Pub Date : 2024-04-30DOI: 10.1021/acs.oprd.4c00099
Bradley J. Paul-Gorsline
The synthesis of mixed thiourea 4 was performed via a 1,1′-thiocarbonyldiimidazole (TCDI)-mediated coupling with 1 to form intermediate isothiocyanate 2 prior to reaction with amine 3. A critical undesired thiourea impurity─5─is formed via the overreaction of 2 with an additional equivalent of 1. This work describes a mechanism-based kinetic model toward understanding the formation of 2 and impurity 5. Critical to the construction of this model is the inclusion of imidazole autocatalysis. This experimentally validated model allows for the identification of improved process conditions for reducing the level of formation of 5. This report also describes the newfound role of imidazole in the decomposition of 4 and the impact of imidazole on the solubility of both 4 and 5.
{"title":"Development of a Mechanism-Based Kinetic Model and Process Optimization Incorporating Imidazole Autocatalysis in a 1,1′-Thiocarbonyldiimidazole-Mediated Thiocarbonyl Transfer","authors":"Bradley J. Paul-Gorsline","doi":"10.1021/acs.oprd.4c00099","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00099","url":null,"abstract":"The synthesis of mixed thiourea <b>4</b> was performed via a 1,1′-thiocarbonyldiimidazole (TCDI)-mediated coupling with <b>1</b> to form intermediate isothiocyanate <b>2</b> prior to reaction with amine <b>3</b>. A critical undesired thiourea impurity─<b>5</b>─is formed via the overreaction of <b>2</b> with an additional equivalent of <b>1</b>. This work describes a mechanism-based kinetic model toward understanding the formation of <b>2</b> and impurity <b>5</b>. Critical to the construction of this model is the inclusion of imidazole autocatalysis. This experimentally validated model allows for the identification of improved process conditions for reducing the level of formation of <b>5</b>. This report also describes the newfound role of imidazole in the decomposition of <b>4</b> and the impact of imidazole on the solubility of both <b>4</b> and <b>5</b>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817442","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}
Pub Date : 2024-04-30DOI: 10.1021/acs.oprd.4c00091
Ryusei Oketani, Riku Naito, Ichiro Hisaki
This study outlines a practical, semicontinuous method for temperature cycle-induced deracemization (TCID) using a batch-mode crystallizer. We employed an axially chiral naphthamide derivative as a model compound and deracemized the crystalline phase by conventional TCID. To achieve continuity of deracemization, we harvested a part of the suspension after the conventional TCID, and then we fed a new racemic suspension into the enriched suspension and applied temperature cycles. By leaving a highly enriched crystalline phase as seed crystals to direct the chirality of the following enrichment, the enrichment process was significantly accelerated, verifying a stable and high production efficiency. Furthermore, from the perspective of process productivity, the moderate suspension density is optimal for efficient deracemization. In the naphthamide system, up to 7.71 g·L–1·h–1 of productivity was achieved. Thanks to the simple operation, the method described here is applicable for most batch-mode deracemizations reported to date. In terms of industrial applications, semicontinuous deracemization could be a good option to utilize the existing batch-mode crystallizers.
{"title":"Semicontinuous Temperature Cycle-Induced Deracemization Using an Axially Chiral Naphthamide","authors":"Ryusei Oketani, Riku Naito, Ichiro Hisaki","doi":"10.1021/acs.oprd.4c00091","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00091","url":null,"abstract":"This study outlines a practical, semicontinuous method for temperature cycle-induced deracemization (TCID) using a batch-mode crystallizer. We employed an axially chiral naphthamide derivative as a model compound and deracemized the crystalline phase by conventional TCID. To achieve continuity of deracemization, we harvested a part of the suspension after the conventional TCID, and then we fed a new racemic suspension into the enriched suspension and applied temperature cycles. By leaving a highly enriched crystalline phase as seed crystals to direct the chirality of the following enrichment, the enrichment process was significantly accelerated, verifying a stable and high production efficiency. Furthermore, from the perspective of process productivity, the moderate suspension density is optimal for efficient deracemization. In the naphthamide system, up to 7.71 g·L<sup>–1</sup>·h<sup>–1</sup> of productivity was achieved. Thanks to the simple operation, the method described here is applicable for most batch-mode deracemizations reported to date. In terms of industrial applications, semicontinuous deracemization could be a good option to utilize the existing batch-mode crystallizers.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814978","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}
Boronate esters are commonly used starting materials in the Suzuki–Miyaura coupling reaction for the C–C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO2 (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [Tmin/B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03–0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. The method was successfully applied for the estimation of 16 structurally different boronate esters with no chemical derivatization or hydrolysis.
{"title":"Analytical Strategy for Low-Level Estimation of Unstable Genotoxic Boronate Ester Impurities","authors":"Bhoopendra Singh Kushwah, Santosh Gandhi, Devikumar Purandharan, Ashok Kumar Rajendran, Karthik Jayaraman, Venkata Phanikrishna Sharma Mangalampalli, Joel Young, Lakshmikant Bajpai","doi":"10.1021/acs.oprd.4c00065","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00065","url":null,"abstract":"Boronate esters are commonly used starting materials in the Suzuki–Miyaura coupling reaction for the C–C bond formation due to their cost-effectiveness and ease of manufacturing process. However, most of them are highly sensitive to moisture and pose challenges during their in-process analysis, with conversion to acids under reversed-phase analytical conditions. They are prone to hydrolysis under moisture, pH, and even on-column stationary phases under neutral conditions. At the same time, boronate esters are considered as potential genotoxic substances; hence, their estimation is very important from the patient safety perspective. There are inherent challenges in the existing methods of analysis of these compounds. In this paper, a convenient, simple, highly sensitive, and greener SFC-MS method was developed for the screening of such unstable boronate esters. The optimized method consisted of Celeris Arginine column (250 mm × 4.6 mm; 5 μm) with CO<sub>2</sub> (A) as a solvent with a cosolvent of ACN: MeOH (80:20) containing 0.2% 7N methanolic ammonia (B) in gradient mode [<i>T</i><sub>min</sub>/B %: 0.01/05, 0.50/05, 5.00/50, 7.00/50, 7.10/05, and 10.00/05]. Critical method parameters such as ABPR pressure, makeup solvent, additives, and pump flow rate were optimized to enhance the sensitivity with a model compound, i.e., 1-(benzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-<i>b</i>]pyridine (CAS no. 886547-94-0). The robustness of the method was demonstrated by validating the method as per the ICH guidelines on the same model compound in the concentration range of 0.03–0.3 ppm. The LOD and LOQ for this compound were determined as 0.01 and 0.03 ppm (1 and 3 ppm with respect to API concentrations of 10 mg/mL), respectively. The method was successfully applied for the estimation of 16 structurally different boronate esters with no chemical derivatization or hydrolysis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817330","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}
Pub Date : 2024-04-30DOI: 10.1021/acs.oprd.4c00098
Nathan March, Bradley J. Paul-Gorsline
While investigating a 1,1′-thiocarbonyldiimidazole (TCDI)-mediated coupling in the synthesis of an aryl isothiocyanate, imidazole autocatalysis was observed. Although reported for 1,1′-carbonyldiimidazole (CDI), imidazole autocatalysis with TCDI has not been described. In this study, we explore the mechanism of imidazole autocatalysis in TCDI-mediated couplings of aniline. Notably, acids and non-nucleophilic bases were not shown to catalyze this reaction, suggesting that imidazole autocatalysis occurs via an alternative mechanism. We propose that imidazole acts as a nucleophilic catalyst leading to a more reactive cationic TCDI species. Inverse first-order kinetics with respect to imidazole anion and rapid equilibration with deuterated imidazole resulting in the release of free imidazole from TCDI support this conclusion. Increased catalytic activity with several known nucleophilic catalysts was observed, further supporting the role of imidazole as a nucleophilic catalyst. A density functional theory (DFT)-based computational model was constructed to identify other potential nucleophilic catalysts in this reaction. This model was successful in identifying several classes of nucleophilic catalysts that proved to be even more reactive catalysts for TCDI-mediated couplings of aniline compared to imidazole.
{"title":"Mechanistic Studies of Imidazole Autocatalysis in 1,1′-Thiocarbonyldiimidazole-Mediated Couplings of Aniline","authors":"Nathan March, Bradley J. Paul-Gorsline","doi":"10.1021/acs.oprd.4c00098","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00098","url":null,"abstract":"While investigating a 1,1′-thiocarbonyldiimidazole (TCDI)-mediated coupling in the synthesis of an aryl isothiocyanate, imidazole autocatalysis was observed. Although reported for 1,1′-carbonyldiimidazole (CDI), imidazole autocatalysis with TCDI has not been described. In this study, we explore the mechanism of imidazole autocatalysis in TCDI-mediated couplings of aniline. Notably, acids and non-nucleophilic bases were not shown to catalyze this reaction, suggesting that imidazole autocatalysis occurs via an alternative mechanism. We propose that imidazole acts as a nucleophilic catalyst leading to a more reactive cationic TCDI species. Inverse first-order kinetics with respect to imidazole anion and rapid equilibration with deuterated imidazole resulting in the release of free imidazole from TCDI support this conclusion. Increased catalytic activity with several known nucleophilic catalysts was observed, further supporting the role of imidazole as a nucleophilic catalyst. A density functional theory (DFT)-based computational model was constructed to identify other potential nucleophilic catalysts in this reaction. This model was successful in identifying several classes of nucleophilic catalysts that proved to be even more reactive catalysts for TCDI-mediated couplings of aniline compared to imidazole.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140817497","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}
Pub Date : 2024-04-29DOI: 10.1021/acs.oprd.4c00033
Steven Tymonko, Brenda J. Burke, Jean-Philippe Crochard, Olivier Dirat, Kenneth J. Fraunhoffer, Cristian Harrison, Timothy Kramer, Heewon Lee, Vlad Liberman, Kanwar P. S. Sidhu, Randi Smith, Neil A. Strotman, Nil Tandogan, Alan Triman, Haitao Zhang
The designation and justification of active pharmaceutical ingredient starting materials (API SMs) is a crucial aspect of the drug substance (DS) commercialization process. Over the past decade, significant efforts have been made by both the pharmaceutical industry and regulatory authorities to clarify and harmonize requirements for API SM selection and justification, including the introduction of the ICH Q11 guideline in 2011 and the Q&A document to Q11 in 2017. In 2018, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) established the API SM Working Group to evaluate the impact of the ICH Q11 Q&A on API SM selection and approval, as well as cross-regulatory alignment. The API SM Working Group collected metrics from 19 IQ member companies on drug substances marketing applications submitted since 2014, including the associated API SM selection, justification, and associated ICH regulatory approval experiences. Data representing a total of 115 API SMs used to manufacture 38 new chemical entities were obtained. The outcomes of API SM proposals in initial marketing applications across ICH countries and regions prior to and following the publication of the ICH Q11 Q&A document are presented. The data showed significant differences in acceptance rates of API SM proposals across ICH regulatory agencies, with the highest proportion of API SMs being rejected by the European Medicines Agency (EMA). The data also revealed a higher proportion of rejections for API SMs that contain impurities impacting the DS quality and when a lower number of solid isolations exist between the point of introduction of the API SM and the DS. Feedback received from health authorities during development phases prior to marketing application submissions generally aided sponsor companies in their strategic approach to API SM designation and resulted in improved overall acceptance rates of API SMs in marketing applications. The data indicated that subjectivity and variability of the interpretation of guidelines persists and that greater alignment among ICH health authorities is still needed to achieve a single, global API SM designation approach and facilitate the timely delivery and continued global supply of innovative medicines to patients through a unified supply chain.
活性药物成分起始原料（API SM）的指定和论证是药物物质（DS）商业化过程中的一个关键环节。在过去十年中，制药行业和监管机构为明确和统一 API SM 选择和论证要求做出了巨大努力，包括 2011 年引入 ICH Q11 指南和 2017 年 Q11 的 Q&A 文件。2018年，国际药品开发创新与质量联盟（IQ联盟或IQ）成立了原料药SM工作组，以评估ICH Q11 Q&A对原料药SM选择和批准的影响，以及跨监管的一致性。API SM 工作组收集了 19 家 IQ 成员公司自 2014 年以来提交的药物物质上市申请的指标，包括相关的 API SM 选择、理由和相关的 ICH 监管审批经验。共获得了用于生产 38 种新化学实体的 115 种原料药 SM 的数据。文中介绍了ICH Q11 Q&A文件发布前后ICH国家和地区首次上市申请中原料药SM提案的结果。数据显示，各 ICH 监管机构对原料药 SM 建议的接受率存在明显差异，其中欧洲药品管理局 (EMA) 拒绝的原料药 SM 比例最高。数据还显示，如果原料药SM含有影响DS质量的杂质，以及原料药SM的引入点和DS之间存在较低数量的固体分离，则原料药SM被拒绝的比例较高。在提交上市申请之前的开发阶段，卫生部门提供的反馈意见通常有助于申办公司采用战略方法指定原料药SM，从而提高原料药SM在上市申请中的总体接受率。数据表明，对指南的解释仍然存在主观性和多变性，ICH卫生主管部门之间仍需加强协调，以实现单一的全球原料药SM指定方法，并通过统一的供应链促进创新药物的及时交付和持续全球供应。
{"title":"Impact of ICH Q11 Questions and Answers on the Outcome of Active Pharmaceutical Ingredient Starting Material Proposal Acceptance by ICH Regulatory Members","authors":"Steven Tymonko, Brenda J. Burke, Jean-Philippe Crochard, Olivier Dirat, Kenneth J. Fraunhoffer, Cristian Harrison, Timothy Kramer, Heewon Lee, Vlad Liberman, Kanwar P. S. Sidhu, Randi Smith, Neil A. Strotman, Nil Tandogan, Alan Triman, Haitao Zhang","doi":"10.1021/acs.oprd.4c00033","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00033","url":null,"abstract":"The designation and justification of active pharmaceutical ingredient starting materials (API SMs) is a crucial aspect of the drug substance (DS) commercialization process. Over the past decade, significant efforts have been made by both the pharmaceutical industry and regulatory authorities to clarify and harmonize requirements for API SM selection and justification, including the introduction of the ICH Q11 guideline in 2011 and the Q&A document to Q11 in 2017. In 2018, the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) established the API SM Working Group to evaluate the impact of the ICH Q11 Q&A on API SM selection and approval, as well as cross-regulatory alignment. The API SM Working Group collected metrics from 19 IQ member companies on drug substances marketing applications submitted since 2014, including the associated API SM selection, justification, and associated ICH regulatory approval experiences. Data representing a total of 115 API SMs used to manufacture 38 new chemical entities were obtained. The outcomes of API SM proposals in initial marketing applications across ICH countries and regions prior to and following the publication of the ICH Q11 Q&A document are presented. The data showed significant differences in acceptance rates of API SM proposals across ICH regulatory agencies, with the highest proportion of API SMs being rejected by the European Medicines Agency (EMA). The data also revealed a higher proportion of rejections for API SMs that contain impurities impacting the DS quality and when a lower number of solid isolations exist between the point of introduction of the API SM and the DS. Feedback received from health authorities during development phases prior to marketing application submissions generally aided sponsor companies in their strategic approach to API SM designation and resulted in improved overall acceptance rates of API SMs in marketing applications. The data indicated that subjectivity and variability of the interpretation of guidelines persists and that greater alignment among ICH health authorities is still needed to achieve a single, global API SM designation approach and facilitate the timely delivery and continued global supply of innovative medicines to patients through a unified supply chain.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814943","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}
Pub Date : 2024-04-25DOI: 10.1021/acs.oprd.4c00130
Senling Guan, Wenfeng Zhou, Yongtang Yue, Songhe Wang, Bo Chen and Haishen Yang*,
Nicotine is the chief addictive ingredient in cigarettes, cigars, and snuff, and has extensive applications in the agricultural and pharmaceutical industries. The synthesis of nicotine using free enzyme systems has been widely reported in literature; this approach chiefly utilizes the alkaloid myosmine and the enzymes imine reductase (IRED) as well as glucose dehydrogenase (GDH), and generates the intermediate (S)-nornicotine. Free enzymes are not reusable, thereby resulting in higher cost of production. The use of recyclable immobilized enzymes is an efficient approach for lowering the costs and improving the efficiency of production. In the current study, we present an efficient and environment-friendly approach utilizing immobilized enzymes for synthesizing (S)-nornicotine using batch and continuous flow reaction processes. A highly active coimmobilized enzyme system was successfully obtained by coimmobilizing IRED and GDH on the resin LXTE-706. The immobilized enzymes were amenable to repeated usage for at least 40 operation cycles in the batch mode of operation and yielded a product with a high chiral purity of >99.90%, effectively reducing the overall production cost. Furthermore, a space–time yield of 211.47 g/Lh was obtained using a continuous mode of operation, which is 289.7-fold higher than that obtained with batch mode.
{"title":"Efficient Synthesis of (S)-Nornicotine using Co-Immobilized IRED and GDH in Batch and Continuous Flow Reaction Systems","authors":"Senling Guan, Wenfeng Zhou, Yongtang Yue, Songhe Wang, Bo Chen and Haishen Yang*, ","doi":"10.1021/acs.oprd.4c00130","DOIUrl":"10.1021/acs.oprd.4c00130","url":null,"abstract":"<p >Nicotine is the chief addictive ingredient in cigarettes, cigars, and snuff, and has extensive applications in the agricultural and pharmaceutical industries. The synthesis of nicotine using free enzyme systems has been widely reported in literature; this approach chiefly utilizes the alkaloid myosmine and the enzymes imine reductase (IRED) as well as glucose dehydrogenase (GDH), and generates the intermediate (<i>S</i>)-nornicotine. Free enzymes are not reusable, thereby resulting in higher cost of production. The use of recyclable immobilized enzymes is an efficient approach for lowering the costs and improving the efficiency of production. In the current study, we present an efficient and environment-friendly approach utilizing immobilized enzymes for synthesizing (<i>S</i>)-nornicotine using batch and continuous flow reaction processes. A highly active coimmobilized enzyme system was successfully obtained by coimmobilizing IRED and GDH on the resin LXTE-706. The immobilized enzymes were amenable to repeated usage for at least 40 operation cycles in the batch mode of operation and yielded a product with a high chiral purity of >99.90%, effectively reducing the overall production cost. Furthermore, a space–time yield of 211.47 g/Lh was obtained using a continuous mode of operation, which is 289.7-fold higher than that obtained with batch mode.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643225","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}
Pub Date : 2024-04-25DOI: 10.1021/acs.oprd.3c00498
Michelle-Rose Ryan, Denis Lynch, Stuart G. Collins* and Anita R. Maguire*,
Thermal N-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of N-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl N-Boc group in the presence of an alkyl N-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl N-Boc group from 9h followed by benzoylation and deprotection of the remaining alkyl N-Boc group to form amide 13 proved successful.
{"title":"Selective Thermal Deprotection of N-Boc Protected Amines in Continuous Flow","authors":"Michelle-Rose Ryan, Denis Lynch, Stuart G. Collins* and Anita R. Maguire*, ","doi":"10.1021/acs.oprd.3c00498","DOIUrl":"10.1021/acs.oprd.3c00498","url":null,"abstract":"<p >Thermal <i>N</i>-Boc deprotection of a range of amines is readily effected in continuous flow, in the absence of an acid catalyst. While the optimum results were obtained in methanol or trifluoroethanol, deprotection can be effected in a range of solvents of different polarities. Sequential selective deprotection of <i>N</i>-Boc groups has been demonstrated through temperature control, as exemplified by effective removal of an aryl <i>N</i>-Boc group in the presence of an alkyl <i>N</i>-Boc group. As a proof of principle, a telescoped sequence involving selective deprotection of an aryl <i>N</i>-Boc group from <b>9h</b> followed by benzoylation and deprotection of the remaining alkyl <i>N</i>-Boc group to form amide <b>13</b> proved successful.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.3c00498","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140643182","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}
Pub Date : 2024-04-23DOI: 10.1021/acs.oprd.4c00034
Pablo Chourreu, Olivier Guerret, Eric Gayon, Guillaume Lefèvre
We describe in this report a convenient convergent synthesis of the pheromonal blend of Spodoptera frugiperda, relying on a key ligand- and additive-free iron-catalyzed cross-coupling, operating at a low 0.1 mol % catalytic charge. This approach relies on the use of the same electrophilic partner for the preparation of the three components of the blend, which can be prepared altogether in a single step in 94% isolated yield. Overall, the pheromonal blend is obtained with a 61% yield at a 20 g scale, with accurate control of the distribution of its three components.
{"title":"An Easy and Adjustable One-Pot Access to Pheromonal Blends of Fall Armyworm (Spodoptera frugiperda) Relying on a Key Ligand- and Additive-Free Iron-Catalyzed Cross-Coupling","authors":"Pablo Chourreu, Olivier Guerret, Eric Gayon, Guillaume Lefèvre","doi":"10.1021/acs.oprd.4c00034","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00034","url":null,"abstract":"We describe in this report a convenient convergent synthesis of the pheromonal blend of <i>Spodoptera frugiperda</i>, relying on a key ligand- and additive-free iron-catalyzed cross-coupling, operating at a low 0.1 mol % catalytic charge. This approach relies on the use of the same electrophilic partner for the preparation of the three components of the blend, which can be prepared altogether in a single step in 94% isolated yield. Overall, the pheromonal blend is obtained with a 61% yield at a 20 g scale, with accurate control of the distribution of its three components.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640573","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}
Pub Date : 2024-04-19DOI: 10.1021/acs.oprd.4c00053
Oriana Brea, Julia Buck, Nessa Carson, Andrew M. Derrick, Steven J. Fussell, Adam E. S. Gymer, Michael Hawksworth, Adam W. Hopkins, Heather Ingram, Rebecca A. Johnson, Daniel A. Laity, Jinu S. Mathew, Ian B. Moses, James Rellegue, Emily K. Rose, Steven J. R. Twiddle, Adam West
The target compound PF-06878031 is a key structural fragment of a range of oral late-stage glucagon-like peptide-1 receptor agonists (GLP-1-RA) under development in our laboratories for the indications of type-2 diabetes mellitus (T2DM) and weight loss. This article describes the identification of a selective alkylation route and development of a process, capable of delivering multikilo quantities of PF-06878031. Process development afforded improved safety, increased yield, reduced step count, and lowered PMI. The new process has been scaled up at multiple facilities to generate >1.5MT of high purity PF-06878031.
{"title":"Development of the Synthetic Route to PF-06878031 Part 1: Selective Alkylation Route","authors":"Oriana Brea, Julia Buck, Nessa Carson, Andrew M. Derrick, Steven J. Fussell, Adam E. S. Gymer, Michael Hawksworth, Adam W. Hopkins, Heather Ingram, Rebecca A. Johnson, Daniel A. Laity, Jinu S. Mathew, Ian B. Moses, James Rellegue, Emily K. Rose, Steven J. R. Twiddle, Adam West","doi":"10.1021/acs.oprd.4c00053","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00053","url":null,"abstract":"The target compound <b>PF-06878031</b> is a key structural fragment of a range of oral late-stage glucagon-like peptide-1 receptor agonists (GLP-1-RA) under development in our laboratories for the indications of type-2 diabetes mellitus (T2DM) and weight loss. This article describes the identification of a selective alkylation route and development of a process, capable of delivering multikilo quantities of <b>PF-06878031</b>. Process development afforded improved safety, increased yield, reduced step count, and lowered PMI. The new process has been scaled up at multiple facilities to generate >1.5MT of high purity <b>PF-06878031</b>.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640478","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}
Pub Date : 2024-04-16DOI: 10.1021/acs.oprd.4c00049
Douglas J. Critcher, Christopher Paul Ashcroft, Alan J. Pettman, Matthew Badland, Robert Szpera, William Waddington
Our route scouting efforts toward finding the most efficient construction of PF-07265807 (ARRY-067) in readiness for process development prior to commercial manufacture are described. ARRY-067 contains the azaindazole (1H-pyrazolo [3,4-b]pyridine) building block that is common to many pharmaceuticals and bioactive agents. Herein, our novel approach to this challenging structural motif is described where an oxazoline ring-opening cyclization cascade triggered by the addition of hydrazine reveals the target 3-alaninol-substituted azaindazole in one step. An improved synthesis of the uracil carboxylic acid coupling partner is also described. Overall, the new route is six steps shorter than the enabling route, minimizes protecting group manipulations, and avoids the use of transition metal catalysis.
{"title":"Commercial Route Development Toward PF-07265807, an AXL-MER Inhibitor Oncology Candidate","authors":"Douglas J. Critcher, Christopher Paul Ashcroft, Alan J. Pettman, Matthew Badland, Robert Szpera, William Waddington","doi":"10.1021/acs.oprd.4c00049","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00049","url":null,"abstract":"Our route scouting efforts toward finding the most efficient construction of PF-07265807 (ARRY-067) in readiness for process development prior to commercial manufacture are described. ARRY-067 contains the azaindazole (1<i>H</i>-pyrazolo [3,4-<i>b</i>]pyridine) building block that is common to many pharmaceuticals and bioactive agents. Herein, our novel approach to this challenging structural motif is described where an oxazoline ring-opening cyclization cascade triggered by the addition of hydrazine reveals the target 3-alaninol-substituted azaindazole in one step. An improved synthesis of the uracil carboxylic acid coupling partner is also described. Overall, the new route is six steps shorter than the enabling route, minimizes protecting group manipulations, and avoids the use of transition metal catalysis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557139","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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