Novel Synthesis and Spectral Characterization of Nelfinavir
YAN Jian-hui1,YAO Guo-wei1,YANG Li-na1,HU Gao-fei1，2,YANG Xin-lin1
1. School of Life Science and Technology, Beijing Institute of Technology, Beijing 100081, China 2. College of Science, Beijing University of Chemical Technology, Beijing 100029, China
Abstract：An efficient and environmentally friendly procedure for the one-pot synthesis of (3S,4aS,8aS)-2-((2R,3R)-3-amino-2-hydroxy-4-(phenylthio)butyl)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅶ), the intermediate of nelfinavir, was described, and activating ester was applied to getting nelfinavir(Ⅸ). Under the catalysis of potassium hydroxide, benzyl (R)-1-((S)-oxiran--yl)-2-(phenylthio) ethyl carbamate was obtained(Ⅳ) in methanol. Then Ⅳ and (3S,4aS,8aS)-N-tert-butyl-decahydroisoquinoline-3-carboxamide(Ⅴ) were refluxed in methanol until the reaction was finished. Potassium hydroxide(w(KOH)=40％) in water was added to remove benzyloxycarbonyl group in water bath with a yield of 89.0%. 3-acetoxy-2-methylbenzoic acid-succinimide ester(Ⅱ) reacted with Ⅶ and acetyl group was removed by dense aqueous ammonia, giving nelfinavir(Ⅸ). The vibrations of functional groups of this compound corresponding to the main infrared absorption peaks were discussed. The molecular ion and quasi molecular ion peaks were obtained via MALDI-TOF MS, and 1H NMR and 13CNMR shifts of this compound were assigned by means of DEPT(distortionless enhancement by polarization transfer spectrum), HMBC(1H detected heteronuclearmultiple bond correlation spectrum), HSQC(1H detected heteronuclear single-quantum coherence spectrum) and DQF-COSY(double-quantum filtered-correlated spectroscopy). The results provided useful information for structure characterization and quality control of nelfinavir.
[1] PENG Si-xun(彭司勋). Recent Developments in Pharmaceutical Chemistry(The first volume)(药物化学进展, 第1卷). Beijing: Chemical Industry Press(北京: 化学工业出版社),2004. 1. [2] Stephen W K, Vincent J K, Jay F D, et al. J. Med. Chem., 1997, 40(24): 3979. [3] Takashi Inaba, Angela G. Birchler, Yasuki Yamada. J. Org. Chem., 1998, 63(22): 7582. [4] Dale L Rieger. J. Org. Chem., 1997, 62(24): 8546. [5] Scott E Zook, Juliette K Busse, Bennett C Borer. Tetrahedron Letters,2000, 41(36): 7017. [6] Takashi Inaba, Yasuki Yamada, Hiroyuki Abe, et al. J. Org. Chem.,2000, 65(6): 1623. [7] Kim F Albizati, Srinivasan Babu, Angela Birchler. Tetrahedron Letters,2001, 42(37): 6481. [8] Michael E Deason, Kathleen R Whitten. USP 6303786 B1,2001-10-16. [9] Dawei Ma, Bin Zou, Wei Zhu, et al. Tetrahedron Letters,2002, 43(47): 8511. [10] XU Chun-yan, HUANG Ming-zhi, XUE Chuan-xin(徐春艳, 黄明智, 薛传薪). Spectroscopy and Spectral Analysis(光谱学与光谱分析),2005,25(11): 1772. [11] WU Bo-wan, ZHANG Bing, YU Xin-qiao, et al(仵博万, 张 兵, 于新桥, 等). Spectroscopy and Spectral Analysis(光谱学与光谱分析),2006,26(1): 106. [12] Ghring W, Gokhale S, Hilpert H, et al. Chimia., 1996, 50(11): 532. [13] Jenny C Gilbert, Sally Redshaw, Heather S Simmonlte, et al. J. Chem. Soc. Perkin Trans., 1993,2(3): 475. [14] NING Yong-cheng(宁永成). Structural Identification of Organic Compounds and Organic Spectroscopy(有机化合物结构鉴定与有机波谱学). Beijing: Science Press(北京: 科学出版社),2001. 98. [15] YU De-quan, YANG Jun-shan(于德全，杨峻山). Handbook of Analytical Chemistry(7)—Spectral Analysis of Nuclear Magnetic Resonance(分析化学手册(7)—核磁共振波谱分析). Beijing: Chemical Industry Press(北京：化学工业出版社)，1999. 620.
