.

Herein, we describe a two-step alkylation and asymmetric transfer hydrogenation telescope process for the synthesis of an enantioenriched substituted tetralol, a key intermediate in the synthesis of active pharmaceutical ingredient udifitimod (BMS-986166). A hydrogen borrowing alkylation catalyzed by an iridium catalyst was developed to replace an asymmetric alkylation that utilized an alkyl iodide with a costly stoichiometric chiral auxiliary under cryogenic conditions. In the following step, construction of the key stereocenter on the tetralin core was enabled by dynamic kinetic resolution using Ru-catalyzed asymmetric transfer hydrogenation. Process optimization allowed for a telescoped process that delivered the chiral alcohol product with high yield, purity, and enantio- and diastereoselectivity as well as controlled levels of residual metal content acceptable for downstream processing.

International audience

Herein, process improvement work on the phosphodiesterase-4 inhibitor crisaborole is described. The starting material 2-bromo-5-hydroxybenzaldehyde was replaced with the low-cost m-cresol. The process involves the purification of the low-melting-point bromophenol by a cocrystal strategy, selective debromination of the gem-dibromide byproduct, boronation through a telescoped process, and design of experiments optimization in the active pharmaceutical ingredient (API) synthesis stage. The economic, efficient, and practical synthesis of crisaborole was successfully achieved. It is worth noting that filtration unit operations were applied in the scale-up process of Miyaura borylation to address the common issue of incomplete conversion in this process.