(3R,4R,5S)-4,5-二氨基-3-(1-乙基丙氧基)-环己烯-1-羧酸乙酯的合成
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摘要
目的对(3R,4R,5S)-4,5-二氨基-3-(1-乙基丙氧基)-环己烯-1-羧酸乙酯合成工艺进行研究及优化。方法以(3R,4S,5S)-4,5-环氧-3-(1-乙基丙氧基)-环己烯-1-羧酸乙酯为起始原料,通过开环、环合、二次开环、还原等反应合成目标化合物。结果目标化合物与中间体的结构均经过1H NMR、MS谱确证,反应总收率24%。结论使用三苯基膦还原叠氮的方法操作简便可行,产率虽然有所下降,但克服了反应条件苛刻、反应时间长的缺点。
Objective To synthesize(3 R,4 R,5 S)-4,5-diamino-3-(1-ethylpropoxy)-cyclohexene-1-carboxylic acid ethyl ester and optimize the synthetic process. Methods Starting from ethyl(3 R,4 S,5 S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate,the target product was synthesized by the reaction of ring opening,cyclization and reduction reactions. Results The structures of intermediates and target compound were confirmed by MS and1 H NMR. The overall yield of the target compound was24%. Conclusion Ph3 P could be used to reduct azide conveniently and practicably,which makes it possible to overcome such disadvantage of previous synthetic processes,as the severe reaction conditions and long reaction times,even though the product yield was slightly reduced.
Objective To synthesize(3 R,4 R,5 S)-4,5-diamino-3-(1-ethylpropoxy)-cyclohexene-1-carboxylic acid ethyl ester and optimize the synthetic process. Methods Starting from ethyl(3 R,4 S,5 S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate,the target product was synthesized by the reaction of ring opening,cyclization and reduction reactions. Results The structures of intermediates and target compound were confirmed by MS and1 H NMR. The overall yield of the target compound was24%. Conclusion Ph3 P could be used to reduct azide conveniently and practicably,which makes it possible to overcome such disadvantage of previous synthetic processes,as the severe reaction conditions and long reaction times,even though the product yield was slightly reduced.
引文
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[3] Wu X,Wu X,Sun Q,et al. Progress of small molecular inhibitors in the development of anti-influenza virus agents[J]. Theranostics,2017,7(4):826-845.
[4] Rohloff JC,Kent KM,Postich MJ,et al. Practical total synthesis of the anti-influenza drug GS-4104[J]. J Org Chem,1998,63:4545-4550.
[5] Federspiel M,Fischer R,Hennig M,et al. Industrial synthesis of the key precursor in the synthesis of the anti-influenza drug oseltamivir phosphate(ro 64-0796/002,gs-4104-02):ethyl(3R,4S,5S)-4,5-epoxy-3-(1-ethyl-propoxy)-cyclohex-1-ene-1-carboxylate[J]. Org Process Res Dev,1999,3:266-274.
[6] Kim CU,Lew WL,Williams MA,et al. Influenza neuraminidase inhibitors possessing a novel hydrophobic interaction in the enzyme active site:design,synthesis,and structural analysis of carbocyclic sialic acid analogues with potent anti-influenza activity[J]. J Am Chem Soc,1997,119:681-690.
[7] Morita M,Sone T,Yamatsugu K,et al. A method for the synthesis of an oseltamivir PET tracer[J]. Bioorg Med Chem Lett,2008,18(2):600-602.
[8] Yamatsugu K,Yin L,Kamijo S,et al. A synthesis of Tamiflu by using a barium-catalyzed asymmetric Diels-Alder-type reaction[J]. Angew Chem Int Ed Engl,2009,48(6):1070-1076.
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[10] Li H,Shen SJ,Zhu CL,et al. Enantioselective synthesis of oseltamivir phosphate(Tamiflu)via the iron-catalyzed stereoselective olefin diazidation[J]. J Am Chem Soc,2018,140(33):10619-10626.