折江大學(xué)學(xué)報(工學(xué)版)第40卷第7期ul2006 '2006年7月Journal of Zhejiang University( Engineering Science)Ju. 2006氨基吡啶的合成研究李曉娟,戴立言,陳英奇(浙江大學(xué)材料與化學(xué)工程學(xué)院，浙江杭州310027)摘要:研究了重要的有機(jī)中間體氨基吡啶的合成工藝.分別以2- .3- 、4氰基吡啶為起始原料,以水和丙酮為混合溶劑，在稀賊(NaOH)溶液中,以過氧化氫為催化劑,水解得到相應(yīng)的甲酰胺基吡啶，然后用新制備的次溴酸鈉進(jìn)行霍夫曼降解反應(yīng),制得相應(yīng)的2-3-.4氨基吡啶.以4氨基毗啶的合成為例,對兩步反應(yīng)的反應(yīng)條件進(jìn)行了優(yōu)化,得出適宜的條件為:氰基水解反應(yīng)中,氫氧化鈉溶液最佳質(zhì)量分?jǐn)?shù)為1.0 % ;霍夫曼降解反應(yīng)中,氫氧化鈉溶液最佳質(zhì)量分?jǐn)?shù)為12.5 %.反應(yīng)適宜溫度為75 C.關(guān)鍵詞:氨基吡啶;2_氨基吡啶;3-氨基吡啶;4~氨基吡啶;合成中圖分類號: TQ253.2文獻(xiàn)標(biāo)識碼: A文章編號: 1008 - 973X(2006)07 - 1272 -04Study on synthesis of aminopyridineLI Xiao-juan, DAI Li-yan, CHEN Ying-qi(College of Materials and Chemical Engineering , Zhejiang University, Hangzhou 310027, China)Abstract: A general synthetic route of aminopyridines which are useful organic intermediates was investiga-ted. The target compounds were synthesized starting from corresponding cyanopyridines, via incompletehydrolysis in the presence of hydrogen peroxide using mixture of acetone water and dilute base as solvent,and Hoffman degradation reaction with freshly made NaBrO. The feasible conditions of the above syntheticprocess were discussed taking the preparation of 4-aminopyridine as example. The optimum concentration ofsodium hydroxide solution in the transformation of cyanopyridine to pyridinecarboxamide was 1.0 %. And theHoffman degradation would be eficiently carried out at 75 C in 12. 5 % sodium hydroxide solution.Key words: aminopyridine; 2-aminopyridine; 3-aminopyridine; 4-aminopyridine; synthesis氨基吡啶類化合物(2- .3-.4-氨基吡啶)是含氨備較繁雜,且僅用于4-氨基吡啶的制備.本文以方的具有雜環(huán)結(jié)構(gòu)的物質(zhì)([-2] ,其合成方法主要有:1)法4)為3種氨基吡啶制備的通用路線,并參考文獻(xiàn)吡啶與氨基鈉進(jìn)行氨化反應(yīng)[3] ,此反應(yīng)條件苛刻,反[1,7]對氰基水解步驟作出改進(jìn),以水和與水互溶的應(yīng)試劑難得,且副產(chǎn)物較多,收率不高;2)由鹵代吡有機(jī)介質(zhì)為混合溶劑,在堿性條件下加人過氧化氫啶在鈀炭[1]或銅鹽[2]等催化劑的作用下進(jìn)行氨解反催化氰基水解.整個合成路線操作簡便,反應(yīng)條件溫應(yīng),此類方法或是催化劑成本高,或是鹵代吡啶不易和收率高.合成步驟如圖1所示..獲得,且設(shè)備要求嚴(yán)格,實(shí)際操作困難,不適于工業(yè)應(yīng)用;3)吡啶經(jīng)雙氧水氧化、發(fā)煙硝酸硝化成硝基氧1實(shí)驗(yàn)部分化吡啶,再進(jìn)行還原反應(yīng)得到氨基吡啶[56]此制備過程周期長、污染重、成本高;4)以氰基吡啶為原料經(jīng)1.1 化學(xué)試劑過催化水解、霍夫曼降解得到氨基吡啶[6],此法原料氰基吡啶(上虞三和醫(yī)藥化工有限公司);氫氧廉價易得,收率較高,但原文獻(xiàn)中金屬鹽催化劑的制中國煤化工驗(yàn)化工廠);液溴收稿日期: 2005 -06 - 25.浙江大學(xué)學(xué)報(工學(xué)版)網(wǎng)址: www. joqYHCNMHG作者簡介:李曉娟(1981-).女.浙江嘉興人,碩士生.主要從事藥物中間體有機(jī)合成的研究.通訊聯(lián)系人:戴立盲,男,副教授. E-maildailiyan@cnsce. zju. edu. cn第7期李曉娟,等:氨基吡啶的合成研究1273(上虞三和醫(yī)藥化工有限公司);丙酮(分析純,上海應(yīng)0.5 h,再升溫至60 C反應(yīng)2 h,停止反應(yīng).反應(yīng)液.三鷹化學(xué)試劑有限公司);乙醇(分析純，杭州長征冷卻,用30 mL乙酸乙酯萃取兩次,有機(jī)相用30化工廠);過氧化氫,質(zhì)量分?jǐn)?shù)為27. 5% (杭州臨安.mL水洗兩次,干燥,濃縮得紅色液體,減壓蒸餾得金龍化工化工有限公司);乙酸乙酯(分析純，上海白色固體9.1 g,質(zhì)量收率88. 1%,熔點(diǎn)60~61 C試劑總廠);二氯甲烷(分析純，上海三鷹化學(xué)試劑有(文獻(xiàn)[10]中熔點(diǎn):58~60 C).限公司);苯(分析純，上海三鷹化學(xué)試劑有限公'H-NMR(CDCl)8:4.625 (br, 2H, NH2)，司);甲苯(分析純，上海三鷹化學(xué)試劑有限公司);石6. 459~6.600 (m, 2H,吡啶環(huán)H), 7. 375 (m,油醚(分析純,杭州高晶精細(xì)化工有限公司);亞硫酸1H,吡啶環(huán)H)，8.044 (m, 1H,吡啶環(huán)H).氫鈉(化學(xué)純,浙江省永嘉縣化工試劑廠).1.3.53~氨基吡啶(2b)的合成 將 6.3 mL Br21.2 分析儀器(0. 12 mol)于0 C以下滴加到107.5 mL NaOH溶AVANCE DMX500型核磁共振儀(三甲基氯液(12.0%)中,配制得到NaBrO溶液.在另一反應(yīng).硅烷為內(nèi)標(biāo));X4顯微熔儀(溫度計未校正). .瓶中加入13.4 g 3-甲酰胺基吡啶(1b)(0.11 mol)1.3 典型實(shí)驗(yàn)和64.4 mL NaOH溶液(12. 0%),降溫至- 5~1.3.1 2-甲酰胺 基吡啶(1a)的合成‘20.8 g(0. 20 "C,將上述新制NaBrO溶液滴加至其中,滴畢撤mol) 2-氰基吡啶投人140 mL NaOH水溶液去冰鹽浴,室溫反應(yīng)0.5 h后升溫到70~75 C,繼(1.0%)和70 mL丙酮的混合溶劑中,攪拌下在15續(xù)反應(yīng)2 h,降至室溫,以二氯甲烷為萃取劑,連續(xù)min內(nèi)滴加58.4 mL H2O2(27. 5%),升溫至50 C，萃取20 h,濃縮至干,得紅色固體粗產(chǎn)品8.8g,收繼續(xù)攪拌2.5 h,停止反應(yīng),加100 mL丙酮,置于冰率85.2%,熔點(diǎn)60~61 C,用苯/石油醚、活性炭及箱冷凍,抽濾,烘干后得到白色固體2-甲酰胺基吡亞硫酸氫鈉精制可得淡黃色晶體(文獻(xiàn)[10]中熔點(diǎn):啶23.4 g,質(zhì)量收率95.9 %,熔點(diǎn)102 C(文獻(xiàn)[8]60~61 'C).中熔點(diǎn):102 C)1 H-NMR(CDCl;)8:3.873 (br, 2H, NH2),1.3.2 3-甲酰胺基吡啶(1b)的合成 140 mL丙酮6. 958~7.028 (m, 2H,吡啶環(huán)H), 7. 988~8.079中溶解41.6 g(0. 40 mol) 3-氰基吡啶,攪拌下加人.(m, 2H,吡啶環(huán)H).280 mL NaOH水溶液(1.0%)，滴加116.8 mL 1.3.6 4~氨基吡啶(2c)的合成 于0 C以下將6.3H2O2(27. 5%),加熱至50 C反應(yīng)2.5 h,反應(yīng)完畢，mL Br2(0. 12 mol)滴加到107.5 mL NaOH溶液將反應(yīng)混合物濃縮至干,再加入200 mL丙酮,冷凍(12. 0%)中,得到的NaBrO溶液于同樣的溫度下，過夜,減壓抽濾,烘干濾餅,得到白色粉末狀固體3-滴加到盛有13.4 g 4-甲酰胺基吡啶(1c) (0. 11甲酰胺基吡啶45. 8g,質(zhì)量收率93.9% ,熔點(diǎn)為128mol)和64.4 mL NaOH溶液(12.0%)的另- -反應(yīng)~131 C(文獻(xiàn)[9]中熔點(diǎn):128~131 C).器中,滴加完后先在室溫下反應(yīng)0.5 h,再將油浴升1.3.3 4-甲酰胺基吡啶(1c)的合成 將20.8 g溫到70~75 C,反應(yīng)2 h后冷卻反應(yīng)液,以二氯甲(0.2 mol)4-氰基吡啶溶于70 mL丙酮和140 mL烷為萃取劑,連續(xù)萃取20 h,減壓濃縮至干,得到黃NaOH(1.0%)的混合溶液中,攪拌下滴加58. 4 mL色固體5. 83 g,質(zhì)量收率56. 5%.熔點(diǎn)157~ 160H2O2(27. 5%),油浴加熱至50 C,恒溫反應(yīng)2.5h° C,用甲 苯/石油醚、活性炭精制可得白色晶體(文獻(xiàn)后,減壓蒸餾濃縮溶液,加人100 mL丙酮,冷卻過[10]中熔點(diǎn):158~159 C).夜,抽濾,烘干,得到23.5 g白色固體,加60 mL乙H-NMR ( DMSO-d;) 8: 6. 028 (br, 2H,醇將粗品煮沸回流,趁熱濾去酸副產(chǎn)物,將濾液濃縮NH2),6.467(m,2H,吡啶環(huán)H),7.978(m,至干,得4-甲酰胺基吡啶21.6g,質(zhì)量收率88.5%，2H, 吡啶環(huán)H)熔點(diǎn)156~158 C(文獻(xiàn)[6]中熔點(diǎn):155~157 C).1.3.42-氨基吡啶 (2a)的合成反應(yīng)瓶中投入2結(jié)果與討論107. 5 mL NaOH溶液(12.0%),冰鹽浴降溫至0~5 C,攪拌下滴加6.3 mL Br2(0. 12 mol),制得以4-氨基吡啶的合成為例,對兩步反應(yīng)中的氫NaBrO.在另- .反應(yīng)瓶中加入13.4 g2-甲酰胺基吡氧化中國煤化工P反應(yīng)溫度進(jìn)行了啶(1a)(0.11mol)和64.4mLNaOH溶液考HCNMHG(12.0%),在5~0C將新制的NaBrO溶液緩慢滴2.1度對收率的影響加到此反應(yīng)瓶中,滴加完畢，撤去冰鹽浴,于室溫反表1中4-氰基吡啶的投料量為20.8 g(0.21274浙江大學(xué)學(xué)報(工學(xué)版)第40卷mol),反應(yīng)溫度50 C,質(zhì)量分?jǐn)?shù)為27. 5%的H2O22.3氰基水解副反 應(yīng)后處理58.4mL(0.52mol).由表1可以看出,氰基吡啶水對于4-氰基吡啶水解反應(yīng),4-吡啶甲酰胺繼續(xù)解在過氧化氫用量相同的情況下,當(dāng)氫氧化鈉水溶水解而得的異煙酸是主要的副產(chǎn)品.根據(jù)它在沸醇液質(zhì)量分?jǐn)?shù)為1. 0%時,產(chǎn)物收率較高.如堿液濃度中與酰胺吡啶溶解性的較大差異"1 ,將粗品投入至太低,反應(yīng)進(jìn)行不完全;濃度過高,易導(dǎo)致酰胺產(chǎn)物繼適量乙醇煮沸回流,趁熱濾去大部分異煙酸，以此使續(xù)水解成酸,使收率下降.粗品純度達(dá)到98. 8%(HPLC),有利于下一步反應(yīng)表1w(NaOH)對4甲酰胺基吡啶質(zhì)收率的影響收率的提高.Tab.1 Effect of concentration of sodium hydroxide on yield2.4霍夫曼 降解反應(yīng)后處理of 4-pyridinecarboxamide霍夫曼降解反應(yīng)后,將反應(yīng)液用二氣甲烷連續(xù)w(NaOH) /%η/%萃取,避免傳統(tǒng)方法中使用大量乙醚[11或苯[12]進(jìn)行80. 3單次萃取,不僅降低操作難度,減少溶劑污染,而且1.088. 5有利于溶劑回收.1.569.42.2霍夫曼降解反 應(yīng)中反應(yīng)溫度、氫氧化鈉溶液3結(jié)論質(zhì)量分?jǐn)?shù)對收率的影響本實(shí)驗(yàn)采用先以w(NaOH)=12.0%的溶液自(1)研究了以氰基吡啶為原料,以水和與水互制次溴酸鈉溶液，再將新制次溴酸鈉溶液滴加到堿溶的有機(jī)介質(zhì)丙酮為混合溶劑，在稀堿(NaOH)溶液(NaOH)中進(jìn)行霍夫曼降解反應(yīng),主要考察反應(yīng)液中,以過氧化氫為催化劑,水解得到相應(yīng)的甲酰胺溫度和堿液(NaOH)質(zhì)量分?jǐn)?shù)對產(chǎn)品收率的影響，基吡啶,然后經(jīng)過霍夫曼降解反應(yīng),制得相應(yīng)2-、3-.并用薄層層析跟蹤檢測反應(yīng)程度,獲得了比較適宜.4-氨基吡啶的通用合成路線..的反應(yīng)條件,結(jié)果見表2和3.由表2可見4-甲酰胺基吡啶投料量為13.4 gH.O,NaBrONaOH- CONH,-NH,(0.11 mol) ,霍夫曼降解反應(yīng)在75 C時反應(yīng)收率最佳.溫度過低會降低反應(yīng)速度,延長反應(yīng)時間,而且反應(yīng)不完全;溫度過高雖然反應(yīng)速度加快，反應(yīng)時間(2)以4氨基吡啶為例對反應(yīng)條件進(jìn)行了優(yōu)縮短,但有雜質(zhì)隨之生成,降低了收率.化,得到較為合適的條件:氰基水解反應(yīng),氫氧化鈉由表3可見4-甲酰胺基吡啶投料量為13.4 g溶液最佳的質(zhì)量分?jǐn)?shù)為1%;同時使用過氧化氫水(0.11mol),氫氧化鈉溶液質(zhì)量分?jǐn)?shù)對霍夫曼降解溶液取代了制備繁瑣的金屬鹽催化劑,有效地避免反應(yīng)的收率影響很大,在反應(yīng)溫度為75 C時最適宜了氰基完全水解成酸的副反應(yīng),收率高于88. 0%;的質(zhì)量分?jǐn)?shù)是12. 5%.霍夫曼降解反應(yīng),氫氧化鈉溶液最佳的質(zhì)量分?jǐn)?shù)為12. 5% ,適宜溫度為75 C ,收率在56. 0%以上.表2反應(yīng)溫度對 4氨基吡啶質(zhì)f隆收率的影響Tab.2 Eft of reaction temperature on yield of 4-pyridi-參考文獻(xiàn)(References) :amine[1]戴立言,王曉鐘,陳英奇.制備2-氨基吡啶及其烷基衍生8/C_t/h物的方法:中國,1539822A[P].2004.5040.3DAI Li-yan, WANG Xiao zhong, CHEN Ying-qi. 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Preparation of 4-aminopyridine and its derivatives: .2- pyridoin, 1- pheny)-2 ( 2- pyridy) -1, 2-ethenediol, andCN,1311185A [P]. 2000.下期論文摘要預(yù)登基于流體體積的兩棲車輛阻力并行數(shù)值計算李玉良,潘雙夏(浙江大學(xué)機(jī)械與能源工程學(xué)院，浙江杭州310027)摘要:為了在概念設(shè)計階段評價兩棲車輛的水上性能,研究了采用流體體積函數(shù)(VOF)多流模型對兩棲車輛進(jìn)行模擬計算的可行性,提出了使網(wǎng)格單元體積變化均勻的混合網(wǎng)格劃分方法,比較了并行計算環(huán)境下的不同網(wǎng)格分割方法,給出了計算結(jié)果收斂的評價指標(biāo),并分別采用穩(wěn)態(tài)靜網(wǎng)格、瞬態(tài)靜網(wǎng)格和瞬態(tài)動網(wǎng)格三種模型對輪式兩棲車輛的阻力進(jìn)行了計算,結(jié)果表明,模擬和試驗(yàn)的誤差可控制在10%內(nèi),在當(dāng)前技術(shù)條件下瞬態(tài)靜網(wǎng)格模擬方法是比較可靠的兩棲車輛阻力計算方法.關(guān)鍵詞:兩棲車輛;流體體積函數(shù);阻力;并行中圈分類號: TP301.6文獻(xiàn)標(biāo)識碼: A文章編號: 1008- 973X(2006)08 -01 -05Volume of fluid model based parallel numericalcomputation of resistance for amphibious vehiclesLI Yu-liang, PAN Shuang xia(College of Mechanical and Energy Engineering, Zhejiang University, Hangzhou 310027, China)Abstract: To evaluate the performance of amphibious vehicles during the conceptual design phase, volumeof fluid (VOF) multiphase model was taken to simulate the amphibious vehicle running on the water. Ahybrid meshing method that lessened the grid cell volume gradient was proposed and mesh cell partitionmethods for parallel computing were compared. The computation convergence evaluation rules were given,and the steady-state static grid, the transient static grid, the transient dynamic grid calculations were takento compute the running resistance for roller vehicles. The.中國煤化工red with those ofexperiments，and showed that the error was within 10%，imulation methodwas the most reliable one for computing the resistance ofYHCNMH GKey words: amphibious vehicle; volume of fluid; resistance; parallel