Silodosin is a novel selective a1A-adrenoceptor (AR) antagonist developed by Kissei Pharmaceutical Co. in Japan. It is indicated for the treatment of the signs and symptoms of benign prostatic hyperplasia (BPH). Common signs and symptoms associated with BPH are related to bladder outlet obstruction, which is caused by the increase of smooth muscle tone in the prostate and bladder neck. Due to its high selectivity for the a1a receptor to a1b receptor, silodosin causes relaxation of the smooth muscle resulting in improvement of BPH symptoms while minimizing the effect on blood pressure. In the preparation of silodosin using the patented route (Scheme 1), four important impurities were observed: IM-A and IM-B are starting materials for the synthesis of SI-III, IM-C is the disubstituted by-product from SI-III, and IM-D is the S-enantiomer of silodosin (Figure 1). It is necessary to control the formation of these impurities and the subsequent impurities they become in downstream chemical steps. In the present work, the preparation of silodosin was optimized to ensure high quality, aiming at the effective control of the process-related impurities and degradation products. In the formation of SI-III, the substitution of SI-II was conducted in tert-butanol with sodium carbonate under reflux. During the course of the reaction, SI-II was substituted with IM-A to afford SI-III and the disubstituted product IM-C. An excess of IM-A was used to achieve completion, resulting in the formation of SI-III with a high level of IM-C, which was difficult to remove by crystallization. With the addition of an acid, however, the secondary amine SI-III precipitated in the form of a salt, and the tertiary amine IM-C still remained dissolved in the solution. By use of this concept, a variety of inorganic and organic acids were screened in the present work to maximize the yield of precipitate and to reduce the level of impurity IM-C below the acceptable threshold limit (Table 1). In the patented route, SI-IV was obtained as its oxalate salt to be isolated from the mixture. Instead, we found that the combination of L-tartaric acid and isopropanol was the most effective combination for the formation of salt and

中文翻译：

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西洛多辛的改进制备

Silodosin 是日本 Kissei Pharmaceutical Co. 开发的一种新型选择性 a1A-肾上腺素能受体 (AR) 拮抗剂。它适用于治疗良性前列腺增生 (BPH) 的体征和症状。与 BPH 相关的常见体征和症状与膀胱出口梗阻有关，这是由前列腺和膀胱颈平滑肌张力增加引起的。由于其对 a1a 受体对 a1b 受体的高选择性，西洛多辛导致平滑肌松弛，从而改善 BPH 症状，同时最大限度地减少对血压的影响。在使用专利路线（方案 1）制备西洛多辛时，观察到四种重要杂质：IM-A 和 IM-B 是合成 SI-III 的起始原料，IM-C 是 SI-的双取代副产物。三、IM-D 是西洛多辛的 S-对映异构体（图 1）。有必要控制这些杂质的形成以及它们在下游化学步骤中变成的后续杂质。在目前的工作中，对西洛多辛的制备进行了优化，以确保高质量，旨在有效控制与工艺相关的杂质和降解产物。在SI-III的形成中，SI-II在叔丁醇中用碳酸钠在回流下取代。在反应过程中，SI-II被IM-A取代得到SI-III和二取代产物IM-C。过量的 IM-A 用于完成，导致形成 SI-III 和高水平的 IM-C，难以通过结晶去除。然而，加入酸后，仲胺SI-III以盐的形式沉淀，而叔胺IM-C仍保持溶解在溶液中。通过使用这个概念，在目前的工作中筛选了各种无机和有机酸，以最大限度地提高沉淀物的产率并将杂质 IM-C 的水平降低到可接受的阈值以下（表 1）。在获得专利的路线中，SI-IV 以其草酸盐的形式从混合物中分离出来。相反，我们发现 L-酒石酸和异丙醇的组合是形成盐和异丙醇的最有效组合。在目前的工作中筛选了各种无机和有机酸，以最大限度地提高沉淀物的产率并将杂质 IM-C 的水平降低到可接受的阈值以下（表 1）。在获得专利的路线中，SI-IV 以其草酸盐的形式从混合物中分离出来。相反，我们发现 L-酒石酸和异丙醇的组合是形成盐和异丙醇的最有效组合。在目前的工作中筛选了各种无机和有机酸，以最大限度地提高沉淀物的产率并将杂质 IM-C 的水平降低到可接受的阈值以下（表 1）。在获得专利的路线中，SI-IV 以其草酸盐的形式从混合物中分离出来。相反，我们发现 L-酒石酸和异丙醇的组合是形成盐和异丙醇的最有效组合。