2009年第25卷第2期VoL25No.22009JOURNAL OF BAOTOU MEDICAL COLLEGE119Flavopiridol合成工藝的改進李艷玲12方浩2徐文方2(1.包頭醫(yī)學(xué)院藥學(xué)系,內(nèi)蒙古包頭014060;2.山東大學(xué)藥學(xué)院)摘要目的:改進 Flavopiridol的合成工藝。方法:以1-甲基-4-(24,6-三甲氧基)-1,2,3,6-四氫吡啶為原料,利用Dlon反應(yīng)制得環(huán)氧而后經(jīng)AH1還原制得 Flavopiridol的關(guān)鍵中間體3-哌啶醇,后經(jīng)拆分、?；?、選擇性脫甲基、羥醛縮合、查爾酮氧化關(guān)環(huán)、脫甲基制得 Flavopiridol,結(jié)果:目標化合物經(jīng)H-NMR、質(zhì)譜確證;總收率為11.8%比文獻報道的收率提高4.8%。結(jié)論:改進后的方法不僅條件溫和、反應(yīng)的立體選擇性大為提高,而且操作簡關(guān)鍵詞 Dalton反應(yīng);AlH2還原;查爾酮路線mprovement in Synthetic Technology of FlavopiridolLI Yanling FANG Hao, XU Wenfan(1. Department of Pharmacy, Baotou Medical College, Baotou 014000, China;2. School of Pharmacy, Shandong University)Abstract Objective To improve the synthetic technology of flavopiridol. Methods: Dalton reaction was employedproduce the synthesis of expoxide from 1-methyl-4-(2, 4, 6-trimethoxyphenyl)-1, 2, 3,6-tetrahydropyridine, thenkey intermediate of flavopiridol-piperidol was got by means of AlH, reduction of expoxide finally, flavopiridol was pre-ared via acylation, selective demethylation, adol consendation, chalcone closure, demethylation. Results: The structure oftarget compound was confirmed by 'H-NMR. ms and the overall yield was 11. 8%. Compared with that reported in theliterature,the overall yield was increased by 4.8%. Conclusion: This synthetic process is suitable for the preparation ofmultigram quantities by its convenient operation, mild reaction conditions and higher stereoselectivity. This method habeen reported at home.Key words Dalton reaction; AlH, reduction: Chalcone route細胞周期蛋白依賴激酶(CDKs)是一類依賴 cylin酮用硼氫化鈉還原上述酮后得到順式醇和反式醇的的絲/蘇氨酸蛋白激酶在細胞周期的調(diào)控中起重要作混合物,用重結(jié)晶法分離出順式醇中間體④,拆分后經(jīng)用由于其功能失調(diào)和腫瘤發(fā)生之間的密切關(guān)系已使過量BF3-OEt催化、醋酐?；瑫r脫去乙?；徫黄湟种苿┑难芯砍蔀槟壳翱鼓[瘤藥物研究與開發(fā)的熱甲氧基的甲基得到中間體酚⑤,以該酚為原料,專利都點之一, Flavopiridol是第一個進入臨床試驗的采用B-二酮法制得甲氧黃酮其中B一二酮法又包括CDK抑制劑,化學(xué)結(jié)構(gòu)為黃酮最初來源于一種印度Aan- Robinson縮合以及 Baker- Venkataraman重植物 rohitukin,目前已可人工合成口2,研究表明排(,甲氧黃酮用鹽酸吡啶法脫去甲基后制得FaFlavopiridol對包括肺癌乳腺癌等的多種腫瘤細胞系 vopiridol本文作者以②為原料,在查閱相關(guān)文獻的均具有抗腫瘤活性而且可以抑制異種嫁接模型中胂基礎(chǔ)上0),將中間體④的合成作了改進方法如下:首瘤的生長先采用 Dalton反應(yīng)制得環(huán)氧③,而后利用氫化鋁還原1合成路線環(huán)氧③后接著用鋅粉一甲醇脫溴即制得中間體④,與有關(guān) Flavopiridol I的合成,僅在幾篇專利文獻中前面所述專利文獻的方法相比改進后的工藝不僅使有報道,主要步驟以圖1為例說明:將②經(jīng)硼氫化反應(yīng)產(chǎn)中國煤化工體選擇性直接得氧化反應(yīng)制得反式醇該醇經(jīng) swern氧化得到相應(yīng)的到順CNMH Gern氧化要求超低溫條件),操作簡單。與此同時,我們嘗試用查爾酮路基金項目:國家科技部863課題(2007AA02Z314)線完成了 Flavopiridol的關(guān)環(huán)反應(yīng)。 Flavopiridol合成120包頭醫(yī)學(xué)院學(xué)報第25卷路線見圖1。(1H,m),2.81-2.84(1H,m),2.49-2.54(1H,m),2.37-2.40(1H,m),2.28-2.31(3H,s),1,96-2.012.3(-)-(3R,4S)-1-甲基-4-(2,4,6-三甲氧基苯基)哌啶-3一醇(4)的合成在20℃,將3g四氫鋁鋰(0.080mol)加入50mL四氫呋喃中,于25℃將此混懸液攪拌4小時后靜置20小時,在0士1℃攪拌下,加2.7g無水氯化鋁,之后將溫度升高到20℃,將混合物攪拌15分鐘即得還原劑AH3。將上述AH3THF混懸液冷卻到0±1℃,并于此溫度加10g③(0.028mol)和60 mL THF,混合物攪拌2小時后緩慢加入100mL5%NaOH繼續(xù)攪拌1小時后溫度升高到圖1 Flavopiridol改進合成路線20℃,將所得到的膠胨狀物過濾濾液在減壓蒸餾下濃(a)(i) DMSo, H: O, CF3 COOH:(ii) NBS, Naz SOs縮至原體積一半,將150mL甲醇加入上述溶液中,在30% NaOH,(b)(i)AlH,, THF,(ii)50%KOH.攪拌此混合液的同時加入35mL50%KOH,而后加CH,OH, Zn(c)(i) BF3- OEt, Ace O, CHz Clz入10g鋅粉,混合物回流16小時后冷卻到20℃,抽濾(ii5%KOH, CH, OH:(d)10% KOH, Cr Hs Oh并用10mL無水甲醇洗滌濾液和洗滌液合并后減壓(e)l/DMSO/ H, SO i(D) pyridinium HCl濃縮,加入100mL去離子水并冷卻到0℃,攪拌1小2實驗部分熔點用RY-1熔點儀測定(溫度未經(jīng)校正)。核時抽濾,用10mL去離子水洗滌,干燥得6.08g化合物磁共振譜用 Bruker advance400,AP140型質(zhì)譜儀④,收率為76.0%,m,p122-123c(Ref:124125℃)。HNMR(CDCl3):86.16(2H,s),3.80核磁共振儀測定。所用試劑均為分析純。3.84(9H,s),3.35-3.39(1H,m),2.96-3.012.11一甲基-4-(2,4,6-三甲氧基)-1,2,3,6(2H,m),2.87-2.90(1H,m),2.31-2.34(3H,s),四氫吡啶(2)的合成方法見參考文獻[4],m.p1182.12-2.15(2H,m),2.01-2.07(2H,m)。~120℃(文獻為118~122℃),改用石油醚:乙酸乙酯將消旋的3一羥基哌啶醇9g(0.032mol)溶于(10:1)重結(jié)晶比文獻單純用石油醚效果好。HNMR30mL甲醇,加人用20mL甲醇溶解的(+)-二苯甲(CDC.):6.13(2H,s),5.55(1H,m),3.81(3H,),酰酒石酸12.6g(0.034mol),混合液加熱至沸騰后,緩375(3H,s),3.112H,m),2.65(Hx,m),.36(3H,s),慢加入約50mL異丙醚冷卻酒石酸鹽緩慢析出,抽2.34(2H,m)。濾,用上述方法重結(jié)晶所得酒石酸鹽4.3g(0.01mol)226-(3-溴-2,4,6-三甲氧苯基)-3-甲基一7加入20mL水和2N鹽酸10mL,攪拌混合物用氧雜-3-氮雜一雙環(huán)(4,1,0)庚烷(3)的合成取100mL乙酸乙酯萃取水相用碳酸鈉堿化后用氯仿萃10g②(.038mo),加入5 ML DMSO后,將此混懸液取,分取氯仿層無水硫酸鈉干燥,回收溶劑后得(-)冷卻至15℃,于20℃加入15mL去離子水,混合物冷一3-羥基哌啶醇17.7g,[a]D=-54.13°(甲醇)卻至5士1℃,加入3.5mLCF3COOH后,于5士1℃攪2.4(-)-1-(2-羥基-3-((3R,4S)-3-羥基拌15分鐘。在5±1℃,將8.5gNBS(0.095mol)加人-1-甲基哌啶-4-基)-4.6-二甲氧基苯乙酮(5)上述溶液中,并于此溫度將混合物攪拌90分鐘,而后的合成在冰浴下,將10.8mLBF3·Et2O加入0.25gNa2S2O,以除去未反應(yīng)的NBS,滴加(0.076mol)滴加到含3.5g化合物4(0.012mol)的5mL30%NaOH到前面的溶液中將此混合物于5士50mL二氯甲烷的溶液中,接著滴加7.6mL乙酸酐1℃攪拌15分鐘,再加15mL30%NaOH后繼續(xù)攪拌(0.073mol),溶液于室溫攪拌24小時后,用適量水稀90分鐘。將此反應(yīng)混合物倒人100mL去離子水并于釋,再田碳酸調(diào)小為.,知甲烷萃取幾次后,合7~10℃攪拌1小時,抽濾,并用去離子水洗滌,干燥得并有中國煤化工于瓶壁析出棕黃色10.6g化合物③,收率為81.0%,m.p133~134℃.粉末CNMHG醇,加入50mL5%HNMR(CDCI3):86.29(1H,s),3.95(3H,s),3.KOH后于室溫攪拌2小時,混合物減壓濃縮后加入(3H,s),3.87(3H,s),3.34(1H,s),3.02-310%NaOH適量,抽濾,不溶物棄去,濾液再用2N鹽第2期李艷玲,等. Flavopiridol合成工藝的改進酸調(diào)pH8~9,析出淡黃色粉末收集干燥后為28g.(2H,m),3.10(1H,m),3.01-3.072H,m),2.52收率為76%;m.p214~216c(Ref:215~218℃,鹽酸(3H,s),2.50(2H,m)鹽)ESI-MS:m/z[M+1]310.4;HNMR(CDCl):2.7 flavopiridol(1)的合成方法見參考文獻4,mp8599(1H,s),3.92(6H,s),3.41-3.45(1H,m),191~193℃(Ref:190~194℃,鹽酸鹽) ESI MS:m3.22-3.25(1H,m),3.16-3.18(2H,m),2.62[M+1]+402.3;HNMR(DMSO-d6):87.76(3H,s),2.57(3H,s),2,40-2.47(2H,m)。(1H,m),7.74(1H,m),7.60(1H,m),7.54(1H,m),2.5(-)-2-羥基-3-((3R,4S)-3一羥基-1-6.30(1H,s),5.80(1H,s),3.40(1H,m),3.30-3.37甲基哌啶-4—基)-46-二甲氧基查爾酮(6)的合成(2H,m),3.24(lH,m),3.14-3.21(2H,m),2.KOH10.0g(0.18mol)溶于乙醇80mL和水20mL(3H,s),2.49-2.51(2H,m)。的混合液中,再投入化合物⑤6.2g(0.02mol)和鄰氯苯甲醛37g(0.03mol),室溫攪拌3小時。用2N鹽參考文獻酸溶液調(diào)pH8~9,析出大量固體。抽濾,固體用水洗1] Yun Dai, Steven G. Cyclin- dependent kinase inhibitors至中性,干燥得6.9g化合物⑥,收率為80.0%,m.p[J]. Current Opinon in Pharmacology, 2003, 3:362-370.158-159C. ESI MS:m/z[M+1]+432. 4: HNMR [2] Senderowicz AM Flavopiridol: the first cyclin-dependent(CDCl3):87.90-7.92(1H,d,J=15.8Hz),7.72kinase inhibitor in human clinical trials []. Invest New7.76(1H,d,J=15.8Hz),7.53-7.55(1H,m),7.41Drugs,199917:13-20.-7.46(2H,),7. 35-7. 39(1H, m),6. 26(lH, s). [3] Edward C, Grendys JR, John A, et al. A phase Il evalua-tion of flavopiridol as second-line chemotherapy of endo3.84-3.86(6H,s),3.24-3.27(1H,m),2.90-2.97metrial carcinoma: A Gynecologic Oncology Group study(2H,m),2.73-2.75(1H,m),2.65-2.70(2H,m),U]. Gynecologic Oncology, 2005, 98: 249-253.2.50(3H,s),2.28(2H,m)2.6(-)-2-(2一氯苯基)-8—((3R,4S)-3一羥pyran-4-one compounds which have anti-inflamatory基-1-甲基哌啶-4一基)—5.7一二甲氧基黃酮(7)or immunodulating action[P].US,4,900,727,1990-2的合成將1.0g(2.37mmol)化合物⑥溶于DMSO32mL中而后加入L20.1g,硫酸043mL于85~90℃[] Christine AT, Arish KM,Kolp, et al. Application of加熱6小時,減壓蒸出DMSO,加水100mL稀釋后,用odified flavone closure for the preparation of racemic2%NaOH,調(diào)pH8~9,水層用CH2C2(3×40mL)萃L86-8275[J] Organic Process Research & Development,1999,3:256-259取,合并有機層后,無水Na2SO干燥,回收溶劑后得[6] Brion FB, Richard C, Bois RS, et al. Preparation of 40.51g化合物⑦,收率為50.0%。m.p108~110℃phenyl-1, 2, 3, 6-tetrahydropyridines[ P]. US, 6, 136,(Ref: 110 C)IESI MS: m/z[M+1]*430.3: HNMR81,2000-10-24(DMSO-d6):87.81-7.83(1H,m),7.66-7.68稿日期:2008-1226)(1H,m),7.52-7.61(2H,m),6.69(1H,s),6.33(1H,s),3.91-3.93(6H,s),3.30(1H,m),3.29歌迎投稿飾打中國煤化工CNMHG