Organic Process Research & Development最新文献

{"title":"Process Development for the First GMP Synthesis of SGD-9501-TFA, Part 2: Synthesis of the Payload, Linker, and Drug Linker","authors":"Katherine Payne, Jeremy C. Tran, Brooke Gill, William Guy, Caitlyn McNichol, Kareem Bdeir, Malcolm Reider, Andrea Stair, Lorenzo Pontini, Gabriele Cerai, Jacopo Roletto, Aaron M. Whittaker","doi":"10.1021/acs.oprd.4c00318","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00318","url":null,"abstract":"The discovery of novel auristatin-derived antibody drug conjugates (ADCs) with attenuated bystander activity is an area of intense research. Recently, drug-linker SGD-9501-TFA emerged as a promising clinical candidate possessing a favorable off-target toxicity profile. To support the clinical development of ADCs utilizing this drug linker, we set out to develop a first-in-human amenable Good Manufacturing Practice manufacturing route. In this report, we describe the discovery and development of three of seven synthetic steps in convergent solution-phase synthesis. The activation of the linker is achieved with SOCl₂ in NMP (step 6), and solutions to the challenges associated with isolation and stability are described. Next, novel HTE platforms used to explore peptide coupling and crystallization for the synthesis of the payload, auristatin S, are unveiled (step 5). Finally, the synthesis of the quaternary ammonium drug linker, SGD-9501-TFA, with a NaI-mediated benzylic amination, is described (step 7). We also discuss solutions to a eutectic gelation risk to direct precipitation of the crude drug linker and a trifluoroacetate ester impurity forming during lyophilization.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231593","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":"Benchtop NMR-Based In-Line Analysis of Diastereoselective Enzymatic α-Amino Acid Synthesis: Quantification and Validation","authors":"Luca F. Schmidt, Logia Jolly, Leon Hennecke, Fernando Lopez Haro, Harald Gröger, Andreas Liese","doi":"10.1021/acs.oprd.4c00076","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00076","url":null,"abstract":"This study investigates the application of a commercial low-field benchtop NMR for real-time monitoring of enzymatically catalyzed reactions, focusing on the diastereoselectivity of the threonine aldolase-catalyzed stereoselective aldol reaction between glycine and benzaldehyde. Despite the signal overlap inherent in the weak electromagnetic field of the benchtop NMR system, a complemental hard modeling (CHM) approach effectively differentiates between diastereomers, enabling the determination of enzymatic diastereoselectivity and the transition from kinetic to thermodynamic control. In particular, the achievement of thermodynamic equilibrium in the enzymatic aldol reaction is observed for the first time using in-line methods, occurring at 30% benzaldehyde conversion after 2 h. In-line NMR analysis reveals a diastereomeric excess of 37:63 (<i>erythro</i>/<i>threo</i>), which closely aligns with off-line measurements via GC and HPLC (36:64). This determination of diastereomers using CHM enhances the efficiency of in-line monitoring in enzymatic reactions, promising significant advancements in pharmaceutical process development. Overall, the study underscores the utility of benchtop NMR systems for in-line analysis of enzymatic reactions, offering insights into reaction mechanisms, selectivity, and equilibrium dynamics, thereby facilitating more efficient process optimization in the area of fine chemicals.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231589","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":"Optimized Enzyme Production for the Escherichia coli Whole-Cell Biocatalytic Synthesis of Codeine from Thebaine","authors":"Ali Jahanian,&nbsp;Andres Velasquez Agudelo,&nbsp;Carlos Horacio Luna-Flores,&nbsp;Xu Li,&nbsp;Fiona Fry,&nbsp;George Mutch,&nbsp;Geoffrey W. Stevens,&nbsp;Sally L. Gras and Robert E. Speight*,&nbsp;","doi":"10.1021/acs.oprd.4c0019510.1021/acs.oprd.4c00195","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00195https://doi.org/10.1021/acs.oprd.4c00195","url":null,"abstract":"<p >Codeine, the most widely used medicinal opiate in the world, can be produced from thebaine by using an environmentally friendly biocatalytic process using purified enzymes or microbial cells. However, this biotransformation is either inefficient or not systematically characterized for industrial use, as microbial fermentation and enzyme expression have not been optimized, and the production of the undesirable side product neopine reduces yields. In this study, the expression of the required enzymes in a reengineered<i>Escherichia coli</i> system was optimized using a two-step design of experiments approach. Higher yields of biomass and enzyme expression were achieved in a defined minimal medium using lactose for induction. The interaction between temperature and lactose concentration was optimized, leading to an improvement in the apparent volumetric activity of thebaine 6-<i>O</i>-demethylase (T6ODM) from 45 to 776 U·L^–1 using glycerol as the carbon source and an improvement in the apparent volumetric activity of codeinone reductase (COR) from 120 to 3707 U·L^–1 using glucose. The productivity for T6ODM and COR was also increased 4.5 and 5.7-times to 8.0 and 28.3 U·L^–1·h^–1, respectively, in fed-batch cultivations compared to in shake flasks. With the optimized conditions for enzyme expression, the whole-cell biotransformation led to an 80% yield of codeine from thebaine and a final codeine/neopine molar ratio of 85:15. The inclusion of coexpressed neopinone isomerase, which catalyzes the production of codeinone from neopinone, reduced neopine production at the start of the reaction when the concentration of neopinone was low but did not improve the final codeine/neopine ratio as the reaction progressed and the concentration of neopinone increased. This observation may provide a further understanding of the differences between catalytic conditions in a bioreactor and the poppy plant, where the concentration of pathway intermediates such as neopinone is likely to be low and no neopine is observed. Overall, the process improvements reported here provide progress toward an industrial biocatalytic production of codeine from thebaine.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142270170","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":"Optimized Enzyme Production for the Escherichia coli Whole-Cell Biocatalytic Synthesis of Codeine from Thebaine","authors":"Ali Jahanian, Andres Velasquez Agudelo, Carlos Horacio Luna-Flores, Xu Li, Fiona Fry, George Mutch, Geoffrey W. Stevens, Sally L. Gras, Robert E. Speight","doi":"10.1021/acs.oprd.4c00195","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00195","url":null,"abstract":"Codeine, the most widely used medicinal opiate in the world, can be produced from thebaine by using an environmentally friendly biocatalytic process using purified enzymes or microbial cells. However, this biotransformation is either inefficient or not systematically characterized for industrial use, as microbial fermentation and enzyme expression have not been optimized, and the production of the undesirable side product neopine reduces yields. In this study, the expression of the required enzymes in a reengineered<i>Escherichia coli</i> system was optimized using a two-step design of experiments approach. Higher yields of biomass and enzyme expression were achieved in a defined minimal medium using lactose for induction. The interaction between temperature and lactose concentration was optimized, leading to an improvement in the apparent volumetric activity of thebaine 6-<i>O</i>-demethylase (T6ODM) from 45 to 776 U·L^–1 using glycerol as the carbon source and an improvement in the apparent volumetric activity of codeinone reductase (COR) from 120 to 3707 U·L^–1 using glucose. The productivity for T6ODM and COR was also increased 4.5 and 5.7-times to 8.0 and 28.3 U·L^–1·h^–1, respectively, in fed-batch cultivations compared to in shake flasks. With the optimized conditions for enzyme expression, the whole-cell biotransformation led to an 80% yield of codeine from thebaine and a final codeine/neopine molar ratio of 85:15. The inclusion of coexpressed neopinone isomerase, which catalyzes the production of codeinone from neopinone, reduced neopine production at the start of the reaction when the concentration of neopinone was low but did not improve the final codeine/neopine ratio as the reaction progressed and the concentration of neopinone increased. This observation may provide a further understanding of the differences between catalytic conditions in a bioreactor and the poppy plant, where the concentration of pathway intermediates such as neopinone is likely to be low and no neopine is observed. Overall, the process improvements reported here provide progress toward an industrial biocatalytic production of codeine from thebaine.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171203","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 Safer Continuous Flow Process for B2(OH)4-Mediated Chemoselective Reduction of Nitroarenes to Anilines","authors":"Omkar Revu, Maksim Vasilev, Praveen Gajula, Nageswara Rao Kalikinidi, Madhusudhan Reddy Gadi, Huiping Zhao, Shanika M. P. Gamage, Graham Hibbert, Ongolu Ravikumar, Lalitha Gummidi, Venkatarathnam Nasipireddy, Arun Vinodini, Jonathan Bietsch, Zhirui Wang, Jack D. Brown, Gopal Sirasani, Joseph D. Armstrong, III, Aravind S. Gangu, Bo Qu, Chris H. Senanayake","doi":"10.1021/acs.oprd.4c00267","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00267","url":null,"abstract":"Tetrahydroxydiboron [B₂(OH)₄] is a chemoselective reducing reagent for nitro reductions in the presence of other labile functional groups. However, there are significant process safety challenges associated with the application of this reducing reagent, including rapid heat release and thermal instability of B₂(OH)₄ in aprotic polar solvents. Herein, we report the development of a safer continuous flow process applying B₂(OH)₄-mediated chemoselective nitro reduction conditions. The safety challenges were addressed by employing continuous flow technology along with identifying a suitable protic cosolvent EtOH. Functional group tolerance toward cyano groups, halides, carboxylic acids, olefins, imines, and benzylic alcohols was demonstrated in flow with higher reaction yield compared to that in batch synthesis. The modified reaction conditions provide a potentially scalable approach to widespread applications of this key transformation for the generation of highly functionalized diversified aniline derivatives.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142171251","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":"Study on Continuous-Flow Process for Direct Synthesis of p-Aminophenol from Nitrobenzene","authors":"Jinpeng Huang,&nbsp;Changlu Zhou,&nbsp;Chunping Li and Zhong Xin*,&nbsp;","doi":"10.1021/acs.oprd.4c0027510.1021/acs.oprd.4c00275","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00275https://doi.org/10.1021/acs.oprd.4c00275","url":null,"abstract":"<p ><i>p</i>-Aminophenol (PAP) is an important organic chemical raw material and a pharmaceutical intermediate. Catalytic hydrogenation of nitrobenzene (NB) is an environmentally friendly and economical production method. However, the one-pot method in a traditional batch reactor often leads to a low reaction rate and low PAP yield at low hydrogen pressure. In this work, a continuous-flow process for direct synthesis of PAP by the hydrogenation–rearrangement of NB was established, which provides a safe, green, and efficient method for the synthesis of PAP. The effects of various reaction conditions were investigated. Under the optimal reaction conditions, a 94.5% yield of phenylhydroxylamine (PHA) was achieved in the hydrogenation process under atmospheric pressure. The catalyst activity remained good for 50 h of continuous operation. Solvent tetrahydrofuran (THF) and additive 4-dimethylaminopyridine (DMAP) are more conducive to the synthesis of PHA than other solvents. For different acid catalysts in the Bamberger rearrangement with an equivalent concentration of 2 N, stronger acidity led to greater conversion of PHA. The Bamberger rearrangement is solvent-sensitive, and aprotic solvents will reduce the conversion of PHA. The full continuous process for direct synthesis of PAP from NB was studied by mixing sulfuric acid solution and PHA/THF solution with a microfluidic chip. The conversion of PHA was 100% with a low H₂SO₄ concentration of 1 wt % at a residence time of 13.6 min. The process was reduced from the hour level of the batch process to the minute level, and the H₂SO₄ concentration was reduced.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273906","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":"PAT Aided Feasibility Study on Continuous Crystallization of Benzotriazole","authors":"Yang Zhang, Lu Zhang, Guangzheng Zhou, Jian Heng, Xue Zhong Wang","doi":"10.1021/acs.oprd.4c00201","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00201","url":null,"abstract":"As an important fine chemical with a wide range of applications, benzotriazole has traditionally been purified by batch crystallization. Batch operation has some potential known disadvantages compared with continuous mode operation, including batch-to-batch variations, the need for large inventories, and being more challenging to process control. In this feasibility study, continuous mixed-suspension-mixed-product removal (MSMPR) crystallization is investigated for benzotriazole purification with the support of online microscopic imaging and attenuated total reflectance ultraviolet (ATR-UV) spectroscopy. The metastable zone width is determined by the in situ imaging method, and the growth rate of needle-shaped crystals is found to be independent of their dimensions. The ATR-UV spectroscopy is utilized to provide real-time concentration measurements with a calibration model established by a chemometric method. The steady state of the crystallization process is online-identified by spectrum analysis, which always becomes stable around 7–8 residence times, regardless of initial solution concentration and residence time. The optimum process parameters of continuous crystallization are determined according to the product yield and particle size distribution.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166488","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":"Study on Continuous-Flow Process for Direct Synthesis of p-Aminophenol from Nitrobenzene","authors":"Jinpeng Huang, Changlu Zhou, Chunping Li, Zhong Xin","doi":"10.1021/acs.oprd.4c00275","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00275","url":null,"abstract":"<i>p</i>-Aminophenol (PAP) is an important organic chemical raw material and a pharmaceutical intermediate. Catalytic hydrogenation of nitrobenzene (NB) is an environmentally friendly and economical production method. However, the one-pot method in a traditional batch reactor often leads to a low reaction rate and low PAP yield at low hydrogen pressure. In this work, a continuous-flow process for direct synthesis of PAP by the hydrogenation–rearrangement of NB was established, which provides a safe, green, and efficient method for the synthesis of PAP. The effects of various reaction conditions were investigated. Under the optimal reaction conditions, a 94.5% yield of phenylhydroxylamine (PHA) was achieved in the hydrogenation process under atmospheric pressure. The catalyst activity remained good for 50 h of continuous operation. Solvent tetrahydrofuran (THF) and additive 4-dimethylaminopyridine (DMAP) are more conducive to the synthesis of PHA than other solvents. For different acid catalysts in the Bamberger rearrangement with an equivalent concentration of 2 N, stronger acidity led to greater conversion of PHA. The Bamberger rearrangement is solvent-sensitive, and aprotic solvents will reduce the conversion of PHA. The full continuous process for direct synthesis of PAP from NB was studied by mixing sulfuric acid solution and PHA/THF solution with a microfluidic chip. The conversion of PHA was 100% with a low H₂SO₄ concentration of 1 wt % at a residence time of 13.6 min. The process was reduced from the hour level of the batch process to the minute level, and the H₂SO₄ concentration was reduced.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166489","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":"PAT Aided Feasibility Study on Continuous Crystallization of Benzotriazole","authors":"Yang Zhang,&nbsp;Lu Zhang,&nbsp;Guangzheng Zhou*,&nbsp;Jian Heng and Xue Zhong Wang*,&nbsp;","doi":"10.1021/acs.oprd.4c0020110.1021/acs.oprd.4c00201","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00201https://doi.org/10.1021/acs.oprd.4c00201","url":null,"abstract":"<p >As an important fine chemical with a wide range of applications, benzotriazole has traditionally been purified by batch crystallization. Batch operation has some potential known disadvantages compared with continuous mode operation, including batch-to-batch variations, the need for large inventories, and being more challenging to process control. In this feasibility study, continuous mixed-suspension-mixed-product removal (MSMPR) crystallization is investigated for benzotriazole purification with the support of online microscopic imaging and attenuated total reflectance ultraviolet (ATR-UV) spectroscopy. The metastable zone width is determined by the in situ imaging method, and the growth rate of needle-shaped crystals is found to be independent of their dimensions. The ATR-UV spectroscopy is utilized to provide real-time concentration measurements with a calibration model established by a chemometric method. The steady state of the crystallization process is online-identified by spectrum analysis, which always becomes stable around 7–8 residence times, regardless of initial solution concentration and residence time. The optimum process parameters of continuous crystallization are determined according to the product yield and particle size distribution.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142273881","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":"Green Chemistry Articles of Interest to the Pharmaceutical Industry","authors":"Melissa A. Ashley, Miles H. Aukland, Marian C. Bryan, Megan A. Cismesia, Theresa Dutschei, Oliver D. Engl, Pascal S. Engl, Álvaro Enriquez Garcia, Vanessa Harawa, George Karageorgis, Christopher B. Kelly, Alexandre Leclair, Johnny W. Lee, Zhen Lei, Wei Li, Jan Pawlas, Paul F. Richardson, Samuel C. Scott, Alan Steven, Balaram S. Takale, Dauzhan Yerkozhanov, Mingshuo Zeng","doi":"10.1021/acs.oprd.4c00300","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00300","url":null,"abstract":"This article has not yet been cited by other publications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160905","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}