Organic Process Research & Development最新文献

Reversible addition–fragmentation chain transfer(RAFT)polymerization is a key tool in modern macromolecular design. Centralto its success is the availability of versatile chain transfer agents(CTAs), typically based on thiocarbonylthio compounds. Herein, wereport a refined, scalable, and high-yield synthesis of a family oftrithiocarbonate RAFT agents based on a propanoic acid leaving group,mimicking the propagating radical of acrylic acid, which permits efficientmediation of the polymerization of a wide range of monomers. We reportthe synthesis of 2-{[(butylsulfanyl)carbonothioyl]sulfanyl}propanoicacid (BPTC), commonly known as (Propanoic Acid)yl Butyl TrithioCarbonate(PABTC), a highly oil-soluble derivative, 2-{[(dodecylsulfanyl)carbonothioyl]sulfanyl}propanoicacid (DoPAT), and a highly water-soluble derivative, 3-[[[(1-carboxyethyl)thio]carbonothioyl]thio]propanoicacid (CETCP). By optimizing the aqueous-based reaction conditions,we achieved yields of 80% or higher of high-purity products acrossall three derivatives on a tens of grams scale, without the necessityof intensive organic solvent extraction or multiple recrystallizationsteps.

A multikilogram-scale, scalable, and cGMP-compliant synthesisof4-aminoimidazo[1,5-a]quinoxaline-8-carboxylic acid(TM), a key intermediate for the MTA-cooperative PRMT5 inhibitor GTA182,has been developed to address the limitations of the original medicinalchemistry route. The initial synthesis suffered from poor reproducibility,cumbersome workups, and a high-pressure carbonylation step that introducedequipment constraints and elevated metal residues, creating a supplybottleneck for early clinical development. The redesigned route startsfrom commercially available 3-fluoro-4-nitrobenzoic acid (SM6), alow-cost commodity chemical, and proceeds through seven steps, includinga continuous-flow amination and chromatography-free purifications.This approach improves the overall yield from 7% to 24%, eliminatesthe need for specialized high-pressure equipment, and ensures metalresidues are compliant with ICH guidelines. The process has been successfullydemonstrated on a multikilogram scale under cGMP conditions, enablingreliable supply of TM to support ongoing early-stage clinical studiesof GTA182.

Wet milling is a critical operation in drug substancemanufacturing,enabling control of the particle size distribution of active pharmaceuticalingredients. Scaling up of the wet milling process usually involvesequipment change. Due to material availability limitations duringthe early stage of development, there is a limited opportunity toexperimentally determine optimal operating conditions for scale-upequipment. As a result, model-based approaches are essential for areliable transition from the laboratory to commercial production.Existing population balance modeling (PBM) frameworks have enabledmodel-aided scale-up but typically employ empirical linear relationshipsbetween the breakage rate and the shear number, limiting their mechanisticinterpretability and cross-scale robustness. This study presents anenhanced PBM kernel formulation that introduces an exponential dependenceof the breakage rate on the shear number, reflecting a stress-activatedmechanism analogous to barrier-crossing kinetics observed in materialdeformation and fracture. The proposed kernel retains the structureof the conventional PBM while embedding physical meaning into theshear dependence. Using experimental data from laboratory- and pilot-scalewet mills, the model successfully predicts clinical-scale performancewithout empirical refitting, demonstrating improved predictive capability.The exponential shear-activated formulation strengthens the physicalfoundation of the PBM-based scale-up and provides a more generalizableframework for wet milling process design. In addition, a model credibilityand regulatory validation framework is proposed to support the regulatoryacceptance of model-based digital design approaches for pharmaceuticalmanufacturing processes.

Efficientand scalable methods for the C3 acylation of 2-arylindolesremain limited despite the importance of 3-acyl-2-arylindoles as versatileintermediates in medicinal and synthetic chemistry. Herein, a practicalVilsmeier–Haack acylation protocol employing readily available N,N-dialkylamides and phosphorus oxychlorideis described. Systematic reaction optimization identified conditionsthat provide highly regioselective C3 acylation across a broad rangeof 2-arylindoles and acylating agents, affording the correspondingproducts in high isolated yields without chromatographic purification.The operational simplicity of the method, together with its broadfunctional-group tolerance and gram-scale applicability, makes ita practical alternative to conventional acylation protocols. The syntheticutility of the resulting 3-acyl-2-arylindoles was demonstrated byconcise syntheses of representative fused indole heterocycles relatedto biologically active alkaloids, including fluorescent indoloquinoline,indoloisoquinoline, and carbazole derivatives.

Described is the coupling of carboxylic acids with aminesin isopropanol,followed by the direct isolation of amide products from the reactionmixture. Phosphorus-based reagents were found to be uniquely capableof mediating productive amidation, with diphenylphosphinic chloride(DPPCl) specifically providing the greatest advantage. After reactioncompletion, direct isolation of desired products can be accomplishedby addition of water, where DPPCl reagent byproducts are purged inthe filtrate. This experimentally simple all-in reaction and directisolation protocol was demonstrated across functionally diverse examplesand provides a streamlined amidation option when products can be isolatedfrom aqueous isopropanol.

A key step in the manufacture of casdatifan involvesa Noyori transferhydrogenation of a stereochemically complex difluorodiketone 4 that establishes three contiguous stereocenters in a singletransformation. Herein, we describe a systematic quality-by-design(QbD)-driven optimization of this reaction, involving risk assessmentto identify critical process parameters, multivariate design of experimentsto evaluate their effects, and targeted one-variable-at-a-time (OVAT)studies to further refine operating conditions. Implementation ofthe optimized, buffer-free conditions resulted in a robust processdelivering 74–75% isolated yield with >99% high-performanceliquid chromatography purity.

The synthetic alkyl-lysophospholipid (ALP) Edelfosinehas garneredattention due to its potent in vivo activity, oraladministration route, and synergistic effects with other therapies.Its development as a preclinical candidate, however, is constrainedby challenges associated with the economical, large-scale preparationof the enantiopure compound. Herein, we describe the development ofa novel synthetic route that provides enantiopure (S)-Edelfosine in a scalable manner, amenable to industrial implementation.Through several iterations, we achieve synthetic improvements viaa more convergent assembly of the substituted glycerol portion ofthe title compounds. By exploiting a chiral benzylglycidyl ether asthe key synthon, we demonstrate the successful four-step, formal,and total syntheses of (S)- and (R)-Edelfosine respectively─the shortest demonstrably scalableroutes of their kind. Finally, we establish phenyl trimethylammoniumiodide as a suitable green alternative to carcinogenic iodomethanein this context. Our streamlined chiral pool approach thus furnishesa significant improvement in the synthetic accessibility of opticallypure Edelfosine and paves the way for the parallel development ofboth medicinally relevant ALP enantiomers.

Bead mills are widelyused in industry for particle size reductionacross diverse applications; however, their use as reactors for mechanochemicalsynthesis has largely remained limited to laboratory studies, withno prior demonstration at a manufacturing-relevant scale. Here, wereport the direct scale-up of a mechanochemical amidation using agitatorbead mills. Starting from a laboratory protocol, the process was translatedvia a pilot unit to an industrial mill, achieving a 22-fold increasein scale (up to 15 kg per batch) without altering core reaction parameters.Ethyl acetate was used in small quantities as a liquid-assisted grindingadditive, while equimolar reagent conditions were maintained throughout,eliminating the need for excess reagents and enabling straightforwardproduct isolation without organic solvents, thereby minimizing wastegeneration. Both semicontinuous and continuous single-pass operationmodes delivered high conversion and selectivity within short residencetimes. At the largest scale, product formation rates reached 65 kg/h.The close consistency between equipment across scales enabled a straightforwardtransfer, demonstrating that bead milling under reactive conditionsprovides a viable and scalable platform for sustainable mechanochemicalmanufacturing.

We report the continuous flow synthesisof clothianidinas a modelsystem, in which a reaction kinetic model was rapidly establishedthrough dynamic experiments. However, kinetic modeling alone providesno strategy for resolving trade-offs between conflicting objectives.Multiobjective Bayesian optimization (MOBO) addresses this gap bymapping the Pareto front across the parameter space, with the kineticmodel serving as a virtual experiment surrogate within the iterativecycle to replace physical experiments entirely. The coupled frameworksimultaneously minimized the E-factor and maximized the productionrate, yielding a well-resolved Pareto front that quantifies the trade-offbetween these two objectives. Optimization was further extended toa pilot-scale continuous flow system incorporating a static mixer,with transfer learning employed to leverage prior knowledge and reduceexperimental burden at the new scale. A maximum production rate of1.32 g/min and a minimum E-factor of 1.53 were achieved via Meta-Learning-assistedMOBO (Meta-MOBO), with an average reaction yield of approximately79.8% across the scale-up optimization. These results demonstratethat coupling kinetic modeling with MOBO and transfer learning offersan efficient and scalable strategy for bridging laboratory-scale synthesisand industrial production.