Pub Date : 2024-10-14DOI: 10.1021/acs.oprd.4c00336
Vasantha Krishna Kadambar, Bhoopendra Singh Kushwah, Riddhi Gupta, Denna Sunny, Himanshu Vachhani, Joel Young, Lakshmikant Bajpai
Mismatch in the potency from quantitative 1H NMR (∼96%) and the calculated potency (∼94%) of an aldehyde intermediate led to the investigation of an unknown impurity peak observed in the chromatography. The HR-MS/MS analysis of the unknown impurity suggested it to be the cyanohydrin derivative of the corresponding aldehyde intermediate with the addition of ∼27 amu. Further investigation was performed using analogous 3-methyl iso-nicotinaldehyde as a model compound. A postcolumn hydrogen to deuterium exchange (H/D exchange) experiment further supported the proposed impurity structure as cyanohydrin. The source of HCN for the possible generation of this impurity was traced to certain brands of acetonitrile used duirng the analysis, where the presence of HCN as a contaminant was confirmed and quantified using ion chromatography. The aforementioned model compound was used to investigate the effect of other parameters like diluent composition, sample temperature and storage time, pH of the diluent, and duration of sonication, which impact the formation of such artifact impurity. Based on the results of all the experiments, mitigation strategies were proposed to avoid/control the formation of these impurities during the analytical processing such as use of methanol or HCN-free acetonitrile as a sample diluent, reduced composition of acetonitrile in the diluent, and use of freshly prepared solutions for injections to avoid longer storage time specially when certain sensitive substrates like aldehydes and ketones are analyzed. To evaluate if the formation of this impurity is limited to the compound of interest or if it is a common artifact peak for other similar compounds, various substrates involving aldehyde and ketone functional groups were analyzed under similar analytical conditions. The results indicated that aldehydes were more reactive than ketones, specifically the aldehydes containing a heterocyclic ring such as pyridine were prone to generate the cyanohydrin impurity.
{"title":"Analytical Artifact Due to Residual HCN in Acetonitrile: Identification and Control Strategies","authors":"Vasantha Krishna Kadambar, Bhoopendra Singh Kushwah, Riddhi Gupta, Denna Sunny, Himanshu Vachhani, Joel Young, Lakshmikant Bajpai","doi":"10.1021/acs.oprd.4c00336","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00336","url":null,"abstract":"Mismatch in the potency from quantitative <sup>1</sup>H NMR (∼96%) and the calculated potency (∼94%) of an aldehyde intermediate led to the investigation of an unknown impurity peak observed in the chromatography. The HR-MS/MS analysis of the unknown impurity suggested it to be the cyanohydrin derivative of the corresponding aldehyde intermediate with the addition of ∼27 amu. Further investigation was performed using analogous 3-methyl iso-nicotinaldehyde as a model compound. A postcolumn hydrogen to deuterium exchange (H/D exchange) experiment further supported the proposed impurity structure as cyanohydrin. The source of HCN for the possible generation of this impurity was traced to certain brands of acetonitrile used duirng the analysis, where the presence of HCN as a contaminant was confirmed and quantified using ion chromatography. The aforementioned model compound was used to investigate the effect of other parameters like diluent composition, sample temperature and storage time, pH of the diluent, and duration of sonication, which impact the formation of such artifact impurity. Based on the results of all the experiments, mitigation strategies were proposed to avoid/control the formation of these impurities during the analytical processing such as use of methanol or HCN-free acetonitrile as a sample diluent, reduced composition of acetonitrile in the diluent, and use of freshly prepared solutions for injections to avoid longer storage time specially when certain sensitive substrates like aldehydes and ketones are analyzed. To evaluate if the formation of this impurity is limited to the compound of interest or if it is a common artifact peak for other similar compounds, various substrates involving aldehyde and ketone functional groups were analyzed under similar analytical conditions. The results indicated that aldehydes were more reactive than ketones, specifically the aldehydes containing a heterocyclic ring such as pyridine were prone to generate the cyanohydrin impurity.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431242","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 : 2024-10-14DOI: 10.1021/acs.oprd.4c00274
Wouter Van Hecke, Marta Martinez-Garcia, Yamini Satyawali, Christof Porto-Carrero, Heleen De Wever
Production of esters using chemical catalysts often entails off-odors, colors, or environmentally harmful reagents. Lipases play a pivotal role in enhancing product purity and sustainability. Despite their acknowledged substrate promiscuity, quantitative characterization of biocatalytic ester production remains scarce. Moreover, their behavior in solvent-free conditions, particularly in the presence of potentially inhibitory organic acids, is unknown. A systematic quantitative approach was conducted, which culminated in the development of a substrate preference heat map. A subsequent in-depth examination led to the identification and validation of a novel rate equation. While mechanistic in nature, an empirical adjustment is incorporated to account for inhibition effects. Specifically, this adjustment involves raising the acid concentration within the inhibition term to the power of n. This advancement is poised to facilitate scale-up endeavors to produce biocatalytic esters derived from short-chain fatty acids.
使用化学催化剂生产酯类往往会产生异味、色素或对环境有害的试剂。脂肪酶在提高产品纯度和可持续性方面发挥着关键作用。尽管脂酶具有公认的底物混杂性，但生物催化酯类生产的定量表征仍然很少。此外，它们在无溶剂条件下的行为，特别是在存在潜在抑制性有机酸的情况下的行为，也是未知的。我们采用了一种系统的定量方法，最终绘制出底物偏好热图。随后的深入研究确定并验证了一个新的速率方程。虽然该方程是机械式的，但其中加入了经验调整，以考虑抑制效应。具体来说，这种调整是将抑制项中的酸浓度提高到 n 的幂。这一进展将有助于扩大生产短链脂肪酸生物催化酯的规模。
{"title":"Unraveling Lipase’s Promiscuous Behavior: Insights into Organic Acid Inhibition during Solventless Ester Production","authors":"Wouter Van Hecke, Marta Martinez-Garcia, Yamini Satyawali, Christof Porto-Carrero, Heleen De Wever","doi":"10.1021/acs.oprd.4c00274","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00274","url":null,"abstract":"Production of esters using chemical catalysts often entails off-odors, colors, or environmentally harmful reagents. Lipases play a pivotal role in enhancing product purity and sustainability. Despite their acknowledged substrate promiscuity, quantitative characterization of biocatalytic ester production remains scarce. Moreover, their behavior in solvent-free conditions, particularly in the presence of potentially inhibitory organic acids, is unknown. A systematic quantitative approach was conducted, which culminated in the development of a substrate preference heat map. A subsequent in-depth examination led to the identification and validation of a novel rate equation. While mechanistic in nature, an empirical adjustment is incorporated to account for inhibition effects. Specifically, this adjustment involves raising the acid concentration within the inhibition term to the power of n. This advancement is poised to facilitate scale-up endeavors to produce biocatalytic esters derived from short-chain fatty acids.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431750","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 : 2024-10-14DOI: 10.1021/acs.oprd.4c00351
Anamaria Hanganu, Maxim Maximov, Oana-Cristina Maximov, Codruta C. Popescu, Nicoleta Sandu, Mihaela Florea, Anca G. Mirea, Cristian Gârbea, Mihaela Matache, Daniel P. Funeriu
There has been increased interest in the synthesis of benfotiamine during the past few years, most likely as a direct consequence of growing market demand. It has much higher bioavailability than thiamine (vitamin B1) and therefore is more suitable for therapeutic purposes, especially in oral form. We report herein our research in an academic-private R&D project in which we investigate all aspects of the process on small and large scales. The procedure involves two labor-intensive steps, starting from thiami3ne chloride hydrochloride with the key intermediate thiamine monophosphate phosphate (TMP─the phosphate ester of thiamine monophosphate). We obtained the crystalline form of benfotiamine directly from the synthesis in the crystalline form required on the market, as proven by XRD powder spectroscopy, IR, and RAMAN.
{"title":"Insights into Large-Scale Synthesis of Benfotiamine","authors":"Anamaria Hanganu, Maxim Maximov, Oana-Cristina Maximov, Codruta C. Popescu, Nicoleta Sandu, Mihaela Florea, Anca G. Mirea, Cristian Gârbea, Mihaela Matache, Daniel P. Funeriu","doi":"10.1021/acs.oprd.4c00351","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00351","url":null,"abstract":"There has been increased interest in the synthesis of benfotiamine during the past few years, most likely as a direct consequence of growing market demand. It has much higher bioavailability than thiamine (vitamin B1) and therefore is more suitable for therapeutic purposes, especially in oral form. We report herein our research in an academic-private R&D project in which we investigate all aspects of the process on small and large scales. The procedure involves two labor-intensive steps, starting from thiami3ne chloride hydrochloride with the key intermediate thiamine monophosphate phosphate (TMP─the phosphate ester of thiamine monophosphate). We obtained the crystalline form of benfotiamine directly from the synthesis in the crystalline form required on the market, as proven by XRD powder spectroscopy, IR, and RAMAN.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431243","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 : 2024-10-11DOI: 10.1021/acs.oprd.4c00194
Ankush Chakraborty, Bardia Soltanzadeh, Nicholas R. Wills, Arvind Jaganathan, Babak Borhan
This report presents a rapid, ecofriendly technique for the formation of commonly used N-bromo and N-iodinating reagents by reacting readily available N-chloro derivatives with inorganic bromide and iodide salts. All reagents were easily handled, commercially available, and bench stable. This strategy illustrates the expeditious formation of these halogenating reagents in multigram scale in high-yields and purity with an operationally straightforward recrystallization. The mechanistic details suggest an in situ generation of an interhalogen species.
{"title":"Synthesis of N-Bromo and N-Iodo Imides: A Rapid Redox-Neutral and Bench Stable Process","authors":"Ankush Chakraborty, Bardia Soltanzadeh, Nicholas R. Wills, Arvind Jaganathan, Babak Borhan","doi":"10.1021/acs.oprd.4c00194","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00194","url":null,"abstract":"This report presents a rapid, ecofriendly technique for the formation of commonly used <i>N</i>-bromo and <i>N</i>-iodinating reagents by reacting readily available <i>N</i>-chloro derivatives with inorganic bromide and iodide salts. All reagents were easily handled, commercially available, and bench stable. This strategy illustrates the expeditious formation of these halogenating reagents in multigram scale in high-yields and purity with an operationally straightforward recrystallization. The mechanistic details suggest an in situ generation of an interhalogen species.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405635","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 : 2024-10-03DOI: 10.1021/acs.oprd.4c00199
Ákos Borsos, Csaba Hámori, Emőke Szilágyi, András Spaits, Ferenc Farkas, László Százdi, Katalin Kátainé Fadgyas, Balázs Volk, Botond Szilágyi
Despite the spread of digital (model and AI-based) techniques, the industry-standard pharmaceutical crystallization design and scale-up is still based on experiments’ design (DoE). Many orthogonally designed and usually relatively lightly monitored experiments are performed as a part of it. The final design/scale-up is inherently truncated by experimental and statistical modeling errors and assumptions, compromising the reliability of the calculated design space (DS). This study proposes to apply process modeling in a complementary way: utilize the experiments from the DoE to calibrate an application-driven model, quantify its accuracy, and use it─in parallel with the statistical interpretation of the DoE─to design the process. Both the DoE and model-based DS determination involve workflow-specific assumptions, simplifications, and errors, but the overlap between the independent results may be considered a derisked DS. We demonstrate this workflow on the design of a fed-batch salting-out crystallization for a commercial active pharmaceutical ingredient (API). The model was identified based on product particle size distribution data of a DoE set from a small-scale reactor (0.25 L) and a manufacturing batch (ca. 4000 L). Although reactors with intermediate volumes are also generally applied as a part of scale-up, included in the presented case study, those were not included in the model development and verification. The kinetic equations were taken from our previously developed cooling crystallization model of the same API. After calibration and accuracy evaluation, the critical process parameters were determined using interpretable machine learning via Shapley diagrams, and the DS was mapped and visualized using Monte Carlo sampling-based simulations. The DS was validated for 0.25 L experiments. The model-based DS was somewhat narrower than the DoE-based DS on a small scale. The DS determined for plant-scale crystallization can guide the manufacturing-scale process design and operation. The extrapolation capabilities of the model were stressed by external validation by defining and validating experimentally the DS for a 1 L crystallization. These results indicate that models developed in this application-centric way can enhance the robustness of the processes, and the modeling branch does not add any risk. In the worst-case scenario, if the modeling fails, one still has the results from the traditional design approach.
尽管数字化（基于模型和人工智能的）技术已经普及，但行业标准的制药结晶设计和放大仍以实验设计（DoE）为基础。作为其中的一部分，要进行许多正交设计且通常监测相对较少的实验。实验和统计建模误差和假设必然会截断最终的设计/放大，从而影响计算出的设计空间 (DS) 的可靠性。本研究建议以一种互补的方式应用工艺建模：利用 DoE 的实验来校准应用驱动模型，量化其准确性，并将其与 DoE 的统计解释并行用于工艺设计。DoE 和基于模型的 DS 确定都涉及特定工作流程的假设、简化和误差，但独立结果之间的重叠可被视为去风险 DS。我们在设计一种商业活性药物成分 (API) 的进料批次盐析结晶时演示了这一工作流程。模型是根据一个小规模反应器（0.25 升）和一个生产批次（约 4000 升）的 DoE 集的产品粒度分布数据确定的。虽然中等容积的反应器通常也作为放大的一部分应用，并包括在所提交的案例研究中，但这些反应器并未包括在模型开发和验证中。动力学方程取自我们之前开发的相同原料药冷却结晶模型。经过校准和精度评估后，通过 Shapley 图使用可解释的机器学习确定了关键工艺参数，并使用基于蒙特卡罗抽样的模拟绘制了 DS 图并将其可视化。在 0.25 升的实验中对 DS 进行了验证。在小尺度上，基于模型的 DS 比基于 DoE 的 DS 更窄。为工厂规模结晶确定的 DS 可以指导生产规模的工艺设计和操作。通过定义和实验验证 1 L 结晶的 DS，外部验证强调了模型的外推能力。这些结果表明，以这种以应用为中心的方式开发的模型可以增强工艺的稳健性，而且建模分支不会增加任何风险。在最坏的情况下，如果建模失败，人们仍然可以获得传统设计方法的结果。
{"title":"Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design","authors":"Ákos Borsos, Csaba Hámori, Emőke Szilágyi, András Spaits, Ferenc Farkas, László Százdi, Katalin Kátainé Fadgyas, Balázs Volk, Botond Szilágyi","doi":"10.1021/acs.oprd.4c00199","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00199","url":null,"abstract":"Despite the spread of digital (model and AI-based) techniques, the industry-standard pharmaceutical crystallization design and scale-up is still based on experiments’ design (DoE). Many orthogonally designed and usually relatively lightly monitored experiments are performed as a part of it. The final design/scale-up is inherently truncated by experimental and statistical modeling errors and assumptions, compromising the reliability of the calculated design space (DS). This study proposes to apply process modeling in a complementary way: utilize the experiments from the DoE to calibrate an application-driven model, quantify its accuracy, and use it─in parallel with the statistical interpretation of the DoE─to design the process. Both the DoE and model-based DS determination involve workflow-specific assumptions, simplifications, and errors, but the overlap between the independent results may be considered a derisked DS. We demonstrate this workflow on the design of a fed-batch salting-out crystallization for a commercial active pharmaceutical ingredient (API). The model was identified based on product particle size distribution data of a DoE set from a small-scale reactor (0.25 L) and a manufacturing batch (ca. 4000 L). Although reactors with intermediate volumes are also generally applied as a part of scale-up, included in the presented case study, those were not included in the model development and verification. The kinetic equations were taken from our previously developed cooling crystallization model of the same API. After calibration and accuracy evaluation, the critical process parameters were determined using interpretable machine learning via Shapley diagrams, and the DS was mapped and visualized using Monte Carlo sampling-based simulations. The DS was validated for 0.25 L experiments. The model-based DS was somewhat narrower than the DoE-based DS on a small scale. The DS determined for plant-scale crystallization can guide the manufacturing-scale process design and operation. The extrapolation capabilities of the model were stressed by external validation by defining and validating experimentally the DS for a 1 L crystallization. These results indicate that models developed in this application-centric way can enhance the robustness of the processes, and the modeling branch does not add any risk. In the worst-case scenario, if the modeling fails, one still has the results from the traditional design approach.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142369576","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}
Electrophilic aromatic bromination using N-bromosuccinimide (NBS) is the most widely used reaction to synthesize highly functionalized aromatic compounds. We encountered catalytic activity of triphenylphosphine for aromatic bromination. This catalytic activity was successfully applied to a wide range of organic solvents and enabled the addition of NBS below the flash point of various organic solvents. Toward the industrial implementation of this bromination, we evaluated the process safety including the reaction heat and thermal decomposition. The analysis revealed that the characteristic behavior of the reaction heat made it difficult to suppress the increase of the internal temperature. However, precise evaluation of the reaction heat suggested the sequential addition of NBS. This procedure suppressed the increase of the internal temperature below 5 °C, which made the industrial implementation of this bromination feasible with process safety.
{"title":"Catalytic Activity of Triphenylphosphine for Electrophilic Aromatic Bromination Using N-Bromosuccinimide and Process Safety Evaluation","authors":"Masahiro Hosoya, Kenichi Ishibashi, Takafumi Ohara, Atsunori Mori, Kentaro Okano","doi":"10.1021/acs.oprd.4c00307","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00307","url":null,"abstract":"Electrophilic aromatic bromination using <i>N</i>-bromosuccinimide (NBS) is the most widely used reaction to synthesize highly functionalized aromatic compounds. We encountered catalytic activity of triphenylphosphine for aromatic bromination. This catalytic activity was successfully applied to a wide range of organic solvents and enabled the addition of NBS below the flash point of various organic solvents. Toward the industrial implementation of this bromination, we evaluated the process safety including the reaction heat and thermal decomposition. The analysis revealed that the characteristic behavior of the reaction heat made it difficult to suppress the increase of the internal temperature. However, precise evaluation of the reaction heat suggested the sequential addition of NBS. This procedure suppressed the increase of the internal temperature below 5 °C, which made the industrial implementation of this bromination feasible with process safety.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142363288","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 : 2024-10-01DOI: 10.1021/acs.oprd.4c00292
Lars Gössl, Kai Dahms, Gabriele Menges-Flanagan, Michael Maskos
Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc reagen
{"title":"Organozinc Reagents: Highly Efficient Scalable Continuous Conversion in Various Concentrations and Reaction Types","authors":"Lars Gössl, Kai Dahms, Gabriele Menges-Flanagan, Michael Maskos","doi":"10.1021/acs.oprd.4c00292","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00292","url":null,"abstract":"Organometallic reagents play a crucial role in today’s synthetic chemistry. They are used in the production of active pharmaceutical ingredients (APIs), fragrances, and agrochemicals, among other things, as they are instrumental and invaluable to form new carbon–carbon bonds. In addition to the widely used organolithium and organomagnesium compounds, better known as Grignard reagents, organozinc compounds are predestined coupling partners in C–C bond formation. Even though organozinc compounds are among the oldest organometallic compounds, they have long been superseded by the more reactive Grignard reagents (RMgX) and lithium organyls (RLi). The low reactivity of organozinc compounds in combination with a high sensitivity to oxygen and moisture lead to difficult handling and problematic storage. Their usefulness for C–C bond formation was therefore underestimated for a long time but has experienced a renaissance in recent decades. In a previous publication, the scalable continuous synthesis of organozinc compounds in different concentrations and solvents was demonstrated. The organozinc compounds were produced in both laboratory and pilot scale with good to very good yields and the formation of highly concentrated organozinc compounds was also confirmed. To build on this work, the continuous conversion of organozinc compounds is described below. Two different reaction types were investigated: the noncatalyzed Saytzeff reaction and the palladium-catalyzed Negishi cross-coupling reaction. The former was carried out in both a two-step and a one-pot approach. The reactive allylzinc bromide was chosen as the organometallic reagent, which was reacted with various aldehydes and ketones to yield secondary or tertiary homoallyl alcohols. In the Saytzeff reaction, residence times of 2.0 min were sufficient to achieve complete conversion of the carbonyl compound and isolated yields of 66–98%. The conversion of the carbonyl compound was monitored using an online process IR spectrometer with flow cell. In the case of the Negishi coupling, a fixed-bed reactor filled with Pd catalyst was used. The syntheses investigated were focused on the reaction of benzylzinc bromide with various functionalized organic halides. The Negishi coupling provided complete to near complete conversion of the electrophilic substrate with isolated yields of 72–92% at residence times of 23–32 s. Both the Saytzeff and Negishi reactions were extended to include the conversion of highly concentrated 2.0 M organozinc compounds. The former delivered yields of 83% and 92%, the latter 72% and 79%. The Saytzeff conversion was additionally transferred to pilot scale to demonstrate the ease of scalability. The synthesis of two selected compounds was successfully transferred to pilot scale, where a liquid throughput of 13 L/h was achieved. The main objective of this work was to establish various catalyzed and noncatalyzed conversions of organozinc reagents, particularly at high organozinc reagen","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142360500","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 : 2024-09-30DOI: 10.1021/acs.oprd.4c00139
Caroline A. Blakemore, John M. Humphrey, Eddie Yang, Jeffrey T. Kohrt, Peter Daniel Morse, Roger M. Howard, Hatice G. Yayla, Thomas Knauber, Longfei Xie, Teresa Makowski, Jeffrey W. Raggon, Rebecca B. Watson, Christopher W. am Ende, Tim Ryder, Ormacinda White, Martin R. M. Koos, Rajesh Kumar, Feng Shi, Jie Li, Huan Wang, Like Chen, Julai Wang
Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of >400 g of a single isomer, (3S,5S)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (>98% de and >96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.
{"title":"Synthesis of Enantiopure Fluoropiperidines via Biocatalytic Desymmetrization and Flow Photochemical Decarboxylative Fluorination","authors":"Caroline A. Blakemore, John M. Humphrey, Eddie Yang, Jeffrey T. Kohrt, Peter Daniel Morse, Roger M. Howard, Hatice G. Yayla, Thomas Knauber, Longfei Xie, Teresa Makowski, Jeffrey W. Raggon, Rebecca B. Watson, Christopher W. am Ende, Tim Ryder, Ormacinda White, Martin R. M. Koos, Rajesh Kumar, Feng Shi, Jie Li, Huan Wang, Like Chen, Julai Wang","doi":"10.1021/acs.oprd.4c00139","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00139","url":null,"abstract":"Low-molecular weight chiral amines are valuable components in medicinal chemistry as they serve as core templates, linking units, and substituent appendages. The piperidine scaffold is particularly useful among privileged small amines, with substituted variants having a great number of potential regio- and diastereoisomers, which allow for high stereochemical definition to enable a variety of productive protein interactions. Herein, we describe the successful enablement, scale-up, and delivery of >400 g of a single isomer, (3<i>S</i>,5<i>S</i>)-1-((benzyloxy)carbonyl)-5-fluoropiperidine-3-carboxylic acid (>98% de and >96% ee), via 450 g-scale biocatalytic desymmetrization and 335 g-scale flow photochemical decarboxylative fluorination.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330045","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 : 2024-09-25DOI: 10.1021/acs.oprd.4c00191
Michael Thoenen, Nicholas F. Scherschel, Davin G. Piercey
Diethyl furoxan dicarboxylate (DFD) is a starting material for fields as diverse as drug discovery, energetics, and any application where a furoxan or furazan may be desired. As with many disubstituted furoxans, they are synthesized via the dimerization of the appropriate nitrile oxide. Past procedures to form DFD involve low-yield destructive nitrations, multiple steps, halogenated solvents, or heavy or precious metals. Although these methods are functional enough for lab-scale preparations of DFD, they do not hold up well for economical scale-up. Our reported procedure improves the synthesis of DFD such that it is available from economical and commercially available starting materials in a single-step, one-pot, high-yield (98.5%) synthesis of material with a trivial workup in high purity (98.2% by 1H quantitative NMR against a 2,4,6-trimethoxy-1,3,5-triazene standard). This improved procedure requires no organic solvents or heavy metals and is the most scalable preparation for this material to date.
{"title":"Economic, One-Pot Synthesis of Diethyl Furoxan Dicarboxylate","authors":"Michael Thoenen, Nicholas F. Scherschel, Davin G. Piercey","doi":"10.1021/acs.oprd.4c00191","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00191","url":null,"abstract":"Diethyl furoxan dicarboxylate (DFD) is a starting material for fields as diverse as drug discovery, energetics, and any application where a furoxan or furazan may be desired. As with many disubstituted furoxans, they are synthesized via the dimerization of the appropriate nitrile oxide. Past procedures to form DFD involve low-yield destructive nitrations, multiple steps, halogenated solvents, or heavy or precious metals. Although these methods are functional enough for lab-scale preparations of DFD, they do not hold up well for economical scale-up. Our reported procedure improves the synthesis of DFD such that it is available from economical and commercially available starting materials in a single-step, one-pot, high-yield (98.5%) synthesis of material with a trivial workup in high purity (98.2% by <sup>1</sup>H quantitative NMR against a 2,4,6-trimethoxy-1,3,5-triazene standard). This improved procedure requires no organic solvents or heavy metals and is the most scalable preparation for this material to date.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317778","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 : 2024-09-24DOI: 10.1021/acs.oprd.4c00337
Tobias Prenzel, Nils Schwarz, Jasmin Hammes, Franziska Krähe, Sarah Pschierer, Johannes Winter, María de Jesús Gálvez-Vázquez, Dieter Schollmeyer, Siegfried R. Waldvogel
1H-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.
{"title":"Highly Selective Electrosynthesis of 1H-1-Hydroxyquinol-4-ones–Synthetic Access to Versatile Natural Antibiotics","authors":"Tobias Prenzel, Nils Schwarz, Jasmin Hammes, Franziska Krähe, Sarah Pschierer, Johannes Winter, María de Jesús Gálvez-Vázquez, Dieter Schollmeyer, Siegfried R. Waldvogel","doi":"10.1021/acs.oprd.4c00337","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00337","url":null,"abstract":"1<i>H</i>-1-Hydroxyquinolin-4-ones represent a broad class of biologically active heterocycles having an exocyclic N,O motif. Electrosynthesis offers direct, highly selective, and sustainable access to 1-hydroxyquinol-4-ones by nitro reduction. A versatile synthetic route starting from easily accessible 2-nitrobenzoic acids was established. The broad applicability of this protocol was demonstrated on 26 examples with up to 93% yield, highlighted by the naturally occurring antibiotics Aurachin C and HQNO. The practicability and technical relevance were underlined by multigram scale electrolysis.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317780","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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