CN112724132B - 一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法 - Google Patents

一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法 Download PDF

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CN112724132B
CN112724132B CN202110001691.7A CN202110001691A CN112724132B CN 112724132 B CN112724132 B CN 112724132B CN 202110001691 A CN202110001691 A CN 202110001691A CN 112724132 B CN112724132 B CN 112724132B
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梁永宏
曾兆森
严文广
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SHANGHAI XIANGHUI MEDICAL TECHNOLOGY CO LTD
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Abstract

本发明提供了一种3‑卤代‑5‑三氟甲基‑吡唑并[1,5‑a]吡啶的合成方法。本发明属于医药化学合成领域。本发明以4‑三氟甲基吡啶为原料与2,4,6‑三甲基苯磺酰肼反应成盐,再与丙炔酸乙酯反应得到中间体3,中间体3在酸作用下水解得到中间体4,中间体4与NXS反应得到3‑卤代‑5‑三氟甲基‑吡唑并[1,5‑a]吡啶5。其中X为:Cl、Br、I中的任意一种。本发明反应步骤少、操作简单,原料便宜易得且目标化合物为新化合物无合成报道,系我们首次发明。

Description

一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法
技术领域:
本发明涉及一种医药中间体的合成方法,具体而言,本发明涉及一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法。
Figure BDA0002881575470000011
技术背景
吡唑并吡啶衍生物是一类非常重要的含氮杂环化合物,广泛的用于医药和农药领域。药理学研究表明,这类化合物具有杀菌、抗真菌、抗肿瘤、止痛、抗血小板等诸多活性,在防治克氏阴性和阳性细菌、各种恶性肿瘤、神经性疾病、骨质疏松症和老年痴呆症等方面疗效显著。在农药领域,杂环化合物已成为农药发展的新主流,使农药进入超高效、无公害的绿色农药新时代。吡唑并吡啶类衍生物主要有吡唑并[3,4-a]吡啶、吡唑并[1,5-a]吡啶、吡唑并[4,3-a]吡啶等三类,而研究最多的当属吡唑并[1,5-a]吡啶系列化合物。
发明内容
本发明提供了一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法。本发明属于医药化学合成领域。本发明以4-三氟甲基吡啶为原料与2,4,6-三甲基苯磺酰肼反应成盐,再与丙炔酸乙酯反应得到中间体3,中间体3在酸作用下水解得到中间体4,中间体4与NXS反应得到3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶5。其中X为:Cl、Br、I中的任意一种。其合成路线为:
Figure BDA0002881575470000012
本发明所用的原料和试剂均市售可得。
1.本发明的要点在于:发明了一种3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶新化合物。
2.本发明的优势是:(1)本发明反应步骤少、操作简单,原料便宜易得且目标化合物为新化合物无合成报道,系我们首次发明;(2)本发明化合物具有很好的体外抗结核病菌活性,药代动力学实验同样性质良好而且毒副作用很低,具有很好的成药性。
下面通过实例对本发明作进一步的描述,本领域的技术人员应理解,所举实例只用于解释本发明,并非用于限定本发明的保护范围。
具体实施方案
实施例1:3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶的合成
1. 5-三氟甲基-吡唑并[1,5-a]-3-羧酸乙酯(中间体3)的合成
将1.47g 4-三氟甲基吡啶溶于10ml二氯甲烷中,0℃条件下缓慢分批次加入新买的2.14g 2,4,6-三甲基苯磺酰肼,反应2h后,将溶液减压蒸干。将残余物溶于干燥的20mlN,N-二甲基甲酰胺中,再加入2.76g碳酸钾,搅拌溶清,逐滴加入丙炔酸乙酯0.98g,室温下搅拌反应过夜。TLC检测反应完全后,将反应液用水稀释,乙酸乙酯萃取。所得有机相再用水和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到中间体3(1.03g,产率40%)为类白色固体。
2. 5-三氟甲基-吡唑并[1,5-a]吡啶(中间体4)的合成
将0.9g中间体3在10ml 40%的硫酸溶液中回流3小时,TLC检测反应完全后,冷却至室温,用2N NaOH溶液调节其PH=8。乙酸乙酯萃取,所得有机相再用饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到中间体4(0.54g,产率83%)为类白色固体。
3. 3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶(化合物5)的合成
将0.52g中间体4溶于8ml乙腈中,分批次加入0.69g NIS,升温至回流反应1h。TLC检测反应完全后,将反应液倒入水中,甲基叔丁基醚萃取,所得有机相再用2N NaOH溶液,15%硫代硫酸钠和饱和食盐水洗涤,无水硫酸钠干燥,有机相减压蒸干。残余物通过柱层析纯化,得到化合物5(0.75g,产率86%)为淡黄色固体。1H NMR(400MHz,CDCl3)δ8.44(d,J=7.2Hz,1H),7.94(s,1H),7.43(s,1H),6.83(d,J=7.2Hz,1H)。
实施例2:3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶的生物活性
(1)本发明所述的3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶具有很好的体外抗结核病菌活性,化合物最小抑菌浓度仅为0.005μg/mL。对于耐多药结核菌菌株抑制作用非常显著。体内实验结果显示,本发明所述的3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶在5mg/kg/d的剂量下,就可完全清除小鼠体内H37Ra的感染量。
(2)本发明所述的3-碘-5-三氟甲基-吡唑并[1,5-a]吡啶的药代动力学实验同样性质良好而且很低的毒副作用,具有很好的成药性,发展前景显著。
本发明不限于上述实例。以上所述仅为本发明的实施例,并不用以限制本发明,凡在本发明的精神和原则之内,所作的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。

Claims (1)

1.3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶的合成方法,所述合成方法包括如下步骤:
(1)以4-三氟甲基吡啶为原料与2,4,6-三甲基苯磺酰肼反应成盐,再与丙炔酸乙酯反应得到中间体3:
Figure FDA0003594527510000011
(2)中间体3在酸作用下水解得到中间体4:
Figure FDA0003594527510000012
(3)中间体4与NXS类化合物反应得到3-卤代-5-三氟甲基-吡唑并[1,5-a]吡啶5,其中X为:Cl、Br、I中的任意一种:
Figure FDA0003594527510000013
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105524058A (zh) * 2014-10-21 2016-04-27 中国科学院广州生物医药与健康研究院 吡唑并[1,5-a]吡啶类化合物及其应用
CN107163043A (zh) * 2017-06-16 2017-09-15 上海毕得医药科技有限公司 一种吡唑并[1,5‑a]吡啶‑3‑羧酸酯衍生物的合成方法
CN108884091A (zh) * 2016-03-10 2018-11-23 日产化学株式会社 稠合杂环化合物和有害生物防除剂

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JP2010533173A (ja) * 2007-07-11 2010-10-21 オークランド・ユニサーヴィシズ・リミテッド ピラゾロ[1,5−a]ピリジン、及び癌治療におけるその使用

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105524058A (zh) * 2014-10-21 2016-04-27 中国科学院广州生物医药与健康研究院 吡唑并[1,5-a]吡啶类化合物及其应用
CN108884091A (zh) * 2016-03-10 2018-11-23 日产化学株式会社 稠合杂环化合物和有害生物防除剂
CN107163043A (zh) * 2017-06-16 2017-09-15 上海毕得医药科技有限公司 一种吡唑并[1,5‑a]吡啶‑3‑羧酸酯衍生物的合成方法

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