N-(叔丁基二甲基硅基)-吲哚-4-硼酸的合成研究
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摘要
以4-溴吲哚为起始原料,经氨基保护、硼酸化两步反应成功制得N-(叔丁基二甲基硅基)-吲哚-4-硼酸。其结构经核磁共振氢谱和质谱确证。采用L9(34)正交实验法对合成工艺进行探讨,获得最优工艺参数。中间体N-(叔丁基二甲基硅基)-4-溴吲哚(化合物3)的最优合成条件为:反应温度30～40℃,n4-溴吲哚∶n氢化钠∶nTBDMSCl=1∶1. 3∶1. 4; N-(叔丁基二甲基硅基)-吲哚-4-硼酸的最优合成条件为:析晶溶剂1. 0 L,反应时间6 h,n化合物3∶n硼酸三丁酯=1∶1. 3。反应总收率60. 7%。中试干燥极限条件为目标产品湿品在45～55℃下干燥8～10 h。该合成方法条件温和、后处理简单,适于工业化生产。
1-( tert-butyl dimethylsilyl)-indole-4-boronic acid was successfully obtained by two steps reaction of amino-protection and boration,with 4-bromoindole as the starting material. The structure of the target product was confirmed by nuclear magnetic resonance spectroscopy(1 H NMR) and mass spectrometry( MS). The main influencing factors were evaluated by the orthogonal experimentent of L9( 34),and the optimal process parameters were obtained. Results showed that the optimal process parameters of two step were as follows: reaction temperature of 30 ～ 40℃,n( 4-bromoindole) ∶n( sodium hydride) ∶n( tert-butyldimethylsilyl chloride) = 1 ∶1. 3 ∶1. 4; and then 1. 0 L of crystallization solvent,the reaction time of 6 h,n[1-( tert-butyl dimethylsilyl)-4-bromoindole]∶n( tributyl borate) = 1 ∶1. 3. The total yield of the reaction was 60. 7%. The critical condition of the target product in semi-production was also obtained: the wet product dried at 45 ～ 55℃ for 8 ～ 10 h. The synthesis method is mild,simple in post-treatment,and is suitable for industrial production.
1-( tert-butyl dimethylsilyl)-indole-4-boronic acid was successfully obtained by two steps reaction of amino-protection and boration,with 4-bromoindole as the starting material. The structure of the target product was confirmed by nuclear magnetic resonance spectroscopy(1 H NMR) and mass spectrometry( MS). The main influencing factors were evaluated by the orthogonal experimentent of L9( 34),and the optimal process parameters were obtained. Results showed that the optimal process parameters of two step were as follows: reaction temperature of 30 ～ 40℃,n( 4-bromoindole) ∶n( sodium hydride) ∶n( tert-butyldimethylsilyl chloride) = 1 ∶1. 3 ∶1. 4; and then 1. 0 L of crystallization solvent,the reaction time of 6 h,n[1-( tert-butyl dimethylsilyl)-4-bromoindole]∶n( tributyl borate) = 1 ∶1. 3. The total yield of the reaction was 60. 7%. The critical condition of the target product in semi-production was also obtained: the wet product dried at 45 ～ 55℃ for 8 ～ 10 h. The synthesis method is mild,simple in post-treatment,and is suitable for industrial production.
引文
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[3]张怡,门靖,任亚宁.叔丁基二甲基氯硅烷在药物合成中的应用研究进展[J].有机硅材料,2019,33(2):140-145.
[4] HIGASHINO Y,OKAMOTO T,MORI K,et al. Regioselective synthesis of procyanidin B6,A4-6-condensed(+)-catechin dimer,by intramolecular condensation[J]. Molecules,2018,23(1):205.
[5]陈旺,郝慧琳,张晨露,等. Lycogarubin C和Lycogalic Acid的化学合成及抗肿瘤活性研究[J].有机化学,2014,34(4):797-803.
[6]周妮妮,史倩,谢志翔. Lycogarubin C和Lycogalic Acid A的全合成[J].有机化学,2014,34(6):1104-1109.
[7] SHARMA A,MATHUR A K,GANPATHY J,et al.Effect of abiotic elicitation and pathway precursors feeding over terpenoid indole alkaloids production in multiple shoot and callus cultures of catharanthus roseus[J]. Biologia,2019,74(5):543-553.
[8] EDCON C,TONY G,BOHAN J,et al. N-substituted oxazinopteridines and oxazinopteridinones:US,2012220575(A1)[P]. 2012-02-24.
[9]武田药品工业株式会社. N-取代的噁嗪并喋啶和噁嗪并喋啶酮:CN,103384672A[P]. 2013-11-06.
[10] HOSHINO J,PARK E J,KONDRATYUK T P,et al.Selective synthesis and biological evaluation of sulfate-conjugated resveratrol metabolites[J]. J Med Chem,2010,53(13):5033-5043.
[11] LI Q,LAI Z,YAN,Z,et al. Hedyotis diffusa Willd inhibits proliferation and induces apoptosis of 5-FU resistant colorectal cancer cells by regulating the PI3K/AKT signaling pathway[J]. Mol Med Rep,2018,17(1):358-365.