CAJ | 학술논문

报道了一种维纳卡兰关键中间体(1R,2R)-2-((R)-3-(苄氧基)吡咯烷基)环己醇(RRR-2)的合成方法。以(R)-3-羟基吡咯烷(3)为原料，先经氨基选择性保护和脱保护反应，再与环氧环己烷开环反应制得混旋体2，最后经化学拆分制得光学纯的目标产物RRR-2，总收率达38%(文献收率15%)；同时研究了将拆分母液中异构体SSR-2转化为混旋体2的有效方法，即异构体SSR-2与二氯三苯基膦/三乙胺体系(摩尔比=1：2.1：2.5)在回流的乙腈中发生S N 2取代反应，然后直接水解可重新制到混旋体2，收率为75%。中间体及产物的结构经核磁共振、质谱和手性液相确证。该法反应条件温和，收率良好，操作简便，异构体SSR-2可再生利用，原料成本较低，具有工业化应用前景。
보도료일충유납잡란관건중간체(1R,2R)-2-((R)-3-(변양기)필각완기)배기순(RRR-2)적합성방법。이(R)-3-간기필각완(3)위원료，선경안기선택성보호화탈보호반응，재여배양배기완개배반응제득혼선체2，최후경화학탁분제득광학순적목표산물RRR-2，총수솔체38%(문헌수솔15%)；동시연구료장탁분모액중이구체SSR-2전화위혼선체2적유효방법，즉이구체SSR-2여이록삼분기련/삼을알체계(마이비=1：2.1：2.5)재회류적을정중발생S N 2취대반응，연후직접수해가중신제도혼선체2，수솔위75%。중간체급산물적결구경핵자공진、질보화수성액상학증。해법반응조건온화，수솔량호，조작간편，이구체SSR-2가재생이용，원료성본교저，구유공업화응용전경。
An improved synthetic technology was developed for the preparation of (1R,2R)-2-((R)-3-(benzyloxy)pyrrolidin-1-yl)cyclohexanol (RRR-2) which is a key intermediate in the synthesis of Vernakalant (1). (R)-3-Hydroxypyrrolidine (3) was used as the raw material that first went through an amino group selective protection and deprotection reaction, which was then followed by a ring-opening reaction with epoxy cyclohexane to prepare diastereoisomer-2. The target compound RRR-2 (optical pure) were obtained after separation with a total yield of 38% (literatures yield was 15%). Moreover, the isomer SSR-2 recovered from reaction liquids was further studied. SSR-2 was reacted via SN2 substitution with PPh3Cl2/TEA (molar ratio=1:2.1:2.5) under acetonitrile reflux, and followed by hydrolysis to prepare the diastereoisomer-2 with 75%yield. The structures of the intermediates and the product were confirmed by NMR, MS and chiral HPLC. The advantages of the present procedure include mild reaction condition, satisfactory yields, easy operation and reusability of the isomer SSR-2. Therefore it may be promising for industrial application.