Organic Process Research & Development最新文献_第5页

Optimization and Scale-Up Synthesis of a Lappaconitine Alkaloid Derivative, QG3030, as a Novel Osteoanabolic Agent

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-29 DOI: 10.1021/acs.oprd.4c0034410.1021/acs.oprd.4c00344

Heung Mo Kang, Chang Sang Moon, Yunchan Nam, Jiwoong Lim, Jiewan Kim, Tae-Hee Lee, Junho Lee, Mun Seog Chang* and 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* and Jae Yeol Lee*, ","doi":"10.1021/acs.oprd.4c0034410.1021/acs.oprd.4c00344","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00344https://doi.org/10.1021/acs.oprd.4c00344","url":null,"abstract":"Our previous work revealed that the novel lappaconitine alkaloid derivative, QG3030 (6), has an enhanced osteogenesis effect in the ovariectomized rat model without acute oral toxicity. QG3030 (6) 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 QG3030 (6) motivated the development of a novel synthetic procedure for its clinical studies. We herein report an efficient, safe, and cost-effective synthesis of QG3030 (6) as a clinical candidate for osteoporosis treatment. As an optimized synthetic procedure, the reaction of lappaconitine·HBr (1·HBr, 1.0 kg scale) with co-oxidizing agents PhI(OAc)2-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 (4), which was then treated with aq. NaOH to provide pure QG3030 (6, 352 g) in 58% overall yield with a purity of 99.8% after crystallization from EtOH–CH2Cl2. 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":"28 12","pages":"4328–4337 4328–4337"},"PeriodicalIF":3.1,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858569","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

Process Development to Synthesize SGD-11275 Utilizing a Pd-Catalyzed Acetamide Arylation and Gallium-Mediated Friedel–Crafts Acylation 利用钯催化乙酰胺芳基化和镓介导的 Friedel-Crafts 丙烯酰化合成 SGD-11275 的工艺开发

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-26 DOI: 10.1021/acs.oprd.4c00375

Tristan M. McGinnis, Noah Porter, Apparao Bokka, Kun-Liang Wu, Brooke Gill, Jared Abbruzzese, Aaron M. Whittaker, Srinath Thirumalai rajan

引用次数: 0

Process Development to Synthesize SGD-11275 Utilizing a Pd-Catalyzed Acetamide Arylation and Gallium-Mediated Friedel–Crafts Acylation

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-26 DOI: 10.1021/acs.oprd.4c0037510.1021/acs.oprd.4c00375

Tristan M. McGinnis*, Noah Porter, Apparao Bokka, Kun-Liang Wu, Brooke Gill, Jared Abbruzzese, Aaron M. Whittaker and Srinath Thirumalai rajan,

引用次数: 0

Atom-Economical and Environmentally Friendly Bts-Based Purine PNA Monomers without Base-Protecting Groups 无碱基保护基团的原子经济环保型 Bts 基嘌呤 PNA 单体

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-25 DOI: 10.1021/acs.oprd.4c0041310.1021/acs.oprd.4c00413

Minji Kim, Hyewon Hwang, Yong-Tae Kim and In Seok Hong*,

{"title":"Atom-Economical and Environmentally Friendly Bts-Based Purine PNA Monomers without Base-Protecting Groups","authors":"Minji Kim, Hyewon Hwang, Yong-Tae Kim and In Seok Hong*, ","doi":"10.1021/acs.oprd.4c0041310.1021/acs.oprd.4c00413","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00413https://doi.org/10.1021/acs.oprd.4c00413","url":null,"abstract":"Traditionally, Fmoc/Bhoc or Bts/Bhoc monomers have been employed in the solid-phase peptide synthesis (SPPS) of peptide nucleic acids (PNAs). The primary function of the Bhoc group as a base-protecting group is to prevent the exocyclic amine of the nucleobase from participating in the coupling reaction and to enhance the solubility of the monomer in the coupling solvent. However, regarding the nucleophilicity of the base, only the exocyclic amine at C4 of cytosine exhibits significant nucleophilicity, while the exocyclic amines of adenine (N6) and guanine (N2) have minimal nucleophilic character. In fact, the protection of the exocyclic amine in purine bases during SPPS is unnecessary if the sole objective is to improve the monomer’s solubility. In this study, we synthesized novel purine monomers based on cyclic Bts that lack base-protecting groups. Using these unprotected monomers, PNA oligomers were synthesized via the SPPS method and the crude purities of these oligomers were compared with those synthesized using fully Bhoc-protected monomers. The crude purity of 15-mer PNA oligomers using six purine monomers without protecting groups was superior to that of oligomers synthesized from Bts/Bhoc monomers. Moreover, we demonstrated that these unprotected monomers are effective for synthesizing poly purine PNA oligomers, which are otherwise challenging to synthesize by SPPS. As a result, we have synthesized the first Bts-based purine monomers without base-protecting groups, offering a more atom-efficient and environmentally friendly alternative to conventional Bhoc-protected purine monomers for large-scale PNA oligomer production.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4492–4500 4492–4500"},"PeriodicalIF":3.1,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142867871","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

Atom-Economical and Environmentally Friendly Bts-Based Purine PNA Monomers without Base-Protecting Groups 无碱基保护基团的原子经济环保型 Bts 基嘌呤 PNA 单体

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-25 DOI: 10.1021/acs.oprd.4c00413

Minji Kim, Hyewon Hwang, Yong-Tae Kim, In Seok Hong

{"title":"Atom-Economical and Environmentally Friendly Bts-Based Purine PNA Monomers without Base-Protecting Groups","authors":"Minji Kim, Hyewon Hwang, Yong-Tae Kim, In Seok Hong","doi":"10.1021/acs.oprd.4c00413","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00413","url":null,"abstract":"Traditionally, Fmoc/Bhoc or Bts/Bhoc monomers have been employed in the solid-phase peptide synthesis (SPPS) of peptide nucleic acids (PNAs). The primary function of the Bhoc group as a base-protecting group is to prevent the exocyclic amine of the nucleobase from participating in the coupling reaction and to enhance the solubility of the monomer in the coupling solvent. However, regarding the nucleophilicity of the base, only the exocyclic amine at C4 of cytosine exhibits significant nucleophilicity, while the exocyclic amines of adenine (N6) and guanine (N2) have minimal nucleophilic character. In fact, the protection of the exocyclic amine in purine bases during SPPS is unnecessary if the sole objective is to improve the monomer’s solubility. In this study, we synthesized novel purine monomers based on cyclic Bts that lack base-protecting groups. Using these unprotected monomers, PNA oligomers were synthesized via the SPPS method and the crude purities of these oligomers were compared with those synthesized using fully Bhoc-protected monomers. The crude purity of 15-mer PNA oligomers using six purine monomers without protecting groups was superior to that of oligomers synthesized from Bts/Bhoc monomers. Moreover, we demonstrated that these unprotected monomers are effective for synthesizing poly purine PNA oligomers, which are otherwise challenging to synthesize by SPPS. As a result, we have synthesized the first Bts-based purine monomers without base-protecting groups, offering a more atom-efficient and environmentally friendly alternative to conventional Bhoc-protected purine monomers for large-scale PNA oligomer production.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"34 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142712966","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 Method for the Synthesis of Ethoxy(pentafluoro)cyclotriphosphazene

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-21 DOI: 10.1021/acs.oprd.4c0024310.1021/acs.oprd.4c00243

Lijun Zhu, Desheng Zhang, Zilong Li, Raoling Ge, Banglong Wan, Qiang Tian* and Pengfei Xu*,

{"title":"Development of a Scalable Method for the Synthesis of Ethoxy(pentafluoro)cyclotriphosphazene","authors":"Lijun Zhu, Desheng Zhang, Zilong Li, Raoling Ge, Banglong Wan, Qiang Tian* and Pengfei Xu*, ","doi":"10.1021/acs.oprd.4c0024310.1021/acs.oprd.4c00243","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00243https://doi.org/10.1021/acs.oprd.4c00243","url":null,"abstract":"Ethoxy(pentafluoro)cyclophosphazene (1) exhibits excellent flame retardancy and various biological activities, and there are numerous synthesis methods available. However, most of these methods have certain problems and shortcomings, such as the use of expensive raw materials and toxic and harmful reagents. To address these issues and uncertainties, we reported the development of a facile and sustainable synthesis method of 1, which involves only two concise chemical steps. In this process, the first step contains the reaction of hexachorocyclotriphosphazene (3) with sodium fluoride to yield hexafluorocyclotriphosphazene (2). The second step includes ethoxylation using an ethoxylation reagent, ethanol, and sodium hydroxide as an acid-binding agent to produce 1 with good quality and an overall yield of 76%. Several advantages are offered by this new synthetic approach, including good reactivity, high yield, low cost, environmental friendliness, and, finally, being industrially viable. The optimized process has been successfully demonstrated on a large scale to support the development of the new energy electric vehicle industry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"28 12","pages":"4294–4302 4294–4302"},"PeriodicalIF":3.1,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142858837","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 Method for the Synthesis of Ethoxy(pentafluoro)cyclotriphosphazene 开发可扩展的乙氧基(五氟)环三唑磷合成方法

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-21 DOI: 10.1021/acs.oprd.4c00243

Lijun Zhu, Desheng Zhang, Zilong Li, Raoling Ge, Banglong Wan, Qiang Tian, Pengfei Xu

{"title":"Development of a Scalable Method for the Synthesis of Ethoxy(pentafluoro)cyclotriphosphazene","authors":"Lijun Zhu, Desheng Zhang, Zilong Li, Raoling Ge, Banglong Wan, Qiang Tian, Pengfei Xu","doi":"10.1021/acs.oprd.4c00243","DOIUrl":"https://doi.org/10.1021/acs.oprd.4c00243","url":null,"abstract":"Ethoxy(pentafluoro)cyclophosphazene (1) exhibits excellent flame retardancy and various biological activities, and there are numerous synthesis methods available. However, most of these methods have certain problems and shortcomings, such as the use of expensive raw materials and toxic and harmful reagents. To address these issues and uncertainties, we reported the development of a facile and sustainable synthesis method of 1, which involves only two concise chemical steps. In this process, the first step contains the reaction of hexachorocyclotriphosphazene (3) with sodium fluoride to yield hexafluorocyclotriphosphazene (2). The second step includes ethoxylation using an ethoxylation reagent, ethanol, and sodium hydroxide as an acid-binding agent to produce 1 with good quality and an overall yield of 76%. Several advantages are offered by this new synthetic approach, including good reactivity, high yield, low cost, environmental friendliness, and, finally, being industrially viable. The optimized process has been successfully demonstrated on a large scale to support the development of the new energy electric vehicle industry.","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":"17 1","pages":""},"PeriodicalIF":3.4,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142684789","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

Practical, Large-Scale Preparation of Ni(tmeda)(o-tol)Cl 实用、大规模制备 Ni(tmeda)(邻甲苯)Cl

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c0040810.1021/acs.oprd.4c00408

Morgan E. John*, Daven Foster, Stephen A. Moggach, George A. Koutsantonis, Reto Dorta and Scott G. Stewart*,

引用次数: 0

Practical, Large-Scale Preparation of Ni(tmeda)(o-tol)Cl 实用、大规模制备 Ni(tmeda)(邻甲苯)Cl

IF 3.4 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c00408

Morgan E. John, Daven Foster, Stephen A. Moggach, George A. Koutsantonis, Reto Dorta, Scott G. Stewart

引用次数: 0

Practical and Efficient Approach to Scalable Synthesis of Rucaparib Rucaparib 可扩展合成的实用高效方法

IF 3.1 3区化学

Organic Process Research & Development Pub Date : 2024-11-15 DOI: 10.1021/acs.oprd.4c0036610.1021/acs.oprd.4c00366

Jinjae Park, and , Cheol-Hong Cheon*,

引用次数: 0