Flavopiridol合成工艺的改进

2009年第25卷第2期VoL25No.22009JOURNAL OF BAOTOU MEDICAL COLLEGE119Flavopiridol合成工艺的改进李艳玲12方浩2徐文方2(1.包头医学院药学系,内蒙古包头014060;2.山东大学药学院)摘要目的:改进 Flavopiridol的合成工艺。方法:以1-甲基-4-(24,6-三甲氧基)-1,2,3,6-四氢吡啶为原料,利用Dlon反应制得环氧而后经AH1还原制得 Flavopiridol的关键中间体3-哌啶醇,后经拆分、酰化、选择性脱甲基、羟醛缩合、查尔酮氧化关环、脱甲基制得 Flavopiridol,结果:目标化合物经H-NMR、质谱确证;总收率为11.8%比文献报道的收率提高4.8%。结论:改进后的方法不仅条件温和、反应的立体选择性大为提高,而且操作简关键词 Dalton反应;AlH2还原;查尔酮路线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细胞周期蛋白依赖激酶(CDKs)是一类依赖 cylin酮用硼氢化钠还原上述酮后得到顺式醇和反式醇的的丝/苏氨酸蛋白激酶在细胞周期的调控中起重要作混合物,用重结晶法分离出顺式醇中间体④,拆分后经用由于其功能失调和肿瘤发生之间的密切关系已使过量BF3-OEt催化、醋酐酰化同时脱去乙酰基邻位其抑制剂的研究成为目前抗肿瘤药物研究与开发的热甲氧基的甲基得到中间体酚⑤,以该酚为原料,专利都点之一, Flavopiridol是第一个进入临床试验的采用B-二酮法制得甲氧黄酮其中B一二酮法又包括CDK抑制剂,化学结构为黄酮最初来源于一种印度Aan- Robinson缩合以及 Baker- Venkataraman重植物 rohitukin,目前已可人工合成口2,研究表明排(,甲氧黄酮用盐酸吡啶法脱去甲基后制得FaFlavopiridol对包括肺癌乳腺癌等的多种肿瘤细胞系 vopiridol本文作者以②为原料,在查阅相关文献的均具有抗肿瘤活性而且可以抑制异种嫁接模型中胂基础上0),将中间体④的合成作了改进方法如下:首瘤的生长先采用 Dalton反应制得环氧③,而后利用氢化铝还原1合成路线环氧③后接着用锌粉一甲醇脱溴即制得中间体④,与有关 Flavopiridol I的合成,仅在几篇专利文献中前面所述专利文献的方法相比改进后的工艺不仅使有报道,主要步骤以图1为例说明:将②经硼氢化反应产中国煤化工体选择性直接得氧化反应制得反式醇该醇经 swern氧化得到相应的到顺CNMH Gern氧化要求超低温条件),操作简单。与此同时,我们尝试用查尔酮路基金项目:國家科技部863课题(2007AA02Z314)线完成了 Flavopiridol的关环反应。 Flavopiridol合成120包头医学院学报第25卷路线见图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℃,将3g四氢铝锂(0.080mol)加入50mL四氢呋喃中,于25℃将此混悬液搅拌4小时后静置20小时,在0士1℃搅拌下,加2.7g无水氯化铝,之后将温度升高到20℃,将混合物搅拌15分钟即得还原剂AH3。将上述AH3THF混悬液冷却到0±1℃,并于此温度加10g③(0.028mol)和60 mL THF,混合物搅拌2小时后缓慢加入100mL5%NaOH继续搅拌1小时后温度升高到图1 Flavopiridol改进合成路线20℃,将所得到的胶胨状物过滤滤液在减压蒸馏下浓(a)(i) DMSo, H: O, CF3 COOH:(ii) NBS, Naz SOs缩至原体积一半,将150mL甲醇加入上述溶液中,在30% NaOH,(b)(i)AlH,, THF,(ii)50%KOH.搅拌此混合液的同时加入35mL50%KOH,而后加CH,OH, Zn(c)(i) BF3- OEt, Ace O, CHz Clz入10g锌粉,混合物回流16小时后冷却到20℃,抽滤(ii5%KOH, CH, OH:(d)10% KOH, Cr Hs Oh并用10mL无水甲醇洗涤滤液和洗涤液合并后减压(e)l/DMSO/ H, SO i(D) pyridinium HCl浓缩,加入100mL去离子水并冷却到0℃,搅拌1小2实验部分熔点用RY-1熔点仪测定(温度未经校正)。核时抽滤,用10mL去离子水洗涤,干燥得6.08g化合物磁共振谱用 Bruker advance400,AP140型质谱仪④,收率为76.0%,m,p122-123c(Ref:124125℃)。HNMR(CDCl3):86.16(2H,s),3.80核磁共振仪测定。所用试剂均为分析纯。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),四氢吡啶(2)的合成方法见参考文献[4],m.p1182.12-2.15(2H,m),2.01-2.07(2H,m)。~120℃(文献为118~122℃),改用石油醚:乙酸乙酯将消旋的3一羟基哌啶醇9g(0.032mol)溶于(10:1)重结晶比文献单纯用石油醚效果好。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),混合液加热至沸腾后,缓375(3H,s),3.112H,m),2.65(Hx,m),.36(3H,s),慢加入约50mL异丙醚冷却酒石酸盐缓慢析出,抽2.34(2H,m)。滤,用上述方法重结晶所得酒石酸盐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盐酸10mL,搅拌混合物用氧杂-3-氮杂一双环(4,1,0)庚烷(3)的合成取100mL乙酸乙酯萃取水相用碳酸钠碱化后用氯仿萃10g②(.038mo),加入5 ML DMSO后,将此混悬液取,分取氯仿层无水硫酸钠干燥,回收溶剂后得(-)冷却至15℃,于20℃加入15mL去离子水,混合物冷一3-羟基哌啶醇17.7g,[a]D=-54.13°(甲醇)却至5士1℃,加入3.5mLCF3COOH后,于5士1℃搅2.4(-)-1-(2-羟基-3-((3R,4S)-3-羟基拌15分钟。在5±1℃,将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,并于此温度将混合物搅拌90分钟,而后的合成在冰浴下,将10.8mLBF3·Et2O加入0.25gNa2S2O,以除去未反应的NBS,滴加(0.076mol)滴加到含3.5g化合物4(0.012mol)的5mL30%NaOH到前面的溶液中将此混合物于5士50mL二氯甲烷的溶液中,接着滴加7.6mL乙酸酐1℃搅拌15分钟,再加15mL30%NaOH后继续搅拌(0.073mol),溶液于室温搅拌24小时后,用适量水稀90分钟。将此反应混合物倒人100mL去离子水并于释,再田碳酸调小为.,知甲烷萃取几次后,合7~10℃搅拌1小时,抽滤,并用去离子水洗涤,干燥得并有中国煤化工于瓶壁析出棕黄色10.6g化合物③,收率为81.0%,m.p133~134℃.粉末CNMHG醇,加入50mL5%HNMR(CDCI3):86.29(1H,s),3.95(3H,s),3.KOH后于室温搅拌2小时,混合物减压浓缩后加入(3H,s),3.87(3H,s),3.34(1H,s),3.02-310%NaOH适量,抽滤,不溶物弃去,滤液再用2N盐第2期李艳玲,等. Flavopiridol合成工艺的改进酸调pH8~9,析出淡黄色粉末收集干燥后为28g.(2H,m),3.10(1H,m),3.01-3.072H,m),2.52收率为76%;m.p214~216c(Ref:215~218℃,盐酸(3H,s),2.50(2H,m)盐)ESI-MS:m/z[M+1]310.4;HNMR(CDCl):2.7 flavopiridol(1)的合成方法见参考文献4,mp8599(1H,s),3.92(6H,s),3.41-3.45(1H,m),191~193℃(Ref:190~194℃,盐酸盐) 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-羟基-3-((3R,4S)-3一羟基-1-6.30(1H,s),5.80(1H,s),3.40(1H,m),3.30-3.37甲基哌啶-4—基)-46-二甲氧基查尔酮(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)和邻氯苯甲醛37g(0.03mol),室温搅拌3小时。用2N盐参考文献酸溶液调pH8~9,析出大量固体。抽滤,固体用水洗1] Yun Dai, Steven G. Cyclin- dependent kinase inhibitors至中性,干燥得6.9g化合物⑥,收率为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)-3一羟pyran-4-one compounds which have anti-inflamatory基-1-甲基哌啶-4一基)—5.7一二甲氧基黄酮(7)or immunodulating action[P].US,4,900,727,1990-2的合成将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加热6小时,减压蒸出DMSO,加水100mL稀释后,用odified flavone closure for the preparation of racemic2%NaOH,调pH8~9,水层用CH2C2(3×40mL)萃L86-8275[J] Organic Process Research & Development,1999,3:256-259取,合并有机层后,无水Na2SO干燥,回收溶剂后得[6] Brion FB, Richard C, Bois RS, et al. Preparation of 40.51g化合物⑦,收率为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歌迎投稿饰打中国煤化工CNMHG