盐酸绿卡色林的工艺研究?
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摘要
目的研究减肥药盐酸绿卡色林(1)的合成工艺。方法以N-烯丙基-N-[2-(4-氯苯基)乙基]氨基甲酸叔丁酯(3)为原料,经一步反应同时实现分子内的傅-克烷基化反应和脱Boc保护基反应,再经L-(+)-酒石酸手性拆分和成盐制备得到1。结果合成工艺总收率为24.7%,化学纯度为99.9%,光学纯度ee值>99.8%。各中间体和目标产物经1H NMR、13C NMR、ESI-MS表征。结论所研制的合成工艺路线操作简便、经济实用,适合工业化生产。
OBJECTIVE To study the synthetic process of antiobesity drug lorcaserin hydrochloride(1). METHODS 1 was synthesized form N-allyl-N-[2-(4-chlorobenyl)ethyl]tert-butyl carbamate(3) in a three-step process via one-step intramolecular Friedel-crafts alkylation and deprotection, chiral resolution with L-(+)-tartaric acid, and the final salification.RESULTS In overall yield was 24.7% the purity was 99.9%, and excellent enantioselectivity(ee) >99.8%. The intermediates and target product were confirmed by 1 H NMR, 13 C NMR and ESI-MS. CONCLUSION This convenient and economical procedure is remarkably applicable for industry.
OBJECTIVE To study the synthetic process of antiobesity drug lorcaserin hydrochloride(1). METHODS 1 was synthesized form N-allyl-N-[2-(4-chlorobenyl)ethyl]tert-butyl carbamate(3) in a three-step process via one-step intramolecular Friedel-crafts alkylation and deprotection, chiral resolution with L-(+)-tartaric acid, and the final salification.RESULTS In overall yield was 24.7% the purity was 99.9%, and excellent enantioselectivity(ee) >99.8%. The intermediates and target product were confirmed by 1 H NMR, 13 C NMR and ESI-MS. CONCLUSION This convenient and economical procedure is remarkably applicable for industry.
引文
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[18]MENG T,LIU D,HE C,et al.Study on synthetic process and impurity of lorcaserin hydrochloride hemihydrate[J].Chin JMed Chem(中国药物化学杂志),2018,28(2):128-133.
[19]朱启华,徐云根,卞学国,等.一种减肥药盐酸绿卡色林及其中间体的制备方法:中国,105367497[P].2016-03-02.
[20]ZHU Q H,WANG J W,BIAN X G,et al.Novel synthesis of antiobesity drug lorcaserin hydrochloride[J].Org Pro Res Dev,2015,19(9):1263-1267
[2]KANG Y H,JIN Z.A novel anfiobesity drug lorcaserin hydrochloride[J].Prog Pharm Sci(药学进展),2008,32(9):423-425.
[3]JIANG H Y.The adverse reactions of fluoxetine hydrochloride[J].Chin J Mod Appl Pharm(中国现代应用药学),2008,25(8):763-765.
[4]ZHANG L Z,ZHU Q H,XU Y G.Progress in researches for antiobesity drugs[J].Chin J New Drugs(中国新药杂志),2016,25(15):1721-1725.
[5]SMITH B M,SMITH J M,TSAI J H,et al.Discovery and SAR of new benzazepines as potent and selective 5-HT(2C)receptor agonists for the treatment of obesity[J].Cheminform,2005,15(5):1467-1470.
[6]SMITH B M,SMITH J M,TSAI J H,et al.Discovery and structure-activity relationship of(1R)-8-chloro-2,3,4,5-tetrahydro-1-methy l-1H-3-benzazepine(lorcaserin),a selective serotonin 5-HT2C receptor agonist for the treatment of obesity[J].J Med Chem,2008,51(2):305-313.
[7]HE X,WANG J W,ZHU Q H,et al.Progress in synthesis of lorcaserin hydrochloride[J].Chin J New Drugs(中国新药杂志),2016,25(23):2676-2682.
[8]LIU W Z,WANG D W,WANG G C,et al.Graphical synthetic routes of lorcaserin hydrochloride[J].Chin JPharm(中国医药工业杂志),2016,47(3):347-351.
[9]WEIGL U,PORSTMANN F,STRAESSLER C,et al.Processes for the preparation of 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates related thereto:US,20090143576[P].2009-06-04.
[10]GHARBAOUI T,TANDEL S K,MA Y,et al.Processes for preparing(R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine and intermediates thereto:WO,2008070111[P],2008-06-12.
[11]SMITH B,GILSON C,SCHULTZ J,et al.Benzazepine derivativesuseful for the treatment of 5-HT2C receptors associated diseases:WO,2005003096[P].2005-01-13.
[12]DURAN LóPEZ E.Process for the enantioselective synthesis of a tetrahydrobenzazepine compound:WO,2014060575[P].2014-04-24.
[13]LIU J F.Deuterated Lorcaserin:WO,2009051747[P].2009-04-23.
[14]BURBAUM B W,GILSON C A,AYTES S,et al.Processes for preparing 3-benzazepines:WO,2005019179[P].2005-03-03.
[15]STAVBER G,JEROME C,FRANK R,et al.Novel synthetic process to 8-chloro-1-methyl-benzo[d]azepine,novel intermediates and the production thereof:WO,2014173928[P].2014-10-30.
[16]STAVBER G,CLUZEAU J.Novel synthetic processes to8-chloro-3-benzo[d]azepine via Friedel-Crafts alkylation of olefin:WO,2014187768[P].2014-11-27.
[17]STAVBER G,IVANA G S,JEROME C,et al.Preparation of chiral 1-methyl-2,3,4,5-1H-benzodiazepine via asymmetric reduction of alpha-substituted styrenes:WO,2014202765[P].2014-12-24.
[18]MENG T,LIU D,HE C,et al.Study on synthetic process and impurity of lorcaserin hydrochloride hemihydrate[J].Chin JMed Chem(中国药物化学杂志),2018,28(2):128-133.
[19]朱启华,徐云根,卞学国,等.一种减肥药盐酸绿卡色林及其中间体的制备方法:中国,105367497[P].2016-03-02.
[20]ZHU Q H,WANG J W,BIAN X G,et al.Novel synthesis of antiobesity drug lorcaserin hydrochloride[J].Org Pro Res Dev,2015,19(9):1263-1267