键合型多糖手性固定相超临界流体色谱用于取代苯基哌嗪衍生物的拆分

doi:10.5246/jcps.2013.03.035

键合型多糖手性固定相超临界流体色谱用于取代苯基哌嗪衍生物的拆分

黄珺珺, 袁牧^*

广州医学院药物研究中心, 广东广州 510182

收稿日期:2012-09-05 修回日期:2013-01-05 出版日期:2013-05-08 发布日期:2013-05-08
通讯作者: 袁牧*

Separation of substituted phenylpiperazine derivatives with immobilized polysaccharide-based chiral stationary phases by supercritical and subcritical fluid chromatography

Junjun Huang, Mu Yuan^*

Pharmaceutical Research Center, Guangzhou Medical University, Guangzhou 510182, China

Received:2012-09-05 Revised:2013-01-05 Online:2013-05-08 Published:2013-05-08
Contact: Mu Yuan*

摘要/Abstract

摘要：

合成了六个新型的1-取代苯基-4-[3-(吲哚-4-氧基)-2-羟丙基]-哌嗪消旋体化合物 1-6, 并利用键合型多糖手性固定相超临界流体色谱完成了对其的手性拆分研究。实验表明, 基于固定相Chiralpak IA的拆分优于其它两种键合型固定相(Chiralpak IB、Chiralpak IC), 改性剂异丙醇的效果优于乙醇、甲醇、四氢呋喃、乙腈、二氯甲烷。本文还研究了有机改性剂、背压与柱温对六个化合物对映体拆分的影响。结果表明, 改性剂组成最大程度地影响了分离时间, 柱温的改变对分离时间的影响较小但最大程度地影响了对映体选择性的变化。最优的拆分条件为: 固定相为Chiralpak IA柱, 柱温为35 ºC, 背压为120 bar, 流动相为35%异丙醇(含0.1%二乙胺), 流速为3.0 mL/min, 紫外检测波长为283 nm。该六个消旋体化合物在10分钟内得到了良好的拆分。超临界流体色谱法是拆分该类化合物对映体的有效方法。

关键词: 超临界流体色谱, 键合型多糖手性固定相, 对映体拆分, 苯基哌嗪衍生物

Abstract:

Six newly synthesized racemic 1-(substituted phenyl)-4-[3-(indole-4-yl-oxy)-2-hydroxypropyl]-piperazine 1-6 were successfully resolved by carbon dioxide supercritical fluid chromatography (SFC) on an analytical scale column packed with immobilized polysaccharide-based chiral stationary phases (CSPs). We found that separation on the Chiralpak IA CSP was superior to the other two immobilized CSPs (Chiralpak IB and Chiralpak IC), and isopropanol (IPA) was a superior modifier compared to the other five solvents including ethanol, methanol, tetrahydrofuran, acetonitrile and dichloromethane. The effects of organic modifier composition, back pressure, and column temperature for enantioseparation of all six compounds were studied. Of the physical parameters studied, modifier composition had the greatest impact on retention. Changing temperature generally had less impact on retention but produced the greatest selectivity changes. The optimum condition was found as follows: Chiralpak IA column, column temperature 35 ºC, back pressure 120 bar, 35% IPA containing 0.1% diethylamine (v/v) in mobile phase, flow rate of mobile phase 3.0 mL/min, UV detection 283 nm. Separation of all six racemic compounds was completed within 10 min and excellent resolution was obtained. Thus, SFC was found to be the methodology of choice for resolving the enantiomers of this class of compounds.

Key words: Supercritical fluid chromatography, Immobilized polysaccharide-based chiral stationary phases, Enantiomer resolution, Phenylpiperazine derivatives

中图分类号:

R917

Supporting: Foundation item: Science and Technology Program of Guangzhou City (Grant No. 2010U1-E0531-2).
^*Corresponding author. Tel.: 86-20-81340727

黄珺珺, 袁牧^*. 键合型多糖手性固定相超临界流体色谱用于取代苯基哌嗪衍生物的拆分[J]. , DOI: 10.5246/jcps.2013.03.035.

Junjun Huang, Mu Yuan^*. Separation of substituted phenylpiperazine derivatives with immobilized polysaccharide-based chiral stationary phases by supercritical and subcritical fluid chromatography [J]. , DOI: 10.5246/jcps.2013.03.035.

参考文献

[1] Berger, T.A. Packed Column SFC. RSC Chromatography Monograph Series. London: Royal Society of Chemistry. 1995, 2-5.
[2] Terfloth, G. J. Chromatogr. A. 2001, 906, 301-307.
[3] Anton, K.; Eppinger, J.; Frederiksen, L.; Francotte, E.; Berger, T.; Wilson, W. J. Chromatogr. A. 1994, 666, 395-401.
[4] Gahm, K.H.; Tan, H.; Liu, J.; Barnhart, W.; Eschelbach, J.; Notari, S.; Thomas, S.; Semin, D.; Cheetham, J. J. Pharm. Biomed. Anal. 2008, 46, 831-838.
[5] Mangelings, D.; Vander Heyden, Y. J. Sep. Sci. 2008, 31, 1252-1273.
[6] Jain, K.S.; Bariwal, J.B.; Kathiravan, M.K.; Phoujdar, M.S.; Sahne, R.S.; Chauhan, B.S.; Shah, A.K.; Yadav, M.R. Bioorg. Med. Chem. Lett. 2008, 16, 4759-4800.
[7] Himmel, H.M. Cardiovasc. Drug Rev. 1994, 12, 32-47.
[8] Niebch, G.; Locher, M.; Peter, G.; Borbe, H. Arzneimittel-forschung. 1991, 41, 1027-1032.
[9] Li, L.; Zhou, X.; Yuan, M.; Zhou, H.; Wang, D.P. Acta Pharm. Sin. 2006, 41, 80-84.
[10] Antelo, F.; Santana, C.C.; Alves, T.L.M.; Barreto Jr, A.G. Sep. Sci. Technol. 2012, 47, 636-640.
[11] Shimazawa, R.; Nagai, N.; Toyoshima, S.; Okuda, H. J. Health Sci. 2008, 54, 23-29.
[12] Klunder, J.M.; Ko, S.Y.; Sharpless, K.B. J. Org. Chem. 1986, 51, 3710-3712.
[13] Pollard, C.; Christie, J.B. J. Org. Chem. 1958, 23, 1333-1335.
[14] Zhang, T.; Nguyen, D.; Franco, P. J. Chromatogr. A. 2008, 1191, 214-222.
[15] Zhang, T.; Nguyen, D.; Franco, P.; Isobe, Y.; Michishita, T.; Murakami, T. J. Pharm. Biomed. Anal. 2008, 46, 882-891.
[16] Xie, J.; Cheng, J.; Han, H.; Sun, B.; Yanik, G.W. Food Chem. 2011, 124, 1107-1112.
[17] Kot, A.; Sandra, P.; Venema, A. J. Chromatogr. Sci. 1994, 32, 439-448.
[18] Subramanian, G. Chiral Separation Techniques: A Practical Approach. Vch Verlagsgesellschaft Mbh. 2007.
[19] Zhang, T.; Kientzy, C.; Franco, P.; Ohnishi, A.; Kagamihara, Y.; Kurosawa, H. J. Chromatogr. A. 2005, 1075, 65-75.
[20] Zhang, T.; Nguyen, D.; Franco, P.; Murakami, T.; Ohnishi, A.; Kurosawa, H. Anal. Chim. Acta. 2006, 557, 221-228.
[21] Zhang, T.; Schaeffer, M.; Franco, P. J. Chromatogr. A. 2005, 1083, 96-101.
[22] Cirilli, R.; Ferretti, R.; Gallinella, B.; La Torre, F.; Mai, A.; Rotili, D. J. Chromatogr. Sci. 2006, 29, 1399-1406.
[23] Ghanem, A.; Aboul-Enein, H.Y. Anal. Chim. Acta. 2005, 548, 26-32.
[24] Cirilli, R.; Simonelli, A.; Ferretti, R.; Bolasco, A.; Chimenti, P.; Secci, D.; Maccioni, E.; La Torre, F. J. Chromatogr. A. 2006, 1101, 198-203.
[25] Ali, I.; Naim, L.; Ghanem, A.; Aboul-Enein, H.Y. Talanta. 2006, 69, 1013-1017.
[26] Zhang, T.; Nguyen, D.; Franco, P. J. Sep. Sci. 2006, 29, 1517-1524.
[27] Cirilli, R.; Orlando, V.; Ferretti, R.; Turchetto, L.; Silvestri, R.; De Martino, G.; La Torre, F. Chirality. 2006, 18, 621-632.
[28] Ghanem, A.; Naim, L. J. Chromatogr. A. 2006, 1101, 171-178.
[29] Wainer, I.W.; Alembik, M.C.; Smith, E. J. Chromatogr. A. 1987, 388, 65-74.
[30] Kunath, A.; Theil, F.; Wagner, J. J. Chromatogr. A. 1994, 684, 162-167.
[31] Okamoto, Y.; Kaida, Y. J. Chromatogr. A. 1994, 666, 403-419.
[32] Zhang, T.; Nguyen, D.; Franco, P.; Murakami, T.; Ohnishi, A.; Kurosawa, H. Anal. Chim. Acta. 2006, 557, 221-228.
[33] O’Brien, T.; Crocker, L.; Thompson, R.; Thompson, K.; Toma, P.; Conlon, D.; Feibush, B.; Moeder, C.; Bicker, G.; Grinberg, N. Anal. Chem. 1997, 69, 1999-2007.
[34] Yang, Y.; Su, B.; Yan, Q.; Ren, Q. J. Pharm. Biomed. Anal. 2005, 39, 815-818.
[35] Mourier, P.A.; Eliot, E.; Caude, M.H.; Rosset, R.H.; Tambute, A.G. Anal. Chem. 1985, 57, 2819-2823.