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

Reaction Calorimetry Study of Hydrogenation of Nitroaniline Isomers to Phenylenediamine Isomers 硝基苯胺异构体加氢制苯二胺异构体的反应量热法研究

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-07 DOI: 10.1021/acs.oprd.5c00077

Rajendra Kumar, Pradip Mane and Nilesh Atmaram Mali*,

{"title":"Reaction Calorimetry Study of Hydrogenation of Nitroaniline Isomers to Phenylenediamine Isomers","authors":"Rajendra Kumar, Pradip Mane and Nilesh Atmaram Mali*, ","doi":"10.1021/acs.oprd.5c00077","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00077","url":null,"abstract":"In this work, a detailed reaction calorimetry study of hydrogenation of ortho-, meta-, and para- isomers of nitroaniline to the corresponding phenylenediamine isomers was carried out. An automated high-pressure power compensation reaction calorimeter was used in an isothermal mode in the temperature range of 60–150 °C and pressure ranging from 7 to 20 bar. Reactions were performed using heterogeneous palladium- and ruthenium-based catalysts in the presence of solvent. The process safety data comprising heat rate, heat of reaction (ΔH), adiabatic temperature rise (ΔTad), maximum temperature of the synthesis reaction (MTSR), and pressure rise in the case of cooling failure were determined for these reactions. The maximum heat rate of the hydrogenation process was found to be 14.30, 27.47, and 10.81 W for ortho-nitroaniline, meta-nitroaniline, and para-nitroaniline, respectively. The heat of reaction was found to be −567.54 kJ/mol, −611.41 kJ/mol, and −555.01 kJ/mol for ortho-nitroaniline, meta-nitroaniline, and para-nitroaniline hydrogenation, respectively. The highest MTSR for all isomers is estimated along with the corresponding pressure rise.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1740–1748"},"PeriodicalIF":3.5,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807637","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

An Ultrafast Production of Imidazoles at Low Temperature with a 3D-Printed Microflow Reactor 用3d打印微流反应器低温超快生产咪唑

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-04 DOI: 10.1021/acs.oprd.4c00456

Yu Qi, Cheng-Cheng Gu, Hao-Xing Xu, Yu-Hong Tao and Xiao Wang*,

引用次数: 0

Continuous Crystallization of Atorvastatin Calcium at a Multitonnage Scale Using Dynamically Mixed Flow Reactors for Target Polymorph Control 动态混流反应器多吨位连续结晶阿托伐他汀钙的靶晶型控制

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-04 DOI: 10.1021/acs.oprd.4c00478

Naga Lakshmi Ramana Susarla, Dharma Jaganadha Rao Velaga, Mohammed Yakoob Sardar, Anirban Ghosh, Ravi Kumar Gorle, Suhas Jawlekar, Rajeev Rehani Budhdev and Srividya Ramakrishnan*,

{"title":"Continuous Crystallization of Atorvastatin Calcium at a Multitonnage Scale Using Dynamically Mixed Flow Reactors for Target Polymorph Control","authors":"Naga Lakshmi Ramana Susarla, Dharma Jaganadha Rao Velaga, Mohammed Yakoob Sardar, Anirban Ghosh, Ravi Kumar Gorle, Suhas Jawlekar, Rajeev Rehani Budhdev and Srividya Ramakrishnan*, ","doi":"10.1021/acs.oprd.4c00478","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00478","url":null,"abstract":"At Dr Reddy’s, we have developed an integrated continuous manufacturing process for the generation of atorvastatin calcium drug substance encompassing a series of three reactions, followed by downstream unit operations of crystallization, filtration, and drying. The current work focuses on the design of the continuous crystallization process while integrating with upstream reactions and downstream filtration and minimizing the risk of fouling. The batch process was successfully translated to flow by understanding the critical process parameters and designing a crystallization strategy to achieve the desired polymorph (trihydrate, Form-I) and crystal size distribution. A novel and important feature of the present work is the utilization of Coflore dynamically mixed flow reactors in process development and manufacturing. The ability to achieve excellent macromixing in the dynamically mixed flow reactors irrespective of the flow rates helped in crystal growth with minimal fouling. This enabled better filtration for integration with downstream continuous operations. Overall, a continuous seeded antisolvent plus cooling crystallization process was established with a system consisting of Coflore reactors, followed by three CSTRs in series for a controlled cooling profile to promote uniform crystal growth and maximize yield. This process was successfully demonstrated at lab scale (5.6 g/h) and plant scale (12 kg/h of API output) while seamlessly integrating it within the continuous manufacturing train.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1662–1676"},"PeriodicalIF":3.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807761","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

New Saturated Bicyclic Pyrrolidines: The Multigram Synthesis and Orthogonal Functionalization 新型饱和双环吡咯烷：多重图合成及正交功能化

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-04 DOI: 10.1021/acs.oprd.5c00135

Kostiantyn Levchenko*, Daria Menshykova and Nazariy Pokhodylo*,

{"title":"New Saturated Bicyclic Pyrrolidines: The Multigram Synthesis and Orthogonal Functionalization","authors":"Kostiantyn Levchenko*, Daria Menshykova and Nazariy Pokhodylo*, ","doi":"10.1021/acs.oprd.5c00135","DOIUrl":"10.1021/acs.oprd.5c00135","url":null,"abstract":"A practical and scalable strategy for the synthesis and functionalization of saturated pyrrolidine-based bicyclic scaffolds has been developed. Starting from commercially available cyclic β-keto esters, a two- or four-step sequence enabled efficient access to condensed 2-pyrrolidones in high yields. Seven structurally distinct bicyclic systems were prepared, each bearing a carboxyl group at the nodal 3a-position, serving as a versatile handle for downstream transformations. Strategic use of orthogonal protecting groups (Bn, Boc, and Cbz) facilitated purification and enabled selective modifications. Curtius rearrangement allowed direct conversion of the carboxylic acid into the corresponding amine, while further diversification included reduction to alcohols, Swern oxidation to aldehydes, mesylation–azidation–reduction, and thiolation–oxidation to sulfonyl chlorides. All transformations were conducted under mild, operationally simple conditions and demonstrated good functional group tolerance. The described methodology provides a robust platform for accessing medicinally relevant pyrrolidine-based bicyclic building blocks and offers practical advantages for application in drug discovery and process chemistry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1792–1808"},"PeriodicalIF":3.5,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566505","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

Practical Synthesis of 3-Substituted Pyrimidin-4-ones and 4(3H)-Quinazolinones from Nitriles: Mechanistic Insights, Scope, and Scale-Up 从腈合成3-取代嘧啶-4-酮和4(3H)-喹唑啉酮：机理、范围和规模

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-03 DOI: 10.1021/acs.oprd.5c00124

Luca Alessandro Perego, Seppe Hermans, Matthew P. Mower*, Alexander Zhdanko*, Simon Wagschal* and Sébastien Lemaire,

{"title":"Practical Synthesis of 3-Substituted Pyrimidin-4-ones and 4(3H)-Quinazolinones from Nitriles: Mechanistic Insights, Scope, and Scale-Up","authors":"Luca Alessandro Perego, Seppe Hermans, Matthew P. Mower*, Alexander Zhdanko*, Simon Wagschal* and Sébastien Lemaire, ","doi":"10.1021/acs.oprd.5c00124","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00124","url":null,"abstract":"Pyrimidin-4-ones and (3H)-quinazolin-4-ones are widely occurring heterocyclic motifs found in biologically active substances. This report presents a practical and scalable three-step, two-pot synthesis of 2-unsubstituted-3-alkyl/aryl derivatives of these heteroaromatics. During the mechanistic investigation of the hexafluorophosphate azabenzotriazole tetramethyl uronium (HATU)-mediated coupling of 4-hydroxyquinazolines with amines, we found that the N-activated heterocycle underwent nucleophilic attack on the methine atom with subsequent ring opening and ring closing (ANRORC mechanism). Building on the new mechanistic insight, we designed and developed an efficient synthesis of 2-unsubstituted-3-substituted pyrimidin-4-ones through the condensation of β-aminoacrylates with dimethylformamide dimethylacetal (DMF-DMA), followed by cyclization with primary amines. The required β-aminoacrylates were easily obtained in a single step via ZnCl2-mediated decarboxylative Blaise–Reformatsky reaction of nitriles, which was extended to aliphatic substrates using an improved protocol. The methodology described herein is particularly suited to execution on a large scale as it requires no chromatography, utilizes no solvents of very high concern, and has been successfully demonstrated on the liter scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1775–1787"},"PeriodicalIF":3.5,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144807512","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

Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 1: Step 1 Synthesis 巴洛昔韦马博西连续生产工艺的开发。第1部分：步骤1综合

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-02 DOI: 10.1021/acs.oprd.5c00156

Hannah Nguyen, Wei Wu, Rita C. Barral, Rajshree Chakrabarti, Qinglin Su, Youhua Li, Anjana Ramnath, Bhavya Singh, Ke Wen, Yazid Al Khatib, Khrystyna Shvedova, Stephen C. Born, Chuntian Hu*, Bayan Takizawa, Paul Stonestreet, Michael Berg and Salvatore Mascia*,

{"title":"Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 1: Step 1 Synthesis","authors":"Hannah Nguyen, Wei Wu, Rita C. Barral, Rajshree Chakrabarti, Qinglin Su, Youhua Li, Anjana Ramnath, Bhavya Singh, Ke Wen, Yazid Al Khatib, Khrystyna Shvedova, Stephen C. Born, Chuntian Hu*, Bayan Takizawa, Paul Stonestreet, Michael Berg and Salvatore Mascia*, ","doi":"10.1021/acs.oprd.5c00156","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00156","url":null,"abstract":"Annually, influenza viruses have a substantial impact on global health, often resulting in severe illness and death. While influenza vaccines are accessible, antiviral medications, such as baloxavir marboxil (marketed as Xofluza), play a vital role in both postexposure prevention and treatment, specifically targeting seasonal influenza A and influenza B. The Step 1 synthesis of baloxavir marboxil is from S199AL to S-033447 and includes four unit operations (i.e., reactive crystallization to S-033447·CSA (camphorsulfonic acid), continuous rotary filtration of S-033447·CSA, neutralization and purification of S-033447·CSA to S-033447, and continuous rotary filtration of S-033447). S-033447·CSA was formed from S199AL and S199AR through a continuous reactive crystallization in a 500 mL five-stage CSTR cascade. The solid yield was 66.2% with a residence time of 28 h. The neutralization of S-033447·CSA and crystallization of S-033447 were performed in a two-stage MSMPR cascade. A pH probe was located in the first stage (i.e., neutralization stage), and a ReactIR probe was placed in the second stage (i.e., crystallization stage) to monitor the antisolvent addition. The crystallization yield was 91–93% for a 65% water volume fraction. The filtration processes of S-033447·CSA and S-033447 slurry were conducted with a continuous rotary filter, and steady state was achieved.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1857–1868"},"PeriodicalIF":3.5,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144806768","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

Biocatalytic Synthesis of (R)-3-Aminotetrahydropyran through a Direct Transamination at Kilogram Scale 千克级直接转氨法生物催化合成(R)-3-氨基四氢吡喃

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-01 DOI: 10.1021/acs.oprd.5c00142

Hao Wu*, Xu Ma, Joe Ju Gao, Jose Santiago-Rivera, Clement Valentin, Jon C. Lorenz, Xiaole Shao, Jing Liu and Frederic Buono,

引用次数: 0

Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 2: Step 2 Synthesis 巴洛昔韦马博西连续生产工艺的开发。第二部分：步骤2综合

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-07-01 DOI: 10.1021/acs.oprd.5c00157

Rita C. Barral, Hannah Nguyen, Rajshree Chakrabarti, Bhavya Singh, Wei Wu, Shalabh S. Yeole, Youhua Li, Anjana Ramnath, Uma Raul, Aibolat Koishybay, Taryn Sparacino, Michael Stamm, Chuntian Hu*, Bayan Takizawa, Paul Stonestreet, Michael Berg and Salvatore Mascia*,

{"title":"Process Development for Continuous Manufacturing of Baloxavir Marboxil. Part 2: Step 2 Synthesis","authors":"Rita C. Barral, Hannah Nguyen, Rajshree Chakrabarti, Bhavya Singh, Wei Wu, Shalabh S. Yeole, Youhua Li, Anjana Ramnath, Uma Raul, Aibolat Koishybay, Taryn Sparacino, Michael Stamm, Chuntian Hu*, Bayan Takizawa, Paul Stonestreet, Michael Berg and Salvatore Mascia*, ","doi":"10.1021/acs.oprd.5c00157","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00157","url":null,"abstract":"The pharmaceutical manufacturing sector is steadily transitioning from batch to continuous operations, as the drawbacks of batch operations and the advantages of continuous operations have increasingly provided compelling motivation for change. This study, which details the Step 2 synthesis of baloxavir marboxil (from S-033447 to S-033188), provides an example of how continuous manufacturing implementation can offer significant operational benefits. The process includes four unit operations (i.e., reaction to S-033188, crystallization and purification of S-033188, continuous rotary filtration of S-033188, and continuous wet milling and drying of S-033188). S-033188 was formed in a three-stage 500 mL CSTR cascade with a ReactIR in the third stage. The total residence time was 10.5 h, and the high-performance liquid chromatography (HPLC) area% of S-033188 and S-033447 in the third stage was 96.6 and 0.6%, respectively. The continuous crystallization of S-033188 was performed in a three-stage MSMPR system, and the crystallization yield was 97.1% with a 15-fold antisolvent addition. Focused beam reflectance measurement (FBRM) was located in the third stage to monitor the start-up and steady state during the run. A continuous rotary filter was used to process the S-033188 slurry, and it operated with a vacuum pressure of approximately −15 kPa and a cake height of 4 mm after reaching a steady state. Wet milling was applied to achieve the required quality attribute of S-033188 on particle size distribution (PSD), and heptane/ethyl acetate (50:1, v/v) was selected as the resuspension solvent. After wet milling, S-033188 was dried with a continuous drum dryer, resulting in desired Form I.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 7","pages":"1843–1856"},"PeriodicalIF":3.5,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805958","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

Optimizing the CHF6523 Isocoumarin Core Scaffold: From the Preclinical Stage to Large-Scale Production CHF6523异香豆素核心支架的优化：从临床前期到大规模生产

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-30 DOI: 10.1021/acs.oprd.5c00133

Rocco Bussolati*, Paolo Ronchi*, Fausto Pivetti, Claudio Fiorelli, Emanuele Ferrari, Diego Copelli, Massimiliano Mari, Paolo Bruno, Matteo Biagetti, Piotr Malysa, Xiaoping Tang, Jonathan Simmons, Max Espensen, Benjamin Rowley, Peter Mullens, Huihua Lu, Junqiang Wang, Huajun Ge and Zhongwei Zhang,

引用次数: 0

Correction to “Thermal Hazard Assessment of the Synthesis of 1,1′-Azobis-1,2,3-triazole” 对“合成1,1′-偶氮双-1,2,3-三唑的热危害评价”的修正

IF 3.5 3区化学

Organic Process Research & Development Pub Date : 2025-06-30 DOI: 10.1021/acs.oprd.5c00169

Hao Li, Jin-Xi Wu, Guang-Yuan Zhang, Ning-Ning Du, Le-Wu Zhan, Jing Hou* and Bin-Dong Li*,

引用次数: 0