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Combined experimental and quantum mechanical elucidation of the synthetically accessible stereoisomers of Hydroxyestradienone (HED), the starting material for vilaprisan synthesis
Journal of Computer-Aided Molecular Design ( IF 3.5 ) Pub Date : 2020-10-23 , DOI: 10.1007/s10822-020-00353-7
Tobias A Plöger 1 , Stefan Koep 2 , Hans-Christian Militzer 3 , Andreas H Göller 4
Affiliation  

Selective progesterone receptor modulators are promising therapeutic options for the treatment of uterine fibroids. Vilaprisan, a new chemical entity that was discovered at Bayer is currently in clinical development. In this study we provide a combined experimental and quantum chemical approach providing the data that allowed to present hydroxyestradienone as an acceptable starting material for drug substance synthesis. Hydroxyestradienone has four stereogenic centers leading to 8 diastereomers and 16 enantiomers of which only six diastereomers were synthetically accessible but two not. A computational multistep protocol resulting in density functional P2PLYP-D3(BJ)/dev2-TZVPP Gibbs free energies and SMD solvation free energies led to a clear separation between the existing and the synthetically not accessible enantiomers, whereas multiple geometry-based and cheminformatic descriptors were not able to explain experimental findings.



中文翻译:

羟基雌二烯酮 (HED) 的可合成立体异构体的结合实验和量子力学阐明,羟基雌二烯酮合成的起始材料

选择性孕酮受体调节剂是治疗子宫肌瘤的有希望的治疗选择。Vilaprisan 是一种在拜耳发现的新化学实体,目前正处于临床开发阶段。在这项研究中,我们提供了一种结合实验和量子化学的方法,提供了允许将羟基雌二烯酮作为可接受的原料药合成原料的数据。羟基雌二烯酮有四个立体中心,产生 8 种非对映异构体和 16 种对映异构体,其中只有 6 种非对映异构体可以合成,但两种不能。导致密度泛函 P2PLYP-D3(BJ)/dev2-TZVPP 吉布斯自由能和 SMD 溶剂化自由能的计算多步协议导致现有和合成不可访问的对映异构体之间的明确分离,

更新日期:2020-10-26
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