CN108794488A - 芳基取代的含三氮唑的稠杂环类化合物及制备和应用 - Google Patents
芳基取代的含三氮唑的稠杂环类化合物及制备和应用 Download PDFInfo
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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
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
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Abstract
本发明提供一种芳基取代的含三氮唑的稠杂环类化合物,将2‑氨基‑1,3,5‑三嗪类化合与氰类化合物混合加入溶剂中,在铜催化剂和金属锌化合物存在下,在60~135℃温度下搅拌反应15‑30小时,反应结束后,反应液后处理制得目标化合物。本发明的制备方法设计合理,工艺反应条件温和,原料易得,操作方便,成本低,有着广泛的工业应用前景。本发明所提供的芳基取代的含三氮唑的稠杂环类化合物显示一定的抗菌活性,可在制备抗菌药物中的应用,本发明为新药筛选及开发奠定了基础,具有较好的实用价值。通式(III)结构如下:
Description
技术领域
本发明属于制药领域,涉及一种芳基取代的含三氮唑的稠杂环类化合物及其制备方法和应用。
背景技术
三氮唑类化合物是重要的氮杂环化合物,具有抗癌、抗菌等多种生物活性。含三氮唑的稠杂环类是一类新的杂环化合物,该类化合物的制备方法报道较少,限制了应用。因此,开发新的、简便的合成含三氮唑的稠杂环类化合物的制备方法重要的理论和实际意义。
发明内容
本发明提供一类新的芳基取代的含三氮唑的稠杂环类化合物,通式(III)结构如下:
其中:
R1,R2各自独立为C1~C10烷基或者R1,R2和两者之间的N组合形成含N或含N、O 的C4~C8的杂环,优选R1,R2各自独立为乙基或者R1,R2和两者之间的N组合形成哌啶环、四氢吡咯或吗啉环;
Ar为C4~C10芳基,优选Ar为芳杂环、苯基或取代苯基;更优选Ar为噻吩、吡啶、苯基或氯苯。
本发明的另一个目的是提供所述芳基取代的含三氮唑的稠杂环类化合物的制备方法,通过以下步骤实现:
将式(I)所示的2-氨基-1,3,5-三嗪类化合与式(II)所示的氰类化合物混合加入溶剂中,在铜催化剂作用下,在金属锌化合物存在下,在60~135℃温度下搅拌反应15~30小时,反应结束后,反应液后处理制得式(III)所示的芳基取代的含三氮唑的稠杂环类化合物。
式(I)所示的2-氨基-1,3,5-三嗪类化合物式(I)与式(II)所示的氰类化合物、金属铜催化剂、金属锌化合物的量比为1:1.0~10:0.1~0.4:0.1~1.0;
式(I)和式(II)结构式如下所示:
Ar-CN (II)
其中R1,R2和Ar的定义同通式(III)。
所述的溶剂为芳烃类;优选为取代苯类,优选为氯苯或甲苯。所述溶剂的体积用量通常以2-氨基-1,3,5-三嗪的质量计为2~10mL/mmol。
所述金属铜催化剂为一价铜化合物;优选为溴化亚铜、氯化亚铜或氧化亚铜。
所述的金属锌化合物为二价锌化合物;优选为氯化锌或氧化锌。
本发明所述制备方法中,所述后处理可采用如下方法:反应结束后,加水,用二氯甲烷萃取萃取,合并有机层,用无水硫酸钠干燥,过滤,浓缩滤液,柱层析(CH2Cl2:EtOAc=30:1,V:V),收集含目标化合物的洗脱液,减压蒸馏,残渣干燥后经核磁共振(NMR)检测确认为目标化合物(III)。
本发明的再一个目的是提供芳基取代的含三氮唑的稠杂环类化合物在制备抗菌药物中的应用。
本发明开发了一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,该工艺反应条件温和,原料易得,操作方便,成本低,有着广泛的工业应用前景。本发明所提供的芳基取代的含三氮唑的稠杂环类化合物显示一定的抗菌活性,为新药筛选及开发奠定了基础,具有较好的实用价值。
具体实施方式
下面将通过实施例对本发明作进一步的说明,但本发明的保护范围不限于此。
实施例1化合物(III-1)的制备:
将2-氨基-4-二乙胺基-1,3,5-三嗪(120.1mg,0.7mmol),苯甲腈(377.9mg,3.66mmol),氯化亚铜(14.5mg,0.15mmol)和氯化锌(9.5mg,0.07mmol)在氯苯(2mL)中混合,在125℃条件下反应,反应20h,反应结束后,加水50mL,用二氯甲烷萃取(20mL×3),合并有机层,用无水硫酸钠干燥,过滤,浓缩,柱层析(洗脱剂为CH2Cl2:EtOAc=10:1,V:V),收集Rf值0.3~0.35 的洗脱液(TLC监测,展开剂同洗脱剂),减压蒸馏除去溶剂,干燥得目标化合物(III-1)142.6mg,收率75%。1H NMR(500MHz,CDCl3):δ8.93(s,1H),8.29-8.25(m,2H),7.49-7.46(m,3H),3.74 (q,J=7.1Hz,4H),1.29(t,J=7.1Hz,3H),1.26(t,J=7.1Hz,3H).
实施例2:
将氯化亚铜改为溴化亚铜(10.8mg,0.07mmol),30h,其他操作同实施例1,得量57mg,收率30%。
实施例3:
将氯化亚铜改为氧化亚铜(40.1mg,0.28mmol),15h,其他操作同实施例1,得量78mg,收率41%。
实施例4:
将苯腈的量改为(720mg,7.0mmol),氯化锌改为氧化锌(61.3mg,0.7mmol),温度改为135℃,其他操作同实施例1,得量67mg,收率35%。
实施例5:
将苯腈的量改为(72mg,0.7mmol),氯苯改为甲苯(7mL),温度改为60℃,其他操作同实施例1,得量19.1mg,收率10%。
实施例6:
将2-氨基-4-二乙胺基-1,3,5-三嗪改为2-氨基-4-哌啶基-1,3,5-三嗪(120.3mg,0.7mmol),其他操作同实施例1,目标化合物(III-2)117.3mg,收率63%。1H NMR(500MHz,CDCl3):δ8.91 (s,1H),8.27-8.24(m,2H),7.49-7.47(m,3H),3.94(t,J=5.6Hz,3H),7.73-7.26(m,6H).
实施例7:
将2-氨基-4-二乙胺基-1,3,5-三嗪改为2-氨基-4-吗啉基-1,3,5-三嗪(119.9mg,0.7mmol),其他操作同实施例1,目标化合物(III-3)100.8mg,收率54%。1H NMR(500MHz,CDCl3):δ8.94 (s,1H),8.26-8.24(m,2H),7.49-7.46(m,3H),3.97(t,J=5.2Hz,4H),3.77(t,J=5.2Hz,4H).
实施例8:
将2-氨基-4-二乙胺基-1,3,5-三嗪(I-1)改为2-氨基-4-四氢吡咯基-1,3,5-三嗪(120.0mg, 0.7mmol),将苯腈改为对氯苯腈(499.6mg,3.6mmol),其他操作同实施例1,目标化合物 (III-4)116.6mg,收率53%.1H NMR(500MHz,CDCl3):δ8.93(s,1H),8.21(d,J=8.6Hz,2H), 7.46(d,J=8.6Hz,2H),3.74-3.69(m,4H),2.07-2.04(m,4H).
实施例9:
将苯腈改为2-氰基噻吩(391.6mg,3.6mmol),其他操作同实施例1,目标化合物(III-5)119.5mg,收率61%。1H NMR(500MHz,CDCl3):δ8.89(s,1H),7.91(dd,J=3.7Hz,1.2Hz,1H),7.47(dd,J=5.0Hz,1.2Hz,1H),7.15(dd,J=5.0Hz,3.7Hz,1H),3.73(q,J=7.1Hz,2H),3.72(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H),1.25(t,J=7.1Hz,3H).
实施例10:
将苯腈改为4-氰基吡啶(373.6mg,3.6mmol),其他操作同实施例1,目标化合物(III-6)103.5mg,收率54%。1H NMR(500MHz,CDCl3):δ8.94(s,1H),8.74(d,J=5.3Hz,2H),8.08(d,J=5.3Hz,2H),3.72(q,J=7.0Hz,2H),3.71(q,J=7.0Hz,2H),1.27(t,J=7.0Hz,3H), 1.24(t,J=7.0Hz,3H).
实施例11:对大肠杆菌(E.coli,Ec)的体外抑菌活性测试
采用扩散法(打孔法)研究了目标化合物在浓度为10mg/mL时对大肠杆菌(E.coli,Ec) 的体外抑菌作用。
方法:用灭过菌的打孔器在涂布菌液的平皿上十字对称打6个孔,用无菌微量注射器分别加入100μL质量浓度为10mg/mL的样品二甲基亚砜溶液,并以0.85%的无菌生理盐水作对照.。将培养皿置于恒温培养箱中培养,其中细菌平板倒置于37℃恒温培养箱中培养24h, 霉菌倒置于28℃恒温培养箱中培养48h,取出观察有无抑菌作用,结果见表1。
表1化合物浓度为10mg/mL体外抗菌活性
测试编号 | 化合物 | Ec |
1 | (III-1) | + |
2 | (III-4) | +++ |
3 | (III-5) | ++ |
4 | (III-6) | ++ |
对照品 | 氨苄青霉素 | +++ |
Claims (10)
1.一种芳基取代的含三氮唑的稠杂环类化合物,其特征在于,结构通式(III)如下:
(III)
其中:
R1,R2各自独立为C1~C10烷基或者R1,R2和两者之间的N组合形成含N或含N、O的C4~C8的杂环;
Ar为C4~C10芳基。
2.根据权利要求1所述的一种芳基取代的含三氮唑的稠杂环类化合物,其特征在于,R1,R2各自独立为乙基或者R1,R2和两者之间的N组合形成哌啶环、四氢吡咯或吗啉环。
3.根据权利要求1所述的一种芳基取代的含三氮唑的稠杂环类化合物,其特征在于,Ar选为芳杂环、苯基或取代苯基。
4.根据权利要求3所述的一种芳基取代的含三氮唑的稠杂环类化合物,其特征在于,Ar选为噻吩、吡啶、苯基或氯苯。
5.权利要求1所述的一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,其特征在于,通过以下步骤实现:
将式(I)所示的2-氨基-1,3,5-三嗪类化合与式(II)所示的氰类化合物混合加入溶剂中,在铜催化剂作用下,在金属锌化合物存在下,在60~135℃温度下搅拌反应15~30小时,反应结束后,反应液后处理制得式(III)所示的芳基取代的含三氮唑的稠杂环类化合物;其中式(I)、式(II)、金属铜催化剂、金属锌化合物的量比为1:1.0~10:0.1~0.4:0.1~1.0;
式(I)和式(II)结构式为:
(I) (II)
其中R1,R2和Ar的定义同权利要求1的通式(III)。
6.根据权利要求5所述的一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,其特征在于,所述的溶剂为芳烃类;所述溶剂的体积用量通常以2-氨基-1,3,5-三嗪的质量计为2~10 mL/mmol;其中所述芳烃类溶剂选为取代苯类,选用氯苯或甲苯。
7.根据权利要求5所述的一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,其特征在于,所述金属铜催化剂为一价铜化合物,选用溴化亚铜、氯化亚铜或氧化亚铜。
8.根据权利要求5所述的一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,其特征在于,所述的金属锌化合物为二价锌化合物,,选用氯化锌或氧化锌。
9.根据权利要求5所述的一种芳基取代的含三氮唑的稠杂环类化合物的制备方法,其特征在于,所述后处理采用如下方法:反应结束后,加水,用二氯甲烷萃取萃取,合并有机层,用无水硫酸钠干燥,过滤,浓缩滤液,柱层析,CH2Cl2:EtOAc=30:1,V:V,收集洗脱液,减压蒸馏,残渣干燥后经核磁共振检测确认为目标化合物(III)。
10.根据权利要求1所述的一种芳基取代的含三氮唑的稠杂环类化合物在制备抗菌药物中的应用。
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