Pub Date : 2025-02-20DOI: 10.1021/acs.oprd.5c00017
Jianglin Colin Liang, Hongming Li, Kevin M. Cottrell, Yong Liu, John P. Maxwell, Zhengyang Xin, Luigi Anzalone, Magnus Ronn, Michael A. Palmieri, Jr.
TNG908 is a potent, selective, and brain-penetrant MTA-cooperative PRMT5 inhibitor for the treatment of MTAP-deleted tumors. We describe here the chemical process development for the synthesis of TNG908 and the improvements that were achieved over the medicinal chemistry route with much higher yields and better purities. This commercial ready process is convergent, diastereoselective, safe, reproducible, and robust. A total of eight GMP batches have been successfully manufactured, resulting in high-purity API meeting all specifications.
{"title":"Development of a Commercial Ready Process for TNG908: A Potent, Selective, and Brain-Penetrant MTA-Cooperative PRMT5 Inhibitor","authors":"Jianglin Colin Liang, Hongming Li, Kevin M. Cottrell, Yong Liu, John P. Maxwell, Zhengyang Xin, Luigi Anzalone, Magnus Ronn, Michael A. Palmieri, Jr.","doi":"10.1021/acs.oprd.5c00017","DOIUrl":"https://doi.org/10.1021/acs.oprd.5c00017","url":null,"abstract":"<b>TNG908</b> is a potent, selective, and brain-penetrant MTA-cooperative PRMT5 inhibitor for the treatment of <i>MTAP</i>-deleted tumors. We describe here the chemical process development for the synthesis of <b>TNG908</b> and the improvements that were achieved over the medicinal chemistry route with much higher yields and better purities. This commercial ready process is convergent, diastereoselective, safe, reproducible, and robust. A total of eight GMP batches have been successfully manufactured, resulting in high-purity API meeting all specifications.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"230 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463018","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 : 2025-02-19DOI: 10.1021/acs.oprd.4c00501
Remi Nguyen, Samy Halloumi, Irene Malpartida, Christophe Len
Impact in Continuous Flow Heated Mechanochemistry (ICHeM) was utilized for the biphasic acetylation of glycerol with immiscible acetic anhydride in the presence of homogeneous acid catalysts. This innovative technology combines efficient phase dispersion with continuous flow, offering the following benefits: (i) improved mixing of the two immiscible components (liquid glycerol and highly reactive acetic anhydride); (ii) mechanochemical energy generated by bead impact in continuous flow, eliminating the need for additional heating energy; and (iii) an alternative to single- and double-screw extruders, which are ineffective with liquid reaction media. Under our optimized conditions, triacetin “t” can be obtained with a 99% yield (100% conversion and 99% selectivity) in a solvent-free biphasic continuous flow process with a residence time of 15–30 min, using efficient homogeneous Lewis acids like iron triflate II or Brönsted acids like sulfuric acid.
{"title":"Solvent-Free Production of Triacetin from Glycerol through Complementary Mechanochemical, Biphasic, and Catalytic Approaches Using ICHeM Technology","authors":"Remi Nguyen, Samy Halloumi, Irene Malpartida, Christophe Len","doi":"10.1021/acs.oprd.4c00501","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00501","url":null,"abstract":"Impact in Continuous Flow Heated Mechanochemistry (ICHeM) was utilized for the biphasic acetylation of glycerol with immiscible acetic anhydride in the presence of homogeneous acid catalysts. This innovative technology combines efficient phase dispersion with continuous flow, offering the following benefits: (i) improved mixing of the two immiscible components (liquid glycerol and highly reactive acetic anhydride); (ii) mechanochemical energy generated by bead impact in continuous flow, eliminating the need for additional heating energy; and (iii) an alternative to single- and double-screw extruders, which are ineffective with liquid reaction media. Under our optimized conditions, triacetin “<i>t</i>” can be obtained with a 99% yield (100% conversion and 99% selectivity) in a solvent-free biphasic continuous flow process with a residence time of 15–30 min, using efficient homogeneous Lewis acids like iron triflate II or Brönsted acids like sulfuric acid.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"19 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462974","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 : 2025-02-19DOI: 10.1021/acs.oprd.4c00404
Hao Li, Jin-Xi Wu, Guang-Yuan Zhang, Ning-Ning Du, Le-Wu Zhan, Jing Hou, Bin-Dong Li
Azo energetic compounds have attracted much attention due to their high heat of formation and high oxygen balance. However, due to a lack of safety research on this manufacturing process, industrial production cannot be carried out. 1,1′-Azobis-1,2,3-triazole was chosen as an example to identify hazardous scenarios in the synthesis of azo-energetic materials. First, the properties of the 1,1′-azobis-1,2,3-triazole synthesis experiment were studied using a reaction calorimeter (RC1). Afterward, the thermal stability of the composite materials used in the synthesis process was evaluated using accelerating rate calorimetry (ARC) and differential scanning calorimetry (DSC). DSC results showed that the heat release of the mixture was significantly reduced in all three steps. ARC experiments showed that the TD24 values of the three substances are in the range of 100.00–300.00 °C. RC1 experiments showed that the adiabatic temperature rises (ΔTad) in the whole process are 91.26 54.19, 51.49, and 4.10 K, respectively. These findings indicate that the exothermic reaction involved in the synthesis of 1,1′-azobis-1,2,3-triazole is initiated during the dosing phase and is affected by the dosing rate. The overall 1,1′-azobis-1,2,3-triazole synthesis process is a criticality class 1 of a chemical reaction. This holistic approach furnishes valuable data and insights for improving the engineering safety protocols of 1,1′-azobis-1,2,3-triazole, aimed at mitigating risks in industrial operations.
{"title":"Thermal Hazard Assessment of the Synthesis of 1,1′-Azobis-1,2,3-triazole","authors":"Hao Li, Jin-Xi Wu, Guang-Yuan Zhang, Ning-Ning Du, Le-Wu Zhan, Jing Hou, Bin-Dong Li","doi":"10.1021/acs.oprd.4c00404","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00404","url":null,"abstract":"Azo energetic compounds have attracted much attention due to their high heat of formation and high oxygen balance. However, due to a lack of safety research on this manufacturing process, industrial production cannot be carried out. 1,1′-Azobis-1,2,3-triazole was chosen as an example to identify hazardous scenarios in the synthesis of azo-energetic materials. First, the properties of the 1,1′-azobis-1,2,3-triazole synthesis experiment were studied using a reaction calorimeter (RC1). Afterward, the thermal stability of the composite materials used in the synthesis process was evaluated using accelerating rate calorimetry (ARC) and differential scanning calorimetry (DSC). DSC results showed that the heat release of the mixture was significantly reduced in all three steps. ARC experiments showed that the <i>T</i><sub>D24</sub> values of the three substances are in the range of 100.00–300.00 °C. RC1 experiments showed that the adiabatic temperature rises (Δ<i>T</i><sub>ad</sub>) in the whole process are 91.26 54.19, 51.49, and 4.10 K, respectively. These findings indicate that the exothermic reaction involved in the synthesis of 1,1′-azobis-1,2,3-triazole is initiated during the dosing phase and is affected by the dosing rate. The overall 1,1′-azobis-1,2,3-triazole synthesis process is a criticality class 1 of a chemical reaction. This holistic approach furnishes valuable data and insights for improving the engineering safety protocols of 1,1′-azobis-1,2,3-triazole, aimed at mitigating risks in industrial operations.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452313","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 : 2025-02-19DOI: 10.1021/acs.oprd.4c00521
Kelvin J. Y. Wu, Priscilla Liow, Andrew G. Myers
A new, more scalable route for the synthesis of the common oxepanoproline southern fragment of the antibiotic candidates iboxamycin, cresomycin, and BT-33 is presented. A key transformation in the route is a diastereoselective TiCl4-mediated conjugate addition of an allylsilane to an Evans N-acryloyloxazolidinone, followed by syn-aldol addition of the resultant titanium enolate to (R)-Garner’s aldehyde, which assembles all the stereocenters within the target molecule in a single operation.
{"title":"Practical Synthesis of Oxepanoprolines","authors":"Kelvin J. Y. Wu, Priscilla Liow, Andrew G. Myers","doi":"10.1021/acs.oprd.4c00521","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00521","url":null,"abstract":"A new, more scalable route for the synthesis of the common oxepanoproline southern fragment of the antibiotic candidates iboxamycin, cresomycin, and BT-33 is presented. A key transformation in the route is a diastereoselective TiCl<sub>4</sub>-mediated conjugate addition of an allylsilane to an Evans <i>N</i>-acryloyloxazolidinone, followed by <i>syn</i>-aldol addition of the resultant titanium enolate to (<i>R</i>)-Garner’s aldehyde, which assembles all the stereocenters within the target molecule in a single operation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"32 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452314","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 : 2025-02-19DOI: 10.1021/acs.oprd.4c00495
Souvagya Biswas, Jason S. Fisk, Michael Telgenhoff, Karin Spiers, Muhunthan Sathiosatham, Thu Vi, Matthew S. Jeletic, Jessica E. Nichols, Travis W. Scholtz
This study details the route selection, process development, and scale-up of a reactive silicone acrylate monomer, 3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-yl)propyl methacrylate. A direct hydrosilylation reaction between allyl (meth)acrylate and 1,1,1,3,5,5,5-heptamethyltrisiloxane in the presence of Karstedt’s catalyst yielded the desired monomer in 46% yield. Two other byproducts were identified: an oxy-silyl ester and a propene hydrosilylated product. Prior to scale-up, the heat release associated with the hydrosilylation reaction was measured using a combination of isothermal reaction microcalorimetry and postreaction differential scanning calorimetry (DSC). The total heat release of hydrosilylation in the observed microcalorimetry experiment was −415 J/g. DSC studies detected the decomposition of the monomer at 280 °C, thereby revealing the risk of decomposition at elevated temperatures. Finding an inhibitor to prevent unwanted free radical polymerization of the monomer during scale-up and product isolation was crucial. 4-Hydroxy TEMPO was identified as the inhibitor of choice during the scale-up and distillation steps to isolate the monomer. Overall, the process optimization described here enabled a reliable, robust, and scalable method to produce multikilogram quantities of the 3-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)propyl methacrylate monomer. This approach is also expected to be suitable for other reactive silicone-acrylate-based monomers.
{"title":"A Scalable Process for Synthesizing a Reactive Silicone-Acrylate Monomer","authors":"Souvagya Biswas, Jason S. Fisk, Michael Telgenhoff, Karin Spiers, Muhunthan Sathiosatham, Thu Vi, Matthew S. Jeletic, Jessica E. Nichols, Travis W. Scholtz","doi":"10.1021/acs.oprd.4c00495","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00495","url":null,"abstract":"This study details the route selection, process development, and scale-up of a reactive silicone acrylate monomer, 3-(1,1,1,3,5,5,5-heptamethyltrisiloxane-3-yl)propyl methacrylate. A direct hydrosilylation reaction between allyl (meth)acrylate and 1,1,1,3,5,5,5-heptamethyltrisiloxane in the presence of Karstedt’s catalyst yielded the desired monomer in 46% yield. Two other byproducts were identified: an oxy-silyl ester and a propene hydrosilylated product. Prior to scale-up, the heat release associated with the hydrosilylation reaction was measured using a combination of isothermal reaction microcalorimetry and postreaction differential scanning calorimetry (DSC). The total heat release of hydrosilylation in the observed microcalorimetry experiment was −415 J/g. DSC studies detected the decomposition of the monomer at 280 °C, thereby revealing the risk of decomposition at elevated temperatures. Finding an inhibitor to prevent unwanted free radical polymerization of the monomer during scale-up and product isolation was crucial. 4-Hydroxy TEMPO was identified as the inhibitor of choice during the scale-up and distillation steps to isolate the monomer. Overall, the process optimization described here enabled a reliable, robust, and scalable method to produce multikilogram quantities of the 3-(1,1,1,3,5,5,5-heptamethyltrisiloxan-3-yl)propyl methacrylate monomer. This approach is also expected to be suitable for other reactive silicone-acrylate-based monomers.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"15 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143462973","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 : 2025-02-18DOI: 10.1021/acs.oprd.4c00422
Jeongki Kang, Jongwook Park, Jinsoo Kim, Woo-Sik Kim
This study proposed a method for inverse phase transformation of stable γ-glycine into metastable α-glycine by using the characteristic that solubility increases as crystal size decreases according to the Ostwald–Freundlich equation. First, we measured the change in solubility according to the particle size of glycine. The solubility of γ-glycine bulk crystals at 10 °C in water was 173 g/L, and when the crystal size decreased to about 0.9 μm, the solubility increased to about 185 g/L. This concentration was higher than the solubility of α-glycine bulk crystals, 180 g/L. Based on the above results, γ-glycine can be inverse transformed into α-glycine in aqueous solution. To demonstrate this inverse transformation, in a glycine solution, γ-glycine crystals with a size of about 2 μm were ground with glass beads for 24 h to reduce the crystal size to about 0.8 μm. And the concentration of the solution was made higher than the solubility of α-glycine bulk. α-Glycine bulk crystals (about 110 μm) were placed into this solution and grown to 170 μm. Through this, inverse phase transformation was achieved in which γ-glycine crystals were dissolved and α-glycine crystals grew. The above inverse phase transformation process was confirmed using a microscope, XRD, and ATR–FTIR.
{"title":"Inverse Transformation of Glycine by Crystal Size Control","authors":"Jeongki Kang, Jongwook Park, Jinsoo Kim, Woo-Sik Kim","doi":"10.1021/acs.oprd.4c00422","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00422","url":null,"abstract":"This study proposed a method for inverse phase transformation of stable γ-glycine into metastable α-glycine by using the characteristic that solubility increases as crystal size decreases according to the Ostwald–Freundlich equation. First, we measured the change in solubility according to the particle size of glycine. The solubility of γ-glycine bulk crystals at 10 °C in water was 173 g/L, and when the crystal size decreased to about 0.9 μm, the solubility increased to about 185 g/L. This concentration was higher than the solubility of α-glycine bulk crystals, 180 g/L. Based on the above results, γ-glycine can be inverse transformed into α-glycine in aqueous solution. To demonstrate this inverse transformation, in a glycine solution, γ-glycine crystals with a size of about 2 μm were ground with glass beads for 24 h to reduce the crystal size to about 0.8 μm. And the concentration of the solution was made higher than the solubility of α-glycine bulk. α-Glycine bulk crystals (about 110 μm) were placed into this solution and grown to 170 μm. Through this, inverse phase transformation was achieved in which γ-glycine crystals were dissolved and α-glycine crystals grew. The above inverse phase transformation process was confirmed using a microscope, XRD, and ATR–FTIR.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"52 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452315","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 : 2025-02-12DOI: 10.1021/acs.oprd.4c00459
Alejandro Mata, Caroline de Fraipont, Céline Hervieux, Lucas Giacchetti, Oicime Hadj-Sassi, Alexandra Bogicevic, Vincent Marichez, Thomas M. Hermans
Flow chemistry is rapidly growing as it can outperform batch processes in terms of production costs, product quality, and overall environmental footprint. However, the reaction scope in flow is currently restricted due to solid handling limitations. Solids such as heterogeneous catalysts (powders) or precipitates are known to clog flow reactors, leading to periods of downtime to clean (or sometimes even replace) the reactor. Here, we report on liquid-walled continuous flow reactors that are virtually insensitive to clogging (or abrasion) and mix an order of magnitude faster than do solid-wall analogs. Our walls consist of chemically inert ferrofluids that are held in place with permanent magnets, leading to a stable liquid–liquid interface. We show efficient formylation of aryl bromides that is normally plagued by in-line precipitation.
{"title":"Nonclogging Liquid-Walled Continuous Flow Reactors","authors":"Alejandro Mata, Caroline de Fraipont, Céline Hervieux, Lucas Giacchetti, Oicime Hadj-Sassi, Alexandra Bogicevic, Vincent Marichez, Thomas M. Hermans","doi":"10.1021/acs.oprd.4c00459","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00459","url":null,"abstract":"Flow chemistry is rapidly growing as it can outperform batch processes in terms of production costs, product quality, and overall environmental footprint. However, the reaction scope in flow is currently restricted due to solid handling limitations. Solids such as heterogeneous catalysts (powders) or precipitates are known to clog flow reactors, leading to periods of downtime to clean (or sometimes even replace) the reactor. Here, we report on liquid-walled continuous flow reactors that are virtually insensitive to clogging (or abrasion) and mix an order of magnitude faster than do solid-wall analogs. Our walls consist of chemically inert ferrofluids that are held in place with permanent magnets, leading to a stable liquid–liquid interface. We show efficient formylation of aryl bromides that is normally plagued by in-line precipitation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"16 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143401629","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 : 2025-02-12DOI: 10.1021/acs.oprd.4c0045910.1021/acs.oprd.4c00459
Alejandro Mata, Caroline de Fraipont, Céline Hervieux, Lucas Giacchetti, Oicime Hadj-Sassi, Alexandra Bogicevic, Vincent Marichez* and Thomas M. Hermans*,
Flow chemistry is rapidly growing as it can outperform batch processes in terms of production costs, product quality, and overall environmental footprint. However, the reaction scope in flow is currently restricted due to solid handling limitations. Solids such as heterogeneous catalysts (powders) or precipitates are known to clog flow reactors, leading to periods of downtime to clean (or sometimes even replace) the reactor. Here, we report on liquid-walled continuous flow reactors that are virtually insensitive to clogging (or abrasion) and mix an order of magnitude faster than do solid-wall analogs. Our walls consist of chemically inert ferrofluids that are held in place with permanent magnets, leading to a stable liquid–liquid interface. We show efficient formylation of aryl bromides that is normally plagued by in-line precipitation.
{"title":"Nonclogging Liquid-Walled Continuous Flow Reactors","authors":"Alejandro Mata, Caroline de Fraipont, Céline Hervieux, Lucas Giacchetti, Oicime Hadj-Sassi, Alexandra Bogicevic, Vincent Marichez* and Thomas M. Hermans*, ","doi":"10.1021/acs.oprd.4c0045910.1021/acs.oprd.4c00459","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00459https://doi.org/10.1021/acs.oprd.4c00459","url":null,"abstract":"<p >Flow chemistry is rapidly growing as it can outperform batch processes in terms of production costs, product quality, and overall environmental footprint. However, the reaction scope in flow is currently restricted due to solid handling limitations. Solids such as heterogeneous catalysts (powders) or precipitates are known to clog flow reactors, leading to periods of downtime to clean (or sometimes even replace) the reactor. Here, we report on liquid-walled continuous flow reactors that are virtually insensitive to clogging (or abrasion) and mix an order of magnitude faster than do solid-wall analogs. Our walls consist of chemically inert ferrofluids that are held in place with permanent magnets, leading to a stable liquid–liquid interface. We show efficient formylation of aryl bromides that is normally plagued by in-line precipitation.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"472–478 472–478"},"PeriodicalIF":3.1,"publicationDate":"2025-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452400","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 : 2025-02-11DOI: 10.1021/acs.oprd.4c00508
Matthew J. Takle, Linden Schrecker, Benjamin J. Deadman, Joachim Dickhaut, Andy Wieja, Klaus Hellgardt, King Kuok Mimi Hii
The robustness of the flash thermal racemization of optically active 1-phenylethylamine over Pd/γ-Al2O3 was studied by applying split-plot design-of-experiments (DoE), where the effects of temperature, flow rate, and concentration (3-factors) on the e.e. and selectivity (2-responses) were examined and quantified. The same effects were also interrogated using multivariate ramps in transient flow to produce response surfaces for the reaction space. The same set of optimal conditions for the process was identified by both approaches, and the same relationships between the variables were observed: while the extent of racemization (e.e.) can be directly correlated to temperature, a more complex relationship between temperature and flow rate on the selectivity was uncovered.
{"title":"Flash Thermal Racemization of Chiral Amine in Continuous Flow: An Exploration of Reaction Space Using DoE and Multivariate Transient Flow","authors":"Matthew J. Takle, Linden Schrecker, Benjamin J. Deadman, Joachim Dickhaut, Andy Wieja, Klaus Hellgardt, King Kuok Mimi Hii","doi":"10.1021/acs.oprd.4c00508","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00508","url":null,"abstract":"The robustness of the flash thermal racemization of optically active 1-phenylethylamine over Pd/γ-Al<sub>2</sub>O<sub>3</sub> was studied by applying split-plot design-of-experiments (DoE), where the effects of temperature, flow rate, and concentration (3-factors) on the e.e. and selectivity (2-responses) were examined and quantified. The same effects were also interrogated using multivariate ramps in transient flow to produce response surfaces for the reaction space. The same set of optimal conditions for the process was identified by both approaches, and the same relationships between the variables were observed: while the extent of racemization (e.e.) can be directly correlated to temperature, a more complex relationship between temperature and flow rate on the selectivity was uncovered.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"121 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143385059","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 : 2025-02-11DOI: 10.1021/acs.oprd.4c0050810.1021/acs.oprd.4c00508
Matthew J. Takle, Linden Schrecker, Benjamin J. Deadman, Joachim Dickhaut, Andy Wieja, Klaus Hellgardt and King Kuok Mimi Hii*,
The robustness of the flash thermal racemization of optically active 1-phenylethylamine over Pd/γ-Al2O3 was studied by applying split-plot design-of-experiments (DoE), where the effects of temperature, flow rate, and concentration (3-factors) on the e.e. and selectivity (2-responses) were examined and quantified. The same effects were also interrogated using multivariate ramps in transient flow to produce response surfaces for the reaction space. The same set of optimal conditions for the process was identified by both approaches, and the same relationships between the variables were observed: while the extent of racemization (e.e.) can be directly correlated to temperature, a more complex relationship between temperature and flow rate on the selectivity was uncovered.
{"title":"Flash Thermal Racemization of Chiral Amine in Continuous Flow: An Exploration of Reaction Space Using DoE and Multivariate Transient Flow","authors":"Matthew J. Takle, Linden Schrecker, Benjamin J. Deadman, Joachim Dickhaut, Andy Wieja, Klaus Hellgardt and King Kuok Mimi Hii*, ","doi":"10.1021/acs.oprd.4c0050810.1021/acs.oprd.4c00508","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00508https://doi.org/10.1021/acs.oprd.4c00508","url":null,"abstract":"<p >The robustness of the flash thermal racemization of optically active 1-phenylethylamine over Pd/γ-Al<sub>2</sub>O<sub>3</sub> was studied by applying split-plot design-of-experiments (DoE), where the effects of temperature, flow rate, and concentration (3-factors) on the e.e. and selectivity (2-responses) were examined and quantified. The same effects were also interrogated using multivariate ramps in transient flow to produce response surfaces for the reaction space. The same set of optimal conditions for the process was identified by both approaches, and the same relationships between the variables were observed: while the extent of racemization (e.e.) can be directly correlated to temperature, a more complex relationship between temperature and flow rate on the selectivity was uncovered.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"29 2","pages":"545–554 545–554"},"PeriodicalIF":3.1,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00508","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143452588","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}
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