Organic Process Research & Development最新文献

Following the discovery of a chiral P(V) reagent to enablediastereoselectivesynthesis of stereogenic thiophosphoramidates, we have developed ascalable synthesis to deliver kilogram quantities of the STING agonistBMS-986301. The route not only reduced the number of steps comparedto the enabling route but also avoided the use of hazardous reagents.Further development enabled the use of crystallizations to isolateintermediates, effectively eliminating six chromatographic purifications.This resulted in an eightfold improvement in yield and 90% reductionin process mass intensity (PMI). The route was successfully implementedin a pilot-plant campaign to deliver 1.65 kg of BMS-986301 (1) and was therefore deemed suitable as a long-term optionfor commercial synthesis.

A practical synthesis of methyl N²-(tert-butoxycarbonyl)-N⁴-(1-(tert-butyl)-1H-pyrazol-4-yl)-L-asparaginyl-L-phenylalaninate(5)utilizing two continuous-flow processes is reported. The first isthe trickle-bed continuous-flow hydrogenation of the nitro compound1-tert-butyl-4-nitro-1H-pyrazole (1)on a multikilogram scale, followed by T₃P-mediated amidecoupling in flow with the dipeptide (S)-3-((tert-butoxycarbonyl)amino)-4-(((S)-1-methoxy-1-oxo-3-phenylpropan-2-yl)amino)-4-oxobutanoicacid (4) to obtain compound 5 in an overall80–84% yield and >99.9 A% HPLC purity. In situ ReactIR was applied for real-time reaction monitoring. A catalyst-bedpacking protocol was engineered to mitigate pressure drop and maintaincatalyst-bed reactivity and longevity, which enabled a low catalystloading of 0.1 mol % Pd/C for nitro reduction on a multikilogram scale.

Reports of new ligandsor precatalysts based on non-platinumgroupmetal (pgm) catalysis, as well as the number of publications describingnew methodology that relies on non-pgm catalysts, are at an all-timehigh. Catalyst screening groups and process chemists are now beginningto seriously investigate and evaluate non-pgm-based processes whencarrying out route scouting and process optimization. The million-dollarquestion is how many already established manufacturing processes andhow many launched drugs may have benefited from the use of non-pgmcatalysis, had it been available and considered at the time of processoptimization and launch? We wanted to explore one such example andidentified a previously reported palladium-catalyzed selective formalmonoarylation of ammonia, from the process used to make abemaciblib,as a suitable model reaction. This article describes our lessons learnedfrom evaluating this specific reaction in a high-throughput screeningstudy to identify a suitable nickel-based catalyst for the monoarylationof ammonia (NH₃), process optimization, and product isolationattempts. The preformed complex (NHP-DalPhos)Ni(o-tol)Cl) Cat5 was identified as the best-performingcatalyst and provided the desired primary amine 2 in82% conversion. The DalPhos family of ligands has been proven to providegood reactivity in cases where other ligands have failed, and thereason behind this has so far only been partially understood. Crucially,as part of our study, a structure-activity relationship (SAR) modelbased on three distinct catalyst descriptors (buried volume, P–Ni–Pbond angle, and electron richness) was uncovered. This has previouslynot been described for nickel catalysis while being known in broadterms for palladium catalysis and could fill a gap as an up-until-nowmissing insight for the successful implementation of nickel-catalyzedreactions. Through this model, we achieved a better understandingof the ligand parameters that proved to be important for a highlyactive and selective catalyst. Overall, we expect that by sharingour lessons learned, our story can act as a trigger to encourage moreresearchers to evaluate nickel catalysis alongside palladium whileavoiding having to tackle the same issues we encountered, and thatthe SAR model can provide a useful tool to aid and accelerate theidentification of the most effective nickel catalyst by maximizingthe coverage of chemical space.

At present, the key nicergoline intermediate 10α-methoxy-9,10-dihydrolyserol(3) is predominantly synthesized by photomethoxylationin batch photoreactors, a conventional method plagued by issues suchas poor light penetration, low energy efficiency, severe scale-upbarriers, and potential safety risks. In this work, a novel continuous-flowphotochemical process for manufacturing this intermediate has beendeveloped using a plate-type mesoscale photoreactor. This approachoffers substantial advantages over the traditional batch synthesis,including higher yields, shorter reaction time, excellent stereoselectivity,milder conditions, and enhanced scalability. Optimal conditions werefound that led to considerably higher productivity, achieving a throughputof up to 0.73 mol/h of 2 with a residence time of only20 s. The photochemical sequence was demonstrated at the kilogramscale, highlighting its viability, efficiency, and robustness.

Developing crystallization processes for the productionof pharmaceuticalsthat are both cost-effective and environmentally friendly is a highlycomplex challenge, since it is often the case that too many candidatesystems exist for them to all be studied experimentally. The widespreaduse and high fidelity of systematic process modeling tools enablestudy of crystallization systems in silico priorto conducting experimental trials, thereby allowing rapid identificationof promising processes toward accelerating drug development and wasteminimization. Moreover, these tools can be implemented without determiningcrystallization kinetics, as each system can be cast as a simple solid–liquidequilibrium (SLE) problem using established thermodynamic models alone.Consequently, this paper explores the use of data-led SLE models toassess total plant cost and environmental impact of different solventsystems for crystallizing pregabalin (an anticonvulsant and anxiolyticdrug for treating epilepsy, anxiety, and neuropathic pain), via reliablecosting methodologies and environmental impact metrics (process massintensity, scope-1 and -2 CO₂ emissions). Methanol-waterand isopropanol-water emerge as the best mixed solvent systems, bothoutperforming pure solvent options: the former achieves a 3.2% lowerplant cost (but at 25% higher emissions) vs. the latter.

A practical and scalable deprotection protocol for O- and N-benzyl protecting groups has beendevelopedusing wet Pd/C and organosilanes, notably 1,1,3,3-tetramethyldisiloxane(TMDS) and poly(methylhydrosiloxane) (PMHS), as hydrogen-donor reagents.The use of these cost-effective hydrogen sources eliminates the needfor molecular hydrogen, significantly improving process safety whileproviding a rapid and efficient approach to debenzylation. Operatingunder mild reaction conditions and ambient pressure, this methodologyis designed for pharmaceutical applications where avoiding hazardousgas handling is a priority. The developed system efficiently cleavesbenzyl esters, benzyl ethers, and N-benzyl amines,affording the corresponding deprotected products in short reactiontimes and consistently high yields (82–98%). Importantly, thereaction byproducts can be readily removed by standard industrialunit operations, including extraction, distillation, and crystallization,eliminating the need for labor-intensive purification techniques suchas column chromatography. Additionally, the utility of the catalyticsystem was extended to the efficient, gram-scale reductive cleavageof aromatic azo compounds into primary aromatic amines. This operationallysimple approach offers a sustainable alternative for both laboratoryand large-scale industrial syntheses.

Omidenepagisopropyl (OMDI) is the only marketed antiglaucoma drugthat acts as a prostaglandin E receptor 2 (EP2) agonist. It exhibitshigh receptor-binding affinity (K_i = 3.6nM) and potent agonistic activity (EC₅₀ = 8.3 nM). Moreimportantly, OMDI circumvents key limitations commonly associatedwith prostaglandin analogues, such as periorbital fat atrophy, hyperpigmentation,and drug tolerance, thereby offering greater clinical applicationvalue. However, the three previously reported synthetic routes toOMDI suffer from limitations that affect efficiency and scalability;for example, the isolated yields of routes I–III range from20.5 to 51.2%. All of these routes involve the use of hazardous reagents(e.g., sodium hydride, borane) and often rely on column chromatographypurification, which compromises material efficiency and process scalability.To address these issues, we report four new synthetic routes to OMDIdeveloped through iterative optimization that systematically overcomethe aforementioned limitations. Among them, route IV (accomplishedin only four steps) avoids the use of high-hazard reagents and requiresno column chromatography throughout the entire process, ultimatelyaffording an improved overall isolated yield of 64.2% with 99.86%high-performance liquid chromatography (HPLC) purity. Notably, thisprocess has been successfully validated on a hundred-gram scale, providinga reliable foundation for pilot-scale translation and potential industrialapplication.

Ozone is an attractive, sustainable oxidant for organicsynthesis,yet its adoption in pharmaceutical process development is often limitedby safety concerns, poor gas–liquid mass transfer, solventincompatibilities, and challenges in scaling. Herein, a robust, high-throughputworkflow for the rapid development and optimization of scalable ozonolysisreactions is reported. Miniaturized screening using a 96-well high-pressurereaction block in which ozone-containing gas flows through the headspaceenabled rapid evaluation of solvent systems, cosolvents, and quenchingagents under controlled low-temperature conditions, allowing hundredsof experiments to be conducted with minimal material consumption.Key reaction parameters were efficiently translated to larger-scalesparged tube and bubble reactor platforms, demonstrating a consistentperformance across scales. Reaction progress monitoring and temperature-dependentstudies suggest that the ozonolysis reaction is influenced by gas–liquidmass-transfer control rather than intrinsic kinetic limitation. Theuse of immiscible solvent mixtures and sodium sulfite as a quenchingagent provided clean phase separations and operationally simple workupswhile mitigating the safety risks associated with peroxide formation.Collectively, this workflow enables the identification, scale-up,and validation of practical ozone-based oxidations within weeks, providinga general and scalable approach for integrating ozone chemistry intosustainable pharmaceutical process development.

By definition, continuousflow (CF) production implies continuityin the products; however, virtually all CF products are derived frombatched reactants. Consequently, virtually all aliquots of CF productionshould retain certain batch characteristics.Roncone, A.; et al. ( Trends Analyt. Chem.2024, 174, 117666., and referencestherein) demonstrated the highly specific nature of natural-abundancestable isotopes in individual batches of pharmaceutical and chemicalmaterials. Here, we employ elemental analysis/isotope-ratio mass spectrometry(EA-IRMS) to quantify the natural-abundance stable-isotopic variationsin CF production of products. We show that the batch nature of thereactants (6-bromonaphth-2-ol and methyl iodide) is transmitted tothe product (6-bromonaphth-2-yl methyl ether). Instead of maintaininga smooth, continuous isotopic composition during CF production, theepisodically batch-varying isotopic values (δ¹³C,δD, δ¹⁸O) of the reactant batches are transmitteddownstream to the products. Although the batch nature of CF productionis evident, only an initial evaluation of using isotope effects toparametrize yield (via fraction remaining of the starting material)is possible with the present relatively narrow range of yields. Theseearly observations open new areas for process research. Beyond demonstratingthe batch nature of CF production, there are at least two additionalutilities in measuring isotopic compositions during CF production:(i) product authentication (batch/aliquot auditing) and (ii) processunderstanding (monitoring the continuity of the continuous flow reaction).

Herein we report our efforts to identify a convergentand efficientroute to the highly substituted 7-azaindazole core of GDC-8025, a potent pan-TEAD inhibitor. We investigated two orthogonal routesto access the requisite 4-iodo-1-aryl-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile intermediate. The first of thesefeatured a one-flask halogen dance rearrangement/acylation to enableconstruction of the pyrazole ring around a pyridine starting material.The second route relied on elaboration of a highly substituted aminopyrazoleto a Meldrum’s acid derivative, which then engaged in a Gould–Jacobscyclization to form the pyridine ring. Both routes were found to beeffective and efficient means of accessing the target GDC-8025 precursor in 6 steps from economical starting materials.