乙酰苯胺及其衍生物的氯甲基化反应 (1)

研究简报乙酰苯胺及其衍生物的氯甲基化反应于丽君1,宁兆伦2,王恩思1,2,张福中3,杨世忠4(1.吉林大学药学院,长春130021; 2.吉林大学生命科学学院,长春130023;3.通辽出入境检验检疫局,通辽028000;4.长春中医学院附属医院,长春130021)摘要:考察了乙酰苯胺及其衍生物在多聚甲醛-盐酸体系下的氯甲基化反应,结果表明,N -氯甲基化反应的产物是主要产物.关键中间体及最终化合物的结构经核磁共振氢谱及碳谱确证.关键词:乙酰苯胺;衍生物;氯甲基化;反应中图分类号:O621.26 文献标识码:A 文章编号:1671-5489(2004)01-0110-03Studies on chloromethylation of acetanilide and its derivativesYU Li-jun 1,NING Zhao-lun 2,WANG En-si 1,2,ZHANG Fu-zhong 3,YANG Shi-zhong 4(1.College of P har macy ,J ilin U niversity ,Chang chun 130021,China ; 2.College of L if e Science ,J ilin U niv er sity ,Changchun 130021,China ; 3.T ong liao Entry -Ex it I nsp ection and Quarantine Br eau ,T ongliao 028000,China ;4.College of Changchun Chinese M ed icine A ttach H osp ital ,Changchun 130021,China )Abstract :The chlorom ethylation of acetanilide and its derivatives in a poly formaldehyde -HCl system gave N -substituted products as the major product.T he structures of the interm ediates and the targ et m olecule w ere confirmed by 1H NMR and 13C NMR spectra in our experiments.Keywords :acetanilide ;derivative ;chloromethylation ;reaction收稿日期:2003-02-20.作者简介:于丽君(1965～),女,硕士研究生,从事药物化学研究,E-mail:zhangfuzh ong @.联系人:王恩思(1955～),男,博士,教授,博士生导师,从事天然药物合成及绿色化学研究,E-m ail:W angss@.N -( -烷氧基烷基)芳胺在生物有机化学和有机合成中具有重要作用[1,2].Barluenga 等人[3]报道芳胺在醇钠存在下与多聚甲醛反应制备该类化合物.Weinberg 等人[4]在氢氧化钾的甲醇体系中电解合成该类化合物.Katritzky 等人[2]利用醇钠/醇体系的置换法制备该类化合物.我们在前文[5]报道利用芳胺的氯甲基化继之以醇解可获较好收率的该类化合物.本文考察了乙酰苯胺及其衍生物的氯甲基化反应,实验结果表明,该反应的主要产物为N -氯甲基化产物产物.反应式如下: G NHAc (CH 2O)nHCl G N CH 2ClAc EtOH G N CH 2OEt Ac ,G=H(化合物2,3);o -M e(化合物4,5);m -M e(化合物6,7);o -Cl(化合物8,9);p -Ac(化合物10,11);m -CO 2Et(化合物12,13);m -CO 2Et-p -OEt(化合物14,15).1　实　验1.1　仪器与试剂　熔点用XT4显微熔点仪测定,温度未经校正.红外光谱用FTS-135型(BIO-RAD第42卷　第1期 吉林大学学报(理学版) V ol.42　N o.12004年1月 JOU RN A L OF JIL IN U N IV ERSIT Y (SCIEN CE EDIT ION )Jan 2004公司)红外光谱仪测定,KBr 压片.1H NMR 和13C NM R 用U NIT Y -400型(Varian 公司)核磁共振仪测定,TM S 为内标.柱层析用青岛海洋化工厂分厂硅胶G(200～300目或300～400目);其余试剂及溶剂均为国产A.R.级试剂.1.2　氯甲基化反应　在带有气体导入管的装置中,依次加入干燥苯30mL 、乙酰胺苯0.6g (4.4m mol),40℃搅拌下使乙酰胺苯溶解,加入多聚甲醛0.3g (9.6mmol),在回馏搅拌下通入干燥HCl 气体1～2h,用T LC 跟踪反应进程,反应结束后冷至室温,有机层用饱和NaCl 洗至中性(3×20mL ),无水Na 2SO 4干燥,过滤,旋转蒸除溶剂得粗品,粗品经硅胶G 柱层析[洗脱液:V (乙酸乙酯) V (石油醚)=2 1]得精品化合物20.6g (71%).用类似方法可得化合物4,6,8,10,12和14.化合物4粗品未经精制直接用于下一步醇解反应,化合物6,8,10,12和14的1H NM R 和13C NM R 分析数据见表1和表2.Table 1　1H NMR data of compounds 3～15[CDCl 3/TMS , ,J (Hz )]37.45～7.33(m ,3H ,A r );7.29～7.21(m ,2H ,Ar ); 5.08(s ,2H ,NCH 2O ); 3.65(q ,J =6.8,2H ,O C 2H 5); 1.88(s,3H,CH 3CO ); 1.21(t,J =6.8,3H,O C 2H 5)57.35～7.13(m ,4H ,Ar ); 5.42(d ,J =12,1H ,N CH 2O ); 4.67(d ,J =6,1H ,N CH 2O ); 3.67(q ,J =6,2H ,OC 2H 5); 2.25(s,3H,CH 3CO ); 1.81(d,J =12,3H,A rCH 3); 1.21(t,J =12,3H,OC 2H 5)67.34～7.19(m ,4H ,Ar ); 5.14(s ,2H ,NCH 2Cl ); 2.38(s ,3H ,CH 3CO ); 2.09(s ,3H ,A rCH 3)77.29～7.26(m ,1H,A r );7.17～7.10(m,1H,A r );7.02～7.00(m ,2H,Ar ); 5.07(s,2H,N CH 2O ); 3.64(q ,J =8,2H ,O C 2H 5); 2.38(s ,3H ,CH 3CO ); 1.89(s ,3H ,A r CH 3); 1.22(t ,J =8,3H ,OC 2H 5)87.53～7.34(m ,4H,Ar ); 5.57(d,J =10,1H,NCH 2Cl); 4.54(d,J =10,1H,NCH 2Cl); 1.85(s,3H,CH 3CO )97.51～7.48(m ,2H ,Ar );7.35～7.29(m ,2H ,A r ); 5.53(d ,J =10,1H ,N CH 2O ); 4.61(d ,J =10,1H ,N CH 2O );3.68(q,J =7.2,2H,OC 2H 5); 1.82(s,3H,CH 3CO ); 1.20(t,J =7.2,3H,OC 2H 5)108.07(d,J =4.8,1H,A r );7.94(d,J =8.8,1H,A r);7.62(d,J =8.8,1H,Ar );7.44(d,J = 4.8,1H,Ar ); 5.52(s,2H,N CH 2Cl); 2.63(s,3H,CH 3CO); 2.57(s,3H,CH 3CO)117.89(d,J =8.4,2H,A r );7.23(d,J =8.4,2H,A r); 4.94(s,2H,N CH 2O); 3.47(q,J = 6.8,2H,OC 2H 5); 2.47(s,3H,CH 3CO ); 1.82(s,3H,CH 3CO); 1.08(t ,J =6.8,3H,OC 2H 5)128.06～7.90(m ,2H,Ar );7.52～7.46(m ,2H,A r); 5.16(d,J =12,2H,NCH 2Cl); 4.38(q,J =6,2H,OC 2H 5);1.88(s,3H,CH 3CO );1,41(t,J =6,3H,O C 2H 5)138.06(s,1H,Ar );7.91(d,J =4,1H,Ar );7.51～7.46(m,2H,A r ); 5.16(d,J =8,2H,N CH 2O ); 4.40(q,J =4,2H,O C 2H 5); 3.72(q,J =4,2H,OC 2H 5); 1.88(s,3H,CH 3CO ); 1.40(t ,J =4,3H,OC 2H 5); 1.24(t ,J =4,3H ,OC 2H 5)147.64(d,J =2,1H,A r );7.34(dd,J =2,J =7.2,1H,Ar ); 6.98(d,J =6.8,1H,A r); 5.03(s,2H,N CH 2Cl); 4.39(q ,J = 5.6,2H ,O C 2H 5); 4.15(q ,J = 5.6,2H ,O C 2H 5); 1.89(s ,3H ,CH 3CO ); 1.47(t ,J =5.6,3H ,OC 2H 5);1.38(t ,J =5.6,3H,OC 2H 5)157.62(s,1H,A r );7.29(d,J =7.2,1H,A r ); 6.99(d,J = 6.8,1H,Ar ); 5.06(s,2H,N CH 2O C 2H 5); 4.39(q ,J =6,2H ,O C 2H 5); 4.15(q ,J = 5.6,2H ,O C 2H 5); 3.66(q ,J =8,2H ,N CH 2O C 2H 5); 1.88(s ,3H ,CH 3CO );1.49(t ,J =5.6,3H,OC 2H 5); 1.37(t,J =6,3H,OC 2H 5); 1.23(t,J =8,3H,N CH 2OC 2H 5)Tabl e 2　13C NMR data of compounds 3～15(CD 3Cl /TMS , )3171.3,142.1,129.4,129.4,128.3,128.3,128.0,77.0,64.0,22.7,15.05170.9,139.9,134.7,130.5,128.4,127.7,126.4,75.9,63.8,21.5,16.7,14.37171.3,142.1,139.4,129.2,128.7,128.5,125.0,76.9,64.0,22.7,21.1,15.08172.0,139.3,132.6,130.0,130.0,129.9,128.0,72.4,22.110196.8,170.0,144.9,137.2,129.9,129.7,128.1,118.9,77.1,26.4,22.611196.6,170.5,146.1,136.0,129.3,129.2,129.1,127.7,77.2,63.9,26.3,22.5,14.812171.0,165.3,142.1,132.7,132.4,129.6,129.1,128.9,75.3,61.2,22.7,14.113171.0,165.3,142.1,132.6,132.0,129.5,129.0,128.8,76.0,61.1,57.8,22.6,18.1,14.014172.2,165.4,157.8,134.4,132.3,130.4,121.7,114.0,73.1,64.8,61.0,22.5,14.4,14.0111　第1期于丽君,等:乙酰苯胺及其衍生物的氯甲基化反应 1.3　醇解反应　在室温下,化合物20.6g (9.6m mol )经硅胶G 柱层析(洗脱液:乙醇),得精品化合物30.6g (71%).用类似方法可得化合物5,7,9,11,13和15.化合物3,5,7,9,11,13和15的1H NMR 和13C NMR 分析数据见表1和表2.2　结果与讨论采用乙酰苯胺及其衍生物在多聚甲醛-盐酸体系下的氯甲基化继之以醇解反应合成N -( -烷氧基烷基)芳胺的衍生物,该法虽收率适中(见表3),但价格较低,毒性较小,且实验操作方便.值得注意的是,化合物7和9的收率较低是由于原料与产物的R f 值接近不能得到很好的分离所致.Tabl e 3　Yield of compounds 2～15Compo und23456789101112131415Y ield(%)8571806684328621735781827480参考文献[1]　Bar lueng a J,Bay on A M ,Campos P.P repar ation of N ,O -aminals as sy nthet ic equiv alents of H 2CN Ar and (H 2C N HA r )+ions [J].J Chem Soc Perk in T r ansl ,1988,(7):1631-1636.[2]　Kat ritzky A R ,F an W Q ,L ong Q H.A conveniet sy nt hesis of N -( -alkox yalkyl)and N -( -alkylthiol)alky lamines [J].Sy nthesis ,1993,(2):229-232.[3]　Bar lueng a J ,Bay on A M ,A sensio G .M onoalkylatione of pr imary aromatic amine via N -(alkox ymethy l )ary lamine[J ].J Chem Soc Chem Commun ,1983,(19):1109-1110.[4]　Weinber g N L ,Brow n E A.T he anodic ox idation of or ganic compounds Ⅱthe electrochemical alkox ylation oftertiar y amines [J].J Or g Chem ,1966,31:4058-4061.[5]　YU L i -jun (于丽君),ZHA NG F u -zhong (张福中),W A NG En -si (王恩思).Studies o n chloromethy latio n of5-acety lamino -2-ethox y -benzoic acid ethyl ester (2-乙氧基-5-乙酰氨基苯甲酸乙酯的氯甲基化反应)[J ].J our nal of I nner M ong olia U niv er sity f or N ationalities [内蒙古民族大学学报(自然科学学报)],2003,18(1):17-19.(责任编辑:李桂英)Brief Introduction to“Journal of Jilin University (Science Edition )”“Journal of Jilin U niversity (Science Edit ion)”is a comprehensive academic Journal in the fields of science sponso red by Jilin U niv er sit y and administr ated by the Educational M inistry of t he people's R epublic of China.T he jour nal start ed publi-cation in 1955.T he original name at star ting publication was “Jour nal o f N atural Science o f N or theast P eople'sU niver sity ”,w hich w as chang ed into “A cta Scient iarum Naturalium Jilinesis “(I SSN 0529-0279)in 1958ow ing to the name change of the university.T he present jo urnal name has been beg un since the beg inning of 2002after a new Jilin U ni-versity w as set up,w hich comes from the amalg amation of the original Jilin U niversity ,Jilin U niv ersity of T echnolo gy ,Bethune M edicine U niversity ,Changchun U niv ersity of Science and T echnology and Chang chun P ost and T elecommuni-cation Institute o n June 12,2000.T he domestic journal number is CN 22-1340/O ,and the international journal number ISSN 1671-5489.T he editorial board of the journal co nsists of 47member s w ho ar e all well kno wn professors.Am ong them ther e are fiv e A cademicians o f the Chinese A cademy of Sciences ,they ar e Pro fs .Shen Jia -co ng (chemist ),Sun Jia -zhong (chemist ),Wu Shi-shu(phy sicist),Xu Ru-ren(chemist )and Z ou Guang-tian(phy sicist).P rof.Qiu Shi-lun (V ice Pr esident of Jilin U -niversity ,T he Chair man of “973”project of P.R.China,Head of M acDiarmid L aborator y)holds the post of the editor-in-chief.T he journal mainly covers the latest scientific resear ch r esults achieved in basic theoretical r esearch ,applied and dev el-oped resear ches,t he contents of w hich are contained in the columns of theses,review s,r esear ch notes and letters in the fields of mathematics,phy sics,chemist ry ,life science,computer science,electricity and electronics,envir onment science and so on 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