CN103980281B - 一种咪唑吡嗪化合物及其制备方法 - Google Patents

一种咪唑吡嗪化合物及其制备方法 Download PDF

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CN103980281B
CN103980281B CN201410231333.5A CN201410231333A CN103980281B CN 103980281 B CN103980281 B CN 103980281B CN 201410231333 A CN201410231333 A CN 201410231333A CN 103980281 B CN103980281 B CN 103980281B
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CN103980281A (zh
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姚庆佳
邴贵芳
徐扬军
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Sphinx Scientific Laboratory Tianjin Co ltd
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
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Abstract

本发明涉及一种咪唑吡嗪化合物及其制备方法，该化合物为为1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪，制备方法如下：(1)以化合物12，4-二甲基咪唑为起始原料，在四丁基硫酸氢铵存在下与2-氯乙胺作用得到化合物2；(2)化合物2经过氨基保护得化合物3；(3)化合物3在HCl作用下去保护得化合物4；(4)化合物4用甲醛闭环得到目标产物化合物5；其制备方法原料便宜易得，合成方法简单，是一种合成咪唑吡嗪化合物的全新方法，适合规模化工业生产的需要，其产物1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪在预防和治疗动脉硬化以及高胆固醇症方面有着广泛的应用前景。

Description

一种咪唑吡嗪化合物及其制备方法
技术领域
本发明涉及化合物生产领域，尤其是一种咪唑吡嗪化合物及其制备方法。
背景技术
根据Pyridinosubstitutedoximesusefulasanti-atherosclerosisandanti-hypercholesterolemicagents。U.S.(1996),US5565468A19961015。Preparationof(hydroximinoalkyl)diazolesasanticholesteremics。PCTInt.Appl.(1993),WO9325553A119931223等文献记载，咪唑吡嗪类化合物广泛应用于药物分子中，以该化合物合成的衍生物，在预防和治疗动脉硬化以及高胆固醇症方面具有巨大的临床药物应用价值。用该化合物做母体能进一步进行合成更为复杂的衍生物，为更广泛地研究该类化合物性质提供条件。
发明内容
本发明所要解决的技术问题在于提供一种咪唑吡嗪化合物。
本发明所要解决的另一技术问题在于提供上述咪唑吡嗪化合物的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种咪唑吡嗪化合物，1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪，其结构式为(Ⅰ)所示，
优选的，上述咪唑吡嗪化合物，1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪的核磁共振氢谱数据为1H-NMR(CDCl3；400MHZ)2.086(s,3H)2.301(s,3H)3.191(t,2H)3.751(t,2H)3.944(s,2H)。
上述咪唑吡嗪化合物的制备方法，具体步骤如下：
(1)以化合物12，4-二甲基咪唑为起始原料，在四丁基硫酸氢铵存在下与2-氯乙胺作用得到化合物2；
(2)化合物2经过氨基保护得化合物3；
(3)化合物3在HCl作用下去保护得化合物4；
(4)化合物4用甲醛闭环得到目标产物化合物5，其中，
上述咪唑吡嗪化合物的制备方法的具体反应方程式如下：
本发明的有益效果是：
上述咪唑吡嗪化合物的制备方法，原料便宜易得，合成方法简单，是一种合成咪唑吡嗪化合物的全新方法，适合规模化工业生产的需要，其产物1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪在预防和治疗动脉硬化以及高胆固醇症方面有着广泛的应用前景。
附图说明
图1为1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪的HNMR谱图。
具体实施方式
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施方式对本发明所述技术方案作进一步的详细说明。
实施例1
如图1所示，1，3-二甲基-咪唑-5，6，7，8-四氢吡嗪的制备方法，具体步骤如下：
(1)将50g氢氧化钠，11g四丁基硫酸氢铵加入30g化合物1(2，4-二甲基咪唑)的乙腈溶液(300ml)中，室温搅拌30分钟，加入43.3g2-氯乙胺盐酸盐，加热至75℃回流；14小时后反应完全，抽滤除去白色固体，浓缩除去乙腈，得粗品(化合物2)43克.TLC信息：原料Rf＝0.35，产品Rf＝0.20。展开剂：二氯甲烷：甲醇＝10：1。
(2)氮气保护下，将43g化合物2溶于乙腈中，冰浴加入67gBoc2O，120mlTEA(三乙醇胺)，室温搅拌120min；反应完全后浓缩除去乙腈，过40g硅胶柱得7.2g；LC-MS监测反应结束，得产品(化合物3)7.2g黄色，2步收率9.65％。
(3)将浓盐酸滴入6.7g化合物3的1,4二氧六环溶液中加热至100℃；8小时后反应完全，浓缩除去1,4二氧六环得到粗品(化合物4)。TLC信息：原料Rf＝0.35，产品Rf＝0.20。展开剂：二氯甲烷：甲醇＝10：1，得粗品3.89g。
(4)将4g化合物4溶于甲醇中加入40ml甲醛，室温搅拌15分钟，加热80℃回流2小时；加入18g氢氧化钠，升温80℃回流过夜，18小时候反应完全；加水100ml，用EA(乙酸乙酯)(100ml*3)萃取，干燥，浓缩得到产品(化合物5)0.8g，2步收率为19.07％。1H-NMR(CDCl3；400MHZ)2.086(s,3H)2.301(s,3H)3.191(t,2H)3.751(t,2H)3.944(s,2H)。
应用试验例
取实施例1所得化合物20mg溶于5ml甲基纤维素溶液作为测试溶液。
取14周雄性鼠6只，口服测试溶液，5mg/kg，30分钟后，继续口服0.2ml含有2μCi[3H]-胆固醇/鼠的INERALIPIDTM，五小时后对动物实施安乐死，并且收集肝和血液。对肝和血浆中的胆固醇量进行测定，胆固醇吸收抑制百分比约为85.7％。
上述参照具体实施方式对该一种咪唑吡嗪化合物及其制备方法进行的详细描述，是说明性的而不是限定性的，可按照所限定范围列举出若干个实施例，因此在不脱离本发明总体构思下的变化和修改，应属本发明的保护范围之内。

Claims (1)

1.一种咪唑吡嗪化合物的制备方法，其特征在于：具体步骤如下：
(1)将每50g氢氧化钠，11g四丁基硫酸氢铵加入30g化合物12，4-二甲基咪唑的乙腈溶液中，室温搅拌30分钟，加入43.3g2-氯乙胺盐酸盐，加热至75℃回流；14小时后反应完全，抽滤除去白色固体，浓缩除去乙腈，得粗品化合物2；
(2)氮气保护下，将每43g化合物2溶于乙腈中，冰浴加入67gBoc2O，120ml三乙醇胺，室温搅拌120min；反应完全后浓缩除去乙腈，过硅胶柱，LC-MS监测反应结束，得化合物3；
(3)将浓盐酸滴入化合物3的1,4二氧六环溶液中加热至100℃；8小时后反应完全，浓缩除去1,4二氧六环得到化合物4；
(4)将每4g化合物4溶于甲醇中加入40ml甲醛，室温搅拌15分钟，加热80℃回流2小时；加入18g氢氧化钠，升温80℃回流过夜，18小时候反应完全；加水100ml，用乙酸乙酯萃取，干燥，浓缩得到目标产物化合物5，
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1081678A (zh) * 1992-06-17 1994-02-09 厄普约翰公司 吡啶基、吡咯烷基和吖庚因基取代的肟类及它们用作抗动脉粥样硬化和抗血胆甾醇过多剂
WO2007137819A1 (en) * 2006-05-30 2007-12-06 Elbion Gmbh 4-AMINO-PYRIDO[3,2-e]PYRAZINES, THEIR USE AS INHIBITORS OF PHOSPHODIESTERASE 10, AND PROCESSES FOR PREPARING THEM
CN101568542A (zh) * 2006-12-22 2009-10-28 埃科特莱茵药品有限公司 5,6,7,8-四氢-咪唑并[1,5-a]吡嗪衍生物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1081678A (zh) * 1992-06-17 1994-02-09 厄普约翰公司 吡啶基、吡咯烷基和吖庚因基取代的肟类及它们用作抗动脉粥样硬化和抗血胆甾醇过多剂
WO2007137819A1 (en) * 2006-05-30 2007-12-06 Elbion Gmbh 4-AMINO-PYRIDO[3,2-e]PYRAZINES, THEIR USE AS INHIBITORS OF PHOSPHODIESTERASE 10, AND PROCESSES FOR PREPARING THEM
CN101568542A (zh) * 2006-12-22 2009-10-28 埃科特莱茵药品有限公司 5,6,7,8-四氢-咪唑并[1,5-a]吡嗪衍生物

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