Organic Process Research & Development最新文献_第3页

Bulk Mixing in a Milligram-Scale Solid Phase Batch Reactor 在毫克级固相间歇式反应器中进行散装混合

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-09-01 DOI: 10.1021/acs.oprd.5c00194

Sebastián Pinzón-López, Dominik Ebert, Emelie E. Reuber, Matthias Kraume, Peter H. Seeberger and José Danglad-Flores*,

{"title":"Bulk Mixing in a Milligram-Scale Solid Phase Batch Reactor","authors":"Sebastián Pinzón-López, Dominik Ebert, Emelie E. Reuber, Matthias Kraume, Peter H. Seeberger and José Danglad-Flores*, ","doi":"10.1021/acs.oprd.5c00194","DOIUrl":"10.1021/acs.oprd.5c00194","url":null,"abstract":"Adequate mixing is essential during reactions, especially in heterogeneous systems such as Solid Phase Synthesis (SPS), where the reagents transit from the fluid phase into the solid support. Despite the importance of mixing, a quantitative analysis within a theoretical framework is missing for SPS reactors. We analyze mechanical stirring (100–1300 rpm) and argon bubbling (1–30 cm3/min; 0.02–0.70 cm/s) as mixing methods in a milligram-scale batch reactor. Digital Image Analysis (DIA) was used to characterize the liquid mixing and particle dispersion. Typical solvents for SPS of biomolecules─acetonitrile (ACN), dichloromethane (DCM), and dimethylformamide (DMF)─were studied. The dispersion model represented the mixing process. Both mixing methods homogenize the liquid in times as short as 1s. Particle dispersion is accomplished in DCM and DMF but is limited in ACN, where the Archimedes number (Ar) was larger. The synthesis of various glycan probes through Automated Glycan Assembly (AGA) suggests that adequate mixing and thermal conditions are indispensable for process optimization.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2275–2286"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.5c00194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144931378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Recent Advances in Catalytic Asymmetric Hydrogenation of β-Ketoesters β-酮酯催化不对称加氢研究进展

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-27 DOI: 10.1021/acs.oprd.5c00258

Xue Song, Qingsong Chen, Liuzeng Chen, Banfeng Ruan*, Bin Li* and Xingxing Zhang*,

引用次数: 0

Process Development of a Model Solvate for Drying Research 一种用于干燥研究的模型溶剂的工艺开发

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-26 DOI: 10.1021/acs.oprd.5c00095

Nicholas H. McCarthy, Norah S. Alsaiari, Thomas Brown, Faiz M. Mahdi, Andrew E. Bayly, Sadie Finn and Frans L. Muller*,

{"title":"Process Development of a Model Solvate for Drying Research","authors":"Nicholas H. McCarthy, Norah S. Alsaiari, Thomas Brown, Faiz M. Mahdi, Andrew E. Bayly, Sadie Finn and Frans L. Muller*, ","doi":"10.1021/acs.oprd.5c00095","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00095","url":null,"abstract":"Drying of organic solvates remains hard to scale down and fully understand, as (a) residual solvent is typically hard to remove due to high solid-phase transport resistances, and (b) precise control over crystal properties is challenging. These issues are especially relevant to the pharmaceutical sector and its stringent quality criteria. We have identified a Schiff base forming a methanol solvate (derived from o-vanillin and para-aminobenzoic acid) with chemical complexity representative of pharmaceutical active ingredients that is cost-effective and a straightforward process for its manufacture has been developed. Initial attempts to crystallize the compound resulted in the formation of a slurry with a high yield stress caused by extremely high product supersaturation. By seeding the crystallization and controlling the addition rate of the catalyzing reagent, the process was successfully scaled up into one which was both high-yielding (93% at 1 L scale) and concentrated. These changes altered the crystal morphology, with crystal growth being favored over nucleation, resulting in larger, higher aspect ratio crystals (from 8 to 20). Powder X-ray diffraction (XRD) showed that the solvated Schiff base gradually transformed into a distinct desolvated polymorph, and a quantitative method for assessing solvent content with XRD was developed. The compound is a promising candidate as a model solvate system for drying trials on account of its (a) high-aspect-ratio morphology typical of many organic products; (b) stability at room temperature, facilitating handling and analysis; (c) desolvation temperature exceeding the boiling point of methanol, separating the drying of the free solvent from the period of desolvation. In conclusion, this relatively unexplored Schiff-base was identified as a promising model solvate for studying drying under industrially relevant conditions.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2200–2209"},"PeriodicalIF":3.5,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.5c00095","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Three-Pronged Approach (Active Pharmaceutical Ingredients, Excipients, and NOx-Free Air) Successfully Suppressed the Formation of Nitroso-atomoxetine to 0.097 ppm 三管齐下（有效药物成分，赋形剂和无nox空气）成功地将亚硝基托莫西汀的形成抑制到0.097 ppm

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-22 DOI: 10.1021/acs.oprd.5c00182

Ryota Nomura*, Takahiko Taniguchi, Koji Kitada, Mamoru Otsuki, Takuma Tamai, Kazuya Suzuoki, Rintaro Yokoi, Kanako Kondo and Osamu Uchikawa,

引用次数: 0

A Continuous Manufacturing Line Generating Organozinc Species in Flow: Enhancing the Simmons-Smith Reaction Including Post-Reaction Processing 在流动中产生有机锌的连续生产线：加强西蒙斯-史密斯反应，包括反应后处理

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-21 DOI: 10.1021/acs.oprd.5c00230

Daniel Moser, Joscha Boehm, Luis Correia, Sebastian Soritz, Peter Neugebauer, Dirk Kirschneck, Peter Pöchlauer and Heidrun Gruber-Woelfler*,

{"title":"A Continuous Manufacturing Line Generating Organozinc Species in Flow: Enhancing the Simmons-Smith Reaction Including Post-Reaction Processing","authors":"Daniel Moser, Joscha Boehm, Luis Correia, Sebastian Soritz, Peter Neugebauer, Dirk Kirschneck, Peter Pöchlauer and Heidrun Gruber-Woelfler*, ","doi":"10.1021/acs.oprd.5c00230","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00230","url":null,"abstract":"The cyclopropyl fragment is paramount in the pharmaceutical industry, as a wide range of active pharmaceutical ingredients inhere this versatile molecular structure. Recently, even higher importance has been attributed to the cyclopropane ring since many transition drug candidates utilize this carbon–carbon arrangement’s beneficial features. A reliable way to produce cyclopropanes is via the Simmons-Smith reaction, which utilizes a zinc–copper couple to transfer the methylene group of a dihalomethane to the double bond of a target molecule. The whole process involves a quenching and filtration step and is usually completed by a time-consuming extraction of metal salts and other impurities. This work presents a reliable and reproducible method to perform all unit operations continuously. It includes the synthesis step in a packed-bed reactor filled with a zinc–copper couple, activated in flow, eliminating the need for a filtration unit. It is followed by a two-stage cross-flow extraction for simultaneous quenching and removal of zinc salts from the product solution. Finally, the extraction efficiency is monitored atline by an in-house-developed method using chromophoric reagents in continuous flow.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2361–2369"},"PeriodicalIF":3.5,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.5c00230","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Differential Scanning Calorimetry Evaluation and Orthogonal Projection to Latent Structure Prediction of Thermal Hazards Associated with Five-Membered Aromatic Heterocycles with at Least Two Heteroatoms 含有至少两个杂原子的五元芳杂环的差示扫描量热法评价和正交投影对潜在结构的热危害预测

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-19 DOI: 10.1021/acs.oprd.5c00195

Han Xia*, Qiang Yang*, Syed Tanweer Ahmed, Vishaal Gopalakrishnan, Li Fan, Lou Zhang, Sha Li, Hongwei Yang and Nathan Torpoco,

引用次数: 0

Recovery of a Peptide Intermediate from a Reaction Mixture Contaminated with a Large Quantity of Silicone Oil Coolant 从被大量硅油冷却剂污染的反应混合物中回收多肽中间体

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-19 DOI: 10.1021/acs.oprd.5c00203

Yasuhiro Kondo*, Katsunori Dan, Hiroki Serizawa, Masao Tsukazaki, Hiroshi Iwamura and Kenji Maeda,

{"title":"Recovery of a Peptide Intermediate from a Reaction Mixture Contaminated with a Large Quantity of Silicone Oil Coolant","authors":"Yasuhiro Kondo*, Katsunori Dan, Hiroki Serizawa, Masao Tsukazaki, Hiroshi Iwamura and Kenji Maeda, ","doi":"10.1021/acs.oprd.5c00203","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00203","url":null,"abstract":"Accidental cracking at the bottom of a glass reactor vessel allowed silicone oil coolant to contaminate the reaction mixture of an N-terminal-free tripeptide intermediate (3) in the synthesis of a mid-sized cyclic peptide. Approximately 20 kg of silicone oil was leached from the reactor jacket and mixed with 35 kg of the reaction mixture. Our preliminary investigations showed that although the silicone oil and its degradation products could not be sufficiently removed by using heptane extraction from an acetonitrile solution of 3, these silicone-derived components could be successfully removed from an acidic aqueous solution of 3. Because 3 is an acid-sensitive N-alkylated peptide tert-butyl ester, it was essential to find an aqueous acidic solution that minimized decomposition while efficiently retaining 3 in solution. Using this approach, the silicone-derived components were reduced to a residual amount of 0.02 wt % relative to 3, with a 90% recovery of 3 from the contaminated reaction mixture.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2321–2326"},"PeriodicalIF":3.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094327","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

Development of a Reliable Low-Loading Palladium-Catalyzed Monoamination Process for the Large-Scale Synthesis of 3-Bromo-2,5-difluoroaniline 一种可靠的低负荷钯催化单胺化大规模合成3-溴-2,5-二氟苯胺工艺的开发

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-19 DOI: 10.1021/acs.oprd.5c00103

Christopher D. Parsons*, Carl J. Mallia, Matthew R. Tatton, Calum R. Cook, Cristina García Morales, Andrew D. Campbell, Okky Dwichandra Putra and Steven D. Bull,

{"title":"Development of a Reliable Low-Loading Palladium-Catalyzed Monoamination Process for the Large-Scale Synthesis of 3-Bromo-2,5-difluoroaniline","authors":"Christopher D. Parsons*, Carl J. Mallia, Matthew R. Tatton, Calum R. Cook, Cristina García Morales, Andrew D. Campbell, Okky Dwichandra Putra and Steven D. Bull, ","doi":"10.1021/acs.oprd.5c00103","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00103","url":null,"abstract":"The development of a manufacturing process for the multikilogram synthesis of 3-bromo-2,5-difluoroaniline required as a starting material for the anticancer KRASG12C inhibitor AZD4625 is described. Two potential synthetic routes to this aniline were identified involving Fe/HCl dissolving metal reduction of the nitro group of 1-bromo-2,5-difluoro-3-nitrobenzene or Pd(0)-catalyzed monoamination of 1,3-dibromo-2,5-difluorobenzene with benzophenone imine to give a haloaryl-imine intermediate that was then hydrolyzed. Optimization of the Pd(0) catalyzed C–N bond-forming step and associated mechanistic studies identified that 0.5 mol % Pd(dba)2/Xantphos and four equivalents of K3PO4 in iPrOAc at 80 °C could be used to produce 100 kg batches of a haloaryl-imine intermediate. Solutions of this imine in iPrOAc were then hydrolyzed through treatment with aqueous HCl allowing the desired aniline 1 to be isolated as its crystalline HCl salt. Process improvements include reduction of the amount of expensive Pd(dba)2 precatalyst used from 1.5 to 0.5 mol %, with iPrOAc used as a process-friendly solvent that allowed the C–N bond formation and imine hydrolysis steps to be telescoped into a single process. Detailed mechanistic investigations identified that use of excess K3PO4 as a heterogeneous base was necessary to minimize catalyst deactivation and impurity formation in the low-loading Pd(0)-catalyzed C–N bond-forming step.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2210–2221"},"PeriodicalIF":3.5,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094323","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

Early Process Development and Scale-up of a Tetrazole-Containing Soluble Guanylate Cyclase Stimulator 含四氮唑的可溶性鸟苷酸环化酶刺激剂的早期工艺开发和规模化生产

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-18 DOI: 10.1021/acs.oprd.5c00178

Takayoshi Tajima*, Takamasa Tanaka, Yoshinori Kohmura and Masahito Yoshida,

{"title":"Early Process Development and Scale-up of a Tetrazole-Containing Soluble Guanylate Cyclase Stimulator","authors":"Takayoshi Tajima*, Takamasa Tanaka, Yoshinori Kohmura and Masahito Yoshida, ","doi":"10.1021/acs.oprd.5c00178","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00178","url":null,"abstract":"This paper describes the research and development of a practical and efficient process for manufacturing a soluble guanylate cyclase stimulator, 1. The newly developed process includes an efficient telescoped process consisting of four consecutive reactions: tetrazole formation, difluoromethylation of a tetrazole moiety, deprotection, and tert-butyldiphenylsilyl (TBDPS) protection. Although regioselectivity in difluoromethylation of the tetrazole moiety was moderate, the selective TBDPS protection gave the desired regioisomer exclusively. We addressed safety issues related to thermally unstable tetrazole compounds and developed a safe process based on the thermal analysis results in which operating temperatures were controlled and the dangerous compounds were not isolated. Notably, the need for chromatographic purifications was avoided for all synthetic steps. This highly efficient and safe process was successfully demonstrated on a pilot scale to yield 24.6 kg of 1 with high quality. Overall yield was improved from 35% by the medicinal chemistry route to 45%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2238–2250"},"PeriodicalIF":3.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094352","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

Lessons Learned during 50 kg Manufacturing of Suzuki–Miyaura Coupling Reaction 铃木-宫浦偶联反应50公斤生产的经验教训

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-08-18 DOI: 10.1021/acs.oprd.5c00207

Yuhei Yamamoto*, Kotaro Yamaguchi and Kentaro Yaji,

{"title":"Lessons Learned during 50 kg Manufacturing of Suzuki–Miyaura Coupling Reaction","authors":"Yuhei Yamamoto*, Kotaro Yamaguchi and Kentaro Yaji, ","doi":"10.1021/acs.oprd.5c00207","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00207","url":null,"abstract":"This study presents the lessons learned from scaling up the Suzuki–Miyaura coupling reaction to a 50 kg scale. The reaction conditions were optimized at 89–90 °C, corresponding to the boiling point of the solvent system (2-BuOH/H2O, 7/3). Manufacturing at this scale was conducted at a contract manufacturing organization (CMO) situated at high altitude, requiring the use of a pressure vessel to maintain the internal temperature within the desired range. Reaction, workup, and crystallization processes were performed under stringent anaerobic conditions to prevent adverse events typically associated with palladium-catalyzed reactions. However, the obtained crystals exhibited unexpected impurity levels and elevated residual palladium concentrations. Comprehensive investigations identified elevated external temperatures during the reaction and strict anaerobic conditions during workup and crystallization as the primary contributors to these deviations. The findings underscore critical considerations for scaling up palladium-catalyzed reactions and highlight potential blind spots in temperature and oxygen control.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 9","pages":"2339–2345"},"PeriodicalIF":3.5,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.5c00207","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145094353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0