CN104356066B - 一种多取代4‑羟基吡唑类衍生物的制备方法 - Google Patents

一种多取代4‑羟基吡唑类衍生物的制备方法 Download PDF

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CN104356066B
CN104356066B CN201410540869.5A CN201410540869A CN104356066B CN 104356066 B CN104356066 B CN 104356066B CN 201410540869 A CN201410540869 A CN 201410540869A CN 104356066 B CN104356066 B CN 104356066B
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hydroxyl
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CN104356066A (zh
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黄卫
刘燊
陈斌辉
郭晓
俞永平
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Zhejiang University ZJU
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

本发明提供一种4‑羟基‑1,3,5‑三取代吡唑类衍生物的制备方法，将易化学合成的烯基叠氮类衍生物和肼类化合物在室温条件下生成。本发明提供的制备方法设计合理、原料易得、无需任何辅助添加剂参与、操作简单方便，所述的多取代4‑羟基吡唑类衍生物的通式I如下：

Description

一种多取代4-羟基吡唑类衍生物的制备方法
技术领域
本发明属化合物合成，主要涉及多取代4-羟基吡唑类衍生物新的制备方法的开发。
背景技术
4-羟基吡唑类衍生物据报道具有较好的药效学性质和重要的生理活性，比如抗菌、抗病毒以及抗血栓。吡唑类衍生物特别是多取代的吡唑环已报道在一些上市药物结构中，如塞来昔布、氟虫腈。因此，这类多取代吡唑类衍生物是药物化学中非常重要的一类五元杂环化合物。
多取代吡唑类衍生物的合成方法有很多，常见的通过1，3-二酮类衍生物与肼类化合物的环合构建，或者通过重氮化合物与炔烃的1,3-偶极环加成反应得到。有报道利用过渡金属催化合成吡唑类化合物在目前报道的方法中，或是反应条件恶劣、需借助金属催化亦或是取代基受限，以上因素促使开发一类新的构建多取代吡唑的方法。本发明中所提供的是一类简单、快速、多元化的构建多取代咪唑的方法。
发明内容
本发明的目的是提供一种多取代4-羟基吡唑类衍生物的制备方法，即将烯基叠氮类衍生物和肼类化合物在室温条件下进行反应就可以得到目标化合物-多取代4-羟基吡唑类衍生物。本发明所述的衍生物的结构通式如下：
其中：R1为氢、单取代或多取代的芳环（取代基可为卤素、硝基、烷氧基、烷基）、杂环、C1-C3链烷烃、芳烷烃。
R2为氢、单取代或多取代的芳环（取代基可为卤素、硝基、烷氧基、烷基）、C1-C3链烷烃。
R3为氢、C1-C3链烷基、芳烷烃。
本发明的一种多取代4-羟基吡唑类衍生物的制备方法具体通过以下步骤实现：
将烯基叠氮类衍生物A和肼类化合物B在相应的溶剂中进行室温反应，得到化合物I。所用的溶剂多选用偶极溶剂，通常是二甲基甲酰胺（DMF）。所得目标产物通过硅胶色谱柱层析的方法纯化（石油醚：乙酸乙酯为洗脱剂），反应式为：
。
所述的式I化合物为如下任一化合物：
3,5-二苯基-4-羟基-1H -吡唑（实施例1）
3-苯基-5-（4-溴苯基）-4-羟基-1H -吡唑（实施例2）
3-苯基-5-（4-甲氧基苯基）-4-羟基-1H -吡唑（实施例3）
3-苯基-5-（2-呋喃）-4-羟基-1H -吡唑（实施例4）
3-苯基-5-异丙基-4-羟基-1H -吡唑（实施例5）
3-（4-氯苯基）-5-苯基-4-羟基-1H -吡唑（实施例6）
3-（4-甲氧基苯基）-5-苯基-4-羟基-1H -吡唑（实施例7）
3-（4-甲基苯基）-5-苯基-4-羟基-1H -吡唑（实施例8）
3-（4-硝基苯基）-5-（4-甲基苯基）-4-羟基-1H -吡唑（实施例9）
3-苯基-5-（4-溴苯基）-4-羟基-1- 甲基 -吡唑（实施例10） 。
本发明提供一种4-羟基-1,3,5-三取代吡唑类衍生物的制备方法，即将易化学合成的烯基叠氮类衍生物和肼类化合物在室温条件下生成的。本发明提供的是一类简单、快速、多元化对的构建多取代吡唑的方法，即将烯基叠氮类衍生物和肼类化合物在室温条件下进行反应，其中起始原料可以通过一步法得到，反应原料便宜易得。本发明提供的制备方法设计合理、原料易得、无需任何辅助添加剂参与、操作简单方便。
具体实施方式
本发明结合实施例作进一步的说明。
实施例1：3,5-二苯基-4-羟基-1H -吡唑的制备
原料1：2-叠氮-1,3-二苯基丙烯酮的制备
将2-叠氮苯乙酮322mg（2mmol）和苯甲醛212mg（2mmol）置于20ml圆底烧瓶中，加入8ml乙醇，再分别加入0.5当量的乙酸和0.5当量的哌啶，反应12h，待TLC板检测原料消失。减压蒸出溶剂，粗产品经柱层析纯化（洗脱剂是石油醚：乙酸乙酯=100：1-80:1）得到淡黄色固体，收率70%。HRMS (ESI) calcd. for C15H11N3O[M+H]+= 250.0978, found 250.0977。
2、3,5-二苯基-4-羟基-1H -吡唑的制备
将2-叠氮-1,3-二苯基丙烯酮498mg(2mmol)与水合肼0.24ml（4 mmol）加至反应瓶中，加入5mlDMF，再加入0.304mlDBU（4mmol），室温反应12小时。待TLC板检测原料消失。减压蒸出溶剂，粗产品经柱层析纯化（洗脱剂：石油醚：乙酸乙酯=15：1-7.5:1）得到淡黄色固体，收率69%，熔点：236.2-237.2℃。
其结构式为：
1H NMR (500 MHz, DMSO) δ 12.87 (s, 1H), 8.30 (s, 1H), 7.94 (m, 4H),7.45 (m, 4H), 7.31 (t, J = 6.7 Hz, 2H).HRMS (ESI) calcd. for C15H12N2O[M+H]+=237.1023, found 237.1022。
实施例2：3-苯基-5-（4-溴苯基）-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-苯基-3-（4-溴苯基）丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率75%，熔点：222.6-224.4℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.98 (s, 1H), 8.43 (s, 1H), 7.95-7.85 (m,4H), 7.67-7.32 (m,6H).HRMS (ESI) calcd. for C15H11BrN2O[M+H]+= 315.0129,found315.0128。
实施例3：3-苯基-5-（4-甲氧基苯基）-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-苯基-3-（4-甲氧基苯基）丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率66%，熔点：220.6-221.4℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.74 (s, 1H), 8.18 (s, 1H), 7.88 (s, 4H),7.44 (s, 1H), 7.29 (d, J = 7.0 Hz, 1H), 7.03 (s, 2H), 3.80 (s, 3H).HRMS (ESI)calcd. for C16H14N2O2[M+H]+= 267.1131, found 267.1132。
实施例4：3-苯基-5-（2-呋喃）-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-苯基-3-（2-呋喃）丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率59%，熔点：189.7-190.5℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.93 (s, 1H), 8.38 (s, 1H), 7.92-7.73 (m,3H), 7.45 (t, J = 7.3 Hz, 2H), 7.31 (t, J = 7.3 Hz, 1H), 6.78 -6.59 (m, 2H).HRMS (ESI) calcd. for C13H10N2O2[M+H]+= 227.0819, found227.0819。
实施例5：3-苯基-5-异丙基-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-苯基-3异丙基丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率47%，熔点：184.4-185.5℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.17 (s, 1H), 7.88-7.81 (m, 3H), 7.38 (t, J= 7.1 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1H), 3.11-3.04 (m, 1H), 1.23 (d, J = 7.0Hz, 6H).HRMS (ESI) calcd. For C12H14N2O[M+H]+= 203.1180, found 203.1179。
实施例6：3-（4-氯苯基）-5-苯基-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-（4-氯苯基）-3苯基丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率73%，熔点：230.0-232.1℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.96 (s, 1H), 8.42 (s, 1H), 8.02-7.86 (m,4H), 7.50-7.31 (m, 5H).HRMS (ESI) calcd. For C15H11ClN2O[M+H]+= 271.0634, found271.0633。
实施例7：3-（4-甲氧基苯基）-5-苯基-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-（4-甲氧基苯基）-3苯基丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率68%，熔点：208.4-209.5℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.73 (s, 1H), 8.17 (s, 1H), 7.93 – 7.85 (m,4H), 7.44 (t, J = 7.6 Hz, 2H), 7.30 (t, J = 7.3 Hz, 1H), 7.03 (d, J = 8.4 Hz,2H), 3.80 (s, 1H).HRMS (ESI) calcd. For C16H14N2O2[M+H]+= 267.1130,found267.1131。
实施例8：3-（4-甲基苯基）-5-苯基-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-（4-甲基苯基）-3苯基丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率70%，熔点：242.1-242.9℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 12.80 (s, 1H), 8.22 (s, 1H), 7.97 – 7.78 (m,4H), 7.44 – 7.27 (m, 5H), 2.34 (s, 3H).HRMS (ESI) calcd. For C16H14N2O[M+H]+=251.1182, found 251.1183。
实施例9：3-（4-硝基苯基）-5-（4-甲基苯基）-4-羟基-1H -吡唑的制备
操作过程与实施例1同，只是用2-叠氮-1-（4-硝基苯基）-3-（4-甲基苯基）丙烯酮代替2-叠氮-1,3-二苯基丙烯酮，反应经硅胶柱层析得黄色固体，收率68%，熔点：大于250℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 13.18 (s, 1H), 8.69 (s, 1H), 8.32 (d, J =8.9 Hz, 2H), 8.24 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.29 (d, J =7.9 Hz, 2H), 2.35 (s, 3H).HRMS (ESI) calcd. For C16H13N3O3[M+H]+= 296.1034,found 296.1034。
实施例10：3-苯基-5-（4-溴苯基）-4-羟基-1- 甲基 -吡唑的制备
操作过程与实施例2同，只是用甲基肼代替水合肼并且添加20当量的水，反应经硅胶柱层析得黄色固体，收率68%，熔点：154.0-155.2℃。其结构式为：
1H NMR (500 MHz, DMSO) δ 8.28 (s, 1H), 7.95 (d, J = 7.4 Hz, 2H), 7.73(d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.41 (t, J = 7.6 Hz, 2H), 7.28(t, J = 7.2 Hz, 1H), 3.78 (s, 3H).HRMS (ESI) calcd. For C16H13BrN2O[M+H]+=329.0289, found 329.0287。

Claims (3)

1.一种多取代4-羟基吡唑类衍生物的制备方法，其特征在于，通过以下步骤实现：将烯基叠氮类衍生物A和肼类化合物B在相应的溶剂中进行室温反应，得到目的化合物I，所用的溶剂选用偶极溶剂，所得目标产物通过硅胶色谱柱层析的方法纯化，洗脱剂选择石油醚：乙酸乙酯，反应式为：
其中：
R1为单取代的苯环、2-呋喃基、异丙基，选择的取代基为卤素、烷氧基、烷基，
R2为单取代的苯环，选择的取代基为卤素、硝基、烷氧基、烷基，
R3为氢、甲基。
2.根据权利要求1所述的一种多取代4-羟基吡唑类衍生物的制备方法，其特征在于，偶极溶剂选用二甲基甲酰胺。
3.根据权利要求1或2所述的一种多取代4-羟基吡唑类衍生物的制备方法，其特征在于，所述的目的化合物I为如下任一化合物:
3,5-二苯基-4-羟基-1H -吡唑，
3-苯基-5-（4-溴苯基）-4-羟基-1H -吡唑，
3-苯基-5-（4-甲氧基苯基）-4-羟基-1H -吡唑，
3-苯基-5-（2-呋喃）-4-羟基-1H -吡唑，
3-苯基-5-异丙基-4-羟基-1H -吡唑，
3-（4-氯苯基）-5-苯基-4-羟基-1H -吡唑，
3-（4-甲氧基苯基）-5-苯基-4-羟基-1H -吡唑，
3-（4-甲基苯基）-5-苯基-4-羟基-1H -吡唑，
3-（4-硝基苯基）-5-（4-甲基苯基）-4-羟基-1H -吡唑，
3-苯基-5-（4-溴苯基）-4-羟基-1- 甲基 -吡唑。
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