Organic Process Research & Development最新文献_第5页

Toward Chromatography-Free Convergent Peptide Synthesis via Nanostar Sieving 纳米星筛分法合成聚合肽的研究

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-17 DOI: 10.1021/acs.oprd.6c00123

Mustafa Al-Kadhimi, James Botwright, Adam Oxley, Seok Ju Han, Nil Tandogan Gray, Michael O. Frederick, Ludmila Peeva, Andrew G. Livingston

{"title":"Toward Chromatography-Free Convergent Peptide Synthesis via Nanostar Sieving","authors":"Mustafa Al-Kadhimi, James Botwright, Adam Oxley, Seok Ju Han, Nil Tandogan Gray, Michael O. Frederick, Ludmila Peeva, Andrew G. Livingston","doi":"10.1021/acs.oprd.6c00123","DOIUrl":"10.1021/acs.oprd.6c00123","url":null,"abstract":"Liquid-phase peptide synthesis (LPPS) has emerged asa versatileand efficient method for assembling peptides, offering significantadvantages in purity and yield. In this study, we investigate theapplication of organic solvent nanofiltration (OSN) technology inLPPS for peptide fragment assembly by Nanostar Sieving. We reporthow a nanostar support decorated with solubilizing polymers can beused to achieve solubility at concentrations of up to 40 mM of a 39-merpeptide. This is assembled from eight peptide fragments on an 8-arm,20 kDa nanostar support. OSN enables effective removal of reagents,byproducts, and unreacted fragments after each coupling cycle, enhancingsynthesis efficiency. A photolabile linker was incorporated into thesupport before fragment assembly, enabling periodic analysis withoutfull global deprotection. The Rink amide linker facilitated the finalcleavage of the synthesized peptide using standard global deprotectionprotocols. Following synthesis, OSN was employed to isolate the peptidefrom the support. In contrast to previous OSN-assisted peptide fragmentassembly methods, which required chromatographic purification to removeunreacted fragments at the end of synthesis, nanostar sieving enablestheir removal during synthesis. The potential to eliminate the needfor chromatography could lead to more efficient and scalable therapeuticpeptide production.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2454–2468"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148767012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Technical Note: A Facile and Scalable Synthesis of Versatile Trithiocarbonate Chain Transfer Agents for RAFT Polymerization 技术说明：RAFT聚合用多用途三硫代碳酸盐链转移剂的简易和可扩展合成

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-28 DOI: 10.1021/acs.oprd.6c00204

Gabrielle J. Perrier, Sébastien Perrier

{"title":"Technical Note: A Facile and Scalable Synthesis of Versatile Trithiocarbonate Chain Transfer Agents for RAFT Polymerization","authors":"Gabrielle J. Perrier, Sébastien Perrier","doi":"10.1021/acs.oprd.6c00204","DOIUrl":"10.1021/acs.oprd.6c00204","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2506–2510"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148858865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Multikilogram-Scale Process Development for a Key Intermediate of a Clinical-Stage MTA-Cooperative PRMT5 Inhibitor 临床阶段mta协同PRMT5抑制剂关键中间体的多公斤级工艺开发

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-09-04 DOI: 10.1021/acs.oprd.6c00150

Yanfeng Zhou, Mingxi Li, Lei Ma

{"title":"Multikilogram-Scale Process Development for a Key Intermediate of a Clinical-Stage MTA-Cooperative PRMT5 Inhibitor","authors":"Yanfeng Zhou, Mingxi Li, Lei Ma","doi":"10.1021/acs.oprd.6c00150","DOIUrl":"10.1021/acs.oprd.6c00150","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2469–2483"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895831","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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Enhanced Scale-Up of Rotor-Stator Wet Milling Using Population Balance Modeling with a Novel Exponential Shear-Activated Kernel 基于新型指数剪切激活核的种群平衡建模增强了动静湿铣削的放大

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-20 DOI: 10.1021/acs.oprd.6c00161

Kensaku Matsunami, Álmos Orosz, Varun Sundarkumar, Guanghui Zhu, Neda Nazemifard, Charles D. Papageorgiou, Zoltán K. Nagy

{"title":"Enhanced Scale-Up of Rotor-Stator Wet Milling Using Population Balance Modeling with a Novel Exponential Shear-Activated Kernel","authors":"Kensaku Matsunami, Álmos Orosz, Varun Sundarkumar, Guanghui Zhu, Neda Nazemifard, Charles D. Papageorgiou, Zoltán K. Nagy","doi":"10.1021/acs.oprd.6c00161","DOIUrl":"10.1021/acs.oprd.6c00161","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2484–2494"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Technical Note: A Practical and Scalable Method for the Preparation of 3-Acylindole Scaffold Using N,N-Dimethylamides via the Vilsmeier–Haack Reaction 技术说明：利用N，N-二甲酰胺通过Vilsmeier-Haack反应制备3-酰基吲哚支架的实用且可扩展的方法

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-27 DOI: 10.1021/acs.oprd.6c00282

Nikolay O. Fedorenko, Radmir R. Rakhimov, Egor S. Volkov, Valerii Z. Shirinian

{"title":"Technical Note: A Practical and Scalable Method for the Preparation of 3-Acylindole Scaffold Using N,N-Dimethylamides via the Vilsmeier–Haack Reaction","authors":"Nikolay O. Fedorenko, Radmir R. Rakhimov, Egor S. Volkov, Valerii Z. Shirinian","doi":"10.1021/acs.oprd.6c00282","DOIUrl":"10.1021/acs.oprd.6c00282","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2584–2591"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148822112","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Operationally Simple Amidation in Isopropanol Using Diphenylphosphinic Chloride 二苯基膦氯在异丙醇中的简单酰胺化

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-24 DOI: 10.1021/acs.oprd.6c00267

Yijing Dai, Chintelle James, Melissa Lee, Philipp C. Roosen, Daniel L. Singer, Gerald A. Weisenburger, Jacob Werth

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Process Optimization of a Noyori Transfer Hydrogenation Utilizing a Quality-by-Design Approach: Development of a Robust Step in the Synthesis of Casdatifan 基于质量设计方法的Noyori转移加氢工艺优化：卡达替凡合成稳健步骤的开发

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-24 DOI: 10.1021/acs.oprd.6c00237

Xiaopeng Yin, Chandler B. Nelson, Bruce Kowalczyk, Zhiguo Jake Song

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Development of a Four-Step Scalable Synthesis for the Alkyl-lysophospholipids (S)- and (R)-Edelfosine 四步可扩展合成烷基溶血磷脂(S)-和(R)-雪绒花的研究进展

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-06-03 DOI: 10.1021/acs.oprd.5c00523

Mylène Soudani, Cheng-Hao Chang, Yu Fa Wang, Béchir Zitouni, Noel Riedl, Arian Bajramaj, Nika Podlesnik, Ivana Mickovic, Maithrayan Velliangiri, Kaushik Gurusankaran, Arunachalam Piramanayagam, Michael Ahrweiler, Daniel Perrisoud, Michael Schnürch, Roman Josef Lichtenecker, Roger Marti, Antony Crisp

{"title":"Development of a Four-Step Scalable Synthesis for the Alkyl-lysophospholipids (S)- and (R)-Edelfosine","authors":"Mylène Soudani, Cheng-Hao Chang, Yu Fa Wang, Béchir Zitouni, Noel Riedl, Arian Bajramaj, Nika Podlesnik, Ivana Mickovic, Maithrayan Velliangiri, Kaushik Gurusankaran, Arunachalam Piramanayagam, Michael Ahrweiler, Daniel Perrisoud, Michael Schnürch, Roman Josef Lichtenecker, Roger Marti, Antony Crisp","doi":"10.1021/acs.oprd.5c00523","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00523","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2447–2453"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148980767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction to “Development of Scalable and Commercial Synthesis for GS-441524” 对“开发可扩展和商业合成GS-441524”的更正

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-20 DOI: 10.1021/acs.oprd.6c00281

Praveen Gajula, Maksim Vasilev, Jiezhen Li, Aravind S. Gangu, Bimbisar K. Desai, Daniel Lee, Hsien-Hsin Tung, Manasa Mamunooru, Zhirui Wang, Anji Chen, Jagruti Rana, Jinya Yin, Aurpon W. Mitra, Sridhar Regati, Anupam Karmakar, Angshuman Ghosh, Subhadeep Chatterjee, Ajay K. Yadaw, Subho Roy, Raju Bandu, Kumuduni Dissanayake, Jonathan Bietsch, Chaitanya Wannere, Dhileepkumar Krishnamurthy, Gopal Sirasani, Srinivas Achanta, Joseph D. Armstrong, III, Junfeng Huang, Philip E. Sanderson, Bo Qu, Chris H. Senanayake

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Scale-Up of Mechanochemical Amidation in Agitator Bead Mills: From Laboratory to Commercial Scale 搅拌珠磨机机械化学酰胺化的放大：从实验室到商业规模

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-09-18 Epub Date: 2026-08-13 DOI: 10.1021/acs.oprd.6c00203

Kenneth Banderob, Philippe M. C. Roth, Pietro Caboni, C. Oliver Kappe, Sándor B. Ötvös

{"title":"Scale-Up of Mechanochemical Amidation in Agitator Bead Mills: From Laboratory to Commercial Scale","authors":"Kenneth Banderob, Philippe M. C. Roth, Pietro Caboni, C. Oliver Kappe, Sándor B. Ötvös","doi":"10.1021/acs.oprd.6c00203","DOIUrl":"10.1021/acs.oprd.6c00203","url":null,"abstract":"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.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2511–2519"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0