吲唑的簡(jiǎn)便合成

第29卷第1期蔡可迎等吲唑的簡(jiǎn)便合成53化學(xué)試劑2007 29(1 )53 ~54吲唑的簡(jiǎn)便合成蔡可迎”宗志敏魏賢勇(中國礦業(yè)大學(xué)化工學(xué)院江蘇徐州221008 )摘要:以鄰硝基甲苯為原料在乙醇鈉催化下與草酸二乙酯縮合然后經(jīng)水解、雙氧水氧化、鹽酸酸化得到鄰硝基苯乙酸,收率62%。鄰硝基苯乙酸用8%硫化銨溶液在回流溫度下還原2h后再進(jìn)行重氮化反應將得到的重氮鹽溶液于室溫放置24 h得到吲唑收率71%。兩步總收率44%。關(guān)鍵詞吲唑鄰硝基苯乙酸合成中圖分類(lèi)號:0626文獻標識碼:A文章編號0258-3283( 2007 )01 -0053-02吲唑是重要的有機合成中間體其許多衍生反應瓶中在攪拌下分批投入1.6 g( 70 mmol )切物具有藥物活性[3。例如,吲唑環(huán)在Cu( II )催碎的金屬鈉待金屬鈉全溶后冷卻至室溫，得到化下與芳基硼酸反應可得1-芳基吲唑4] ,1芳基乙醇鈉的無(wú)水乙醇溶液。加入8.8 g( 60 mmol )吲唑可作避孕藥[5] ;吲唑與酸酐或酰氯反應可得草酸二乙酯攪拌待物料混合均勻后滴加8.2 gN_?；胚騕°]其中一些N-?；胚蚓哂序屜x(chóng)活( 60 mmol )鄰硝基甲苯,約0.5 h加完然后于室性。吲唑的合成方法主要有: )以吲唑-3~羧酸為溫反應0.5 h ,升溫回流反應1.0 h。稍冷加入原料進(jìn)行脫羧反應得到72 )以3-腈基吲唑為原30 mL水進(jìn)行水解加熱回流1.5 h。水解完畢料進(jìn)行脫腈基反應得到7]3)以3-氯吲唑為原料經(jīng)水蒸氣蒸餾回收未反應的鄰硝基甲苯。冷至室經(jīng)脫氯得到[8];4)鄰甲基苯胺與乙酐、醋酸鉀和溫滴加30%雙氧水,同時(shí)不斷取反應液用氫氧亞硝酸異戊酯的混合物料反應得到9] 5 )4-醛基化鈉溶液檢測,當 反應液遇氫氧化鈉溶液不變色吡唑與丁二酸二乙酯在叔丁醇鉀催化下縮合得時(shí)表明反應已完成。將物料冷至室溫用鹽酸酸到101。方法1 )2 )和3 )的問(wèn)題是原料不易獲得;化至pH2靜置有結晶析出。抽濾所得固體用方法4 )的反應體系復雜,導致后處理困難收率乙醇/水(體積比1: 3 )重結晶,干燥后得白色針低;方法5 )需在強堿催化下進(jìn)行條件苛刻。狀晶體6.74g收率62%。m.p. 138~140 C(文以?xún)r(jià)廉易得的鄰硝基甲苯為原料,在乙醇鈉獻'2]值:140~141 C )。IR( KBr壓片)n cm-':催化下與草酸二乙酯進(jìn)行縮合反應再經(jīng)水解、氧3 20( - -COOH); 700( C=0);1 600 ,1 500 ,1化及酸化制得鄰硝基苯乙酸后者通過(guò)還原、重氮450(苯環(huán))?；?、環(huán)合及脫羧可得到吲唑:1.2.2吲唑的合成將1.2.1制得的3.62g(20mmol)鄰硝基苯C00HLCOCJHJ,NnOC.H.-NO,_ (NH)S乙酸和35 mL 8%( NH, )S溶液加入100 mL燒凸m,2.H,0.HO,H瓶中,回流反應2 h。將反應液冷卻、過(guò)濾緩慢滴NaNO,H*.加濃鹽酸至pH <3。用冰鹽浴冷卻至5 C以下,攪拌下緩慢滴加4.2mL30%的亞硝酸鈉水溶液,1實(shí)驗部分約10 min加完。加完后再反應10min,用KI淀1.1主要儀器與試劑粉試紙檢驗NaNO2是否過(guò)量，如過(guò)量可加入少量惠普HP6890/5973型氣相色譜/質(zhì)譜聯(lián)用尿素。反應結束后討濾除去未反應的鄰硝基苯乙儀美國Nicolet公司Magna-IR 560紅外光譜儀。中國煤化工斷有固體析出并且有鄰硝基甲苯為工業(yè)品(質(zhì)量分數>99.7% ),TYHCNMHG其他試劑均為分析純。收稿日期2006-05-251.2實(shí)驗步驟基金項目江蘇省高新技術(shù)產(chǎn)業(yè)發(fā)展項目( JHB05-33 )。1.2.1鄰硝基苯乙酸的合成作者簡(jiǎn)介蔡可迎( 1970-)男江蘇沛縣人,博士生,講師,參照文獻11 ]制備:將 20 mL無(wú)水乙醇加入從事有機中間體的合成研究。54化學(xué)試劑2007年1月氣體逸出。抽濾得鱗片狀固體熱水重結晶、真空dazoles[ J ] Tetrahedron Lett. ,2005 ,46( 21 ):3 771-3干燥得淡黃色粉末1. 68 g收率71%(以鄰硝基774.苯乙酸計)。m.p. 145~147 C(文獻8]值:145 ~[5 ]LEBEDEV A Y ,KHARTULYARI A s ,VOSKOBOYNIK-OV A Z. Synthesis of 1-aryl-1H-indazoles via palladium-146.5C)。IR(KBr壓片),v,cm-1:3400catalyzed intramolecular amination of aryl halide[ J] J.(- -NH-);3 300(- -NH- 締合);1 600 ,1 550 ,Org. Chem. 2005 70( 2 ) 596-602.1 500(苯環(huán));700(苯的1 2-二取代)。 MS ,m/z[ 6 ]KINGSBURY W D GYURIK R J ,THEODORIDES V J ,( % ):118( M* ,100)91(37 );78(5 );63(21 )52et al. Synthesis of l-and 2-substituted indazoles as anthel-(8 )。mintic agents[ J ] J. Med. Chem. ,1976 ,19( 6 ) :839-840.2結果與討論. [ 7 ]ROUSSEAU V ,LINDWALL H G. Strueture and ultravio-重氮鹽能和許多具有活潑氫原子的化合物進(jìn)let absorption spectra of indazole ,3-substituted indazole行偶合反應而在鄰氨基苯乙酸形成的重氮鹽中and some of their derivatives[ J ] J. Am. Chem. Soc.苯環(huán).上重氮基鄰位的亞甲基由于羧基吸電子效應1950 72(7 ) 3047-3 048.而具有活潑氫原子,因此重氮鹽能進(jìn)行分子內偶[ 8 ]徐克勛.精細有機化工原料及中間體手冊M]北京:化學(xué)工業(yè)出版社,1998. 431-432.合形成穩定的五元環(huán)羧基同時(shí)脫去,生 成吲唑,[ 9 ]CHRISTOPH R ,VOLKER H. Simplifcation of the jacob-其過(guò)程如下。son indazole synthesis[ J ] Synthesis ,1972 ( 7 ) :375-,C00H~376.“CO0H[ 10 ]GIOVANNI B P ,BARBARA C GIAMPIEROS et al.AN≈N°Crnew synthetic approach to indazole synthesis[ J ] Syn-在吲唑合成過(guò)程中,重氮鹽溶液須置于室溫.thesis ,1997 ( 10):1 140-1 142.(約20C)使其緩慢反應才能有較高的收率。溫[ 11 ]DICARLO F J. Synethesis of oxindole[ J ] J. Am. Chem.度較低反應緩慢,且有重氮鹽分解造成吲唑收Soc. ,1944 66( 8)1 420.率降低溫度較高,反應速度加快,但有焦油狀副[ 12 ]WILIAM B ,WRICHT JR ,KENNETH H C. Cyelie產(chǎn)物生成也使吲唑收率降低。hydroxamic acids derived from indole[ J ] J. Am. Chem.Soc. 1956 78( 1 )221-224.參考文獻:[ 1 ]SONGJJ ,YEE N K. Synthesis of 1-aryl-1 H-indazoles viaSimple synthesis of indazole CAI Ke-ying* ,ZONG Zhi-min ,WEI Xian-yong ( School of Chemical Engineering ,Chinathe palladium-catalyzed cyclization of N-aryl-N'< o-bro-University of Mining and Technology ,Xuzhou 221008 ,Chi-mobenzyl )hydrazines and[ N-aryl-N'< o-bromobenzyI )-hydrazinato-N" ]-triphenyl-phosphonium bromides[ J ]na) ,Huaxue Shiji 2007 29( 1 ) 53 ~54Abstract :o-Nitrophenylacetic acid was synthesized by con-Tetrahedron Lett. 2001 42( 16 ) 2937-2 940.[2 ]HUANG Li-jau ,SHIH Mei-ling ,CHEN Hua-sin ,et al.densation of o-nitrotoluene with diethyl oxalate catalyzed bySynthesis of N2 ( substituted benzyl )-3( 4-methylphe-Cz HAONa followed by hydrolysis poxidation with H2O2 and a-cidification with HCI resulting in an approximate 62% yield.nyl ) indazoles as novel anti-angiogenic agents[ J ].Indazole was synthesized in 71% yield by keeping the diazo-Bioorg. Med. Chem. 2006 ,14( 2 ) 528 536.[ 3 ]HEINZ R S ,BLECKMAN ,MICHAEL T K et al. Synthe-nation solution for 24 h at room temperature ,which was pre-pared from reducing o-nitrophenylacetic acid with 8%sis of disubstituted indazole compounds as cyclin depend-( NH, )2S solution upon refluxing for 2 h and diazotizing withent kinase inhibitors and methods for inhibiting cell pro-HCl and NaNO2. The overall yield was around 44%.liferation :WO 2 001 053 268[ P ].2001 -07-26.[4 ]HARI Y SHOJI Y ,AOYAMA T. Regioselective synthesisKev wnrds indavnle. 'n-nitrnnhenvlacetic acid synthesis中國煤化工of I-arylindazoles via N-arylation of 3-trimethylsilylin-TYHCNMH G .請您繼續支持關(guān)心本刊共同進(jìn)步