(2S,4S)-N-叔丁氧羰基-4-氟脯氨酸的合成  

Synthesis of (2S,4S)-N-tert-butoxycarbonyl-4-fluoroproline

作　　者：刘甜甜[1] 张志光 杨媛媛 马彦涛 张勇[1,2] LIU Tiantian;ZHANG Zhiguang;YANG Yuanyuan;MA Yantao;ZHANG Yong(School of Chemical and Pharmaceutical Engineering,Hebei University of Science and Technology,Shijiazhuang,Hebei 050018,China;State Key Laboratory Breeding Base-Key Laboratory of Molecular Chemistry for Drug of Hebei Province,Shijiazhuang,Hebei 050018,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]河北省药用分子化学重点实验室-省部共建国家重点实验室培育基地,河北石家庄050018

出　　处：《河北科技大学学报》2018年第2期154-158,共5页Journal of Hebei University of Science and Technology

基　　金：河北省引进留学人员资助项目(C2013003018)

摘　　要：为了克服中间体难于分离纯化的缺点,解决季铵盐的去除问题,对多肽及拟肽类药物关键中间体(2S,4S)-N-叔丁氧羰基-4-氟脯氨酸的合成工艺进行了研究。以(2S,4R)-4-羟基脯氨酸为原料,经酯化、氨基保护、羟基活化-氟代-水解反应得到目标化合物。将羟基活化、SN2氟代和酯水解反应采用串联方式,在水解反应后调节pH值的过程中产物从水溶液中析出,经直接过滤得到目的物。对反应条件和参数进行了优化,优化条件如下:酯化反应中,n(氯化亚砜)∶n(底物)=1.2∶1.0;氨基保护反应中,n(二碳酸二叔丁酯)∶n(化合物1)=1.2∶1.0;三氟甲磺酰化反应中,n(三氟甲磺酸酐)∶n(化合物2)=1.1∶1.0,n(吡啶)∶n(化合物2)=1.2∶1.0。结果表明,优化后产物总收率为57.9%,纯度为98.3%,目标化合物结构通过~1H-NMR和^(13)C-NMR得以确证。该方法反应条件温和,操作简单,适合工业化生产。In order to overcome the difficulty to separate and purify the intermediate,solve the problem of quaternary ammonium salt removal,the synthesis of(2S,4S)-N-tert-butoxycarbonyl-4-fluoroproline which is a key intermediate of polypeptides and peptidomimetic drug is studied.The target compound is synthesized from(2S,4R)-4-hydroxyproline via esterification,amino protection,and hydroxyl activation-fluorination-hydrolysis tandem reaction.Hydroxyl activation,S N2 fluorine substitution and ester hydrolysis reaction are completed as a tandem reaction.After the hydrolysis reaction,the product is precipitated from the aqueous solution during the process of adjusting the pH,and the target compound can be directly obtained through filtration.The reaction factors and parameters are optimized,The optimized conditions are as follows:in esterification reaction,n(SOCl 2)∶n(substrate)=1.2∶1.0;in amino protection reaction,n((Boc)2O)∶n(compound 1)=1.2∶1.0;in trifluoromethyl sulfonylation reaction,n((Tf)2O)∶n(compound 2)=1.1∶1.0,n(pyridine)∶n(compound 2)=1.2∶1.0.The total yield rate is 57.9%after optimization,and the purity is 98.3%.The structure of target compound is confirmed by 1H-NMR and 13 C-NMR.This protocol has advantages of mild reaction conditions and simple operation,and is suitable for industrial production.

关 键 词：有机合成化学 非天然氨基酸 中间体 串联反应 SN2反应 

分 类 号：TQ464.7[化学工程—制药化工]