●916●中國醫(yī)藥工業(yè)雜志Chinese Jourmal of Pharmaceuticals 2014, 45(10)黃芩素的簡便合成景臨林'，范小飛”,馬慧萍'，樊鵬程’'， 賈正平1*(1.蘭州軍區(qū)蘭州總醫(yī)院藥劑科，甘肅蘭州730050; 2. 蘭州大學(xué)藥學(xué)院，甘肅蘭州730000)摘要:白楊素通過5,7-雙甲基化保護(hù)羥基得5,7-二甲氧基黃酮，與N-溴代丁二酰亞胺(NBS)進(jìn)行選擇性溴代得5,7-二甲氧基-8-溴黃酮，以DMF為溶劑、溴化亞銅為催化劑，于120 C與甲醇鈉反應(yīng)4 h制得5,7,8-三甲氧基黃酮，最后經(jīng)去甲基化和Wessely-Moser重排反應(yīng)得黃芩素，總收率約56%。關(guān)鍵詞:白楊素;黃芩素;醇解反應(yīng);合成中圖分類號: 0629.9文獻(xiàn)標(biāo)志碼: A文章編號: 1001-8255 (2014) 10-0916-03Convenient Synthesis of BaicaleinJING Linlin', FAN Xiaofeil2, MA Huiping', FAN Pengcheng', JIA Zhengping'(1. Dept. of Pharmacy, Lanzhou General Hospital, Lanzhou Command of CPLA, Lanzhou 730050;2. School of Pharmacy, Lanzhou University, Lanzhou 730000)ABSTRACT: 5,7-Dimethoxyflavone was prepared from chrysin by 5,7 dimethylation, which was subjected toselctive bromination with N-bromosuccinimide (NBS) and reaction with sodium methoxide in DMF with CuBr ascatalyst at 120 C for 4 h to obtain 5,6,7-trimethoxyflavone. Finally, baicalein was prepared by demethylation andWessely-Moser rearrangement with an overall yield of 56%.Key Words: chrysin; baicalein; methanolysis; synthesis黃芩素(baicalein， 1)， 化學(xué)名為5,6,7-三羥基且提取工藝繁瑣、產(chǎn)率低、成本高。因此，利用化黃酮，是從我國傳統(tǒng)中藥黃芩中分離得到的一種多學(xué)合成法制備1日益受到重視。酚類活性成分(1),具有抗炎、抗腫瘤、抗氧化、抗合成1的報道較多[7-9]， 但普遍存在合成步驟病毒及抗變態(tài)反應(yīng)等生物活性[2-6]。目前主要從人長、 產(chǎn)率低和反應(yīng)條件苛刻等不足。后有文獻(xiàn)利用工栽培的黃芩中提取分離。但1在黃芩中含量低,溴代黃酮的醇解反應(yīng)獲得新型黃酮，以價廉易得的白楊素為原料，經(jīng)過7-位單甲基化、溴代、5- 位.收稿日期: 2014-04-12乙?；⒓籽趸腿ゼ谆确磻?yīng)制得1，總收作者筒介:最臨林(1982-)， 男，博士，主管藥師，從事藥物合成率約51% [10]研究.通信聯(lián)系人:賈正平(1957-)， 男，博士，主任藥師，從事藥物合本研究對上法進(jìn)行了改進(jìn)和優(yōu)化:以白楊素為成和制劑研究。Tel: 0931-8994671原料，通過5,7-雙甲基化保護(hù)羥基得5,7-二甲氧基E-mail: zhengping_ jia@yahoo.cn黃酮(2)。2與N-溴代丁二酰亞胺(NBS)在0 C6] 竺偉.陳宇.普拉格雷的合成[J].中國醫(yī)藥工業(yè)雜志，[P]. 2010-05-25.2012, 43 (8): 647-649.9] Pan XH, Rui H, Zhang JS, et al. Efficient synthesis of[7Mezei T, Lukacs G, Molnar E, et al. Process for the prepa-prasugrel, a novel P2Y1z receptor inhibitor [J]. Tetrahedronration of pharmaceutical intermediates: wO, 2009068924Lett, 2012, 53 (40): 5364-5366.[P]. 2010-06-24.10] 何昆侖,周敦峰,雷江，等.普拉格雷中間體及其制備方[8] Erfinder A, Dietz J, Grote T, el al. Preparation of imidazoles法:中國中國煤化工and triazoles as agrochemical fungicides: WO, 2010031848fYHCNMHG.中國醫(yī)藥工業(yè)雜志Chinese Joumal of Pharmaceuticals 2014, 45(10)●917●進(jìn)行8-位選擇性溴代反應(yīng)得5,7-二甲氧基-8-溴黃6.74(s, 1H), 6.46(s, 1H), 4.03 (s, 3H), 4.04(s, 3H); .酮(3)，NBS較文獻(xiàn)所用三溴化四丁銨(TBATB)"C NMR (CDCl, 100 MHz)δ: 177.3, 162.7, 160.8,價廉易得，且所得產(chǎn)物單一，易于純化。制備5,7,8- .160.4, 160.2, 131.4, 131.0, 129.2, 129.0, 128.6, 126.2,三甲氧基黃酮(4)時，文獻(xiàn)認(rèn)為5-位羥基裸露是109.6, 108.2, 92.1, 90.9, 56.6, 56.5。進(jìn)行甲氧基化反應(yīng)的必要條件[10];而本研究表明，5,7,8- 三甲氧基黃酮(4)以DMF為溶劑、溴化亞銅為催化劑，3與甲醇鈉將溴化亞銅(0.7g,5mmol)懸浮于DMF于120 C反應(yīng)4 h即可制得4，最后經(jīng)去甲基化和(15ml)中，室溫攪拌15 min,加入25%甲醇鈉的Wessely-Moser重排反應(yīng)得1。改進(jìn)后的工藝總收率甲醇溶液(50 m)，室溫攪拌1 h,得亮藍(lán)色懸浮液。約56%，反應(yīng)路線見圖1。將3(1.80g，5 mmol)懸浮于DMF(25 ml)中，升溫實(shí)驗部分至120C,將上述亮藍(lán)色懸浮液--次性加至反應(yīng)體5,7-二甲氧基黃酮(2)系中，120C反應(yīng)4h,冷卻至室溫，傾至2 mol/L鹽.將白楊素(1 g, 3.94 mmol)和碳酸鉀(1.63 g,酸(500 ml)中，析出黃色固體。過濾，濾餅用85%11.8 mmol)懸浮于丙酮(30 ml)中，室溫加入硫酸甲醇重結(jié)晶，得無色針狀結(jié)晶4(1.33 g，85% ),二甲酯(1.99 g，15.8 mmol)，加熱至60 C回流反mp 180~ 181 C。ESI-MS (m/z):3l3[M+H]*; 'HNMR應(yīng)6h。冷卻至室溫,加入10%氨水(5ml)淬滅反應(yīng)，(CDCl, 400 MHz)8: 8.00~ 8.02 (m, 2H), 7.54 ~減壓蒸除丙酮。過濾，濾餅用水洗滌，干燥，經(jīng)乙7.57 (m, 3H), 7.22(s, 1H), 6.50(s, 1H), 4.05(s, 3H),酸乙酯重結(jié)晶，得無色晶體2(1.08 g，97% )，mp4.02 (s, 3H), 3.98(s, 3H); 'C NMR (CDCI, 100 MHz)200~201°C(文獻(xiàn):201~202C[10])。δ: 178.1, 156.7, 160.8, 160.4, 160.2, 132.2, 131.0,5,7-二甲氧基-8溴黃酮(3)129.8, 129.0, 128.6, 126.4, 106.5, 108.2, 93.0, 61.7,將2(2.82 g，10 mmol)溶于DMF(50 ml)中，56.7, 56.5。0 C加入NBS(1.78g, 10 mmol)，反應(yīng)2.5h。加入5,6- 二羥基-7-甲氧基黃酮(5)冷的2 mol/L鹽酸(200 ml)淬滅反應(yīng)。過濾，濾餅將4(0.62g，2 mmol)懸浮于冰乙酸(25 m1) .干燥后用甲醇重結(jié)晶，得黃綠色針狀結(jié)晶3(2.89 g,中，加入47%氫溴酸(12 ml)，回流反應(yīng)6h，冷80% )(文獻(xiàn): 80% (10), mp238 ~ 239 C。ESI-MS卻到室溫，將反應(yīng)液傾入冰水(100 ml)中，過濾，(m/z): 363[M+H]*; 'H NMR (CDCl, 400 MHz) δ:濾餅用甲醇重結(jié)晶，得黃色晶體5(0.50g，89% ),8.01(dd, J=2.0、3.6 Hz, 2H), 7.50 ~ 7.53 (m, 3H),mp235~ 236C (文獻(xiàn): 235 ~ 238 C“")。ESI-MS3rMcOCH:COCH3, K2CO3, (CHzOhSO2NBS, DMF6h, 97%0C, 2.5h, 80%HOMe ooMe o2OMeMeOHMeONaMeO-HBr, AcOH MeO-HBr, AcOH_ HO-0CuBr, DMF, 120C,4h回流，6hHO'回流，12hOMe OOH cH0HBt, AcOH,回流, 16h圖11的合成路線中國煤化工Fig.l Synthetic Route of1MYHCNMHG●918●中國醫(yī)藥工業(yè)雜志Chinese Journal of Pharmaceuticals 2014, 45(10)(m/z): 285[M+H]*; 'H NMR (CDCI, 400 MHz)8:2] Chiu YW, Lin TH, Huang WS, e1 al. Baicalein inhibits the12.46(s, 1H), 8.04 ~ 8.06(m, 2H), 7.55 ~ 7.58(m,migration and invasive properties of human hepatoma cells[J]. Toxicol Appl Pharmacol, 2011, 255(3): 316-326.3H), 6.69(s, 1H), 6.63(s, 1H), 5.35(s, 1H), 3.16(s,3] Lee IK, Kang KA, Zhang R, et al. Mitochondria protection3H); "C NMR (CDCI3, 100 MHz)8: 182.7, 164.1,of baicalein against oxidative damage via induction of152.9, 150.7, 145.6, 131.8, 131.5, 129.8, 129.1, 126.2,manganese superoxide dismutase [J]. Environ Toxicol109.8, 106.1, 105.5, 90.5, 56.5。Pharmacol, 2011, 31(1): 233-241.黃芩素(1)4] Lee JH, Kim GH. Evaluation of antioxidant and inhibitory方法一:將4(0.62 g, 2 mmol)懸浮于冰乙酸activities for different subclasses flavonoids on enzymes for(25 ml)中，加入47%氫溴酸(20 ml)，加熱回流反rheumatoid arthritis [J]. J Food Sci, 2010, 75(7): H212-應(yīng)16h,冷卻到室溫，將反應(yīng)液傾入冰水(100 m1)H217.5] Ling Y, Chen Y, Chen P, et al. Baicalein potently suppresses中，過濾，濾餅用甲醇重結(jié)晶，得黃色針狀晶體1angiogenesis induced by vascular endothelial growth factor(0.46g, 85%)，mp261 ~ 262 C (文獻(xiàn): 263 ~through the p53/Rb signaling pathway leading to G1/S cell264 °C ”)。純度99% [HPLC 歸一化法:色譜柱cycle arrest [J]. Exp Biol Med(Maywood), 2011, 236(7):依利特Hypersil ODS2柱(4.6 mmx 150 mm，5 um);851-858.流動相甲醇:水:磷酸(47:53:0.2);流速6] Takahashi H, Chen MC, Pham H, et al. Baicalein, a1.0 m/min;柱溫25 C;檢測波長280 nm]。ESI-MScomponent of Scutellaria baicalensis, induces apoptosis by(m/z): 271[M+H]*; 'H NMR (DMSO-d, 400 MHz)Mcl-1 down-regulation in human pancreatic cancer cells [J].Biochim Biophys Acta, 2011, 1813(8): 1465-1474.8: 12.66(s, 1H), 10.56(s, 1H), 8.83(s, 1H), 8.14(d,7] Schonberg A, Badran N, Starkowsky NA. Furo- chromonesJ=8.4 Hz, 2H), 7.65 (m, 3H), 7.03(s, 1H), 6.62 (s,and -coumarins. X II . Synthesis of fraxinol from bergapten1H); 'C NMR (DMSO-df, 100 MHz)8: 182.3, 162.7,and of baicalein from visnagin [J].J Am Chem Soc, 1955,150.8, 147.4, 142.8, 131.9, 131.1, 129.7, 129.2, 128.1,77 (20): 5390-5392.126.2, 104.5, 103.1。8] Huang WH, Chien PY, Yang CH, et al. Novel synthesis of方法二:將5(0.57 g, 2 mmol)懸浮于冰乙酸flavonoids of Scutellaria baicalensis George [J]. ChemPharm Bull(Tokyo) , 2003, 51 (3): 339-340.應(yīng)12 h,冷卻到室溫，將反應(yīng)液傾入冰水(100 ml)9] Chen DZ, Yang J, Yang B, et al. Total synthesis of baicalein[J].J Asian Nat Prod Res, 2010, 12(2): 124- 128.[10] Righi G, Antoniletti R, Silvestri IP, et al. Convergent(0.47g，87%)。理化常數(shù)和純度與方法一一致。synthesis of mosloflavone, negletein and baicalein fromcrysin [J]. Tetrahedron, 2010, 66(6): 1294- 1298.參考文獻(xiàn):[11] Kiem PV, Minh CV, Huong HT, et al. Phenolic constituents[1] Kim YO, Leem K, Park J, et al. Cytoprotective effect ofwith inhibitory activity against NFAT transcription fromScutellaria baicalensis in CA1 hippocampal neurons of ratsDesmos chinensis [J]. Arch Pharm Res, 2005, 28(12):after global cerebral ischemia [J]. J Ethnopharmacol, 2001,1345-1349.77 (2-3): 183-188.S45-44 IBX 介導(dǎo)的3,5-二芳基異嘻唑和異嘎唑-3-羧酸化合芳基亞甲基丙酮和IBX(3.0eq)反應(yīng)，得到相應(yīng)5-芳基異囈物的合成Desai VG等[Synth Commun, 2014, 44: 1453]唑-3-羧酸,5例收率61%~ 75%。查爾酮(苯乙烯基苯基酮)、.a,β-不飽和酮肟(即取代的苯乙烯基苯基酮肟)和IBX鹽酸羥胺、乙酸鈉、IBX和氯仿“- -鍋煮”可得3,5-二取代異囈唑。(鄰碘?；郊姿?，1.0 eq)在氯仿中加熱回流反應(yīng)4h,得到[張清泉摘]中國煤化工相應(yīng)3,5-二芳基異嚦唑，12 例收率60%~ 82%。相同條件下，MYHCNMHG