雄甾-3,17-二醇衍生物的分子结构研究
收稿日期: 2014-04-17
修回日期: 2014-06-01
网络出版日期: 2014-06-18
基金资助
国家自然科学青年基金（No. 31200451）、江苏省自然科学基金（No. BK2012821）、江苏高校优势学科建设工程资助项目.
Studies of Molecular Structures of 3,17-Androstandiol Derivative
Received date: 2014-04-17
Revised date: 2014-06-01
Online published: 2014-06-18
Supported by
Project supported by the National Natural Science Foundation of China (No. 31200451), the Natural Science Foundation of Jiangsu Province (No. BK2012821) and the Foundation of Priority Academic Program Development (PAPD) of Jiangsu Higher Education Institutions.
罗库溴铵（Rocuronium Bromide）是新的手术前的甾醇类肌松药，其安全性和有效性已得到临床研究和应用的证实. 雄甾-3，17-二醇（1）是合成罗库溴铵的关键中间体. 用硼氢化钠还原（2α，3α，5α，16β）-2，3-环氧基-16-（1-吡咯）-17-氧代雄甾烷（2），然后在吗啉和水中回流使环氧开环得到雄甾-3，17-二醇（1）. 高分辨TOF-MS质谱和1H NMR，13C NMR，1H-1H COSY，HSQC，DEPT，HMBC，2D NOESY等核磁共振谱表征确认其分子构造，并且制备和测定了雄甾-3，17-二醇1的单晶结构，确认了它的立体构型. 雄甾-3，17-二醇（1）的样品的X粉末衍射分析研究表明其衍射谱与根据单晶数据计算的理论谱一致，因此，合成的雄甾-3，17-二醇（1）的分子结构是（2β，3α，5α，16β，17β）-2-（4-吗啉基）-16-（1-吡咯）雄甾-3，17-二醇，其立体构型与罗库溴铵的立体构型一致.
方明锋 , 儲储刚 , 李歆 , 陆国元 . 雄甾-3,17-二醇衍生物的分子结构研究[J]. 有机化学, 2014 , 34(10) : 2119 -2123 . DOI: 10.6023/cjoc201404031
Rocuronium bromide is a new neuromuscular blocking agent in clinical intervention. Its potency, specificity of action and little side effect have been confirmed. The 3,17-androstandiol (1) is a key intermediate for the preparation of rocuronium bromide. In this paper, The 3,17-androstandiol (1) was synthesized from (2α,3α,5α,16β)-2,3-epoxy-16- (1-pyrrolidinyl)-17-oxoandrostane by a reduction with sodium borohydride in methanol and then an epoxy ring opening reaction in morpholine and water. The molecular constitution was confirmed by 1H NMR, 13C NMR, 1H-1H COSY, DEPT, HSQC,HMBC, 2D NOESY and TOF-MS spectra. The single crystal of 3,17-androstandiol (1) was prepared by crystallized from 2-MeTHF and then was subjected to X-ray crystallography analysis that confirmed the stereo configuration of compound 1. And studies of X-ray powder diffractive analysis indicate that the diffractive spectrum of the sample compound 1 is consistent with the diffractive spectrum calculated on the crystal data. Therefore, the compound is (2β,3α,5α,16β,17β)- 2-(4-morpholinyl)-16-(1-pyrrolidinyl)androstan-3,17-diol and its stereochemistry is accordant with that of rocuronium bromide.
Key words： androstandiol; rocuronium bromide; NMR spectra; configuration; crystal structure
[1] Sparr, J.; Beaufort, M.; Fuchs-Buder, T. Drugs 2001, 61(7), 919.
[2] Lee, C. Pharmacol. Ther. 2003, 98(2), 143.
[3] European Pharmacopoeia Commission, European Pharmacopoeia 6.0, Strasbourg, 2008, pp. 2835～2837．
[4] Zhang, Y. M.; Guo, J.; Xiong, T. Chin. J. Med. Chem. 2008, 18(6), 434 (in Chinese).
(张永明, 郭佳, 熊涛, 中国药物化学杂志, 2008, 18(6), 434.)
[5] Savage, D. S.; Sleigh, T.; Carlyle, I. G. EP 287150, 1988 [Chem. Abstr. 1989, 110, 115184].
[6] Buckett, W. R.; Hewett, C. L.; Savage, D. S. J. Med. Chem. 1973, 16, 1116.
[7] Yan, H.; Qiu, F.; Diao, Y. Chin. J. Pharm. 2011, 42(6), 472 (in Chinese).
(严慧, 邱飞, 刁勇, 中国医药工业杂志, 2011, 42(6), 472.)
[8] Sleigh, T.; Savage, D. S.; Mearns, N.; Carlyle, I. G. US 4894369, 1990 [Chem. Abstr. 1989, 110, 115184].
[9] Mendez, J. A.; Mora, M. D.; Rodriguez, A. A. US 7569687, 2009 [Chem. Abstr. 2007, 146, 359039].
[10] Mendes, J. A.; Mora, M. D.; Rodriguez, A. A.; Barragan, E. US 2007/0117975, 2007 [Chem. Abstr. 2007, 146, 359039]
[11] Magni, A.; Grisenti, P. US 6090957, 2000 [Chem. Abstr. 1998, 129, 189525].
[12] Magni, A.; Grisenti, P. US 5808051, 1998 [Chem. Abstr. 1998, 129, 189525].
[13] Wang, H, X. Pharm. Clin. Res. 2012, 212, 135 (in Chinese).
(汪会霞, 药学与临床研究, 2012, 212, 135.)
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