Enantiomeric characterization and structure elucidation of Otamixaban

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• 作者：Jian Shen^a ; ^{jian.shen@simvcd.net" class="auth_mail} ; ^{jian-shen@msn.com" class="auth_mail} ; Jiping Yang^a ; Winfried Heyse^b ; Harald Schweitzer^b ; Norbert Nagel^b ; Doris Andert^b ; Chengyue Zhu^a ; Vincent Morrison^a ; Gregory A. Nemeth^a ; Teng-Man Chen^a ; Zhicheng Zhao^a ; Timothy A. Ayers^a ; Yong-Mi Choi^a
• 关键词：Vibrational circular dichroism ; DFT ; IR ; Absolute configuration ; Vicinal proton&ndash ; proton coupling ; scXRD
• 刊名：Journal of Pharmaceutical Analysis
• 出版年：June 2014
• 年：2014
• 卷：4
• 期：3
• 页码：197-204
• 全文大小：1618 K

文摘

Otamixaban is a potent (Ki=0.5 nM) fXa inhibitor currently in late-stage clinical development at Sanofi for the management of acute coronary syndrome. Being unproductive in obtaining a suitable crystal of Otamixaban, the required enantiomeric characterization has been accomplished using vibrational circular dichroism (VCD) spectroscopy. Selected by a spectrum similarity index, the calculated spectra of several higher energy conformers were found to match well with the observed spectra. The characteristic IR bands of these conformers were also identified and attributed to the solvation effect. Combined with both the single crystal x-ray diffraction results for an intermediate and the proton NMR study, the absolute configuration of Otamixaban is unambiguously determined to be (R,R).