Organic Process Research & Development最新文献

{"title":"Considerations for Recycling of Acetonitrile in Oligonucleotide Synthesis","authors":"Benjamin I. Andrews,&nbsp;Fabienne Chapalain-Guyomard,&nbsp;Yan-Qiao Chen,&nbsp;Lukas Doulakas,&nbsp;Colm Duffy,&nbsp;Gresa Farmer,&nbsp;J. Gair Ford,&nbsp;Harper Kaminski,&nbsp;Francis Ring,&nbsp;Bradley D. Robertson,&nbsp;Muhid Shahid,&nbsp;Rohit Tiwari,&nbsp;Dale Turnacliff,&nbsp;Bastien Viverge,&nbsp;Martin Olbrich","doi":"10.1021/acs.oprd.6c00025","DOIUrl":"10.1021/acs.oprd.6c00025","url":null,"abstract":"<p>Oligonucleotide therapeutics are expanding from rarediseases tomore common conditions, leading to an increased demand for GMP-manufacturedoligonucleotides and consequently acetonitrile solvent. The acetonitrilesupply chain is volatile due to economic, regulatory, and environmentalfactors. Shortages have been driven by production constraints, increaseddemand, factory closures, natural disasters, and global crises. Keydisruptions include the 2008–2009 financial crisis, HurricaneIke, factory closures in China, and the COVID-19 pandemic. Addressingsupply chain security and environmental impact requires strategicplanning, implementation of recycling methods, and regulatory compliance.A comprehensive risk assessment process was designed by experts ofthe European Pharma Oligonucleotide Consortium (EPOC) to evaluatepotential contamination in acetonitrile recycled from oligonucleotideproduction. The severity and probability of contaminants were categorizedas high or low based on their process impact and removal feasibility.Through theoretical calculations and partial waste segregation assumptions,the remaining volume and impact of various contaminants were quantified.Detailed evaluations and risk levels were provided for each contaminant.Given this comprehensive risk assessment, recycling of acetonitrilefrom oligonucleotide synthesis is not only acceptable but also recommendedbased on the ability to effectively mitigate potential contaminationthrough meticulous risk evaluation based on theoretical calculationsand supportive development data, partial waste segregation, and adequatespecification settings, thereby supporting sustainable growth in oligonucleotidetherapeutics. PREAMBLE: The European Pharma Oligonucleotide Consortium(EPOC) is a collaboration between multiple pharma companies with theaim of sharing chemistry, manufacturing, and control (CMC) knowledgeas well as strategies to enable harmonization of oligonucleotide developmentand commercialization. EPOC identifies areas for harmonization ofoligonucleotide CMC development and proposes solutions to influencethe external regulatory environment, expediting patient access torevolutionary medicines.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2119–2135"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148596105","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}

{"title":"A Headspace GC-FID Method for Nitrite Determination in Pharmaceutical Excipients","authors":"Timothy Yaroshuk,&nbsp;Jinjian Zheng,&nbsp;Ahmed M. Aboelenen,&nbsp;Mikhaila D. Ritz,&nbsp;Stephen Bambrick,&nbsp;Tessa Carducci,&nbsp;Xihui Liang,&nbsp;Xiaoyi Gong,&nbsp;Mark D. Mowery","doi":"10.1021/acs.oprd.6c00133","DOIUrl":"10.1021/acs.oprd.6c00133","url":null,"abstract":"<p>We developed a headspace gas chromatography method withflame ionizationdetection (HSGC-FID) for trace nitrite determination in pharmaceuticalexcipients. The approach reacts nitrite with sodium cyclamate to generatecyclohexene, enabling sensitive detection by flame ionization detector(FID) on a nonpolar G27 column (e.g., Rtx-5). Key method performancecharacteristics including sensitivity, accuracy, and specificity wereestablished. The limit of quantitation is 0.2 ng/mL, correspondingto 10 ng/g for common excipients with a sample concentration of 20mg/mL and 2 ng/g for low-nitrite excipients such as microcrystallinecellulose and dibasic calcium phosphate with a sample concentrationof 100 mg/mL. Achieving this sensitivity required a novel procedureto minimize nitrite contamination in the blank, a common challengein nitrite analysis. For excipients with significant matrix effects(e.g., magnesium stearate, sodium lauryl sulfate, and HPMCAS), cyclohexaneis used as an internal standard to achieve the desired accuracy. Toaddress the limited selectivity of FID, an orthogonal confirmationmethod employing a polar G16 column (e.g., DB-Wax) can be used toresolve interferences from residual solvents on a G27 column. Themethod was validated in accordance with ICH Q2(R2) and applied tomore than 20 commonly used excipients. The range is 10 ng/g to 5000ng/g by successfully meeting acceptance criteria for linearity (<em>R</em> ≥ 0.99), spiked recovery (100 ± 30%), andprecision (% RSD ≤ 10%). Given its high sensitivity on commonHSGC-FID instrumentation, the method is readily transferable to QClaboratories for routine nitrite testing in pharmaceutical excipients.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2245–2252"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148564925","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}

{"title":"Electrochemical Synthesis of Renewable Pyridines via Oxidative Ring Expansion","authors":"Silja Hofmann,&nbsp;Astrid Kjær Steffensen,&nbsp;Alexandros Xanthopoulos,&nbsp;Anders Riisager,&nbsp;Helena Lundberg,&nbsp;Tobias Ankner","doi":"10.1021/acs.oprd.6c00091","DOIUrl":"10.1021/acs.oprd.6c00091","url":null,"abstract":"<p>Herein, an electrochemical method for the synthesis of3-hydroxypyridinesfrom renewable furfurylamine is reported under galvanostatic conditions,with current densities up to 100 mA/cm² in an undividedcell and aqueous electrolyte. The process delivers good to excellentyields of 3-hydroxypyridine and substituted analogues and is readilyscalable, as demonstrated in syntheses of up to 100 g in both batchand flow processes.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2203–2211"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148726400","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}

{"title":"Which Molecule Is Involved in the Nitrosation Reaction of Pharmaceuticals: NO or NO2?","authors":"Ryota Nomura,&nbsp;Hideyuki Sogo,&nbsp;Takuma Onai,&nbsp;Misako Iwazawa,&nbsp;Tomohiro Kaku,&nbsp;Osamu Uchikawa","doi":"10.1021/acs.oprd.6c00108","DOIUrl":"10.1021/acs.oprd.6c00108","url":null,"abstract":"<p>We have previouslyclearly identified atmospheric nitrogen oxides(NOx) as a key factor in nitrosamine contamination in pharmaceuticals.To implement more appropriate countermeasures, the nitrosation potentialof nitrogen monoxide (NO) and nitrogen dioxide (NO₂)─theprimary components of NOx─was evaluated using short-term andlong-term gas flow model experiments. The results revealed that NO₂ is required for the nitrosation reaction to occur.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2228–2232"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148476469","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}

{"title":"Synthesis of Danuglipron: Development of a Scalable Alkylation and Chemoselective Hydrolysis Sequence","authors":"Ijaz Ahmed,&nbsp;Russell F. Algera,&nbsp;Aaron F. Baldwin,&nbsp;Andrew M. Derrick,&nbsp;Nga M. Do,&nbsp;David F. Fernández,&nbsp;Steven J. Fussell,&nbsp;Danielle Green,&nbsp;Adam E. S. Gymer,&nbsp;Brian P. Jones,&nbsp;Sarah Karasik,&nbsp;Nahian Khan,&nbsp;Daniel Laity,&nbsp;Taegyo Lee,&nbsp;Jian Li,&nbsp;Chase Mack,&nbsp;Lesly Mejia,&nbsp;Ian Moses,&nbsp;Patrick O’Neill,&nbsp;Dylan Pedro,&nbsp;Angela L. A. Puchlopek-Dermenci,&nbsp;James Rellegue,&nbsp;Giselle P. Reyes,&nbsp;Ursula Sheridan,&nbsp;Vaclav Svoboda,&nbsp;Steven J. R. Twiddle,&nbsp;Aining Wang,&nbsp;Gerald A. Weisenburger,&nbsp;Adam West,&nbsp;Jordan Willie","doi":"10.1021/acs.oprd.6c00144","DOIUrl":"10.1021/acs.oprd.6c00144","url":null,"abstract":"<p>The target compound danuglipron belongsto a family ofglucagon-likepeptide-1 receptor agonist (GLP-1RA) candidates identified in thePfizer laboratories for the treatment of type 2 diabetes mellitusand obesity. This article describes a development approach providinga data-centric, holistic methodology toward process design. The approachstarts with rapid collection and generation of fundamental data throughhigh-throughput experimentation (HTE), followed by lead evaluation,narrowing process options, and concluding with lead process confirmation.This systematic strategy identifies the most efficient process options,anticipates process sensitivities, removes unconscious bias in decisionmaking, leading to fewer process iterations, and identifies an optimalprocess. By adopting this approach to danuglipron, a new 5-step processwas developed, removing two unnecessary process steps, increasingthe yield from 34 to 64%, and reducing PMI from 231 to 73 kg/kgA whilebeing scaled at multiple facilities to generate metric tons of clinical-gradedanuglipron.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2271–2285"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148476470","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}

{"title":"Differential Scanning Calorimetry Sees the Light: Simultaneous Photo-Irradiation and Temperature Ramping of Sealed DSC Crucibles for Thermal Assessment of Photochemical Processes","authors":"Dylan Aljovic,&nbsp;Donald Bachert,&nbsp;Sebastian Toyotoshi,&nbsp;Eric L. Margelefsky","doi":"10.1021/acs.oprd.6c00138","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00138","url":null,"abstract":"<p>Before scaling up a chemical reaction to industrial scale,it isessential to assess and mitigate any safety hazards including thepotential for hazardous exotherms or thermal runaway. Sealed-crucibledifferential scanning calorimetry (sc-DSC) is an essential tool forthermal hazard analysis for both raw materials and reactions, butthis technique is not well-suited to photochemical applications, asit traditionally requires opaque high-pressure metallic cruciblesthat do not allow for light penetration, making simultaneous temperatureramping and irradiation impossible. We report a novel technique involvinga reusable DSC crucible with a transparent polymeric window that allowsfor irradiation of a sample during DSC temperature ramping experimentsup to 250 °C while maintaining pressures of up to 25–36bar depending on window diameter. This technique allows for the assessmentof critical safety data such as decomposition onset temperatures inthe presence of irradiation. The design and optimization of the crucibleand film are discussed, and several proof-of-concept examples arereported, including sealed-crucible DSC analysis of photocuring ofa polymeric resin, exothermic decomposition of dihalodimethylhydantoinsand 2,4-dinitrobenzaldehyde, and photoisomerization of azobenzenederivatives.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2253–2270"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148810330","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}

{"title":"Advancing Fallhammer Impact Testing: Application to Peptide Coupling Reagents","authors":"Shasha Zhang,&nbsp;Sergey Melnikov,&nbsp;Linda Zheng,&nbsp;Tadeusz W. Langner,&nbsp;Simon Shun Wang Leung","doi":"10.1021/acs.oprd.6c00067","DOIUrl":"10.1021/acs.oprd.6c00067","url":null,"abstract":"<p>This study provides a comprehensive assessment of theFallhammerimpact testing methodology, incorporating advanced diagnostics torefine criteria for detecting explosive events. Using both traditionalmetal cells and custom clear cells, the approach integrates high-speedvideography, acoustic monitoring, and post-test imaging to systematicallycharacterize mechanical sensitivity and explosion behavior. The findingschallenge conventional UN DOT guidance by demonstrating that smokeevolution and char formation are more reliable indicators of explosivereactions than audio reports or visible inflammation. Seven peptidecoupling reagents─PyAOP, TDBTU, TCTU, TPTU, HATU, HDMA, andBOP─exhibited impact sensitivity at 39 J, underscoringtheir potential explosion risk. These results advocate for updatedstandard operating procedures that emphasize robust diagnostic criteriaand highlight the need for heightened caution when handling energeticmaterials to ensure safer chemical manufacturing and effective riskmanagement.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2167–2178"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147709112","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}

{"title":"Engineering a Keto-Reductase for the Mass-Efficient Synthesis of a Key Building Block, Trans-Ethyl (3-Hydroxycyclobutyl)Acetate","authors":"Qikang Huang,&nbsp;Wei Wang,&nbsp;Yaqin Peng,&nbsp;Keke Dong,&nbsp;Pan Wu,&nbsp;Qian Yang,&nbsp;Youyong Xu,&nbsp;Yuanxian Wang,&nbsp;Hongjun Gao,&nbsp;Ye Zhang","doi":"10.1021/acs.oprd.6c00230","DOIUrl":"10.1021/acs.oprd.6c00230","url":null,"abstract":"<p>Thechiral building block ethyl (3-hydroxycyclobutyl)acetate isvital for synthesizing several drug classes. Traditional chemicalsynthesis often suffers from multi-step routes with low overall yieldand significant challenges in achieving efficient stereocontrol forthis chiral cyclobutane derivative. This study develops a new routeto its <em>trans</em> isomer via AI-driven enzyme engineering.A tailored keto-reductase (<em>Bu</em>KRED-M3) was createdusing semi-rational design and machine learning method, achieving&gt;98.0% <em>de</em> for this non-native substrate. The resultingbiocatalytic process cuts production costs by 33.8% versus prior routes,featuring a shorter, higher-yielding synthesis with reduced PMI, therebyoffering a promising approach to more efficient manufacturing of thischiral intermediate.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2360–2366"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148476541","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}

{"title":"Continuous Flow Friedel–Crafts Acylation Reaction and Application to the Synthesis of Acetaminophen","authors":"Alexander Raborg-Grullon,&nbsp;Vanessa Kairouz,&nbsp;André B. Charette","doi":"10.1021/acs.oprd.6c00085","DOIUrl":"10.1021/acs.oprd.6c00085","url":null,"abstract":"<p>A three-stepprocess using flow chemistry to produce acetaminophenis described. First, the use of biodegradable methanesulfonic acidas a promoter enables a mild and metal-free flow approach for theFriedel–Crafts acylation of different phenols, thereby addressingthe limited selectivity of this reaction in acetaminophen synthesis.Subsequently, oximation and a Beckmann rearrangement with readilyavailable and inexpensive reagents afford acetaminophen in a viableflow process, utilizing continuous extraction and crystallizationas the sole purification methods, thus avoiding the need for chromatography,which is impractical for large-scale processes. Acetaminophen wasformed in yields of up to 66% (60 g) in a three-step process and upto 75% (436 g) in a two-step process, with a purity of 99.93% afterrecrystallization.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2194–2202"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148408226","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}

{"title":"Development of a Fluoride Scavenging Strategy to Allow a SNAr Reaction in a Glass-Lined Reactor toward the Synthesis of NBI-921352","authors":"Ying Chen,&nbsp;John L. Tucker,&nbsp;Neill Penner,&nbsp;Keegan Start,&nbsp;Bradley Scott,&nbsp;Jean-Francois Vincent-Rocan,&nbsp;Brian M. Cochran","doi":"10.1021/acs.oprd.6c00186","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00186","url":null,"abstract":"<p>A practical fluoridescavenging strategy was developed to enablethe execution of a fluoride-generating S_NAr reaction ina glass-lined reactor during the manufacture of NBI-921352. The DABCO-mediatedsubstitution of an activated aryl fluoride with a secondary aminegenerates hydrogen fluoride, presenting a risk of glass etching duringscale-up. Glass coupon studies confirmed measurable mass loss underboth the standard and stressed reaction conditions. Screening of calciumsalts identified calcium chloride as a soluble and reaction-compatiblefluoride scavenger that preserved the reaction performance while preventingreactor damage. After optimization of downstream workup associatedwith calcium fluoride formation, the process was successfully implementedin a 4000 L glass-lined reactor under cGMP conditions, enabling theproduction of greater than 60 kg of the NBI-921352 intermediate withoutdetectable glass etching.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 8","pages":"2317–2322"},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148810331","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}