Organic Process Research & Development最新文献

{"title":"Machine-Learning-Enabled\u0000Design of Lab-Scale Continuous\u0000Distillation Systems for Pharmaceutical Process Development","authors":"Justin T. Turnage,Andres P. Hyer,Kimberly E. Penzer,James K. Ferri","doi":"10.1021/acs.oprd.6c00279","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00279","url":null,"abstract":"Abstract Predictive tools for continuous distillation design lag behind upstream pharmaceutical synthesis─including AI-enabled digital tooling for retrosynthetic route design─leaving column specification dependent on computationally expensive simulation or extensive experimentation. This work presents a machine-learning surrogate framework trained entirely on first-principles mechanistic simulations, requiring no experimental distillation data, and eliminating the need for commercial tools such as ChemCad or AspenPlus. Three surrogate models for binary tert-butylamine/alcohol systems (methanol, ethanol, isopropanol) predict distillate and bottoms compositions with mean absolute errors below 0.005 mol/mol and R2 > 0.999, completing a single prediction in under 1 ms─a 24-fold speedup. A coupled Pareto optimizer returns capital-versus-operating-cost trade-off curves in under 10 s, with over 93% of designs verified within ±0.010 mol/mol. Applied to a pharmaceutical case study, the framework correctly identifies isopropanol as the optimal solvent without prior thermodynamic knowledge. The system-agnostic architecture could readily integrate with open-source large language model platforms to further lower the barrier to implementation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"71 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210330","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":"Maximizing Pd/C\u0000Hydrogenation Performance with Continuous\u0000Flow CSTR Cascades at Ambient Pressure","authors":"Samarth P. Singh,William P. Hems,Shusaku Asano,Jonty A. M. Thornton,Nikolay Cherkasov","doi":"10.1021/acs.oprd.6c00199","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00199","url":null,"abstract":"Abstract This study demonstrates the efficient implementation of heterogeneous gas–liquid–solid hydrogenation at ambient pressure using a continuous-flow reactor composed of a vertical cascade of ten continuously stirred tank reactors (CSTRs). The system enables simple operation by continuously feeding a suspended catalyst slurry alongside hydrogen gas,without the need for complex catalyst immobilization. Active agitation throughout the cascade ensures homogeneous and vigorous mixing, which in turn facilitates rapid hydrogenation even under ambient pressure conditions. Under optimized conditions, the system achieved 80% conversion of ethyl cinnamate within 4.7 min of residence time and exhibited apparent gas–liquid mass transfer coefficients (kLa) in the range of 1000–5000 h–1,comparable to those reported for advanced microreactors. Moreover, the relatively large reactor volume enabled superior productivity compared to the microstructured reactors under ambient pressure. The results demonstrate the applicability of the reactor to continuous hydrogenation, with efficient mass transfer, simple operation, and compatibility with slurry-based catalytic processes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"25 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149210336","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":"Optimized and Automated Production of [18F]FFNP for Progesterone Receptor PET Imaging","authors":"Kang-Po Li,Ephraim E. Parent,Pooja P. Advani,Juno Van Valkenburgh,Yiqian Shen,Hancheng Cai","doi":"10.1021/acs.oprd.6c00366","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00366","url":null,"abstract":"[18F]FFNP is a promising investigational radiopharmaceutical for PET imaging of progesterone receptor (PR) expression in breast cancer. [18F]FFNP PET imaging enables noninvasive assessment of PR expression and serves as a valuable diagnostic tool for determining the functional endocrine status of ER+ breast tumors to guide endocrine therapy. In this study, we report a robust and fully automated radiosynthesis of [18F]FFNP using a commercially available radiosynthesizer. The ratio of the mesylate precursor to the K2.2.2/K2CO3 complex was found to be critical for optimizing radiochemical yield. The optimized and automated radiosynthesis process was completed within 50 min and successfully passed three consecutive validation runs, producing [18F]FFNP activity in 19.52–23.91% decay-corrected radiochemical yields at the end of synthesis. Approximately 215–265 mCi (7.96–9.81 GBq) of [18F]FFNP activity was obtained with high radiochemical purity (99.65–99.72%) and molar activity (16.83–37.40 Ci/μmol [623–1384 GBq/μmol]) in our cGMP-compliant PET Radiochemistry facility. All drug product specifications passed quality control (QC) testing and met the requirements for clinical investigational use.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"53 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149152193","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":"Explosion Risk\u0000of a Nitration System Triggered by\u0000Coolant Leakage","authors":"Hongfei He,Xinggui Zhou,Min Sheng","doi":"10.1021/acs.oprd.6c00340","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00340","url":null,"abstract":"Abstract In nitration processes, continuous-flow and microchannel reactors reduce hazardous inventory and improve heat transfer. However, their short residence times may necessitate the use of highly concentrated fuming nitric acid to achieve rapid conversion. This creates an inherent safety trade off, particularly when coolants circulated close to the process stream are assumed to be chemically inert. Accidental coolant ingress may therefore introduce an additional reactive pathway that is not represented by conventional loss of cooling scenarios. In this study, differential scanning calorimeter (DSC), antiexplosive reaction calorimeter (E-RC), and liquid-nitrogen-assisted accelerating rate calorimeter (ARC) were used to evaluate the incompatibility between fuming nitric acid above 95 wt % and three representative coolants, namely potassium formate solution, ethylene glycol solution, and calcium chloride brine. Potassium formate showed the fastest initial reaction and most intense gas generation, with a combined heat release of approximately −620 to −572 J/g. Ethylene glycol exhibited the greatest overall heat release, reaching −3236.2 to −3123.2 J/g. Under near-adiabatic conditions, the ethylene glycol system exhibited an apparent onset near −10 °C and a maximum self-heating rate of approximately 2400 °C/min. In contrast, calcium chloride brine showed limited reactivity dominated by mixing and dilution effects. These results demonstrate that reactive coolant ingress can rapidly generate localized hot spots and pressure buildup in nitration processes, which is particularly critical for compact continuous-flow reactors with small channels. The obtained calorimetric and kinetic data provide guidance for coolant selection, assessment of the hazard severity of identified leakage scenarios, and inherently safer design of microchannel nitration processes.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"11 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151260","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 Science-Based\u0000Proposal for the Identification Threshold\u0000of Organic Impurities in Drug–Linker Intermediates Used to\u0000Produce Antibody–Drug Conjugates","authors":"Osama Chahrour,Elizabeth A. Martin","doi":"10.1021/acs.oprd.6c00379","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00379","url":null,"abstract":"Abstract The identification threshold for organic impurities in drug–linker (D–L) intermediates used to manufacture antibody–drug conjugates (ADCs) remains undefined in the current regulatory landscape. Building on our previously established 1.0% w/w qualification threshold, we propose a science-based identification threshold of 0.25% w/w, derived through the simultaneous application of four independent quantitative criteria to a data set of 47 clinical-stage ADCs. The four criteria are (1) maintenance of a >200-fold safety margin relative to both the ICH Q3A allowable daily intake of 1.0 mg/day and the practical worst-case exposure from conventional small-molecule APIs; (2) preservation of a 5-fold safety-factored benchmark relative to the internal threshold of toxicological concern (iTTC) of 25 nmol/day for parenteral exposure; (3) maintenance of cumulative exposure below one-fifth of the ICH M7 acceptable lifetime dose of 38.3 mg over five years of dosing; and (4) a 1:4 identification-to-qualification ratio, more conservative than precedents for small molecules, peptides, and oligonucleotides. The convergence of these constraints uniquely defines 0.25% w/w as the value simultaneously satisfying all criteria, enabling efficient pharmaceutical development while ensuring patient safety across all oncological ADC indications. The proposed value is intended as a class-wide threshold. Higher product-specific thresholds, including 0.5% w/w and, where scientifically justified, values up to 1.0% w/w, may be considered when product-specific exposure calculations demonstrate compliance with the applicable criteria.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"10 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151551","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":"Hydantoin Impurity\u0000Formation During Peptide N-Terminal\u0000Acetylation with Acetic Anhydride","authors":"Yi Yang,Lena Hansen,Ka Zhang,Ileana Rodríguez León,Jean-Marie Receveur","doi":"10.1021/acs.oprd.6c00247","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00247","url":null,"abstract":"Abstract Previously unreported N-terminal hydantoin and N-acetyl hydantoin impurities were observed during peptide N-terminal acetylation with acetic anhydride under commonly used base/solvent conditions. The impurities were isolated and structurally characterized by HRMS and NMR. Systematic studies revealed pronounced solvent dependence and sequence sensitivity and identified conditions that suppressed their formation. Isotope-labeling experiments excluded acetic anhydride as the source of the carbonyl moiety incorporated into the hydantoin and supported solvent participation in the byproduct-forming pathway. Collectively, these results define an unexpected side reaction in widely used acetylation chemistry and provide practical guidance for impurity control in peptide synthesis and process development.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"9 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151261","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":"Synthetic Development and Scale-Up of the Aminoindazole\u0000Fragment of Lenacapavir","authors":"Lennie Lin,Anna M. Wagner,Jason Davy,Chloe Y. Wong,Wen-Tau T. Chang,B. Michael O’Keefe,Alexander F. G. Goldberg,Huy Van Huynh,Hongwei Sun,Wei Wang,Scott A. Wolckenhauer","doi":"10.1021/acs.oprd.6c00302","DOIUrl":"https://doi.org/10.1021/acs.oprd.6c00302","url":null,"abstract":"Abstract We describe herein the development and scale-up of the aminoindazole fragment of lenacapavir, a drug recently approved for long-acting treatment of HIV (Sunlenca) and pre-exposure prophylaxis (as Yeztugo and Yeytuo). This five-step route to fragment 1 was developed from the initial “fit-for-purpose” large-scale synthesis to a commercially viable process. Key improvements include an alternative condition to hydroxylamine-O-sulfonic acid-mediated nitrile formation and a significant overhaul of the key Miyaura borylation process. The culmination of all development efforts improved the final product quality and process safety, resulting in a more efficient and higher-yielding process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"31 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149088161","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":"Optimization of a Biocatalytic Asymmetric Sulfur Oxidation Featuring a Protease Workup to Prepare a Key Intermediate in the Manufacture of Ceralasertib","authors":"Stephanie Y. Y. Yip,&nbsp;Keith R. Mulholland,&nbsp;Luke Trask,&nbsp;Dylan Jones,&nbsp;Jorge Calderon De Anda,&nbsp;Sadie Finn,&nbsp;Brian A. Taylor,&nbsp;James R. R. Morgan,&nbsp;Annabel J. Morris,&nbsp;Thomas O. Ronson,&nbsp;Mark A. Graham","doi":"10.1021/acs.oprd.6c00174","DOIUrl":"10.1021/acs.oprd.6c00174","url":null,"abstract":"<p>This study reports the development of an optimized biocatalyticasymmetric sulfur oxidation using a BVMO enzyme to produce a key ceralasertibintermediate. A design of experiments (DoE) approach established arobust operating window that reduced enzyme loading, improved reactionperformance, and defined failure mode boundaries. A novel subtilisin-basedprotease workup was introduced, eliminating emulsions, simplifyingliquid–liquid extraction, and enabling rapid, scalable removalof protein residues. Improvements to distillation and crystallizationfurther enhanced process efficiency and manufacturability. Together,these advancements deliver a streamlined, high-yielding, and scalableprocess suitable for commercial production.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2495–2505"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805959","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":"Industrial Quench Method for Triethylsilane, Featuring Process Development and Safety Measures","authors":"Nanami Kamiyama,&nbsp;Kenta Komori,&nbsp;Moe Sato,&nbsp;Koto Noguchi,&nbsp;Shigenobu Nishiguchi","doi":"10.1021/acs.oprd.6c00275","DOIUrl":"10.1021/acs.oprd.6c00275","url":null,"abstract":"<p>Safe process operation is criticallyimportant in themanufactureof active pharmaceutical ingredients. We employed an excess of triethylsilane(Et₃SiH) as a reducing agent in the production of the dapagliflozinpropanediol monohydrate. Although unreacted Et₃SiH mustbe safely treated prior to disposal, no industrial quenching methodsfor Et₃SiH have previously been reported. Accordingly,a safe treatment method using KOH in MeOH was developed. The quenchreaction of Et₃SiH under basic conditions was found tobe exothermic and to evolve hydrogen. Therefore, measures to ensuresafe plant-scale operations were required. The heat release profileduring the quenching of Et₃SiH was quantitatively evaluated.On the basis of these results, the quench reaction was controlledby adjusting the addition rate of KOH in MeOH. To safely vent thegenerated flammable hydrogen, it was necessary to maintain the oxygenconcentration in the reactor headspace below the limiting oxygen concentrationby using nitrogen purging. Implementation of these countermeasuressuccessfully enabled the quenching of Et₃SiH at the pilotscale.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2576–2583"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148885505","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":"Evaluation of Potential Second-Generation Manufacturing Routes to Palbociclib","authors":"Srinivas Reddy Dubbaka,&nbsp;Dace Rasiņa,&nbsp;Nikla̅vs U̅dris,&nbsp;Gints Smits,&nbsp;Aigars Jirgensons,&nbsp;Pandiarajan Subramanian,&nbsp;Kuthalingam Subramanian,&nbsp;Sakthivel Anandan,&nbsp;Scott J. Graham,&nbsp;Steven J. Fussell,&nbsp;Jagadeesan Senthilperumal,&nbsp;Sureshpandian Pandi,&nbsp;Sivakami S,&nbsp;Umamaheswararao Kanusu,&nbsp;Sivakumar Venkataraman,&nbsp;Abinaya Mathialagan,&nbsp;Santhoshkumar Selvaraj,&nbsp;CH.Anthony Raju,&nbsp;Johan Granander,&nbsp;Eunice W. Q. Yeap,&nbsp;Browni VaikundaRaj,&nbsp;Pavlinka Ilieva,&nbsp;Sivasankaran Venugopal,&nbsp;Maheshwaran Shanmugham,&nbsp;Naveen Rangarajan,&nbsp;Shivasankar Krishnamoorthy,&nbsp;Seetharaman Sankara Subramanian,&nbsp;Paul McDaid,&nbsp;Carol O’Meara,&nbsp;Patrick O’Neill","doi":"10.1021/acs.oprd.6c00245","DOIUrl":"10.1021/acs.oprd.6c00245","url":null,"abstract":"<p>A potential next-generation manufacturing route to Palbociclibwas developed to reduce step count and cycle time relative to thefirst-generation commercial process while improving overall processsustainability. The final <em>tert</em>-butoxycarbonyl (Boc)deprotection step from the original route was retained to preserveestablished late-stage impurity clearance and API attributes. Therevised synthesis is based on the preparation of a common chloropyridoneintermediate (<strong>8a</strong>) from a readily crystallized hydroxy-pyridoneprecursor (<strong>9</strong>), followed by a convergent late-stage C–Nbond formation between two advanced heterocyclic fragments. Severalcoupling approaches, including nucleophilic aromatic substitutionand palladium-catalyzed Buchwald–Hartwig amination, were evaluated.High-Throughput Experimentation combined with Design-of-Experimentsstudies identified a homogeneous palladium-catalyzed amination asthe preferred manufacturing solution. Isolation of the coupling product(<strong>20</strong>) was achieved by reactive crystallization, enablingdirect preparation of the advanced intermediate in high purity. FinalBoc cleavage with formic acid, followed by basification, affordedpalbociclib in high yield and purity. Overall, the route providesa shorter and operationally streamlined manufacturing process, enablinga two-step synthesis of palbociclib (<strong>1</strong>) from key startingmaterials <strong>10e</strong> and <strong>3b</strong>.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 9","pages":"2530–2539"},"PeriodicalIF":3.3,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148805958","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}