间甲基苯甲脒盐酸盐的合成研究
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摘要
间甲基苯甲脒盐酸盐是农药和医药研究领域一个十分重要的原材料和中间体。间甲基苯甲脒盐酸盐的两步合成法是先以盐酸羟胺制备间甲基苯甲脒肟再通过加氢还原即可得到。在制备间甲基苯脒肟时,单因素考察了常规热反应、微波合成法、超声波合成法对间甲基苯脒肟产率的影响。并探索了一锅法合成间甲基苯甲脒盐酸盐的可行性。所得化合物由沸点、氢谱、质谱确认。实验结果表明:三种方式合成间甲基苯甲脒肟,其产率从大到小依次为:微波合成法>超声波合成法>常规热反应。本实验采用两步法合成间甲基苯甲脒盐酸盐的总产率为58.05%,采用一锅法合成间甲基苯甲脒盐酸盐的产率为78.19%。两步法和一锅法均可用于合成间甲基苯甲脒盐酸盐。
3-Methyl-benzamidine hydrochloride is an important raw material and intermediate in the field of pesticide and pharmaceutical research. There are two routes to synthesize 3-methyl-benzamidine hydrochloride.The one is two-step synthesis method in which 3-methyl-benzonitrile and hydroxylamine hydrochloride react to generate 3-methyl-benzamil-doxime, and then its hydrogenation reduction occurs to get 3-methyl-benzamidine hydrochlor-ide. In the preparation of 3-methyl-benzamildoxime, the effects of conventional heating synthesis,microwave synthesis and ultrasonic synthesis were investigated. Another synthetic method is the reaction of sodium amide and 3-methyl-benzonitrile under reaction conditions close to absolute anhydrous. After the reaction was completed at room temperature, ammonium chloride was directly added to the reaction flask. This synthesis method was called one-pot method. The results were confirmed by the boiling point, MS and1 H NMR spectrum. The experimental results show that the yield relationship of the three synthetic methods for preparing 3-methylbenzamidoxime in the two-step synthesis method is microwave synthesis > ultrasonic synthesis> conventional heating synthesis. The total yield of the two-step synthesis method was 58.05%, and the yield by one-pot synthesis was 78.19%. Both two-step synthesis and one-pot synthesis can be used to synthesize 3-methyl-benzamidine hydrochloride.
3-Methyl-benzamidine hydrochloride is an important raw material and intermediate in the field of pesticide and pharmaceutical research. There are two routes to synthesize 3-methyl-benzamidine hydrochloride.The one is two-step synthesis method in which 3-methyl-benzonitrile and hydroxylamine hydrochloride react to generate 3-methyl-benzamil-doxime, and then its hydrogenation reduction occurs to get 3-methyl-benzamidine hydrochlor-ide. In the preparation of 3-methyl-benzamildoxime, the effects of conventional heating synthesis,microwave synthesis and ultrasonic synthesis were investigated. Another synthetic method is the reaction of sodium amide and 3-methyl-benzonitrile under reaction conditions close to absolute anhydrous. After the reaction was completed at room temperature, ammonium chloride was directly added to the reaction flask. This synthesis method was called one-pot method. The results were confirmed by the boiling point, MS and1 H NMR spectrum. The experimental results show that the yield relationship of the three synthetic methods for preparing 3-methylbenzamidoxime in the two-step synthesis method is microwave synthesis > ultrasonic synthesis> conventional heating synthesis. The total yield of the two-step synthesis method was 58.05%, and the yield by one-pot synthesis was 78.19%. Both two-step synthesis and one-pot synthesis can be used to synthesize 3-methyl-benzamidine hydrochloride.
引文
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[14]郑文丽,薛飞群.对氨基苯甲脒盐酸盐的合成[J].化学试剂,2006, 28(5):315, 317.Zheng W L, Xue F Q. The synthesis of p-amino-benzamidine hydrochloride[J]. Chemical Reagents, 2006, 28(5), 315, 317.
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[16] Dieter D, Oliver S, Frank S, et al. Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors method for producing 4-(benzimidazolyl-methylamino)-benzamidines[J]. Bioorganic&Medicinal Chemistry Letters,2015, 25(7):1597-1602.
[17]韦长梅,嵇鸣.对氨基苯甲脒二盐酸盐合成工艺改进[J].化工时刊, 1998,(10):29-31.Wei C M, Yu M. Improvement of synthetic process of paminobenzamide dihydrochloride[J]. Chemical Industry Times,1998,(10):29-31.
[18] Zerban G. Process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides[J]. Journal of Materials Science Letters, 2011, 5(2):221-222.
[19]秦宁,闵清,付梦蕾,等.间甲基苯脒肟的微波超声波催化合成[J].微波化学, 2018, 2(2):31-36.Qin N, Min Q, Fu M L, et al. Microwave ultrasonic catalysis synthesis of m-methylphenylhydrazine[J]. Journal of Microwave Chemistry, 2018, 2(2):31-36.
[20]杜葩.一种取代苯甲脒类化合物的合成方法:103570584A[P].2014-02-12.Du P. A synthetic method for replacing benzamidine compounds:103570584A[P]. 2014-02-12.
[21] Zi Y G, Lin F, Shi Y Y. Synthesis and characterization of novel fluorinated polyimides derived from 1, 1′-bis(4-aminophenyl)-1-(3-trifluoro-methylphenyl)-2, 2, 2-trifluoroethane and aromatic dianhydrides[J]. European Polymer Journal, 2008, 44(4):1252-1260.
[22]王新图,徐云根,华维一,等. 4-(苯并咪(噻)唑-2-)苯甲脒类化合物的合成及其一氧化氮合酶抑制活性[J].中国药科大学学报, 2004, 35(1):12-15.Wang X T, Xu Y G, Hua W Y, et al. Synthesis and nitric oxide synthase inhibitory activity of 4-(benzimido(thia)azole-2-)benzimidamides[J]. Journal of China Pharmaceutical University,2004, 35(1):12-15.
[23] Gao H F, Niu Y, Xu F R, et al. Design and synthesis of benzamidine BACE1 inhibitors[J]. Journal of China Medical University, 2012, 21(2):124-131.
[24]山东科技大学.一种邻乙氧基苯甲脒盐酸盐的新合成方法:201110355036.8[P].2013-05-08.Shandong University of Science and Technology. A new synthetic method for o-ethoxy benzamidine hydrochloride:201110355036.8[P].2013-05-08.
[25]蔡亮,程原.催化加氢制备对羟基苯甲脒[J].化工中间体,2008, 4(12):29-32.Cai L, Cheng Y. Preparation of p-hydroxybenzamide by catalytic hydrogenation[J]. Chemical Intermediates, 2008, 4(12):29-32.
[26]杜杰,段明,蒋晓慧.用酰胺缩醛法合成单(双)长链烷基脒基化合物[J].合成化学, 2010, 18(5):636-638.Du J, Duan M, Jiang X H. Synthesis of the single(double)longchain alkyl amidine compounds by amide acetal method[J].Chinese Journal of Synthetic Chemistry, 2010, 18(5):636-638.
[27]林文练.苯甲脒衍生物的合成方法:201610967466.8 A[P].2017-04-19.Lin W L. Synthesis of benzamidine derivatives:201610967466.8A[P]. 2017-04-19.
[28]四川青木制药有限公司.一种对氨基苯甲脒盐酸盐的新制备方法:20181072857 8.7[P].2018-11-06.Sichuan Qingmu Medicine Co., Ltd. A new preparation method of p-aminobenzidine hydrochloride:201810728578.7[P]. 2018-11-06.
[29]潘应杰,罗明,华伟,等.微波化学反应器中微波辐射器的一体化设计与优化[J].化工学报, 2010, 61(4):861-866.Pan Y J, Luo M, Hua W, et al. Integrated design for microwave radiator used in microwave chemical reactor[J]. CIESC Journal,2010, 61(4):861-866.
[30]张慧丽.苯甲偕胺肟的合成与性能研究[D].长沙:中南大学,2014.Zhang H L. The synthesis of benzamidoxime and its application[D]. Changsha:Central South University, 2014.
[31]刘明,胡文祥.微波催化有机合成化学反应[J].微波化学,2018, 2(3):70-78.Liu M, Hu W X. Organic synthesis reactions catalysed with microwave irradiation[J]. Journal of Microwave Chemistry, 2018, 2(3):70-78.
[32]陆模文,胡文祥,恽榴红.有机微波化学研究进展[J].有机化学, 1995, 15(6):561-566.Lun M W, Hu W X, Yun L H. Progress in organic microwave chemistry[J].Chin. J. Org. Chem., 1995, 15(6):561-566.
[2]冯小琴.对位含有吸电子基的苯甲腈的脒基化反应的研究[D].太原:中北大学, 2001.Feng X Q. The research of amidine reaction of benzonitrile with electron withdrawing group on its para-position[D]. Taiyuan:North University of China, 2001.
[3]徐凡,孙建华,燕滨,等. Sml催化合成N, N′-二取代脒[C]//全国有机合成学术会议. 2000:304.Xu F, Sun J H, Yan B, et al. Synthesis of N, N′-disubstituted oxime by Sml[C]//National Conference on Organic Synthesis.2000:304.
[4]张娟,刘毅锋.酰胺缩醛法合成N, N, N'-三取代甲脒的研究[J].化学通报, 1998,(5):55-57.Zhang J, Liu Y F. Synthesis of N, N, N'-trisubstituted formazan by amidine acetal method[J]. Chemistry, 1998,(5):55-57.
[5]史东辉,向东.对烷氧基苯甲脒盐酸盐的制备[J].化学试剂,1996,(2):107-109.Shi D H, Xiang D. Preparation of p-alkyl benzamidine hydrochloride[J]. Chemical Reagents, 1996,(2):107-109.
[6]杜杰,段明,蒋晓慧.催化合成取代脒的研究进展[J].化工进展, 2010, 29(S2):170-173.Du J, Duan M, Jiang X H. Research progress of catalytic synthesis of substituted amidine[J]. Chemical Industry and Engineering Progress, 2010, 29(S2):170-173.
[7]纪宝琳. 4-甲砜基苯甲脒盐酸盐的合成[J].广州化工, 2010, 38(3):100-101.Ji B L. Preparation of 4-methanesulfonyl-benzamidine hydrochloride[J]. Guangzhou Chemical Industry, 2010, 38(5):636-638.
[8]郑玉安,王雪梅,祁巍,等.取代苯甲脒盐酸盐类化合物的合成方法研究[J].染料与染色, 2016, 53(2):33-34.Zheng Y A, Wang X M, Qi W, et al. Synthesis of substituted benzamidine hydrochloride compounds[J]. Dyestuffs and Coloration, 2016, 53(2):33-34.
[9]王倩,史东辉,方方.合成脒盐的一种方便方法[J].化学试剂,1993, 15(6):376-377.Wang Q, Shi D H, Fang F. A convenient method for synthesizing amidine salts[J]. Chemical Reagents, 1993, 15(6):376-377.
[10]赵越,程原.对氯苯甲脒盐酸盐的制备方法[J].精细化工中间体, 2008, 38(6):17-18.Zhao Y, Cheng Y. Preparation method of p-chlorobenzoquinone hydrochloride[J]. Fine Chemical Intermediates, 2008, 38(6):17-18.
[11] Hitendra K L, Royana S, Kishore P. Synthesis and biological evaluation of metalcomplexes derived from 3-methylnhydroxybenzamidine as potent inhibitors of thymidylate kinase from mycobacterium tuberculosis[J].World Journal of Pharmacy and Pharmaceutical Sciences, 2014, 3(5):1564-1583.
[12]常州市天华制药有限公司.一种苯甲脒盐酸盐的合成方法:201710455032.4[P]. 2017-11-17.Changzhou Tianhua Pharmaceutical Co., Ltd. A method for synthesizing benzamidine hydrochloride:201710455032.4[P].2017-11-17.
[13]谌聪,程原.对氟苯甲脒盐酸盐的合成研究[J].当代化工研究,2011, 7(1):41-43.Chen C, Cheng Y. Synthesis of p-fluorobenzoic acid hydrochloride[J]. Modern Chemical Research, 2011, 7(1):41-43.
[14]郑文丽,薛飞群.对氨基苯甲脒盐酸盐的合成[J].化学试剂,2006, 28(5):315, 317.Zheng W L, Xue F Q. The synthesis of p-amino-benzamidine hydrochloride[J]. Chemical Reagents, 2006, 28(5), 315, 317.
[15]李娜,王丽颖,王晓静,等.对氨基苯甲脒亚胺基甲酸正己酯盐酸盐的合成[J].化学研究, 2016, 27(5):636-639.Li N, Wang L Y, Wang X J, et al. Synthesis of 4-aminobenzamidine-N-hexylcarbamate hydrochloride[J].Chemical Research, 2016, 27(5):636-639.
[16] Dieter D, Oliver S, Frank S, et al. Identification and optimization of pyridazinones as potent and selective c-Met kinase inhibitors method for producing 4-(benzimidazolyl-methylamino)-benzamidines[J]. Bioorganic&Medicinal Chemistry Letters,2015, 25(7):1597-1602.
[17]韦长梅,嵇鸣.对氨基苯甲脒二盐酸盐合成工艺改进[J].化工时刊, 1998,(10):29-31.Wei C M, Yu M. Improvement of synthetic process of paminobenzamide dihydrochloride[J]. Chemical Industry Times,1998,(10):29-31.
[18] Zerban G. Process for the preparation of the salts of 4-(benzimidazolylmethylamino)-benzamides[J]. Journal of Materials Science Letters, 2011, 5(2):221-222.
[19]秦宁,闵清,付梦蕾,等.间甲基苯脒肟的微波超声波催化合成[J].微波化学, 2018, 2(2):31-36.Qin N, Min Q, Fu M L, et al. Microwave ultrasonic catalysis synthesis of m-methylphenylhydrazine[J]. Journal of Microwave Chemistry, 2018, 2(2):31-36.
[20]杜葩.一种取代苯甲脒类化合物的合成方法:103570584A[P].2014-02-12.Du P. A synthetic method for replacing benzamidine compounds:103570584A[P]. 2014-02-12.
[21] Zi Y G, Lin F, Shi Y Y. Synthesis and characterization of novel fluorinated polyimides derived from 1, 1′-bis(4-aminophenyl)-1-(3-trifluoro-methylphenyl)-2, 2, 2-trifluoroethane and aromatic dianhydrides[J]. European Polymer Journal, 2008, 44(4):1252-1260.
[22]王新图,徐云根,华维一,等. 4-(苯并咪(噻)唑-2-)苯甲脒类化合物的合成及其一氧化氮合酶抑制活性[J].中国药科大学学报, 2004, 35(1):12-15.Wang X T, Xu Y G, Hua W Y, et al. Synthesis and nitric oxide synthase inhibitory activity of 4-(benzimido(thia)azole-2-)benzimidamides[J]. Journal of China Pharmaceutical University,2004, 35(1):12-15.
[23] Gao H F, Niu Y, Xu F R, et al. Design and synthesis of benzamidine BACE1 inhibitors[J]. Journal of China Medical University, 2012, 21(2):124-131.
[24]山东科技大学.一种邻乙氧基苯甲脒盐酸盐的新合成方法:201110355036.8[P].2013-05-08.Shandong University of Science and Technology. A new synthetic method for o-ethoxy benzamidine hydrochloride:201110355036.8[P].2013-05-08.
[25]蔡亮,程原.催化加氢制备对羟基苯甲脒[J].化工中间体,2008, 4(12):29-32.Cai L, Cheng Y. Preparation of p-hydroxybenzamide by catalytic hydrogenation[J]. Chemical Intermediates, 2008, 4(12):29-32.
[26]杜杰,段明,蒋晓慧.用酰胺缩醛法合成单(双)长链烷基脒基化合物[J].合成化学, 2010, 18(5):636-638.Du J, Duan M, Jiang X H. Synthesis of the single(double)longchain alkyl amidine compounds by amide acetal method[J].Chinese Journal of Synthetic Chemistry, 2010, 18(5):636-638.
[27]林文练.苯甲脒衍生物的合成方法:201610967466.8 A[P].2017-04-19.Lin W L. Synthesis of benzamidine derivatives:201610967466.8A[P]. 2017-04-19.
[28]四川青木制药有限公司.一种对氨基苯甲脒盐酸盐的新制备方法:20181072857 8.7[P].2018-11-06.Sichuan Qingmu Medicine Co., Ltd. A new preparation method of p-aminobenzidine hydrochloride:201810728578.7[P]. 2018-11-06.
[29]潘应杰,罗明,华伟,等.微波化学反应器中微波辐射器的一体化设计与优化[J].化工学报, 2010, 61(4):861-866.Pan Y J, Luo M, Hua W, et al. Integrated design for microwave radiator used in microwave chemical reactor[J]. CIESC Journal,2010, 61(4):861-866.
[30]张慧丽.苯甲偕胺肟的合成与性能研究[D].长沙:中南大学,2014.Zhang H L. The synthesis of benzamidoxime and its application[D]. Changsha:Central South University, 2014.
[31]刘明,胡文祥.微波催化有机合成化学反应[J].微波化学,2018, 2(3):70-78.Liu M, Hu W X. Organic synthesis reactions catalysed with microwave irradiation[J]. Journal of Microwave Chemistry, 2018, 2(3):70-78.
[32]陆模文,胡文祥,恽榴红.有机微波化学研究进展[J].有机化学, 1995, 15(6):561-566.Lun M W, Hu W X, Yun L H. Progress in organic microwave chemistry[J].Chin. J. Org. Chem., 1995, 15(6):561-566.