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

Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-10 DOI: 10.1021/acs.oprd.4c0043210.1021/acs.oprd.4c00432

Michael A. Stager*, Carlos Peroza, Julien Villaumie, Christopher Bilham, Cameron Desmond, Marcus Harris, Ramya Sambasivan, Gary Rowe, Lin Chen and Charles Tucker,

{"title":"Optimizing Industrial Solid-Phase Peptide Synthesis: Integration of Raman Spectroscopy as Process Analytical Technology","authors":"Michael A. Stager*, Carlos Peroza, Julien Villaumie, Christopher Bilham, Cameron Desmond, Marcus Harris, Ramya Sambasivan, Gary Rowe, Lin Chen and Charles Tucker, ","doi":"10.1021/acs.oprd.4c0043210.1021/acs.oprd.4c00432","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00432https://doi.org/10.1021/acs.oprd.4c00432","url":null,"abstract":"Peptide therapeutics have exploded in popularity in recent years, motivating the need for advanced manufacturing methods which can be applied across the solid-phase peptide synthesis (SPPS) process. The Food and Drug Administration’s Process Analytical Technology (PAT) initiative offers a platform to implement advanced methods to improve the efficiency and understanding of pharmaceutical manufacturing processes and shows great promise in application toward industrial SPPS. In this work, Raman spectroscopy was used as the main PAT tool to implement methods for on-line and real-time monitoring of the entire SPPS process, from Fmoc removal, to coupling, and through the extensive solvent-washing steps. Raman spectroscopy is a rapid, specific, and nondestructive technique that can provide rich real-time information for SPPS processes and can be used to improve efficiency in solvent use and save process time. Specifically, this work reports on the development of PAT methods for monitoring of amino acid coupling during the coupling stage and residual piperidine concentration during the post-deprotection washing stage of SPPS, to help reduce solvent use and better understand the coupling reaction and its time frame. We show a significant reduction in solvent use is possible by employing Raman spectroscopy along with a partial least squares model to predict the piperidine concentration in real time during continuous wash. In addition, Raman spectroscopy offers a greater understanding of coupling reaction kinetics during SPPS, which could lead to significant improvements in total SPPS process time.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4501–4512 4501–4512"},"PeriodicalIF":3.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858626","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

Can Ultrasound Replace Seeding in Flow Reactive Crystallization of an Aromatic Amine?

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-10 DOI: 10.1021/acs.oprd.4c00385

Biyu Zhang, Georgios D. Stefanidis, Tom Van Gerven

{"title":"Can Ultrasound Replace Seeding in Flow Reactive Crystallization of an Aromatic Amine?","authors":"Biyu Zhang, Georgios D. Stefanidis, Tom Van Gerven","doi":"10.1021/acs.oprd.4c00385","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00385","url":null,"abstract":"Continuous crystallization has gained substantial interest due to its high product reproducibility, high labor efficiency, and low capital and production costs. Continuous seeding is preferable and often even required in the application of pharmaceuticals, which presents a bottleneck in continuous crystallization. This work proposes to apply ultrasound for continuous in situ seeding in the continuous reactive crystallization of an aromatic amine. Flow crystallization experiments with both ultrasound and conventionally prepared seeds were conducted. It was found that sonication initiated nucleation and continuously produced crystals in a stable manner. The nucleation rate could be controlled by adjusting the sonication power, highlighting the advantages of the sonicated seed generation strategy. Experiments under different flow conditions demonstrated that a higher flow rate combined with an appropriate sonication power was favorable for robust particle quality, reduced likelihood of clogging, and better reproducibility. Compared with the conventional addition of seed crystals, sonication-induced crystallization achieved higher yields and produced products with a narrow and unimodal size distribution. All sonicated experiments exhibited high robustness, indicating the feasibility and reliability of this method as a replacement for conventional seeding techniques in the continuous reactive crystallization of the studied compound. In summary, using ultrasound for continuous in situ seeding of the aromatic amine offers unique advantages in process robustness and product quality control, providing a promising strategy for continuous crystallization of similar systems.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142805043","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

Can Ultrasound Replace Seeding in Flow Reactive Crystallization of an Aromatic Amine?

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-10 DOI: 10.1021/acs.oprd.4c0038510.1021/acs.oprd.4c00385

Biyu Zhang, Georgios D. Stefanidis and Tom Van Gerven*,

{"title":"Can Ultrasound Replace Seeding in Flow Reactive Crystallization of an Aromatic Amine?","authors":"Biyu Zhang, Georgios D. Stefanidis and Tom Van Gerven*, ","doi":"10.1021/acs.oprd.4c0038510.1021/acs.oprd.4c00385","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00385https://doi.org/10.1021/acs.oprd.4c00385","url":null,"abstract":"Continuous crystallization has gained substantial interest due to its high product reproducibility, high labor efficiency, and low capital and production costs. Continuous seeding is preferable and often even required in the application of pharmaceuticals, which presents a bottleneck in continuous crystallization. This work proposes to apply ultrasound for continuous in situ seeding in the continuous reactive crystallization of an aromatic amine. Flow crystallization experiments with both ultrasound and conventionally prepared seeds were conducted. It was found that sonication initiated nucleation and continuously produced crystals in a stable manner. The nucleation rate could be controlled by adjusting the sonication power, highlighting the advantages of the sonicated seed generation strategy. Experiments under different flow conditions demonstrated that a higher flow rate combined with an appropriate sonication power was favorable for robust particle quality, reduced likelihood of clogging, and better reproducibility. Compared with the conventional addition of seed crystals, sonication-induced crystallization achieved higher yields and produced products with a narrow and unimodal size distribution. All sonicated experiments exhibited high robustness, indicating the feasibility and reliability of this method as a replacement for conventional seeding techniques in the continuous reactive crystallization of the studied compound. In summary, using ultrasound for continuous in situ seeding of the aromatic amine offers unique advantages in process robustness and product quality control, providing a promising strategy for continuous crystallization of similar systems.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4431–4443 4431–4443"},"PeriodicalIF":3.1,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00385","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867894","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

Regulatory Highlights

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-09 DOI: 10.1021/acs.oprd.4c00492

Andrew Teasdale, Cristiana Campa, Olivier Dirat

引用次数: 0

Regulatory Highlights

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-09 DOI: 10.1021/acs.oprd.4c0049210.1021/acs.oprd.4c00492

Andrew Teasdale*, Cristiana Campa and Olivier Dirat,

引用次数: 0

A Tribute to Ullmann’s Work: Expanding Copper Coil Reactor Applications toward the Hydroxylation of Aryl Bromides

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-08 DOI: 10.1021/acs.oprd.4c00402

Maite Molins, Javier Fernandez-Garcia, Xavier Berzosa

引用次数: 0

A Tribute to Ullmann’s Work: Expanding Copper Coil Reactor Applications toward the Hydroxylation of Aryl Bromides

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-08 DOI: 10.1021/acs.oprd.4c0040210.1021/acs.oprd.4c00402

Maite Molins, Javier Fernandez-Garcia and Xavier Berzosa*,

{"title":"A Tribute to Ullmann’s Work: Expanding Copper Coil Reactor Applications toward the Hydroxylation of Aryl Bromides","authors":"Maite Molins, Javier Fernandez-Garcia and Xavier Berzosa*, ","doi":"10.1021/acs.oprd.4c0040210.1021/acs.oprd.4c00402","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00402https://doi.org/10.1021/acs.oprd.4c00402","url":null,"abstract":"Copper coil flow reactors represent an economic, abundant, and durable platform for conducting copper-catalyzed reactions. These have been used in the past for Ullmann-type reactions starting from aryl iodides. However, no procedures have been described for the activation of less reactive aryl bromides. In this work, we successfully developed a method for the hydroxylation of aryl bromides promoted by a copper coil reactor. Notably, the presence of both a diamine ligand and DMF is key for the reaction to proceed. An inorganic base such as Na2CO3 also improved the reaction yield by minimizing the formation of side products. The setup has been applied to a range of disubstituted aryl bromides in moderate to good yields and was tested under 24 h of continuous operation, showing stable yields, thus proving the robustness of the catalysis. Finally, the lifetime of a copper reactor operating under the described conditions has been calculated for the first time, proving that this technology is safe to operate at an industrial scale.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4477–4484 4477–4484"},"PeriodicalIF":3.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00402","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867798","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 Nonprecious Metal Catalysis

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-12-07 DOI: 10.1021/acs.oprd.4c00417

David J. Bernhardson, Aran K. Hubbell, Robert A. Singer, Robert Szpera, Sergei Tcyrulnikov, Anna Chiara Vicini, Christophe Allais

引用次数: 0

Recent Advances in Nonprecious Metal Catalysis

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-07 DOI: 10.1021/acs.oprd.4c0041710.1021/acs.oprd.4c00417

David J. Bernhardson, Aran K. Hubbell, Robert A. Singer, Robert Szpera, Sergei Tcyrulnikov, Anna Chiara Vicini and Christophe Allais*,

引用次数: 0

An Improved Commercial Process for the Preparation of Lifitegrast

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-12-06 DOI: 10.1021/acs.oprd.4c0035610.1021/acs.oprd.4c00356

Arvind Girkar, Dujon Noronha, Prashant B. Patil, Mustapha Mandewale, Sudhir Sawant, Mohan Anand Chandavarkar and Kishor More*,

{"title":"An Improved Commercial Process for the Preparation of Lifitegrast","authors":"Arvind Girkar, Dujon Noronha, Prashant B. Patil, Mustapha Mandewale, Sudhir Sawant, Mohan Anand Chandavarkar and Kishor More*, ","doi":"10.1021/acs.oprd.4c0035610.1021/acs.oprd.4c00356","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00356https://doi.org/10.1021/acs.oprd.4c00356","url":null,"abstract":"A straightforward, efficient, and scalable commercial manufacturing process was developed for the ophthalmic anti-inflammatory drug lifitegrast via a novel ester intermediate from commercially available starting materials. Lifitegrast (Xiidra) was approved by the FDA on July 11, 2016, for the treatment of signs and symptoms of dry eye, a syndrome called keratoconjunctivitis sicca. The breakthrough step of this new process is the discovery of an N-Boc deprotection reaction that simultaneously transesterifies an intermediate to a new ester by using oxalyl chloride, which has favorable isolation properties. As a result of transesterification, the hydrolysis of the new ester intermediate occurs under milder conditions, which improves the quality of the product by reducing racemization. Lifitegrast prepared from this new process complied with the quality guidelines, as per the International Council for Harmonization (ICH). By using this new process, lifitegrast was produced on a 2 kg scale with an overall yield of 66%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4374–4379 4374–4379"},"PeriodicalIF":3.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867782","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