Organic Process Research & Development最新文献

{"title":"An Alternate, Efficient Synthetic Process for a Hemolytic Anemia Drug: Mitapivat Sulfate","authors":"Ramesh Goura, Surendra Babu Manabolu Surya, Naresh Kumar Katari, Ramprasad Achampeta Kodanda, Pradeep Rebelly, Nagaraju Chakilam","doi":"10.1021/acs.oprd.4c00319","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00319","url":null,"abstract":"A new commercial manufacturing process for producing mitapivat sulfate, crucial for treating hemolytic anemia, is described. Starting from 4-nitrobenzoic acid (<b>14</b>) and N-Boc piperazine (<b>6</b>), the process involves sequential reactions to obtain <i>tert</i>-butyl 4-[4-(quinoline-8-sulfonamido)benzoyl]piperazine-1-carboxylate (<b>7</b>). This compound is then deprotected to yield <i>N</i>-[4-(piperazine-1-carbonyl)phenyl]naphthalene-1-sulfonamide (<b>8</b>), which undergoes reductive amination to produce mitapivat-free base (<b>9</b>). Finally, mitapivat sulfate is obtained with high quality and an overall yield of 81%. The synthesis prevents impurity formation and employs cost-effective raw materials, adhering to environmental sustainability and ICH product quality standards.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142439602","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}

{"title":"Development of a Scalable Process for the Synthesis of Cyclopropyl-Methyl-Proline with Complex Stereochemistry: A Key Building Block of Factor D Inhibitors","authors":"Akihiro Hashimoto, Antonio C. Ferretti, Suresh K. Tipparaju, Justin L. Burt, Ashish Soman, Avinash Phadke, Prabu Chandran, Anand M. Lahoti, Devaraju Bilidegalu N, Anbazhagan Mani, Swarup Datta, Sankappa Rai, Sameerana Huddar, Prasanna Kumara, Tirumani Raju, Guruprasad AN, Suman Ganapathy, Tanish Chukka","doi":"10.1021/acs.oprd.4c00223","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00223","url":null,"abstract":"The development of a scalable process for a complex intermediate featuring a chiral, quaternary cyclopropane moiety presented significant challenges. We report two generations of synthetic strategies appropriate for the respective stages of development. The initial approach utilized a stereoselective Simmons–Smith cyclopropanation of (<i>R</i>)-pyroglutamic acid ester, which predominantly yielded the undesired stereoisomer. To circumvent this issue, we implemented a strategy that combined isomerization, recycling of the undesired isomer, and selective crystallization to improve the yield of the desired product. An important insight was that the Simmons–Smith cyclopropanation exhibited opposite stereoselectivity with a benzoyl ester of a prolinol substrate, resulting in the desired stereoisomer as the major product. This understanding enabled the development of a second-generation process that facilitated the large-scale production of the targeted intermediate, thus supporting the advancement of clinical trials.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142436515","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}

{"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 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.","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}

{"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}

{"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&amp;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}

{"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}

{"title":"Derisking Crystallization Process Development and Scale-Up Using a Complementary, “Quick and Dirty” Digital Design","authors":"Ákos Borsos,&nbsp;Csaba Hámori,&nbsp;Emőke Szilágyi,&nbsp;András Spaits,&nbsp;Ferenc Farkas,&nbsp;László Százdi,&nbsp;Katalin Kátainé Fadgyas,&nbsp;Balázs Volk and Botond Szilágyi*,&nbsp;","doi":"10.1021/acs.oprd.4c0019910.1021/acs.oprd.4c00199","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00199https://doi.org/10.1021/acs.oprd.4c00199","url":null,"abstract":"<p >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.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00199","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450350","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}

{"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}

{"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}

{"title":"Catalytic Activity of Triphenylphosphine for Electrophilic Aromatic Bromination Using N-Bromosuccinimide and Process Safety Evaluation","authors":"Masahiro Hosoya*,&nbsp;Kenichi Ishibashi,&nbsp;Takafumi Ohara,&nbsp;Atsunori Mori and Kentaro Okano*,&nbsp;","doi":"10.1021/acs.oprd.4c0030710.1021/acs.oprd.4c00307","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00307https://doi.org/10.1021/acs.oprd.4c00307","url":null,"abstract":"<p >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.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142450767","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}