Qiang Yang*, Yu Lu, Han Xia, Vishaal Gopalakrishnan, Scott A. Frank, Yungang He, Lixuan Liang, Xin Zhang, Ping Huang, Chuanren Liu, Jing Chen, Qicheng Ma, Sha Li and Li Fan,
{"title":"高能化合物 4-甲基-1,2,5-恶二唑-3-羧酸的安全指导工艺开发和规模化生产","authors":"Qiang Yang*, Yu Lu, Han Xia, Vishaal Gopalakrishnan, Scott A. Frank, Yungang He, Lixuan Liang, Xin Zhang, Ping Huang, Chuanren Liu, Jing Chen, Qicheng Ma, Sha Li and Li Fan, ","doi":"10.1021/acs.oprd.4c00137","DOIUrl":null,"url":null,"abstract":"<p >The synthesis of the highly energetic pharmaceutical intermediate 4-methyl-1,2,5-oxadiazole-3-carboxylic acid via cyclization of (2<i>E</i>,3<i>E</i>)-butane-2,3-dione dioxime followed by selective oxidation of the resulting 3,4-dimethyl-1,2,5-oxadiazole was developed to support the sample production for clinical trials. Rigorous process safety evaluations revealed many potential safety risks associated with the involved highly energetic compounds and the high exothermicity of the oxidation reaction. A continuous flow process was developed for the synthesis of 3,4-dimethyl-1,2,5-oxadiazole to mitigate the potential safety risks associated with the thermal instability of starting material (2<i>E</i>,3<i>E</i>)-butane-2,3-dione dioxime and product 3,4-dimethyl-1,2,5-oxadiazole. A much safer process for the highly exothermic oxidation of 3,4-dimethyl-1,2,5-oxadiazole involving portion-wise addition of potassium permanganate was developed to avoid accumulation of reactive chemicals. The desired product was isolated as <i>N</i>-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to avoid handling of potentially explosive 4-methyl-1,2,5-oxadiazole-3-carboxylic acid in its solid form. The developed process was successfully scaled up to afford a total of 93.52 kg of <i>N</i>-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to support the production of a drug substance.</p>","PeriodicalId":55,"journal":{"name":"Organic Process Research & Development","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Safety Guided Process Development and Scale-Up of the Highly Energetic Compound 4-Methyl-1,2,5-oxadiazole-3-carboxylic Acid\",\"authors\":\"Qiang Yang*, Yu Lu, Han Xia, Vishaal Gopalakrishnan, Scott A. Frank, Yungang He, Lixuan Liang, Xin Zhang, Ping Huang, Chuanren Liu, Jing Chen, Qicheng Ma, Sha Li and Li Fan, \",\"doi\":\"10.1021/acs.oprd.4c00137\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p >The synthesis of the highly energetic pharmaceutical intermediate 4-methyl-1,2,5-oxadiazole-3-carboxylic acid via cyclization of (2<i>E</i>,3<i>E</i>)-butane-2,3-dione dioxime followed by selective oxidation of the resulting 3,4-dimethyl-1,2,5-oxadiazole was developed to support the sample production for clinical trials. Rigorous process safety evaluations revealed many potential safety risks associated with the involved highly energetic compounds and the high exothermicity of the oxidation reaction. A continuous flow process was developed for the synthesis of 3,4-dimethyl-1,2,5-oxadiazole to mitigate the potential safety risks associated with the thermal instability of starting material (2<i>E</i>,3<i>E</i>)-butane-2,3-dione dioxime and product 3,4-dimethyl-1,2,5-oxadiazole. A much safer process for the highly exothermic oxidation of 3,4-dimethyl-1,2,5-oxadiazole involving portion-wise addition of potassium permanganate was developed to avoid accumulation of reactive chemicals. The desired product was isolated as <i>N</i>-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to avoid handling of potentially explosive 4-methyl-1,2,5-oxadiazole-3-carboxylic acid in its solid form. The developed process was successfully scaled up to afford a total of 93.52 kg of <i>N</i>-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to support the production of a drug substance.</p>\",\"PeriodicalId\":55,\"journal\":{\"name\":\"Organic Process Research & Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-07-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Organic Process Research & Development\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00137\",\"RegionNum\":3,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, APPLIED\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Organic Process Research & Development","FirstCategoryId":"92","ListUrlMain":"https://pubs.acs.org/doi/10.1021/acs.oprd.4c00137","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, APPLIED","Score":null,"Total":0}
Safety Guided Process Development and Scale-Up of the Highly Energetic Compound 4-Methyl-1,2,5-oxadiazole-3-carboxylic Acid
The synthesis of the highly energetic pharmaceutical intermediate 4-methyl-1,2,5-oxadiazole-3-carboxylic acid via cyclization of (2E,3E)-butane-2,3-dione dioxime followed by selective oxidation of the resulting 3,4-dimethyl-1,2,5-oxadiazole was developed to support the sample production for clinical trials. Rigorous process safety evaluations revealed many potential safety risks associated with the involved highly energetic compounds and the high exothermicity of the oxidation reaction. A continuous flow process was developed for the synthesis of 3,4-dimethyl-1,2,5-oxadiazole to mitigate the potential safety risks associated with the thermal instability of starting material (2E,3E)-butane-2,3-dione dioxime and product 3,4-dimethyl-1,2,5-oxadiazole. A much safer process for the highly exothermic oxidation of 3,4-dimethyl-1,2,5-oxadiazole involving portion-wise addition of potassium permanganate was developed to avoid accumulation of reactive chemicals. The desired product was isolated as N-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to avoid handling of potentially explosive 4-methyl-1,2,5-oxadiazole-3-carboxylic acid in its solid form. The developed process was successfully scaled up to afford a total of 93.52 kg of N-methyl morpholine 4-methyl-1,2,5-oxadiazole-3-carboxylate to support the production of a drug substance.
期刊介绍:
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools,process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.