Hui Liu, Fei-jie Lv, Yuan Liu
May 4, 2019
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Organic Preparations and Procedures International
Abstract
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