Organic Process Research & Development最新文献_第8页

Practical, Large-Scale Preparation of Ni(tmeda)(o-tol)Cl 实用、大规模制备 Ni(tmeda)(邻甲苯)Cl

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c0040810.1021/acs.oprd.4c00408

Morgan E. John*, Daven Foster, Stephen A. Moggach, George A. Koutsantonis, Reto Dorta and Scott G. Stewart*,

引用次数: 0

Practical, Large-Scale Preparation of Ni(tmeda)(o-tol)Cl 实用、大规模制备 Ni(tmeda)(邻甲苯)Cl

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c00408

Morgan E. John, Daven Foster, Stephen A. Moggach, George A. Koutsantonis, Reto Dorta, Scott G. Stewart

引用次数: 0

Practical and Efficient Approach to Scalable Synthesis of Rucaparib Rucaparib 可扩展合成的实用高效方法

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c0036610.1021/acs.oprd.4c00366

Jinjae Park, and , Cheol-Hong Cheon*,

引用次数: 0

Practical and Efficient Approach to Scalable Synthesis of Rucaparib Rucaparib 可扩展合成的实用高效方法

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c00366

Jinjae Park, Cheol-Hong Cheon

引用次数: 0

Chemical and Biochemical Approaches to an Enantiomerically Pure 3,4-Disubstituted Tetrahydrofuran Derivative at a Multikilogram Scale: The Power of KRED 以化学和生物化学方法制备千克级对映体纯度的 3,4-二取代四氢呋喃衍生物：KRED 的力量

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-14 DOI: 10.1021/acs.oprd.4c00388

Antony Bigot, Alain Rabion, Jean-Bernard Landier, Geoffrey Laronze, Frédéric Petit, Stéphanie Deprets, Jean-Marc Michot, Changxia Yuan, Fenglai Sun, Han Chen, Longlei Hou, Dalin Tang

引用次数: 0

Chemical and Biochemical Approaches to an Enantiomerically Pure 3,4-Disubstituted Tetrahydrofuran Derivative at a Multikilogram Scale: The Power of KRED 在多千克尺度上对映体纯3,4-二取代四氢呋喃衍生物的化学和生化方法：KRED的功率

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-14 DOI: 10.1021/acs.oprd.4c0038810.1021/acs.oprd.4c00388

Antony Bigot*, Alain Rabion*, Jean-Bernard Landier, Geoffrey Laronze, Frédéric Petit, Stéphanie Deprets, Jean-Marc Michot, Changxia Yuan, Fenglai Sun, Han Chen, Longlei Hou and Dalin Tang,

{"title":"Chemical and Biochemical Approaches to an Enantiomerically Pure 3,4-Disubstituted Tetrahydrofuran Derivative at a Multikilogram Scale: The Power of KRED","authors":"Antony Bigot*, Alain Rabion*, Jean-Bernard Landier, Geoffrey Laronze, Frédéric Petit, Stéphanie Deprets, Jean-Marc Michot, Changxia Yuan, Fenglai Sun, Han Chen, Longlei Hou and Dalin Tang, ","doi":"10.1021/acs.oprd.4c0038810.1021/acs.oprd.4c00388","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00388https://doi.org/10.1021/acs.oprd.4c00388","url":null,"abstract":"A scalable synthesis of (3S,4S)-4-methyltetrahydrofuran-3-ol involving a keto reductase-mediated enantio- and diastereoselective reduction of a racemic ketone substrate is reported. This chiral intermediate was initially produced using a low-yielding three-step synthesis from ketone, deemed not usable for future batches. Looking for a scalable and environmental process: an eco-design approach led to a one-step, highly enantio- and diastereoselective biocatalytic reduction of the ketone to the targeted intermediate (3S,4S)-4-methyltetrahydrofuran-3-ol. In addition, the reaction operates via dynamic kinetic resolution under unprecedented mild conditions of temperature and pH, allowing for a full conversion of the ketone substrate into the desired enantiomer. The new route led to a significant improvement of all the key performance indicators, including PMI, solvent, and waste.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4467–4476 4467–4476"},"PeriodicalIF":3.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858757","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

A Journey through Process Development Enhanced by Kinetic Modeling: An Efficient Manufacturing Route to Balcinrenone 通过动力学建模加强工艺开发的历程：生产巴辛酮的高效路线

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-13 DOI: 10.1021/acs.oprd.4c0038710.1021/acs.oprd.4c00387

Cristina García-Morales*, David Dave, Zeina Neouchy, Helen Pointon, Matthew J. Foulkes, Alice Page, Thomas O. Ronson and Robert J. Cox*,

{"title":"A Journey through Process Development Enhanced by Kinetic Modeling: An Efficient Manufacturing Route to Balcinrenone","authors":"Cristina García-Morales*, David Dave, Zeina Neouchy, Helen Pointon, Matthew J. Foulkes, Alice Page, Thomas O. Ronson and Robert J. Cox*, ","doi":"10.1021/acs.oprd.4c0038710.1021/acs.oprd.4c00387","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00387https://doi.org/10.1021/acs.oprd.4c00387","url":null,"abstract":"This work focuses on the accelerated development of a versatile process for synthesizing a key amide intermediate en route to the active pharmaceutical ingredient balcinrenone. The process development was facilitated by the implementation of predictive kinetic models at the early stages of development. The predictive kinetic models effectively guided and expedited route design, process design, and process optimization for both batch and continuous manufacturing of a telescoped asymmetric reduction/amidation process using methylamine in methanol. The implementation of the telescoped batch process led to significant enhancements in throughput, sustainability, and economic efficiency of the synthesis of balcinrenone, resulting in the successful manufacture of the key amide intermediate. Additionally, the utilization of a multilinear regression (MLR)-Kinetics hybrid model enabled the rapid development of an alternative process using methylamine in water, providing a contingency plan for manufacturing campaigns in the event of shortage of methylamine in methanol. In addition to the primary focus, this study expanded the application of kinetic modeling to guide process design and optimization for a second intermediate obtained via pH-controlled addition/cyclization, thereby enhancing understanding and throughput for this step. Finally, the use of a structured experimentation design involving initial kinetic studies led to the discovery of improved conditions for the final amide bond formation to produce balcinrenone.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4455–4466 4455–4466"},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858755","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

A Journey through Process Development Enhanced by Kinetic Modeling: An Efficient Manufacturing Route to Balcinrenone 通过动力学建模加强工艺开发的历程：生产巴辛酮的高效路线

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-13 DOI: 10.1021/acs.oprd.4c00387

Cristina García-Morales, David Dave, Zeina Neouchy, Helen Pointon, Matthew J. Foulkes, Alice Page, Thomas O. Ronson, Robert J. Cox

{"title":"A Journey through Process Development Enhanced by Kinetic Modeling: An Efficient Manufacturing Route to Balcinrenone","authors":"Cristina García-Morales, David Dave, Zeina Neouchy, Helen Pointon, Matthew J. Foulkes, Alice Page, Thomas O. Ronson, Robert J. Cox","doi":"10.1021/acs.oprd.4c00387","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00387","url":null,"abstract":"This work focuses on the accelerated development of a versatile process for synthesizing a key amide intermediate en route to the active pharmaceutical ingredient balcinrenone. The process development was facilitated by the implementation of predictive kinetic models at the early stages of development. The predictive kinetic models effectively guided and expedited route design, process design, and process optimization for both batch and continuous manufacturing of a telescoped asymmetric reduction/amidation process using methylamine in methanol. The implementation of the telescoped batch process led to significant enhancements in throughput, sustainability, and economic efficiency of the synthesis of balcinrenone, resulting in the successful manufacture of the key amide intermediate. Additionally, the utilization of a multilinear regression (MLR)-Kinetics hybrid model enabled the rapid development of an alternative process using methylamine in water, providing a contingency plan for manufacturing campaigns in the event of shortage of methylamine in methanol. In addition to the primary focus, this study expanded the application of kinetic modeling to guide process design and optimization for a second intermediate obtained via pH-controlled addition/cyclization, thereby enhancing understanding and throughput for this step. Finally, the use of a structured experimentation design involving initial kinetic studies led to the discovery of improved conditions for the final amide bond formation to produce balcinrenone.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"38 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142609845","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

Identification of a Novel Process Impurity, Root Cause Investigation, and Its Control Strategy in Process Chemistry of Nevirapine API 奈韦拉平原料药工艺化学中新工艺杂质的鉴定、根本原因调查及控制策略

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-12 DOI: 10.1021/acs.oprd.4c0037710.1021/acs.oprd.4c00377

Jinsheng Lin*, Xiaojian Zheng, Dan Li, Huacui Hou, Xinlei Chen, Jianyang Jin, Xianhua Zhang, Wenbin Chen and Min Li,

{"title":"Identification of a Novel Process Impurity, Root Cause Investigation, and Its Control Strategy in Process Chemistry of Nevirapine API","authors":"Jinsheng Lin*, Xiaojian Zheng, Dan Li, Huacui Hou, Xinlei Chen, Jianyang Jin, Xianhua Zhang, Wenbin Chen and Min Li, ","doi":"10.1021/acs.oprd.4c0037710.1021/acs.oprd.4c00377","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00377https://doi.org/10.1021/acs.oprd.4c00377","url":null,"abstract":"An impurity eluting at RRT of 6.4 was observed during the HPLC testing of nevirapine (1) API for related substances. By using a strategy that combines LC-PDA/UV-MSn with NMR studies, the impurity was identified as 8-n-propyl nevirapine (2), a novel impurity that has not been reported in the literature. This impurity was sometime above 0.10% and difficult to be purged in the downstream of the existing manufacturing process of nevirapine, most likely due to its structural similarity to the API. Hence, this impurity should be controlled from the source of its generation in the process chemistry of nevirapine. During the early stage of the root cause investigation, two critical precursors to the impurity (2), (E)- and (Z)-N-propylidenecyclopropanamine (10 and 10′), were detected along with other relevant impurities, and based upon that, a probable formation mechanism of the impurity was proposed. In the late stage of the investigation, guided by the proposed mechanism, the process parameters of nevirapine manufacturing are optimized, under which the level of the impurity is reduced to 0.02% or below, while the yield of nevirapine is improved by 16%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4407–4419 4407–4419"},"PeriodicalIF":3.1,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142862484","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 the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling 结合脱羧sp2-sp3交叉偶联的局部Pan-Trk抑制剂的生产工艺开发

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-12 DOI: 10.1021/acs.oprd.4c00325

Michael S. Ashwood, Edward I. Balmond, David Fengas, Jane McGuffog, Jonathan Moore, Nicola M. Robas, Neil G. Stevenson, Lisa Wise

{"title":"Process Development for the Manufacture of a Topical Pan-Trk Inhibitor Incorporating Decarboxylative sp2–sp3 Cross-Coupling","authors":"Michael S. Ashwood, Edward I. Balmond, David Fengas, Jane McGuffog, Jonathan Moore, Nicola M. Robas, Neil G. Stevenson, Lisa Wise","doi":"10.1021/acs.oprd.4c00325","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00325","url":null,"abstract":"The development of a synthetic route toward topical pan-Trk inhibitor 1 is described as an eight-stage synthesis from available starting materials. Process improvements include the development of a decarboxylative sp2–sp3 cross-coupling which had not previously been demonstrated on scale. Parameters were explored, balancing the safety aspects with conversion and selectivity, scaling up in a stepwise fashion to multiple successful 0.7 kg batches. The cross-coupling showed high diastereoselectivity, with the opposite diastereomer not observed in the crude 19F NMR. Selectivity was further improved by crystallizing the downstream pyrrolidine salt after Boc deprotection, to give a diastereomer ratio of 99.5:0.5 by UPLC. This route has been reproducibly demonstrated in two GMP campaigns delivering API on kilogram scale, in >98% area purity by HPLC. The route design, solid-form screening, process research, and manufacture have enabled crucial first-in-human (FIH) clinical studies, through focus on speed of delivery.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"19 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142599883","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