Rivaroxaban 1 is an oxazolidinone derivative that is the first representative of a new series of anticoagulants, and it was soon followed by apixaban, betrixaban and darexaban. It is an oral, direct factor Xa inhibitor developed by Bayer and marketed as Xarelto. Factor Xa (FXa) is an essential blood coagulation factor that is responsible for the initiation of the coagulation cascade. Rivaroxaban 1 acts as an anticoagulant to prevent venous thromboembolism after major orthopaedic surgery in particular. It allows predictable anticoagulation with no need of dose adjustments and routine coagulation monitoring. Its pharmacological properties and therapeutic indications are amply summarized in the literature. Several synthetic methods were reported for the preparation of rivaroxaban 1. Three key structures can be used as advanced intermediates to prepare it (Figure 1). The first is derived from 4-(4-aminophenyl)morpholine-3-one 2a, or its alkylated congener 2b or a related carbamate 2c. The second generally used building block for rivaroxaban is derived from 5-chlorothiophene-2-carboxylic acid 3a or its functional derivatives such as chloride 3b and amide 3c. Both advanced intermediates, 2 and 3, are available on the market and their syntheses have been fully described in the literature. A chiral building block is the third and very important advanced intermediate which is needed for rivaroxaban. The synthetic approaches for rivaroxaban differ especially in this crucial chiral building block, which is the source of the 2-oxo-1,3-oxazolidine moiety. Chiral building blocks which have already been used in the synthesis of rivaroxaban are (S)-glycidylphthalimide 4, (S)-3-aminopropane-1,2-diol 5, (R)-epichlorohydrin 6 and (R)-glycidyl butyrate 7 (Figure 1). The procedure mentioned in the basic patent has been carried out by means of (S)glycidylphthalimide 4 as the chiral building block. This process led to the required product 1 in four steps starting from the precursor 2a (see Scheme 1). The second procedure has been carried out by means of (S)-3-aminopropane-1,2-diol 5 as the chiral building block. This led to the desired product 1 in four steps starting from precursor 3b. According to a number of other disclosures, rivaroxaban 1 could also be formed by means of (R)-epichlorohydrin 6 starting from substituted aniline 2a in methods requiring three to five steps (see Scheme 2). A more recent variation uses the (R)-glycidyl

中文翻译：

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从 (S)-环氧氯丙烷方便地合成利伐沙班

利伐沙班1是恶唑烷酮衍生物，是新系列抗凝剂的第一个代表，紧随其后的是阿哌沙班、贝曲沙班和达雷沙班。它是由拜耳开发并以 Xarelto 销售的口服直接 Xa 因子抑制剂。Xa 因子 (FXa) 是一种重要的凝血因子，负责启动凝血级联反应。利伐沙班 1 可作为抗凝剂，特别是在大型骨科手术后预防静脉血栓栓塞。它允许可预测的抗凝作用，无需调整剂量和常规凝血监测。其药理特性和治疗适应症在文献中有充分的总结。报道了几种用于制备利伐沙班 1 的合成方法。三个关键结构可以用作高级中间体来制备它（图 1）。第一个衍生自 4-(4-aminophenyl)morpholine-3-one 2a，或其烷基化同源物 2b 或相关的氨基甲酸酯 2c。利伐沙班的第二种常用结构单元源自 5-氯噻吩-2-羧酸 3a 或其功能衍生物，如氯化物 3b 和酰胺 3c。高级中间体 2 和 3 均可在市场上买到，其合成方法已在文献中进行了全面描述。手性构件是利伐沙班所需的第三个也是非常重要的高级中间体。利伐沙班的合成方法特别是在这一关键的手性结构单元上有所不同，它是 2-oxo-1,3-恶唑烷部分的来源。已经用于合成利伐沙班的手性构件是 (S)-缩水甘油邻苯二甲酰亚胺 4、(S)-3-氨基丙烷-1,2-二醇 5、(R)-表氯醇 6 和 (R)-缩水甘油丁酸酯 7 （图1）。基本专利中提到的程序是通过 (S) 缩水甘油基邻苯二甲酰亚胺 4 作为手性结构单元进行的。该过程从前体 2a 开始，分四步产生所需的产物 1（参见方案 1）。第二个程序是通过 (S)-3-aminopropane-1,2-diol 5 作为手性结构单元进行的。这导致从前体 3b 开始分四步得到所需的产物 1。根据许多其他公开内容，在需要三到五个步骤的方法中，也可以通过(R)-表氯醇6从取代苯胺2a开始形成利伐沙班1(参见方案2)。