伊万卡塞合成研究  

Study on synthetic of evocalcet

作　　者：徐松林 陈金萍 付德才[1] XU Song-lin;CHEN Jin-ping;FU De-cai(College of Chemical and Pharmaceutical Engineering,Hebei Science and Technology University,Shijiazhuang 050018,China;Hebei Zhiheng Pharmaceuticel Co.,Ltd.,Shijiazhuang 050021,China)

机构地区：[1]河北科技大学化学与制药工程学院,河北石家庄050018 [2]河北智恒医药科技有限公司,河北石家庄050021

出　　处：《中国药物化学杂志》2022年第11期839-842,共4页Chinese Journal of Medicinal Chemistry

摘　　要：目的 优化伊万卡塞合成工艺。方法 以(R)-1-Boc-3-羟基吡咯烷为起始原料,经酯化、亲核取代、脱Boc保护基、Buchwald-Hartwig反应、水解共5步反应合成伊万卡塞。结果与结论目标物的结构经~1H-NMR谱确证,总收率约为55%,纯度达99.5%以上(HPLC法)。该合成方法以对硝基苯磺酰氯替代邻硝基苯磺酰氯,中间体易于分离纯化,终产品纯度高,生产成本低廉,操作简便,适合规模化生产。Evocalcet is a new type of calcimimetic for the treatment of hemodialysis and peritoneal dialysis patients with secondary hyperparathyroidism.This paper introduces the solid compound obtained by esterification of chiral compound(R)-1-Boc-3-hydroxypyrrolidine with p-nitrobenzene sulfuryl chloride.The solid compound can be well separated and purified,nucleophilic substitution of(R)-1-naphthalene ethylamine,removal of Boc with hydrochloric acid,and then coupled with p-bromophenylacetate to obtain the target compound evocalcet by hydrolysis.The route introduced in this paper avoids the problem that the multi-step intermediate contains oil and cannot be separated and purified,and plays an important role in improving the purity of subsequent products.The reaction conditions of abandoning the expensive reagent cesium carbonate without affecting the reaction yield was proposed.The total yield was 55%and the purity was over 99.5%.The synthetic route is suitable for mass production.

关 键 词：伊万卡塞 (R)-1-Boc-3-羟基吡咯烷 Buchwald-Hartwig反应 合成工艺 

分 类 号：R914[医药卫生—药物化学]