Organic Process Research & Development最新文献_第9页

Scalable Synthesis of a Masked Thiophenol as an Air-Stable, Odorless Intermediate to the Aurora Kinase Inhibitor Tozasertib (VX-680) 作为极光激酶抑制剂Tozasertib （VX-680）空气稳定、无臭中间体的掩蔽噻吩的规模化合成

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-08-21 Epub Date: 2026-08-06 DOI: 10.1021/acs.oprd.6c00143

Richard Herzog, Olivia L. Munns, Valentin Magne, Stephen P. Argent, Liam T. Ball

引用次数: 0

Enabling Process Development of Tetracyclic Quinolines for Brain-Penetrating KRAS G12C Inhibitors 四环喹啉类脑穿透KRAS G12C抑制剂的启用工艺开发

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-18 DOI: 10.1021/acs.oprd.6c00167

Lin Deng*, Ian S. Young, Julie A. Deichert and Chong Han*,

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Scalable Preparation and Application of Ar2S+-CF3 TfO– Ar2S+- cf3 TfO -的规模化制备与应用

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-26 DOI: 10.1021/acs.oprd.6c00048

Jia-Shuo Liu, Jin-Hong Lin* and Ji-Chang Xiao*,

{"title":"Scalable Preparation and Application of Ar2S+-CF3 TfO–","authors":"Jia-Shuo Liu, Jin-Hong Lin* and Ji-Chang Xiao*, ","doi":"10.1021/acs.oprd.6c00048","DOIUrl":"10.1021/acs.oprd.6c00048","url":null,"abstract":"S-Trifluoromethyl sulfonium salt Ph2S+CF3 TfO– has emerged as a powerful reagent for trifluoromethylation. However, a scalable synthesis of this salt has not been reported to date, and its preparation traditionally relies on highly toxic benzene, which raises significant safety and environmental concerns. In this work, we first achieved a practical tens-of-gram-scale synthesis of Ph2S+CF3 TfO–, and then, we realized a >100 g-scale preparation of an analogue, S-trifluoromethyl bis(4-fluorophenyl)sulfonium triflate (F-Sul). The synthesis of this salt avoids the use of benzene and streamlines the purification (no chromatography required). Comprehensive evaluation revealed that F-Sul exhibits nearly identical reactivity to Ph2S+CF3 TfO– in diverse trifluoromethylation reactions. Furthermore, we demonstrated the scalability and synthetic utility of F-Sul by achieving the hundred-gram-scale synthesis of nonafluorobutyl trifluoromethyl sulfonate (nC4F9SO3CF3, TFNf), a valuable trifluoromethoxylation reagent and an electrolyte additive for lithium-ion batteries.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1863–1871"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336317","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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Toward a Safe, High-Throughput, and Scalable Continuous-Flow Process for the Azide-Mediated Schmidt Reaction of Ketones 一种安全、高通量、可扩展的酮类叠氮化物施密特反应的连续流程

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-23 DOI: 10.1021/acs.oprd.6c00033

Isuru Dissanayake, Ryan Sullivan, Boris Gorin, Arturo Macchi and Stephen G. Newman*,

{"title":"Toward a Safe, High-Throughput, and Scalable Continuous-Flow Process for the Azide-Mediated Schmidt Reaction of Ketones","authors":"Isuru Dissanayake, Ryan Sullivan, Boris Gorin, Arturo Macchi and Stephen G. Newman*, ","doi":"10.1021/acs.oprd.6c00033","DOIUrl":"10.1021/acs.oprd.6c00033","url":null,"abstract":"The Schmidt reaction is a valuable method for converting common functional groups such as ketones, carboxylic acids, and aldehydes into nitrogen-containing products, but its use on scale is restricted by the extreme hazards associated with the key reagent, hydrazoic acid. To address this challenge, we developed a continuous-flow strategy designed to mitigate risk while enabling preparatively useful throughput. A microscale flow reactor was first constructed to study the influence of temperature, pressure, and residence time on the Schmidt reaction of ketones, identifying conditions that balance high conversion with an acceptable regioselectivity. An exogenous nitrogen cofeed was implemented as an additional safety measure to control the concentration of HN3 in the gas phase. Guided by these insights, a mesoscale reactor constructed entirely from compatible polymeric materials delivered over 22 g of amide product in an hour with performance comparable to that of the microscale system. Important limitations, safety considerations, and design challenges associated with HN3 remain unresolved and are discussed to inform future efforts toward larger-scale continuous-flow Schmidt reactions for pharmaceutical and fine-chemical manufacturing.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1844–1851"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336274","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

Optimization of a Resolution Process Allowing Access to Both Enantiomers of the Versatile Chiral Phosphine Ligand sSPhos on Scale 对多用途手性膦配体sSPhos的两种对映体的拆分工艺优化

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-25 DOI: 10.1021/acs.oprd.6c00142

Hamzah Sharif, Thomas D. Svejstrup, Staffan Karlsson and Robert J. Phipps*,

{"title":"Optimization of a Resolution Process Allowing Access to Both Enantiomers of the Versatile Chiral Phosphine Ligand sSPhos on Scale","authors":"Hamzah Sharif, Thomas D. Svejstrup, Staffan Karlsson and Robert J. Phipps*, ","doi":"10.1021/acs.oprd.6c00142","DOIUrl":"10.1021/acs.oprd.6c00142","url":null,"abstract":"Broadly effective, chiral monodentate phosphine ligands in asymmetric catalysis are relatively rare. sSPhos is a versatile, axially chiral phosphine that is capable of inducing high levels of enantioselectivity in a number of palladium-catalyzed transformations, including atroposelective Suzuki-Miyaura cross-coupling, arylative dearomatization, and carboetherification reactions. We have previously reported the chiral resolution of sSPhos by salt formation with quinidine, permitting the isolation of the (R) enantiomer. That process possessed several limitations, including relatively small scale, inability to access the (S) enantiomer, the requirement to presynthesize a trifluoroacetate salt of the dihydroquinine, and a maximum ee of 98% of (R)-sSPhos. In this work, we report further optimization and development of that procedure to permit it to be performed on a large scale. This simplified process permits the protonated, zwitterionic form of (R)-sSPhos to be obtained in >99% ee and (S)-sSPhos in 98% ee. The new modified procedure includes a resolution of racemic sSPhos by crystallization and was demonstrated on an 80 g scale to give access to both enantiomers of sSPhos in high ee and good yield. It is notable that the (S)-sSPhos enantiomer had previously been available only through preparative separation. We anticipate that this will assist in the incorporation of sSPhos as a chiral ligand in screening libraries and facilitate industrial application.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1987–1995"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/pdf/10.1021/acs.oprd.6c00142","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336332","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

Development of a Second-Generation Stereoselective Manufacturing Process for a Key N-Hydroxyamidine Intermediate of GDC-6599 Enabled by Data Science and Mechanistic Understanding 基于数据科学和机理理解的GDC-6599关键n -羟胺中间体第二代立体选择性制备工艺的开发

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-30 DOI: 10.1021/acs.oprd.6c00017

Jacob C. Timmerman*, Allen Y. Hong, Kurt Püntener, Anna-Lena Glass, Sandro Tonazzi, Katarzyna A. Piechowicz, Maud Guillemot-Plass, José G. Napolitano, Breanna Conklin, Haiming Zhang and Francis Gosselin,

{"title":"Development of a Second-Generation Stereoselective Manufacturing Process for a Key N-Hydroxyamidine Intermediate of GDC-6599 Enabled by Data Science and Mechanistic Understanding","authors":"Jacob C. Timmerman*, Allen Y. Hong, Kurt Püntener, Anna-Lena Glass, Sandro Tonazzi, Katarzyna A. Piechowicz, Maud Guillemot-Plass, José G. Napolitano, Breanna Conklin, Haiming Zhang and Francis Gosselin, ","doi":"10.1021/acs.oprd.6c00017","DOIUrl":"10.1021/acs.oprd.6c00017","url":null,"abstract":"We report the development of a second-generation manufacturing process for a key N-hydroxyamidine intermediate (3) en route to GDC-6599 (1). To obviate the safety hazards associated with a decakilogram-scale nucleophilic cyanation used in the first-generation route, we developed a sequence leveraging an enantioselective Pd-catalyzed Hayashi-Heck arylation followed by a stereo- and regioselective Rh-catalyzed hydroformylation reaction. This new route utilizes a synergistic high-throughput experimentation (HTE)/multivariate linear regression (MLR)-driven catalyst selection to establish the key stereochemical dyad of the tetrahydrofuran core. A detailed mechanistic understanding of the regioselective hydroformylation step was established and allowed for implementation on the manufacturing scale. The optimized 5-step sequence proceeds in 38% overall yield, avoiding the use of cyanide reagents and providing a robust control strategy for regio- and stereoisomeric impurities.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1819–1832"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385133","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

Improved Synthesis of a Key Intermediate of Onapristone 奥那匹司酮关键中间体的改进合成

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-07-08 DOI: 10.1021/acs.oprd.6c00013

Fei Lv, Qihua Zhao, Jiaoyang Feng, Ziyang Jia, Erin Zebrowski, Anjiang Yang*, Boyu Zhong* and Tony Yantao Zhang*,

引用次数: 0

Solid-Form Control of the Papaverine–Fumaric Acid Salt-Cocrystal Intermediate through Crystallization Condition Design 通过结晶条件设计控制罂粟碱-富马酸盐-共晶中间体的固相

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-16 DOI: 10.1021/acs.oprd.6c00053

Hiroki Shibata*, Noriyuki Takata, Aya Sakon, Shusuke Hara and Hiroshi Takiyama*,

{"title":"Solid-Form Control of the Papaverine–Fumaric Acid Salt-Cocrystal Intermediate through Crystallization Condition Design","authors":"Hiroki Shibata*, Noriyuki Takata, Aya Sakon, Shusuke Hara and Hiroshi Takiyama*, ","doi":"10.1021/acs.oprd.6c00053","DOIUrl":"10.1021/acs.oprd.6c00053","url":null,"abstract":"Multicomponent crystallization systems often exhibit complex phase behavior because of the coexistence of multiple crystal forms. In this study, the crystallization of an intermediate-state crystal and a salt cocrystal in a papaverine–fumaric acid system was investigated using a slurry method under various feed molar ratios, solvents, and agitation conditions. Screening experiments showed that, in methyl ethyl ketone, the intermediate-state crystal precipitated rapidly under all conditions, whereas transformation to the salt cocrystal required a prolonged time even at high fumaric acid/papaverine ratios. Thermodynamic and kinetic analyses indicated that the intermediate-state crystal is thermodynamically more stable and nucleates faster. By contrast, acetonitrile enabled the rapid formation of the salt cocrystal. Powder X-ray diffraction, thermogravimetry–differential scanning calorimetry, differential scanning calorimetry, and dynamic vapor sorption analysis confirmed the high phase purity and nonsolvated nature of both forms. These results demonstrate solvent-mediated selective crystallization and highlight the importance of intermediate-state crystals in multicomponent crystallization process design.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1872–1884"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148291658","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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Impact of Carbon-Based Anode Materials on Selectivity in a Shono Oxidation and Scale Up to Deca-Kilogram Scale 碳基负极材料对弱氧化选择性的影响及十公斤规模的研究

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-25 DOI: 10.1021/acs.oprd.6c00125

Dan Lehnherr*, Longrui Chen*, Fazel Bateni, Brandon Pilovsky, Michael LaMura, Christopher Nietupski, Jarod Nappi, Mark Weisel, Keith A. Mattern, Ryan D. Cohen, Weidong Tong, Michael J. Di Maso and François Lévesque,

{"title":"Impact of Carbon-Based Anode Materials on Selectivity in a Shono Oxidation and Scale Up to Deca-Kilogram Scale","authors":"Dan Lehnherr*, Longrui Chen*, Fazel Bateni, Brandon Pilovsky, Michael LaMura, Christopher Nietupski, Jarod Nappi, Mark Weisel, Keith A. Mattern, Ryan D. Cohen, Weidong Tong, Michael J. Di Maso and François Lévesque, ","doi":"10.1021/acs.oprd.6c00125","DOIUrl":"10.1021/acs.oprd.6c00125","url":null,"abstract":"We report the development of a selective and scalable Shono oxidation process of Boc-l-proline methyl ester (Boc-l-Pro-OMe) using flow electrosynthesis. A key feature of the reaction is the preferential methoxylation of Boc-l-Pro-OMe at its C5 carbon over oxidation at its C2 carbon. Different forms of carbon-based materials (porous graphite, resin-filled graphite, graphite foil, and graphite felts) were explored for the anode material in a Shono oxidation of Boc-l-Pro-OMe, and their impact on selectivity was characterized. Ultimately, an inexpensive carbon-based anode that is able to accommodate high current density was identified, thus enabling high productivity for the formation of the N,O-acetal product. We demonstrate the electrochemical process on two different scales using a parallel plate electrochemical reactor operating in a recirculating mode. A lab-scale setup with a footprint fitting within a standard fume hood was used to process ca. 0.7 kg of Boc-l-Pro-OMe per day. The use of a pilot-scale parallel plate reactor equipped with 0.4 m2 anode surface area of inexpensive electrode materials enabled deca-kilogram scale deployment of the process suitable to electrolyze 13 kg of Boc-l-Pro-OMe per day.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"30 7","pages":"1947–1960"},"PeriodicalIF":3.3,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148336333","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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Celebrating Lilly: 150 Years of Being a Medicine Company 庆祝礼来公司成立150周年

IF 3.3 3区化学

Organic Process Research & Development Pub Date : 2026-07-17 Epub Date: 2026-06-30 DOI: 10.1021/acs.oprd.6c00201

Sarah O’Keeffe, Sarah E. Langan, Scott A. Frank and Qiang Yang*,

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