Organic Process Research & Development最新文献

英文中文

Kinetic Studies to Enable a Scalable Direct Glycosylation of a GalNAc Donor

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c00487

Shea J. O’Sullivan, James I. Murray, Eric Kircher, Zhou Li, Tsang-Lin Hwang, Seb Caille, Janine K. Tom

A direct glycosylation was developed to enable the supply of a key intermediate in the synthesis of a targeting N-acetylgalactosamine (GalNAc) ligand. Kinetic experiments were performed to elucidate possible mechanistic differences between transformations catalyzed by two potential metal triflate catalysts, revealing a change in the rate-limiting step upon alteration of the metal center. Selection of a bismuth triflate catalyst led to a more efficient and robust process, which halved the number of unit operations, reduced solvent waste by 70%, and increased the isolated yield by 60% compared to traditional indirect glycosylation conditions.

引用次数: 0

Safe and Efficient Continuous Flow Synthesis of (3S,4S)-3-[(R)-1-(t-Butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone via Vertical Dynamic Reactor

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-27 DOI: 10.1021/acs.oprd.4c00507

Kai Fu, Guangbing Zheng, Xibo Guan, Haibo Mu, Xianqiang Meng, Shouxiang Jiang, Bin Wang, Guangkun Dong, Gengxiu Zheng

The H₂O₂-mediated cleavage of chiral auxiliary as a mild and selective method is commonly used in the pharmaceutical industry but they can also introduce unexpected safety hazards due to the O₂ release. Here, a novel safe and efficient continuous flow synthesis process for (3S,4S)-3-[(R)-1-(t-butyldimethylsilyloxy)ethyl]-4-[(R)-1-carboxyethyl]-2-azetizinone (4-BMA), a key intermediate of meropenem was reported. The vertical dynamic reactor (VDR) effectively addresses the safety risk by preventing electrostatic accumulation and eliminating gas-phase space within the reactor. Compared to the current batch process, the continuous flow synthesis method reported in this paper not only significantly improved the safety of the process but also greatly shortened the reaction time (from 600 to 20 min) and increased the yield (from 85 to 91%) due to its high mass and heat transfer efficiency. These results indicated that the VDR provides great potential for the industrial scale-up of 4-BMA.

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引用次数: 0

Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c00426

Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert

This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.

{"title":"Industry Perspective on the Selection of Regulatory Starting Materials for Synthetic Peptides","authors":"Subha Mukherjee, David A. Thaisrivongs, Paridhi Agrawal, Mark R. Berglund, Alec Fettes, Zack Guo, Martin N. Kenworthy, Rasmus Lewinsky, John Lopez, Ogonna Nwajiobi, Yasuhiro Sawai, Kevin D. Seibert","doi":"10.1021/acs.oprd.4c00426","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00426","url":null,"abstract":"This Perspective from the Synthetic Peptide Working Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium or IQ) Drug Substance Leadership Group discusses the selection of regulatory starting materials (RSMs) for peptide manufacture. Given the ubiquity of solid-phase peptide synthesis (SPPS), it has been common practice to simply default to individual amino acids or dipeptides as RSMs. However, as the field of synthetic peptide research has grown and new synthesis technologies have been more widely adopted, this team proposes that there are cases where significant scientific and technical justification exists to consider larger peptide fragments as RSMs that remain consistent with ICH Q11. This framework would provide greater flexibility and support for the adoption of new and superior peptide synthesis technologies, increasing manufacturing process and supply chain robustness and offering opportunities for industry to address sustainability challenges inherent to current practices in synthetic peptide manufacture.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"1 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143496165","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}

引用次数: 0

Development of a Scalable Synthetic Route to (1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one: An Important Intermediate in the Synthesis of Lenacapavir

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-26 DOI: 10.1021/acs.oprd.4c00527

Aline Nunes De Souza, Nagaraju Sakkani, Daryl Guthrie, Rajkumar Lalji Sahani, John M. Saathoff, Samuel R. Hochstetler, Justina M. Burns, Saeed Ahmad, G. Michael Laidlaw, B. Frank Gupton, Douglas A. Klumpp, Limei Jin

(1R,5R)-2,2-Dimethoxybicyclo[3.1.0]hexan-3-one is used in the asymmetric synthesis of lenacapavir. Herein, we report an enantioselective synthesis of this important chiral intermediate from the inexpensive commodity (R)-epichlorohydrin. This synthetic method comprises 6 steps, including a 4-step telescoped bicyclic ketone synthesis, I₂-promoted hydroxylation, and an Albright–Goldman oxidation. This sequence affords (1R,5R)-2,2-dimethoxybicyclo[3.1.0]hexan-3-one in an overall 25% isolated yield as an enantiomerically pure compound. The entire process has been successfully demonstrated on a hundred-gram scale.

引用次数: 0

Development of an Innovative Three-Component Optical Resolution and a Flow Chemistry Process for (R)-Troloxamide Quinone (EPI-589)

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00540

Hirotsugu Usutani, Kiichi Kuroda, Kiyoto Sawamura, Jun Hirabayashi, Kenji Yamamoto, Masahiko Tanaka, Masayuki Ohira, Shigeaki Masuda, Takuya Nakagiri, Rui Ono, Tetsuji Kawamoto, Kazuki Hashimoto

(R)-Troloxamide quinone (EPI-589) is a compound that is under development as a therapeutic agent for Parkinson’s disease and amyotrophic lateral sclerosis (ALS). The compound is derived from Trolox, a vitamin E derivative, using optical resolution and subsequent chemical conversion processes to obtain the active pharmaceutical ingredient (API). However, in the initially developed manufacturing method, pseudoephedrine was used as the optical resolution reagent, although it is restricted for use as a stimulant drug raw material in several countries, and the reproducibility of the optical resolution was not high. Thus, it was necessary to find an alternative chiral amine, which would be more freely usable and give high reproducibility. Among several optical resolution conditions investigated, an unusual three-component complex between (R)-Trolox, (R)-phenylethylamine, and N-methyl-2-pyrrolidone (NMP) was identified as most effective. However, although the optical resolution process showed both high reproducibility and optical purity, the manufacturing method came with the risk of introducing nitrosamines into the active pharmaceutical ingredient, so further extensive investigations were conducted to address this issue. As a result, a flow chemistry process was developed, which could avoid the use of a nitrate reagent in the oxidation step, and thus eliminate the risk of nitrosamine generation. This paper discloses the process development studies and discusses the successful manufacturing of EPI-589 on a scale of several hundred kilograms, utilizing the novel optical resolution and flow chemistry process under GMP conditions.

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引用次数: 0

Development of a Scalable Manufacturing Process for AB-343 Drug Substance: A Potential Candidate for the Treatment of Coronavirus Infections

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00528

Jeremy D. Mason, Jan M. Spink, Mahesh Pallerla, Zhenhua Wu, Rajeev K. Singh, Aravind B. Pulipaka, Jia Liu, Marvin Marcus Vega, Xu Wang, Michael J. Sofia, Ganapati Reddy Pamulapati

A scalable process for manufacturing of the anticoronavirus clinical candidate AB-343 has been developed. The lactam-containing subunit of the molecule was prepared using a novel synthetic route involving a nitro-Michael reaction and a rhodium-catalyzed nitro group hydrogenation followed by in situ translactamization sequence as a key transformation. The drug substance was assembled via sequential amide coupling and deprotection reactions, followed by a final dehydration of a primary amide to the corresponding nitrile using T3P. AB-343 drug substance was successfully manufactured on a multikilogram scale using this route, which was suitable for supporting IND-enabling studies and Phase I clinical development.

引用次数: 0

Comprehensive Synthetic Route Redesign of AZD5991: A High-Complexity Atropisomeric Macrocycle

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-25 DOI: 10.1021/acs.oprd.4c00524

Gareth P. Howell, Lauren R. Agnew, Christoph Bauer, Fiona J. Bell, Andrew D. Campbell, Kuangchu Dai, David Dave, Sam R. Ellis, Matthew J. Foulkes, Malcolm A. Y. Gall, Kilian Garrec, Huajun Ge, Barry R. Hayter, Martin F. Jones, George Karageorgis, Mairi Littleson, Thomas W. Lloyd-Hughes, Harriet C. McNicholl, David T. Mooney, Bethany J. Moore, Rachel H. Munday, Emily Noone, David Perkins, Lyn Powell, Okky Dwichandra Putra, Simone Tomasi, Miriam Turner, Hongxu Wang, Hucheng Zhao, Oliver T. Ring

We describe our approach to the total synthesis of AZD5991 (1) from a process development perspective through the complete redesign of our synthetic strategy from the ground up. The size and complexity of small-molecule therapeutic targets have continued to increase over recent decades. One such example, 1, is arguably the most complex active pharmaceutical ingredient (API) in AstraZeneca’s small molecule development portfolio to date and poses formidable synthetic challenges. The previous racemic synthesis of 1 was sufficient to supply early clinical activities; however, the route was not deemed commercially viable and had significant environmental challenges. The identification of a long-term sustainable route was therefore critical to enable the robust manufacture of drug substance for later clinical activities and launch. We report exploration of asymmetric approaches toward the atropisomeric core, new routes toward each of the four heterocyclic building blocks, including a divergent pyrazole functionalization, and final assembly in a scalable and controlled macrocyclization process. These improvements resulted in a 49% reduction in step count and 95% reduction in projected waste generation.

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引用次数: 0

TFA Cleavage Strategy for Mitigation of S-tButylated Cys-Peptide Formation in Solid-Phase Peptide Synthesis

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-23 DOI: 10.1021/acs.oprd.4c00443

Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio, Beatriz G. de la Torre

Cysteine (Cys) is the most versatile amino acid-forming part of a peptide chain but at the same time the most complex. Its presence is associated with a large number of side reactions. In particular, the formation of S-tert-butylated Cys residues results from the reaction of the liberated Cys thiol with the tBu cations coming from the tBu-based protecting groups. Here, we have studied this side reaction using different scavengers such as alkyl and aryl thiols (DTT, 1,4-BDMT), thioethers (DMS, thioanisole), and sulfur-free compounds such as m-cresol, anisole, PPh₃ and TCEP in addition to TIS and H₂O. Three of these scavengers (DTT, 1,4-BDMT, PPh₃) are disulfide-reducing agents. Furthermore, the study also considered the cleavage duration and the TFA content in the cleavage mixtures. In peptides containing Ser(tBu) and/or Thr(tBu), the reduction of the TFA content led to the incomplete removal of the tBu protecting group. After this feasibility study, it can be concluded that the combined use of thioanisole and DMS in slightly higher quantity than TIS and H₂O in the presence of 1% DTT is beneficial. Furthermore, optimal results are obtained if the cleavage is carried out in two steps: initial treatment of the peptide with TFA/TIS/H₂O/thioanisole/DMS/1% DTT (70:5:5:10:10) for 30 min followed by TFA addition up to an 80% proportion and continued treatment for 150 min.

{"title":"TFA Cleavage Strategy for Mitigation of S-tButylated Cys-Peptide Formation in Solid-Phase Peptide Synthesis","authors":"Sinenhlanhla N. Mthembu, Amit Chakraborty, Ralph Schönleber, Fernando Albericio, Beatriz G. de la Torre","doi":"10.1021/acs.oprd.4c00443","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00443","url":null,"abstract":"Cysteine (Cys) is the most versatile amino acid-forming part of a peptide chain but at the same time the most complex. Its presence is associated with a large number of side reactions. In particular, the formation of S-tert-butylated Cys residues results from the reaction of the liberated Cys thiol with the tBu cations coming from the tBu-based protecting groups. Here, we have studied this side reaction using different scavengers such as alkyl and aryl thiols (DTT, 1,4-BDMT), thioethers (DMS, thioanisole), and sulfur-free compounds such as m-cresol, anisole, PPh3 and TCEP in addition to TIS and H2O. Three of these scavengers (DTT, 1,4-BDMT, PPh3) are disulfide-reducing agents. Furthermore, the study also considered the cleavage duration and the TFA content in the cleavage mixtures. In peptides containing Ser(tBu) and/or Thr(tBu), the reduction of the TFA content led to the incomplete removal of the tBu protecting group. After this feasibility study, it can be concluded that the combined use of thioanisole and DMS in slightly higher quantity than TIS and H2O in the presence of 1% DTT is beneficial. Furthermore, optimal results are obtained if the cleavage is carried out in two steps: initial treatment of the peptide with TFA/TIS/H2O/thioanisole/DMS/1% DTT (70:5:5:10:10) for 30 min followed by TFA addition up to an 80% proportion and continued treatment for 150 min.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"40 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143473536","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}

引用次数: 0

Analytical Control Strategies for Process Chemists

IF 3.1 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-21 DOI: 10.1021/acs.oprd.5c0004010.1021/acs.oprd.5c00040

Saranjit Singh*,

引用次数: 0

Analytical Control Strategies for Process Chemists

IF 3.4 3区化学 Q2 CHEMISTRY, APPLIED

Organic Process Research & Development

Pub Date : 2025-02-21 DOI: 10.1021/acs.oprd.5c00040

Saranjit Singh

Published as part of Organic Process Research & Development special issue “Analytical Control Strategies for Process Chemists”. Increased resource utilization, which can be achieved through atom economy leading to higher selectivity and high yields, minimization of byproducts formation (impurity rejection), and hence waste reduction. Simplicity and safety of processes, which means the involvement of minimal steps and use of readily available, safe, and environmentally friendly reagents and solvents. Also, the use of mild temperatures, pressures, and reagents leads to minimized energy consumption, reduced risk of hazardous conditions, and hence low environmental impact and better sustainability. Scalability and robustness, where the requirement is that the process should be readily scalable from laboratory to industrial production without significant changes in yield or selectivity and insensitive to minor variations in operating conditions or raw materials, ensuring consistent product quality. Cost-effectiveness, which refers to minimizing the overall cost of the process, including raw materials, energy, and waste disposal, to ensure economic viability. Regulatory compliance, in line with increasingly stringent policies from worldwide regulatory bodies toward assurance of product quality and patient safety in the case of pharmaceuticals and biopharmaceuticals. Use of strategies like constant monitoring and precise control of reaction conditions, such as temperature, pressure, pH, cooling rate, rotation speed, etc. The reactions with multiple steps and competing pathways can be challenging to control. In these situations, strategies like selective catalysis, precise dosing of reagents, and real-time monitoring of key intermediates can be used to steer the reaction toward the desired product. Analytical control strategies are essential for ensuring the quality of the product and consistency of organic processes. These strategies involve the use of various analytical techniques to monitor and optimize reaction conditions, track the formation of products and byproducts, and ensure that the final product meets the required specifications. Variations in raw materials, equipment performance, or operating conditions can lead to inconsistencies in product quality between different batches. To address this, strategies like statistical process control, detailed documentation of process parameters, and robust process design are employed. For example, in the production of an active drug substance, monitoring critical process parameters can help ensure consistent product quality across different batches. By providing real-time information about the composition of the reaction mixtures, analytical techniques enable scientists to gain a deeper understanding of reaction mechanisms and kinetics for controlling the product quality and cycle time. This knowledge is crucial for developing efficient and robust processes. Analytical techniques help identify

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引用次数: 0

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