Tanja Poredoš, Marko Trampuž, Tjaša Gornik, Klemen Naveršnik, Maša Sinreih Tisnikar, Samo Pirc, Zdenko Časar
{"title":"Why and How to Control P-Chirality in Phosphorothioated Therapeutic Oligonucleotides: Analytical Challenges Associated with Determination of Stereochemical Composition","authors":"Tanja Poredoš, Marko Trampuž, Tjaša Gornik, Klemen Naveršnik, Maša Sinreih Tisnikar, Samo Pirc, Zdenko Časar","doi":"10.1021/acs.oprd.4c00380","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00380","url":null,"abstract":"A surge in the approval of therapeutic oligonucleotides since 2016 has made this class of chemical modalities an essential toolbox for addressing unmet medical needs in the realm of rare or difficult-to-treat diseases. Therapeutic oligonucleotides are complex drugs, primarily due to the active pharmaceutical ingredient, which presents numerous oligonucleotide-specific impurities that are challenging to address during the manufacturing process. A less common challenge is the control of the stereochemical composition of P-chiral morpholino and phosphorothioate therapeutic oligonucleotides. These are produced in a non-stereoselective manner, resulting in a mixture of different stereoisomers that collectively form the final drug substance. Thus, the control of stereochemical composition has an important role in the manufacturing process of therapeutic oligonucleotides, either as an in-process control or a final characterization test. In this Perspective, we first present the current status of oligonucleotide therapeutics, with a focus on phosphorothioate derivatives. We then highlight the regulatory framework for controlling the stereochemical composition of these drugs, provide brief insights into the biological significance of stereochemical composition for phosphorothioates, and discuss the origin of stereochemical composition in the synthetic and downstream processes. Subsequently, we provide an in-depth analysis of analytical methods used to determine the stereochemical composition of therapeutic oligonucleotides, including liquid chromatography approaches in various separation modes and emerging modern techniques like ion mobility spectrometry. Furthermore, capillary electrophoresis, duplex melting temperature, and NMR spectroscopy are also discussed in the context of stereochemical composition analysis of therapeutic oligonucleotides. Finally, we highlight novel enzymatic methods for cleaving therapeutic oligonucleotides into smaller fragments that can be analyzed for stereochemical composition using standard techniques.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"6 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788387","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}
Matthew Frederick Lopez Villena, Zachary Dean Doorenbos, Kyle Thomas Sullivan and Blair Brettmann*,
{"title":"Evaluating Resonant Acoustic Mixing as a Wet Granulation Process","authors":"Matthew Frederick Lopez Villena, Zachary Dean Doorenbos, Kyle Thomas Sullivan and Blair Brettmann*, ","doi":"10.1021/acs.oprd.4c0034710.1021/acs.oprd.4c00347","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00347https://doi.org/10.1021/acs.oprd.4c00347","url":null,"abstract":"<p >Control of powder properties is crucial for industrial processes across the food, pharmaceutical, agriculture, and mineral processing industries, and granulation is an important tool for providing agglomerated particles with controllable properties. However, existing granulation processes are not readily integrated with other processing steps and are not appropriate for some types of materials. Adding resonant acoustic-based granulation to the toolkit has the potential to widen the achievable parameter space and, importantly, integrate granulation into chemistry and blending operations that are already being performed on the RAM platform, resulting in process intensification. Here, we demonstrate the formation of granules with particle sizes of ca. 1–3 mm in LabRAM II and examine the formation mechanisms in the context of common wet granulation processes. The RAM granulation process followed here involves first forming a large “doughball” agglomerate and then driving its breakup by evaporating the solvent, while impacting the doughball against the container walls. We show that this process is similar to the destructive nucleation model for high-shear wet granulation with the solvent evaporation in our case leading to the decrease in the liquid saturation of the doughball, a corresponding decrease in its tensile strength, and the acceleration in the RAM establishing the impact pressure when the doughball contacts the walls. This work provides a foundation for granulation process design with a resonant acoustic mixer and, through its link to existing granulation mechanisms, provides a path to a deeper understanding of the process.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4338–4347 4338–4347"},"PeriodicalIF":3.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867788","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}
Arvind Girkar, Dujon Noronha, Prashant B. Patil, Mustapha Mandewale, Sudhir Sawant, Mohan Anand Chandavarkar, Kishor More
{"title":"An Improved Commercial Process for the Preparation of Lifitegrast","authors":"Arvind Girkar, Dujon Noronha, Prashant B. Patil, Mustapha Mandewale, Sudhir Sawant, Mohan Anand Chandavarkar, Kishor More","doi":"10.1021/acs.oprd.4c00356","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00356","url":null,"abstract":"A straightforward, efficient, and scalable commercial manufacturing process was developed for the ophthalmic anti-inflammatory drug lifitegrast via a novel ester intermediate from commercially available starting materials. Lifitegrast (Xiidra) was approved by the FDA on July 11, 2016, for the treatment of signs and symptoms of dry eye, a syndrome called keratoconjunctivitis sicca. The breakthrough step of this new process is the discovery of an <i>N</i>-Boc deprotection reaction that simultaneously transesterifies an intermediate to a new ester by using oxalyl chloride, which has favorable isolation properties. As a result of transesterification, the hydrolysis of the new ester intermediate occurs under milder conditions, which improves the quality of the product by reducing racemization. Lifitegrast prepared from this new process complied with the quality guidelines, as per the International Council for Harmonization (ICH). By using this new process, lifitegrast was produced on a 2 kg scale with an overall yield of 66%.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"27 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783003","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}
Matthew Frederick Lopez Villena, Zachary Dean Doorenbos, Kyle Thomas Sullivan, Blair Brettmann
{"title":"Evaluating Resonant Acoustic Mixing as a Wet Granulation Process","authors":"Matthew Frederick Lopez Villena, Zachary Dean Doorenbos, Kyle Thomas Sullivan, Blair Brettmann","doi":"10.1021/acs.oprd.4c00347","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00347","url":null,"abstract":"Control of powder properties is crucial for industrial processes across the food, pharmaceutical, agriculture, and mineral processing industries, and granulation is an important tool for providing agglomerated particles with controllable properties. However, existing granulation processes are not readily integrated with other processing steps and are not appropriate for some types of materials. Adding resonant acoustic-based granulation to the toolkit has the potential to widen the achievable parameter space and, importantly, integrate granulation into chemistry and blending operations that are already being performed on the RAM platform, resulting in process intensification. Here, we demonstrate the formation of granules with particle sizes of ca. 1–3 mm in LabRAM II and examine the formation mechanisms in the context of common wet granulation processes. The RAM granulation process followed here involves first forming a large “doughball” agglomerate and then driving its breakup by evaporating the solvent, while impacting the doughball against the container walls. We show that this process is similar to the destructive nucleation model for high-shear wet granulation with the solvent evaporation in our case leading to the decrease in the liquid saturation of the doughball, a corresponding decrease in its tensile strength, and the acceleration in the RAM establishing the impact pressure when the doughball contacts the walls. This work provides a foundation for granulation process design with a resonant acoustic mixer and, through its link to existing granulation mechanisms, provides a path to a deeper understanding of the process.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"8 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142783005","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}
Tanja Poredoš, Marko Trampuž, Tjaša Gornik, Klemen Naveršnik, Maša Sinreih Tisnikar, Samo Pirc and Zdenko Časar*,
{"title":"Why and How to Control P-Chirality in Phosphorothioated Therapeutic Oligonucleotides: Analytical Challenges Associated with Determination of Stereochemical Composition","authors":"Tanja Poredoš, Marko Trampuž, Tjaša Gornik, Klemen Naveršnik, Maša Sinreih Tisnikar, Samo Pirc and Zdenko Časar*, ","doi":"10.1021/acs.oprd.4c0038010.1021/acs.oprd.4c00380","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00380https://doi.org/10.1021/acs.oprd.4c00380","url":null,"abstract":"<p >A surge in the approval of therapeutic oligonucleotides since 2016 has made this class of chemical modalities an essential toolbox for addressing unmet medical needs in the realm of rare or difficult-to-treat diseases. Therapeutic oligonucleotides are complex drugs, primarily due to the active pharmaceutical ingredient, which presents numerous oligonucleotide-specific impurities that are challenging to address during the manufacturing process. A less common challenge is the control of the stereochemical composition of P-chiral morpholino and phosphorothioate therapeutic oligonucleotides. These are produced in a non-stereoselective manner, resulting in a mixture of different stereoisomers that collectively form the final drug substance. Thus, the control of stereochemical composition has an important role in the manufacturing process of therapeutic oligonucleotides, either as an in-process control or a final characterization test. In this Perspective, we first present the current status of oligonucleotide therapeutics, with a focus on phosphorothioate derivatives. We then highlight the regulatory framework for controlling the stereochemical composition of these drugs, provide brief insights into the biological significance of stereochemical composition for phosphorothioates, and discuss the origin of stereochemical composition in the synthetic and downstream processes. Subsequently, we provide an in-depth analysis of analytical methods used to determine the stereochemical composition of therapeutic oligonucleotides, including liquid chromatography approaches in various separation modes and emerging modern techniques like ion mobility spectrometry. Furthermore, capillary electrophoresis, duplex melting temperature, and NMR spectroscopy are also discussed in the context of stereochemical composition analysis of therapeutic oligonucleotides. Finally, we highlight novel enzymatic methods for cleaving therapeutic oligonucleotides into smaller fragments that can be analyzed for stereochemical composition using standard techniques.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4194–4214 4194–4214"},"PeriodicalIF":3.1,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://pubs.acs.org/doi/epdf/10.1021/acs.oprd.4c00380","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867789","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}
Rodolfo I. Teixeira, Toby H. Waldron Clarke, Ashley Love, Xue-Zhong Sun, Surajit Kayal, Michael W. George
{"title":"Scale-Up of Continuous Metallaphotoredox Catalyzed C–O Coupling to a 10 kg-Scale Using Small Footprint Photochemical Taylor Vortex Flow Reactors","authors":"Rodolfo I. Teixeira, Toby H. Waldron Clarke, Ashley Love, Xue-Zhong Sun, Surajit Kayal, Michael W. George","doi":"10.1021/acs.oprd.4c00262","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00262","url":null,"abstract":"We report the development and optimization of a scalable flow process for metallaphotoredox (Ir/Ni) C–O coupling, a mild and efficient approach for forming alkyl-aryl ethers, a common motif in medicinal and process chemistry settings. Time-resolved infrared spectroscopy (TRIR) highlighted the amine as the major quencher of the photocatalyst triplet excited state, along with the formation of an Ir(II) species that, in the presence of the Ni cocatalyst, has its lifetime shortened, suggesting reductive quenching of Ir(III)*, followed by reoxidation facilitated by the Ni cocatalyst. TRIR and batch reaction screening was used to develop conditions transferrable to flow, and many processing benefits of performing the reaction in flow were then demonstrated using a simple to construct/operate, small-footprint FEP coil flow reactor, including short (<10 min) space times and reduced catalyst loadings (down to 0.1 mol % Ir, 1 mol % Ni) while retaining good yield/conversion. Scalability was demonstrated by increasing the length or diameter of the FEP coil flow reactor tubing, however, due to suspected mass transfer/mixing limitations, the yield decreased upon scale-up in some cases. Therefore, we applied a modified version of our previously reported photochemical Taylor Vortex Flow Reactor (PhotoVortex), where Taylor vortices and a short-irradiated path length allow photochemical reactions to be performed efficiently via excellent mixing. In a small PhotoVortex (8 mL irradiated volume), we have demonstrated projected productivities around 1 kg day<sup>–1</sup> and >10 kg day<sup>–1</sup> in a large PhotoVortex (185 mL irradiated volume) with good product yields (>90%) and low catalyst loadings (0.1 to 0.5 mol % of [Ir{dF(CF<sub>3</sub>)ppy}<sub>2</sub>dtbbpy]PF<sub>6</sub>), enabled by excellent mixing ensuring sufficient mass transfer between short-lived photoexcited and other transient species.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"19 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142763715","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":"Safe and Sustainable Industrial-Scale Production of Anhydrous Diazomethane via a Fully DCS/SIS-Controlled Continuous Flow System: Synthesis of α-Haloketones","authors":"Limin Que, Hanrong Yang, Zhigang Lin, Jie Zheng","doi":"10.1021/acs.oprd.4c00449","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00449","url":null,"abstract":"Anhydrous diazomethane in nitrogen (12% v/v, moisture at <0.5 g/m<sup>3</sup>) has been safely manufactured via a fully automation controlled continuous microchannel reactor on a 1500 kg per month scale while the maximum accumulation of diazomethane was less than 20 g. Treatment of <i>N</i>-methyl-<i>N</i>-nitroso-<i>p</i>-toluenesulfonamide (MNTS, diazald) with KOH generated diazomethane <i>in situ</i>, which was isolated by a custom-designed gas–liquid distributor. Subsequently, the afforded anhydrous diazomethane was used to synthesize α-haloketones, which serve as key intermediates for anti-HIV and antihypertensive drugs such as Atazanavir and Nebivolol. The entire process from TsCl to α-haloketones had been continuously operated at the ABAChem manufacturing site for more than 6 months, affording a total of 5000 kg of pure diazomethane and 15,000 kg of α-haloketones smoothly without any safety issues. The microchannel flow reactor and gas–liquid distributor were designed specifically for the process and equipped with a fully distributed control system and safety instrumented system (DCS/SIS) to ensure safety, quality, and efficiency. The wastewater and solvent had been recycled and reused, while the process mass intensity for the six chemical synthesis steps from TsCl to the corresponding α-haloketones was significantly reduced from 200 to 300 to 40–60. This production protocol paves a safer, sustainable, and expedient access to industrial-scale synthesis of α-haloketones and other intermediates useful for production of pharmaceutical and agrochemical substances involving diazomethane.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"4 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142760240","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}
Jan-Ole Kundoch, Daniel Ohde, Emil Byström, Andreas Liese
{"title":"Screening Platform for Immobilized Biocatalysts Utilizing Miniature Rotating Bed Reactors","authors":"Jan-Ole Kundoch, Daniel Ohde, Emil Byström, Andreas Liese","doi":"10.1021/acs.oprd.4c00107","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00107","url":null,"abstract":"Biocatalysis has matured to become a technology widely applied in the chemical industry. There are numerous potential routes to improve the performance of a biocatalytic process. Immobilizing enzymes can be advantageous as it increases stability and simplifies separating enzymes from reaction mixtures. However, establishing a biocatalytic process based on immobilized enzymes is expensive, time-consuming, and labor-intensive. The reason for this is that a multitude of parameters influence the outcome of the immobilization and the performance in the final process. Screening these parameters in parallel on a small scale is a common strategy to address these issues. However, when screening immobilized enzymes with established methods such as centrifuge tubes, the reaction conditions differ substantially from the process conditions. We present a novel screening platform for immobilized enzymes based on magnetically driven miniature rotating bed reactors (MiniRBRs) to overcome this. This system unites the advantages of small scale operation with immobilizates and the application of rotating bed reactors, which are already established to be scalable at an industrial scale. As a model system, the synthesis of acetyl phosphate from glycolaldehyde catalyzed by a phosphoketolase is used in this study. We were able to significantly increase the stability of the phosphoketolase by immobilizing the phosphoketolase and using the MiniRBR system. In addition, the versatility of the MiniRBR will be demonstrated in terms of compatibility with different enzyme carrier materials, reaction conditions, and modes of operation.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"26 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142756374","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}
Jan-Ole Kundoch, Daniel Ohde, Emil Byström and Andreas Liese*,
{"title":"Screening Platform for Immobilized Biocatalysts Utilizing Miniature Rotating Bed Reactors","authors":"Jan-Ole Kundoch, Daniel Ohde, Emil Byström and Andreas Liese*, ","doi":"10.1021/acs.oprd.4c0010710.1021/acs.oprd.4c00107","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00107https://doi.org/10.1021/acs.oprd.4c00107","url":null,"abstract":"<p >Biocatalysis has matured to become a technology widely applied in the chemical industry. There are numerous potential routes to improve the performance of a biocatalytic process. Immobilizing enzymes can be advantageous as it increases stability and simplifies separating enzymes from reaction mixtures. However, establishing a biocatalytic process based on immobilized enzymes is expensive, time-consuming, and labor-intensive. The reason for this is that a multitude of parameters influence the outcome of the immobilization and the performance in the final process. Screening these parameters in parallel on a small scale is a common strategy to address these issues. However, when screening immobilized enzymes with established methods such as centrifuge tubes, the reaction conditions differ substantially from the process conditions. We present a novel screening platform for immobilized enzymes based on magnetically driven miniature rotating bed reactors (MiniRBRs) to overcome this. This system unites the advantages of small scale operation with immobilizates and the application of rotating bed reactors, which are already established to be scalable at an industrial scale. As a model system, the synthesis of acetyl phosphate from glycolaldehyde catalyzed by a phosphoketolase is used in this study. We were able to significantly increase the stability of the phosphoketolase by immobilizing the phosphoketolase and using the MiniRBR system. In addition, the versatility of the MiniRBR will be demonstrated in terms of compatibility with different enzyme carrier materials, reaction conditions, and modes of operation.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4264–4272 4264–4272"},"PeriodicalIF":3.1,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858621","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}
Heung Mo Kang, Chang Sang Moon, Yunchan Nam, Jiwoong Lim, Jiewan Kim, Tae-Hee Lee, Junho Lee, Mun Seog Chang, Jae Yeol Lee
{"title":"Optimization and Scale-Up Synthesis of a Lappaconitine Alkaloid Derivative, QG3030, as a Novel Osteoanabolic Agent","authors":"Heung Mo Kang, Chang Sang Moon, Yunchan Nam, Jiwoong Lim, Jiewan Kim, Tae-Hee Lee, Junho Lee, Mun Seog Chang, Jae Yeol Lee","doi":"10.1021/acs.oprd.4c00344","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00344","url":null,"abstract":"Our previous work revealed that the novel lappaconitine alkaloid derivative, <b>QG3030</b> (<b>6</b>), has an enhanced osteogenesis effect in the ovariectomized rat model without acute oral toxicity. <b>QG3030</b> (<b>6</b>) recently received approval for the Investigational New Drug application for its osteoporosis treatment from the Korean Ministry of Food and Drug Safety. Therefore, the need for an economical, large-scale production of <b>QG3030</b> (<b>6</b>) motivated the development of a novel synthetic procedure for its clinical studies. We herein report an efficient, safe, and cost-effective synthesis of <b>QG3030</b> (<b>6</b>) as a clinical candidate for osteoporosis treatment. As an optimized synthetic procedure, the reaction of lappaconitine·HBr (<b>1</b>·HBr, 1.0 kg scale) with co-oxidizing agents PhI(OAc)<sub>2</sub>-TEMPO (1.5 and 2 equiv) as a key step in a mixed EtOAc-acetone solution (v/v = 2/1) furnished α,β-unsaturated ketone (<b>4</b>), which was then treated with aq. NaOH to provide pure <b>QG3030</b> (<b>6</b>, 352 g) in 58% overall yield with a purity of 99.8% after crystallization from EtOH–CH<sub>2</sub>Cl<sub>2</sub>. This pilot synthetic procedure was performed three times, and the reproducible results were obtained with both nearly identical yields and purities.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"64 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142742845","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}