右奈必洛尔中间体的手性光谱研究  

Chiroptical Study of the Key Intermediate of Dexnebivolol

作　　者：杨蓓蓓[1] 李莉[1] YANG Bei-bei;LI Li(Institute of Materia Medica,Chinese Academy of Medical Sciences&Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院北京协和医学院药物研究所,北京100050

出　　处：《化学试剂》2022年第11期1665-1669,共5页Chemical Reagents

摘　　要：1-[6-氟-(2R)-3,4-二氢-2H-苯并吡喃-2-基]-(1R)-1,2-乙二醇(INT)是合成选择性β受体阻滞剂右奈必洛尔的关键中间体,其绝对构型决定了产物的立体化学特征。采用手性光谱学方法,对比其左旋异构体(-)-INT的实验电子圆二色谱(ECD)和(1R,2R)/(1S,2S)-INT的理论ECD图谱,以及解析金属试剂Mo_(2)(OAc)_(4)衍生化产生的诱导圆二色谱信号,确定(-)-INT异构体的绝对构型为(1R,2R)。同时,通过基于含时密度泛函理论的量化计算得到(1R,2R)/(1S,2S)-INT的比旋光度,建立了甲醇和氯仿中的比旋光度符号与该结构绝对构型的关联,为快速准确判断其立体结构提供了依据。1-[(2R)-6-Fluorochroman-2-yl)]-(1R)-ethane-1,2-diol(INT) is a key intermediate in the synthesis route of dexnebivolol, which is a selective β-receptor blocker with antihypertensive activity.The absolute configuration of its levorotary isomer(-)-INT was established by multiple chiroptical methods, including comparison of experimental electronic circular dichroism(ECD) spectrum of(-)-INT and the calculated ECD of(1R,2R)/(1S,2S)-INT,and dimolybdenum tetraacetate [Mo_(2)(OAc)_(4)] method for chiral vic-diol moiety.Our results showed that(-)-INT should be 1R,2R configuration.Meanwhile, the specific optical rotation at the sodium D-line was calculated by using time-dependent density functional theory, to further correlate the relationship between the sign of optical rotation in methanol and chloroform and absolute configuration, which could facilitate the rapid and accurate discrimination of its stereostructure.

关 键 词：右奈必洛尔 电子圆二色谱 比旋光度 含时密度泛函理论 绝对构型 

分 类 号：O641.6[理学—物理化学]