Synthesis and manufacture of piperazine and its N-substituted derivatives

doi:10.3969/j.issn.1000-1565.2018.05.005

Abstract

Abstract: The main synthetic route and domestic manufacture of piperazine and its major N-substituted derivatives were reviewed in this paper. Piperazine can be synthesized by using N-β-hydroxyethyl ethylenediamine, diethylenetriamine, ethylenediamine, ethanolamine and other raw materials. Among them, the route using N-hydroxyethyl ethylenediamine as the starting material is believed as the most efficient route for the synthesis of piperazine. N-substituted derivatives of piperazine can be synthesized via either piperazine and N-alkyl agents or related primary amines, ethylene oxide and ammonia. Synthesis and manufacture of piperazine and its N-substituted derivatives have broad prospects of development due to their wide application areas and huge demand.

Key words: piperazine, derivatives, N-β-hydroxyethyl ethylenediamine

CLC Number:

BAI Guoyi, DONG Jie. Synthesis and manufacture of piperazine and its N-substituted derivatives[J]. Journal of Hebei University (Natural Science Edition), 2018, 38(5): 472-479.

References

[1] 江镇海. 21世纪医药中间体重点发展品种[J]. 上海化工, 2015, 40(11):27-31. DOI: 10.3969/j.issn.1004-017X.2015.11.008. JIANG Z H. The key target medicine intermediates in the 21th century[J]. Shanghai Chemical Industry, 2015, 40(11):27-31. DOI: 10.3969/j.issn.1004-017X.2015.11.008.
[2] BASOGLU O, UYGUN C, BAYRAK H, et al. Synthesis and antimicrobial activity of new piperazine-based heterocyclic compounds[J]. Heterocyclic Communications, 2017, 23(1): 43-54. DOI: 10.1515/hc-2016-0125.
[3] HUANG W, LIU L, WU B, et al. Synthesis of chiral piperazines via hydrogenation of pyrazines activated by alkyl halides[J]. Organic Letters, 2016, 18(13): 3082-3085. DOI: 10.1021/acs.orglett.6b01190.
[4] CHANDRIKA N, SHRESTHA S, NGO H, et al. Alkylated piperazines and piperazine-azole hybrids as antifungal agents[J]. Journal of Medicinal Chemistry, 2017, 61(1):158-173. DOI: 10.1021/acs.jmedchem.7b01138.
[5] MONTGOMERY T, RAWAL V. Palladium-catalyzed modular synthesis of substituted piperazines and related nitrogen heterocycles[J]. Organic Letters, 2016, 18(4):740-743. DOI: 10.1021/acs.orglett.5b03708.
[6] 巩宏伟, 綦辉, 孙薇,等. 哌嗪嘧啶类CCR4拮抗剂的设计、合成及生物活性[J]. 高等学校化学学报, 2013, 34(9):2131-2138. DOI: 10.7503/cjcu20120607. GONG H W, QI H, SUN W, et al. Design,synthesis and biological activities of a series of piperazine pyrimidine as CCR4 antagonists[J]. Chemical Journal of Chinese Universities, 2013, 34(9):2131-2138. DOI: 10.7503/cjcu20120607.
[7] 甘淋玲, 卢一卉, 周成合. 哌嗪化合物作为酶抑制剂的研究进展[J]. 中国生化药物杂志, 2009, 30(2):127-131. GAN L L, LU Y H, ZHOU C H. Advances in the research of piperazine compounds as enzyme inhibitors[J]. Chinese Journal of Biochemical Pharmaceutics, 2009, 30(2):127-131.
[8] LUESCHER M, BODE J. Catalytic synthesis of N-unprotected piperazines, morpholines, and thiomorpholines from aldehydes and SnAP reagents [J]. Angewandte Chemie International Edition, 2015, 54(37):10884-10888. DOI: 10.1002/anie.201505167.
[9] 曹琦. 哌嗪类离子液体/表面活性剂双水相的构筑和性能研究[D].杭州: 浙江大学, 2015. CAO Q. Performance study on aqueous two-phase systems composed of piperazinium-based ionic liquids and surfactants[D].Hangzhou: Zhejiang University, 2015.
[10] 张秀芹. 一种高收率焦磷酸哌嗪制备新方法[J]. 广东化工, 2017, 44(15):86-87. DOI: 10.3969/j.issn.1007-1865.2017.15.038. ZHANG X Q. New method of preparation of high yield piperazine pyrophosphate[J]. Guangdong Chemical Industry, 2017,44(15):86-87. DOI: 10.3969/j.issn.1007-1865.2017.15.038.
[11] 魏文德. 有机化工原料大全[M].第2版. 北京: 化学工业出版社, 1999.
[12] GETTYS K, YE Z, DAI M. Recent advances in piperazine synthesis[J]. Synthesis, 2017, 49(12): 2589-2604. DOI: 10.1055/s-0036-1589491.
[13] 孙人杰, 刘清安, 桃李,等. N,N'-二(2-羟丙基)哌嗪的合成及其在烟气脱硫工艺中的应用[J]. 应用化工, 2011, 40(7):1145-1147. DOI: 10.3969/j.issn.1671-3206.2011.07.008. SUN R J, LIU Q A, TAO L, et al. Synthesis of 1,4-bis(2-hydroxypropyl)piperazine and its application in flue gas desulfurization[J]. Applied Chemical Industry, 2011, 40(7):1145-1147. DOI: 10.3969/j.issn.1671-3206.2011.07.008.
[14] 周秀鸳. 新型哌嗪型离子液体的制备及其脱硫性能研究[D]. 杭州:浙江大学, 2017. ZHOU X Y. The synthesis of new piperazinium -based ionic liquids and their annlication[D].Hangzhou: Zhejiang University, 2017.
[15] ROCHELLE G, CHEN E, FREEMAN S, et al. Aqueous piperazine as the new standard for CO₂ capture technology[J]. Chemical Engineering Journal, 2011, 171(3):725-733. DOI: 10.1016/j.cej.2011.02.011.
[16] 张新军. 烟气CO₂捕集新技术及传质特性研究[D]. 青岛:青岛科技大学, 2014. ZHANG X J. Mass transferring rule of power plant flue gas CO₂ capture based on di-amine absorbents[D]. Qingdao:Qingdao University of Science&Technology,2014.
[17] TAN C, CHEN J. Absorption of carbon dioxide with piperazine and its mixtures in a rotating packed bed[J]. Separation & Purification Technology, 2006, 49(2):174-180. DOI: 10.1016/j.seppur.2005.10.001.
[18] FRANZ M, RAYMOD L, MAYHEW. Piperazine and piperazine hydrate: US,3112317[P].1963.
[19] GODFREY N, Method for preparing piperazines: US,3064001[P].1962-11-13.
[20] GEORGE P. Piperazine: US,3138598[P]. 1964-06-23.
[21] JOSEF D, NORBERT F, WERNER H. Process and catalysts for manufacture of 1,4-diazabicyl[2.2.2] octane and piperazine: DE, 3735212[P].1989-04-27.
[22] PAKHIMOV R. Piperazine and ethylenediamine: USSR, 539881[P]. 1976-12-25.
[23] OHASHI Y, KOGOMAKIYOSHI, ASOU H. Piperazines from N-(2-hydroxy-ethyl)ethylenediamine: JP, 76122081[P]. 1976-10-25.
[24] OHASHI Y, ASOU H, ITO F. Piperazine and its derivatives: JP, 74125375[P]. 1974-11-30.
[25] 宋锡瑾, 吴兆立. 合成哌嗪的新工艺[J]. 精细化工, 1995, 12(2):54-57. SONG X J, WU Z L. new technology for preparation of piperazine[J]. Fine Chemicals, 1995, 12(2):54-57.
[26] 孙绍晖, 沈伟, 徐华龙,等. 乙二胺在ZSM-5分子筛催化剂上脱氨制哌嗪[J]. 催化学报, 1998, 19(5): 432-435. SUN S H, SHEN W, XU H L, et al. Study of deamination of ethylenediamine to piperazine on ZSM-5 zeolite catalysts[J]. Chinese Journal of Catalysis, 1998, 19(5): 432-435.
[27] 王多禄, 许正双. 哌嗪合成中催化剂的研究[J]. 化学工业与工程, 1998, 15(4): 25-29. WANG D L, XU Z S. Study on the catalyst for the synthesis of piperazine[J]. Chemical Industry & Engineering, 1998, 15(4): 25-29.
[28] 白国义. 醇催化胺化反应的研究[D].天津: 天津大学, 2003. BAI G Y. Studies on the catalytic amination of alcohols[D]. Tianjin:Tianjin University, 2003.
[29] 周立山, 冯亚青, 郭兵, 等. 2-甲基哌嗪的合成及应用[J]. 化学工业与工程, 1999, 16(4): 229-232. ZHOU L S, FENG Y Q, GUO B, et al. Synthesis and application of 2-methylpiperazine[J]. Chemical Industry & Engineering, 1999, 16(4): 229-232.
[30] 陈立功, 宋芸, 许正双,等. β-羟乙基乙二胺环化合成哌嗪[J]. 化学工业与工程, 2001, 18(1): 40-43. DOI: 10.3969/j.issn.1004-9533.2001.01.007. CHEN L G, SONG Y, XU Z S, et al. Cyclization of β-Hydroxyethylenediamine to Piperazine[J]. Chemical Industry and Engineering, 2001, 18(1): 40-43. DOI: 10.3969/j.issn.1004-9533.2001.01.007.
[31] 陈立功, 白国义. 醇的催化胺化反应及其在医药中间体合成中的应用[J]. 精细与专用化学品, 2004, 12(17):6-9. DOI: 10.3969/j.issn.1008-1100.2004.17.002. CHEN L G, BAI G Y. Catalytic amination of alcohols and pharmaceutical intermediates[J]. Fine & Specialty Chemicals, 2004 12(17):6-9. DOI: 10.3969/j.issn.1008-1100.2004.17.002.
[32] 白国义, 陈立功. 双官能团醇类化合物催化胺化反应的研究进展[J]. 化学进展, 2005, 17(2):293-298. DOI: 10.3321/j.issn:1005-281X.2005.02.015. BAI G Y, CHEN L G. Progress in the catalytic amination of bifunctional alcohols[J]. Progress in Chemistry, 2005, 17(2):293-298. DOI: 10.3321/j.issn:1005-281X.2005.02.015.
[33] 陈立功, 白国义, 许正双,等. 三乙烯二胺的合成催化剂的筛选[J]. 天津大学学报(自然科学与工程技术版), 2000, 33(5): 638-640. DOI: 10.3969/j.issn.0493-2137.2000.05.022. CHEN L G, BAI G Y, XU Z S, et al. Selection of catalysts for synthesis of triethylenediamine[J]. Journal of Tianjin University, 2000, 33(5): 638-640. DOI: 10.3969/j.issn.0493-2137.2000.05.022.
[34] 白国义, 陈立功, 李阳,等. 三乙烯二胺合成催化剂的表征和反应机理的研究[J]. 精细化工, 2004, 21(8): 577-580. DOI: 10.3321/j.issn:1003-5214.2004.08.006. BAI G Y, CHEN L G, LI Y, et al. Characterization of catalysts for the synthesis of triethylenediamine and Studies of the Reaction Mechanism[J]. Fine Chemicals, 2004, 21(8):577-580. DOI: 10.3321/j.issn:1003-5214.2004.08.006.
[35] BAI G, LI Y, YAN X, et al. High efficiency Cu-based catalysts for the cyclization of alkanolamines[J]. Reaction Kinetics & Catalysis Letters, 2004, 82(1):33-39. DOI: 10.1023/B:REAC.0000028802.66602.0f.
[36] WU Z, YANG F, WANG H, et al. A general process for the cyclization of aminoalcohols to the corresponding amines over Cu-Cr-La/ γ-Al₂O₃[J]. Reaction Kinetics Mechanisms & Catalysis, 2012, 106(2):485-493. DOI: 10.1007/s11144-012-0447-z.
[37] YAO L, WANG Y, HUANG K. Synthesis of morpholine or piperazine derivatives through gold catalyzed cyclization reactions of alkynylamines or alkynylalcohols.[J]. Organic Chemistry Frontiers, 2015, 2(6):721-725. DOI: 10.1039/C5QO00060B.
[38] DONG H, CHEN Z, LI R, et al. Convenient and efficient synthesis of disubstituted piperazine derivatives by catalyst-free, atom-economical and tricomponent domino reactions[J]. RSC Advances, 2015, 5(14): 10768-10772. DOI: 10.1039/C4RA14811H.
[39] 唐培堃, 冯亚青. 精细有机合成化学与工艺学[M].第2版.北京:化学工业出版社, 2006.
[40] 吴刚健, 严之光. 由N-羟乙基乙二胺合成哌嗪[J]. 华东理工大学学报(自然科学版), 2001, 27(1): 30-33. DOI: 10.3969/j.issn.1006-3080.2001.01.007. WU G J, YAN Z G. Synthesis of piperazine from N-hydroxyethylethylenediamine[J]. Journal of East China University of Science & Technology, 2001, 27(1): 30-33. DOI: 10.3969/j.issn.1006-3080.2001.01.007.
[41] BAI G, FAN X, WANG H, et al. Effects of the preparation methods on the performance of the Cu-Cr-Fe/γ-Al₂O₃, catalysts for the synthesis of 2-methylpiperazine[J]. Catalysis Communications, 2009, 10(15):2031-2035. DOI: 10.1016/j.catcom.2009.07.025.
[42] BAI G, CHEN L, LI Y, et al. Selective synthesis of cis -2,6-dimethylpiperazine catalyzed by a Cu-Cr-Fe/γ-Al₂O₃ catalyst[J]. Applied Catalysis A General, 2004, 277(1): 253-258. DOI: 10.1016/j.apcata.2004.09.031.
[43] LE G, YANNICK S, HAMON C. Catalyst and method for producing amines from alcohols: US,4209424[P]. 1980.
[44] WU Z, WANG H, SUN M, et al. A novel co-production process for piperazine and its N-monoalkyl derivatives[J]. Research on Chemical Intermediates, 2012, 38(3-5): 1149-1157. DOI: 10.1007/s11164-011-0450-4.
[45] 吴志威. 哌嗪和N-烷基哌嗪的联产研究[D].天津:天津大学, 2012. WU Z W. Study on the co-production of piperazine and N-alkylpiperazine[D].Tiangjin: Tianjin University, 2012.
[46] 王李平, 竹承林, 唐琳钧, 等. 气-固相催化环合N-甲基哌嗪的研究[J]. 江西科技师范大学学报, 2013(6): 10-14. DOI: 10.3969/j.issn.1007-3558.2013.06.003. WANG L P, ZHU C L, TANG L J, et al. Research on catalyzed cyclization of N-methylpiperazine in gas-solid phase[J]. Journal of Jiangxi Science & Technology Normal University, 2013(6): 10-14. DOI: 10.3969/j.issn.1007-3558.2013.06.003.
[47] 孙东岳. 联产哌嗪和N-乙基哌嗪的工艺研究[D].杭州:浙江大学, 2016. SUN D Y. Co-production of piperazine and N-ethylpiperazine[D].Hangzhou: Zhejiang University, 2016.
[48] 彭立, 顾飞燕. N-乙基哌嗪的合成研究[J]. 精细化工, 2000, 17(11): 673-675. DOI: 10.3321/j.issn:1003-5214.2000.11.018. PENG L,GU F Y.Synthesis of N-etlylpiperazine[J]. Fine Chemicals, 2000, 17(11): 673-675. DOI: 10.3321/j.issn:1003-5214.2000.11.018.
[49] 白国义, 陈华, 陈立功,等. 分子间醇的催化胺化反应的铜基催化剂的筛选与表征[J]. 现代化工, 2006, 26(3): 33-35. DOI: 10.3321/j.issn:0253-4320.2006.03.007. BAI G Y, CHEN H, CHEN L G, et al. Selection and characterization of copper based catalysts for intermolecular catalytic amination of alcohols[J]. Modern Chemical Industry, 2006, 26(3):33-35. DOI: 10.3321/j.issn:0253-4320.2006.03.007.
[50] 张洁. N-乙基哌嗪合成工艺及催化剂研究[D].西安: 西北大学, 2008. ZHANG J. Studies on the proeessand catalyst for preparing N-ethylpiperazine[D]. Xian:Northwest University, 2008.
[51] 陈立功, 王军波, 许正双,等. 合成哌嗪副产物综合利用的研究[J]. 化学工业与工程, 2000, 17(6): 341-345. DOI: 10.3969/j.issn.1004-9533.2000.06.007. CHEN L G, WANG J B, XU Z S, et al. The application research of by-products from the manufacture of piperazine[J]. Chemical Industry & Engineering, 2000, 17(6): 341-345. DOI: 10.3969/j.issn.1004-9533.2000.06.007.
[52] 王坤, 陈长生, 丁可,等. 哌嗪的生产工艺与市场综述[J]. 山东化工, 2015, 44(4): 47-49. DOI: 10.3969/j.issn.1008-021X.2015.04.016. WANG K, CHEN C S, DING K, et al. The research of production and market of piperazine[J]. Shandong Chemical Industry, 2015, 44(4): 47-49. DOI: 10.3969/j.issn.1008-021X.2015.04.016.