491833-28-4Relevant articles and documents
Concise and efficient synthesis of eliglustat
Liu, Xiaoyu,Li, Xiaoyu,Yang, Hongguang,Shi, Xiang,Yang, Feilong,Jiao, Xiaozhen,Xie, Ping
, p. 594 - 600 (2018)
Eliglustat, a ceramide glucosyltransferase inhibitor, was synthesized in six steps with 28.4% overall yield. The key features include the use of a diastereoselective aldol reaction to construct two contiguous stereocenters and a selective sulfonylation of a 1,3-diol catalyzed by dibutyltin oxide.
Development of an Efficient and Scalable Asymmetric Synthesis of Eliglustat via Ruthenium(II)-Catalyzed Asymmetric Transfer Hydrogenation
Sun, Guodong,Jian, Weilin,Luo, Zhonghua,Sun, Tengfei,Li, Chao,Zhang, Jiancun,Wang, Zhongqing
, p. 1204 - 1212 (2019)
An efficient and scalable synthesis of eliglustat (1) is herein reported. This novel route features a three-step telescoped process to afford the α-dibenzylamino β-ketoester 6 in 85% overall yield from commercially available 1,4-benzodioxane-6-carboxylic acid 7. The key intermediate 5 was obtained via an efficient ruthenium-catalyzed DKR-ATH reaction, which afforded the desired product in 90% isolated yield with >99:1 dr and 99.7% ee on a 100 g scale. In addition, the amidation of sterically hindered carboxylic acid 14 was optimized and amenable to scale-up. This process not only gives a desirable total yield but also avoids hazardous conditions and chromatographic purification. The robustness of this synthesis was successfully performed on a multigram scale to afford 1 with >99.9% de and >99.9% ee in 56.8% overall yield in nine steps.
Eliglustat intermediate and preparation method thereof
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, (2020/06/17)
The invention relates to an eliglustat intermediate and a preparation method thereof, and provides a series of intermediate compounds for preparing eliglustat, and a preparation method of the intermediates. With the method provided by the invention, raw materials and a transition metal catalyst are subjected to an asymmetric hydrogenation reaction on under certain conditions, and then a series ofreactions are performed to prepare eliglustat. The method provided by the invention is simple and controllable in reaction conditions and easy for industrial production.
Optimization of Eliglustat-Based Glucosylceramide Synthase Inhibitors as Substrate Reduction Therapy for Gaucher Disease Type 3
Wilson, Michael W.,Shu, Liming,Hinkovska-Galcheva, Vania,Jin, Yafei,Rajeswaran, Walajapet,Abe, Akira,Zhao, Ting,Luo, Ruijuan,Wang, Lu,Wen, Bo,Liou, Benjamin,Fannin, Venette,Sun, Duxin,Sun, Ying,Shayman, James A.,Larsen, Scott D.
, p. 3464 - 3473 (2020/11/10)
There remain no approved therapies for rare but devastating neuronopathic glyocosphingolipid storage diseases, such as Sandhoff, Tay-Sachs, and Gaucher disease type 3. We previously reported initial optimization of the scaffold of eliglustat, an approved therapy for the peripheral symptoms of Gaucher disease type 1, to afford 2, which effected modest reductions in brain glucosylceramide (GlcCer) in normal mice at 60 mg/kg. The relatively poor pharmacokinetic properties and high Pgp-mediated efflux of 2 prompted further optimization of the scaffold. With a general objective of reducing topological polar surface area, and guided by multiple metabolite identification studies, we were successful at identifying 17 (CCG-222628), which achieves remarkably greater brain exposure in mice than 2. After demonstrating an over 60-fold improvement in potency over 2 at reducing brain GlcCer in normal mice, we compared 17 with Sanofi clinical candidate venglustat (Genz-682452) in the CBE mouse model of Gaucher disease type 3. At doses of 10 mg/kg, 17 and venglustat effected comparable reductions in both brain GlcCer and glucosylsphingosine. Importantly, 17 achieved these equivalent pharmacodynamic effects at significantly lower brain exposure than venglustat.
