Organic Process Research & Development最新文献

A telescoped two-step fully continuous-flow process forthe synthesisof nevirapine (trade name: Viramune), a key therapeutic agent forthe prevention and treatment of HIV-1 infection, has been developed.The process employs, for the first time, sodium bis(trimethylsilyl)amide(NaHMDS) as a homogeneous, process-friendly base for both reactionstages and enables direct conversion of methyl 2-(cyclopropylamino)nicotinateand 2-chloro-3-amino-4-picoline to nevirapine without isolation ofthe cyclization intermediate. The optimized process operates witha total residence time of 10 min and delivers crude nevirapine in91.9% overall isolated yield across two reaction steps, with a space-timeyield of ∼365 g/h/L and 99.6 A% HPLC purity. Furthermore, wedeveloped an on-demand continuous generation of NaHMDS in diglyme(up to ∼2.0 M) using a sodium packed-bed column reactor. Usingon-demand generated NaHMDS, the telescoped synthesis yielded crudenevirapine in 90.7% isolated yield (∼340 g/h/L space-time yieldand 99.5 A% purity), providing a scalable and cost-effective alternativeto NaH applied in the current commercial synthesis.

Development of the commercial manufacturingstrategy and processemployed for xanomeline tartrate (KTX-001), a key activepharmaceutical ingredient (API) in KarXT, is described. The developmentprocess involved identifying efficient processes for key bond-formingsteps, including the conversion of regulatory starting material nicotinaldehyde(1) to stage 1 regulatory intermediate chlorothiadiazole 2, nucleophilic aromatic displacement of the chlorine atomwithin 2 with 1-hexanol followed by methylation to generatestage 2 regulatory intermediate pyridinium 4, and selectivepartial reduction of the pyridine ring to produce the API freebase,which after tartrate salt formation gave access to stage 3 regulatoryintermediate crude xanomeline tartrate (crude KTX-001). A recrystallization process was developed to provide the drugsubstance xanomeline tartrate (KTX-001) in an overallyield of 35% from nicotinaldehyde (1) with HPLC purityof >99.0% on scales of 500+ kilograms per batch, suitable for reliablesupply of this commercial drug substance.

Ibuzatrelvir is a second-generation, orally administeredinhibitorof the SARS-CoV-2 M^pro that has enhanced metabolic stabilitycompared to nirmatrelvir. Although early manufacturing campaigns enabledrapid large-scale supply, the final amidation–dehydration sequencefaced significant challenges in robustness, impurity control, anddownstream processing. In this report, we detail a streamlined telescopedprocess comprising a robust and efficient 2-chloro-1-methylpyridinium p-toluenesulfonate (CMPT)-mediated amidation followed bya clean trifluoroacetic anhydride (TFAA)-driven dehydration to overcomeexisting limitations. Process refinements in distillation, solventexchange, and crystallization delivered a reproducible, sustainableroute that was demonstrated at multikilogram scale. The optimizedprocess afforded ibuzatrelvir in high yield, purity, and potency whilemarkedly reducing process mass intensity (PMI) and cycle time, establishingan efficient and industrially viable approach for long-term manufacturing.

The extensive useof solvents in pharmaceutical manufacturing hasmajor impacts on overall process performance and final product quality.Solvent selection often requires tedious and resource-intensive experimentalinvestigations. Nevertheless, the growing interest in embedding sustainablepractices in process development workflows has motivated pharmaceuticalmanufacturers and researchers to deploy digital tools for enhancingprocess understanding and guiding the design of greener materialsand processes. In this work, a computer-aided mixture/blend design(CAM^bD) methodology is developed to identifysimultaneously the optimal solvent or solvent/antisolvent mixtures,mixture compositions, and process conditions in end-to-end processes,considering integrated synthesis, crystallization, and isolation.Within the proposed approach, thermodynamic models are used to coupleproperty prediction with process modeling to describe pharmaceuticalprocess systems, while mathematical optimization techniques are appliedto search the large design space of potential solvents and processconditions and identify the most promising designs among thousandsof possible options. Further consideration is also given to the integrateddesign of reaction, crystallization, and wash solvents, where designdecisions across the entire process are interlinked. The methodologyis applied to the synthesis, crystallization, and isolation of mefenamicacid as a case study, while considering a broad range of process-widekey performance indicators (KPIs) that quantify product quality andresource efficiency, such as product purity and process energy consumption.In order to explore the trade-offs between competing KPIs, the proposedapproach is extended to solve multiobjective design problems and generatea list of Pareto-optimal designs. The results highlight that the optimaldesigns are strongly dependent on the criteria considered and motivatethe need for an integrated approach to solvent selection and processdesign. The findings of this study are expected to contribute to thedigitalization of solvent selection for the accelerated developmentof sustainable pharmaceutical processes.

GDC-8025 is a potentpan-TEAD inhibitor that featuresa functionalized 1H-pyrazolo[3,4-b]pyridine core and a reactive acrylamide warhead. The first-generationsynthesis of GDC-8025 relied on a Sharpless asymmetricdihydroxylation of 7 to install the chiral diol moiety(8). This chemistry was not suitable for large scalemanufacturing due to the instability of the requisite 4-vinylpyridineintermediate (7) and occupational toxicity concerns ofosmium tetroxide. To address these challenges, a second-generationroute utilizing a biocatalytic enantioselective reduction of an α-ketoestersubstrate (18) was developed. Together with optimizationof a Chan–Evans–Lam coupling in flow, a tandem ester/nitrilereduction, and a chemoselective acrylamidation, implementation ofthis new route facilitated the robust multikilogram synthesis of GDC-8025 in 8 chemical steps.

The conventional batch manufacturing of clopidogrel bisulfateisconstrained by low process efficiency and poor control over pharmaceuticallypreferred yet metastable Form I. Herein, we report an end-to-end continuousmanufacturing process that combines multistep synthesis with a nucleation–growthdecoupled crystallization strategy to address both challenges. Throughthe integration of solid-acid-catalyzed esterification, three-feedsulfonylation, phase-transfer catalyst (PTC)-enabled S_N2 reaction, membrane-based phase separation, inline solvent exchange,and continuous crystallization, this integrated platform directlyconverts commercially available starting materials into sphericalForm I crystals with a narrow size distribution (Span = 0.42) withoutisolation of intermediates. The system operated continuously for 7.5h, achieving a 70% overall isolated yield and 97% S-enantiomeric purity.Compared with batch processing, the platform reduces total processingtime by 3.8-fold, halves the E-factor and processmass intensity (PMI), and increases space-time yield (STY) by 20-fold.The integrated process offers a scalable approach for continuous productionof pharmaceutical solids while maintaining control over both the molecularsynthesis and product solid form.

A thermal safety investigation wasconducted followingmultiplelaboratory incidents involving difluoromethoxy-substituted aryl boronicacids. Differential scanning calorimetry (DSC) revealed that compoundsbearing both a difluoromethoxy (or difluoromethyl) group and a boronicacid or boronate ester exhibit pronounced low-temperature exothermicdecomposition. This instability was observed both intramolecularlyand through intermolecular interactions among otherwise thermallystable components. The severity of decomposition was enhanced by thesteric proximity between the two functional groups and could be triggeredby catalytic quantities of boron-containing species or contact withborosilicate glass. Structural modifications, notably the replacementof the boronic acid group, significantly improved thermal stability.These findings identify a previously underappreciated thermal hazardassociated with this functional group combination and have importantimplications for compound design, storage, and process safety evaluation.Finally, an initial mechanistic investigation of the decompositionprocess as well as recommendations for compound handling are presented.

Ibuzatrelviris an orally bioavailable, next-generation clinicalcandidate developed for the treatment of COVID-19 infections. It wasidentified during the pandemic, prior to the approval of PAXLOVID,and displays a more favorable pharmacokinetic profile than nirmatrelvir.Consequently, the initial development of ibuzatrelvir proceeded underhighly accelerated timelines. This report details the optimizationof the end-stage synthesis sequence and its advancement throughoutthe initial clinical production campaigns. The study highlights anefficient protecting group-free amidation of tert-leucine and describes a complex isolation process following a telescopedamidation-dehydration cascade leading to ibuzatrelvir with a 30% increasein yield. The finalized synthetic route was successfully scaled up,enabling the manufacture of several hundred kilograms to support clinicalresearch initiatives.

Identificationof process-related impurities is a routine taskin the optimization and manufacturing of APIs. The identificationof these contaminants enables researchers to develop appropriate strategiesto purge them or prevent their formation. In many cases, impurityidentification is straightforward, relying on an understanding ofthe synthetic process and the reactivity of the reagents, which allowsresearchers to hypothesize the formation of specific byproducts thatare often indeed generated during synthesis. In other instances, however,certain impurities are extremely difficult to characterize, and theiridentification becomes a challenging and demanding task, particularlywhen present at very low levels. This article describes the time-and resource-intensive effort required to identify and characterizea nonpurging impurity in efinaconazole that elutes in close proximityto the API peak and is consistently detected at 0.06% (a/a), posinga potential Out of Specification risk during industrial production.The impurity was ultimately identified as an isotopologue of efinaconazoleexhibiting subtly distinct physicochemical properties, an uncommonbehavior for isotopologue species.