Axitinib,an inhibitor of vascular endothelial growth factor(VEGF) under investigation as an oncology drug,was developed by Pfizer and was approved by FDA in January 2012 with the trade name Inlyta.Based on the synthetic method of axitinib in one patent,we optimized and improved the existing process.For example,we used 2-mercapto-benzoic acid methyl ester in the coupling reaction instead of 2-mercaptobenzoic acid methyl amide to improve the yield and avoid using column chromatography in the reaction.In summary,In our designing route,axitinib was synthesized from 6-nitro-1 H-indazole by iodination,THP protection,Heck reaction,reduction,and then coupled with 2-mercapto-benzoic acid methyl ester,deprotection and ammonolysis with an overall yield of about 33.4%,which is higher than that of the reference(23.2%).The structures of axitinib and intermediates were confirmed by 1H-NMR and MS.
{"title":"Synthesis of Axitinib","authors":"P. Kocieňski","doi":"10.1055/s-0035-1560257","DOIUrl":"https://doi.org/10.1055/s-0035-1560257","url":null,"abstract":"Axitinib,an inhibitor of vascular endothelial growth factor(VEGF) under investigation as an oncology drug,was developed by Pfizer and was approved by FDA in January 2012 with the trade name Inlyta.Based on the synthetic method of axitinib in one patent,we optimized and improved the existing process.For example,we used 2-mercapto-benzoic acid methyl ester in the coupling reaction instead of 2-mercaptobenzoic acid methyl amide to improve the yield and avoid using column chromatography in the reaction.In summary,In our designing route,axitinib was synthesized from 6-nitro-1 H-indazole by iodination,THP protection,Heck reaction,reduction,and then coupled with 2-mercapto-benzoic acid methyl ester,deprotection and ammonolysis with an overall yield of about 33.4%,which is higher than that of the reference(23.2%).The structures of axitinib and intermediates were confirmed by 1H-NMR and MS.","PeriodicalId":10117,"journal":{"name":"Chinese Journal of Medicinal Chemistry","volume":"11 1","pages":"1017 - 1017"},"PeriodicalIF":0.0,"publicationDate":"2015-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0035-1560257","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"58092114","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dacarbazine has been prepared started from glycine, which was carried on firstly through a four-step process including esterification, formylation, dehydration, amidation to give 2-isocyanoacetamide with a total yield of 42.9%. 2Isocyanoacetamide was then cyclized with cyanamide under basic condition to afford the important intermediate 5-amino-1H-imidazole-4-carboxamide with yield of 68.2%. This intermediate undergoing diazotization and following coupling reaction with dimethylamine led to the target compound. The overall yield was 22.3%. All the intermediates and the target products dacarbazine were confirmed by H NMR, C NMR and ESI-MS. The current process is economic efficient characterized by applied cheap materials, mild conditions, and good overall yield.
{"title":"Optimization of the Synthetic Process of Antineoplastic Drug Dacarbazine","authors":"Shengwei Xiao, Zhijun Liu, Yang Liu, Heru Chen","doi":"10.6023/CJOC201410026","DOIUrl":"https://doi.org/10.6023/CJOC201410026","url":null,"abstract":"Dacarbazine has been prepared started from glycine, which was carried on firstly through a four-step process including esterification, formylation, dehydration, amidation to give 2-isocyanoacetamide with a total yield of 42.9%. 2Isocyanoacetamide was then cyclized with cyanamide under basic condition to afford the important intermediate 5-amino-1H-imidazole-4-carboxamide with yield of 68.2%. This intermediate undergoing diazotization and following coupling reaction with dimethylamine led to the target compound. The overall yield was 22.3%. All the intermediates and the target products dacarbazine were confirmed by H NMR, C NMR and ESI-MS. The current process is economic efficient characterized by applied cheap materials, mild conditions, and good overall yield.","PeriodicalId":10117,"journal":{"name":"Chinese Journal of Medicinal Chemistry","volume":"35 1","pages":"1161"},"PeriodicalIF":0.0,"publicationDate":"2015-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71336805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lin Lin, Wang Zhe-jiang, Mao Dong-dong, X. You-jun
Aim To investigate an improved synthetic process of oseltamivir phosphate,an antiviral drug.Methods Starting from(-)-shikimic acid,the key intermediate ethyl(3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-carboxylate(2) was synthesized via esterification,ketalization,mesylation,transketalization,reduction and intramolecular SN2 reaction.2 was treated with tert-butylamine for epoxide-opening in the presence of MgCl2,and then brought into mesylation and intramolecular SN2 reaction to form the aziridine ethyl(3R,4S,5R)-4,5-(1,1-dimethylethyl) imino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.After MsOH-promoted opening of the aziridine with diallylamine,followed by acetylation and successive removal of tert-butyl and allyl group,oseltamivir was eventually obtained.Results and conclusion Oseltamivir phosphate was synthesized via a 13-step sequence in a total yield of 29.5% and its structure was identified by 1H-NMR and MS.
{"title":"Synthesis of oseltamivir phosphate","authors":"Lin Lin, Wang Zhe-jiang, Mao Dong-dong, X. You-jun","doi":"10.1055/s-0032-1317719","DOIUrl":"https://doi.org/10.1055/s-0032-1317719","url":null,"abstract":"Aim To investigate an improved synthetic process of oseltamivir phosphate,an antiviral drug.Methods Starting from(-)-shikimic acid,the key intermediate ethyl(3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-1-cyclohexene-1-carboxylate(2) was synthesized via esterification,ketalization,mesylation,transketalization,reduction and intramolecular SN2 reaction.2 was treated with tert-butylamine for epoxide-opening in the presence of MgCl2,and then brought into mesylation and intramolecular SN2 reaction to form the aziridine ethyl(3R,4S,5R)-4,5-(1,1-dimethylethyl) imino-3-(1-ethylpropoxy)-1-cyclohexene-1-carboxylate.After MsOH-promoted opening of the aziridine with diallylamine,followed by acetylation and successive removal of tert-butyl and allyl group,oseltamivir was eventually obtained.Results and conclusion Oseltamivir phosphate was synthesized via a 13-step sequence in a total yield of 29.5% and its structure was identified by 1H-NMR and MS.","PeriodicalId":10117,"journal":{"name":"Chinese Journal of Medicinal Chemistry","volume":"1 1","pages":"263-267"},"PeriodicalIF":0.0,"publicationDate":"2009-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1055/s-0032-1317719","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"58058253","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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