CN104119235B - 一种环丙基甲胺化合物及其制备方法 - Google Patents
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Abstract
本发明涉及一种环丙基甲胺化合物及其制备方法，该化合物为反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐，制备方法如下：(1)甘氨酸乙酯盐酸盐为起始原料，将氨基重氮化得化合物1；(2)水杨醛与溴代异丁烷在磷酸钾下进行取代反应得化合物2；(3)化合物2进行维替格反应得到化合物3；(4)化合物3与化合物1进行闭环反应得到化合物4a和化合物4b；(5)将化合物4a水解得到化合物5；(6)化合物5进行酰基化反应得到化合物6；(7)化合物6形成盐酸盐得到最终产物化合物7；所得终产物在预防和治疗神经系统疾病方面具有广泛应用前景。
Description
技术领域
本发明涉及化合物合成领域，尤其是一种环丙基甲胺化合物及其制备方法。
背景技术
根据RationalDrugDesignLeadingtotheIdentificationofaPotent5-HT2CAgonistLacking5-HT2BActivity(ACSMedicinalChemistryLetters(2011),2(12),929-932)等文献记载，环丙基甲胺盐酸盐化合物广泛存在于具有生物活性的药物分子中，在治疗神经系统疾病方面具有巨大的应用价值，以该化合物合成的衍生物，可能具有更加广泛或突出的生物活性。可见，由于其良好的药理活性及潜在的药用价值，现阶段环丙基甲胺化合物的合成倍受关注。
发明内容
本发明所要解决的技术问题在于提供一种环丙基甲胺化合物。
本发明所要解决的另一技术问题在于提供上述环丙基甲胺化合物的制备方法。
为解决上述技术问题，本发明的技术方案是：
一种环丙基甲胺化合物，反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐，其结构式为(Ⅰ)所示，
优选的，上述环丙基甲胺化合物，所述反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐为类白色固体，其核磁共振数据为：1H-NMR(D2O；400HZ)1.0(m,8H),1.342(m,1H),2.062(m,1H),2.134(m,1H),2.923(q,1H),3.160(q,1H),3.870(m,2H),6.910(m,2H),7.005(m,1H),7.183(m,1H)。
上述环丙基甲胺化合物的制备方法，具体步骤如下：
(1)化合物Q甘氨酸乙酯盐酸盐为起始原料，将氨基重氮化得化合物1；
(2)水杨醛与溴代异丁烷在磷酸钾下进行取代反应得化合物2；
(3)化合物2进行维替格反应得到化合物3；
(4)化合物3与化合物1(重氮乙酸乙酯)进行闭环反应得到化合物4a和化合物4b；
(5)将化合物4a水解得到化合物5；
(6)化合物5进行酰基化反应得到化合物6；
(7)化合物6形成盐酸盐得到最终产物化合物7，其中，
优选的，上述环丙基甲胺化合物的制备方法，所述化合物4a、化合物5、化合物6作为中间产物，为新化合物。
上述环丙基甲胺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：
上述环丙基甲胺化合物的制备方法，是一种原料廉价、合成方法简单的反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐的制备方法，其产物反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐在预防和治疗神经系统疾病方面具有广泛应用前景。
附图说明
图1为反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐的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
一种环丙基甲胺化合物反式-2-(2-异丙基甲氧苯基)环丙基甲胺盐酸盐的制备方法，具体步骤如下：
(1)向反应瓶中加入甘氨酸乙酯盐酸盐67.7g、75ml水、0.713g浓硫酸，150ml二氯甲烷(DCM)，将体系降温到0℃，滴加40.15g亚硝酸钠水溶液，加完反应1h；将体系分液，水相用DCM萃取两次，有机相干燥，浓缩(T≤30℃)得化合物157g，产率100％，为黄色油状。原料Rf＝0.01，化合物1Rf＝0.5。展开剂：石油醚:乙酸乙酯20:1。
(2)向反应瓶中继续加入100g水杨醛、800mlDMSO、327.1g三水合磷酸钾和168.3g溴代异丁烷，将体系升温到85℃至基本无原料；将体系倒入2L冰水中，用MTBE萃取三次，有机相用盐水洗、干燥、浓缩得到化合物2151.1g，产率100％，为红棕色液体。原料Rf＝0.1，化合物2Rf＝0.05。展开剂：石油醚。
(3)向反应瓶中加入100g化合物2，240.51g甲基三苯基溴化磷和30ml四氢呋喃(THF)，将体系降温到0℃，分批加入40.4g氢化钠，加毕室温反应至基本无原料；向体系中滴加水，分液，水相用甲基叔丁基醚(MTBE)萃取两次，有机相干燥、浓缩、过柱(200-300目硅胶柱子)得到化合物385.45g，产率86.41％，为白色固体。原料Rf＝0.2，化合物3Rf＝0.85。展开剂：石油醚:乙酸乙酯50:1。
(4)向反应瓶中加入3.81g乙酰丙酮酸铜、855mlDCM、0.52g苯肼和85.45g化合物3，将体系升温40℃，缓慢滴加111.61g重氮乙酸乙酯的DCM溶液，加毕，回流反应至基本无原料；将体系浓缩得到化合物4a和化合物4b的混合物，过柱(200-300目硅胶柱子)得到化合物4a，54g，产率42.47％，为淡黄色油状。原料Rf＝0.85，化合物4aRf＝0.6，化合物4bRf＝0.55。展开剂：石油醚:乙酸乙酯20:1。
(5)向反应瓶中加入540甲醇﹑23.1gKOH，再加入54g化合物4a，将体系升温至回流，TLC检测至原料基本反应完；将体系冷却，浓缩，再加入水，用盐酸调节PH至3，用DCM萃取，有机相干燥，浓缩得到化合物5，38g，产率78.77％，为黄色油状。原料Rf＝0.6，化合物5Rf＝0.05。展开剂：PE:EA20:1。
(6)向反应瓶中加入30g化合物5﹑300ml甲苯和0.47gDMF，再滴加入91.4g二氯亚砜，滴毕，将体系升温80℃反应过夜；将体系浓缩，向一反应瓶中加入15ml液氨，再加入5ml甲苯，将浓缩的酰氯用甲苯溶解，于-60℃滴加至液氨溶液中，滴毕，保温至原料反应完；向体系中加入EA，分液，水相用EA萃取，有机相干燥，浓缩得到化合物6，28g，产率93.73％，为类白色固体。原料Rf＝0.4，化合物6Rf＝0.15。展开剂：石油醚:乙酸乙酯(PE:EA)＝5:1。
(7)向反应瓶中加入14g化合物6和140mlTHF(四氢呋喃)，滴加270ml硼烷四氢呋喃络合物。滴毕，将体系升温至回流反应至基本无原料；向体系中滴加3M盐酸，浓缩出体系中THF，再加入水和MTBE，分液，水相调节PH至9，MTBE萃取，有机相干燥，浓缩，再加入MTBE，通HCl气体，滴加PE，析出固体，抽滤得到化合物76g，产率39.08％，为类白色固体。原料Rf＝0.7，化合物7Rf＝0.4。展开剂：二氯甲烷:甲醇10:1。经测定，如图1所示，化合物7的核磁共振谱为图1。
实施例1所述制备过程如下：
应用试验例
昆明种小白鼠，体重20-22g，将小白鼠饲养在洁净通风、明暗循环的安静环境中，自由进食饮水。实验分为两组，每组10只，每组动物经口给药，其中，对照组为帕罗西汀1.0mg/kg、试验组为实施例1所得终产物化合物71.0mg/kg。给药后将每只动物轻轻放置在玻璃缸中(缸内蓄满水)，小鼠游泳6分钟，记录后4分钟内累计的不动时间(秒)。数据采用SPSS12.0统计软件处理。试验结果显示，对照组小鼠不动时间为182±13秒，试验组小鼠不动时间为116±11秒。结果说明，实施例1所得化合物7具有抗抑郁作用。
上述参照具体实施方式对该一种环丙基甲胺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)
1.一种环丙基甲胺化合物的制备方法，其特征在于：具体步骤如下：
(1)化合物Q甘氨酸乙酯盐酸盐为起始原料，将氨基重氮化得化合物1；
(2)水杨醛与溴代异丁烷在磷酸钾下进行取代反应得化合物2；
(3)化合物2进行维替格反应得到化合物3；
(4)化合物3与化合物1进行闭环反应得到化合物4a和化合物4b；
(5)将化合物4a水解得到化合物5；
(6)化合物5进行酰基化反应得到化合物6；
(7)化合物6形成盐酸盐得到最终产物化合物7，其中，
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| US20020022643A1 (en) * | 2000-06-27 | 2002-02-21 | Solo Goldstein | 1,1- and 1,2-disubstituted cyclopropane compounds |
| CN102863341A (zh) * | 2012-10-22 | 2013-01-09 | 南通大学 | 一种（1r,2s）-2-芳基环丙胺衍生物的化学合成方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| US20020022643A1 (en) * | 2000-06-27 | 2002-02-21 | Solo Goldstein | 1,1- and 1,2-disubstituted cyclopropane compounds |
| CN102863341A (zh) * | 2012-10-22 | 2013-01-09 | 南通大学 | 一种（1r,2s）-2-芳基环丙胺衍生物的化学合成方法 |
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| Title |
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| Rational Drug Design Leading to the Identification of a Potent 5-HT2C Agonist Lacking 5-HT2B Activity;Chen, Gang等;《ACS Med. Chem. Lett.》;20111010;第12卷;第929−932页 * |
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