CN108191862B - 4-羟基-2-取代吡唑并吡啶类化合物的合成方法 - Google Patents

4-羟基-2-取代吡唑并吡啶类化合物的合成方法 Download PDF

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CN108191862B
CN108191862B CN201810234564.XA CN201810234564A CN108191862B CN 108191862 B CN108191862 B CN 108191862B CN 201810234564 A CN201810234564 A CN 201810234564A CN 108191862 B CN108191862 B CN 108191862B
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葛燕青
段桂运
董建
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Shandong First Medical University and Shandong Academy of Medical Sciences
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Abstract

本发明提供了一种4‑羟基‑2‑取代吡唑并[1,5‑a]吡啶类化合物的新型合成方法，所述方法以碳酸钾为碱，以3‑取代吡唑‑5‑甲酸乙酯、4‑溴代巴豆酸乙酯为原料，通过串联反应一步合成4‑羟基‑2‑取代吡唑并[1,5‑a]吡啶类化合物。此法原料易得，操作简单，无苛刻反应条件，是制备4‑羟基‑2‑取代吡唑并[1,5‑a]吡啶类化合物的有效方法。

Description

4-羟基-2-取代吡唑并吡啶类化合物的合成方法
技术领域
本发明属于化学合成领域，具体地说，涉及一种4-羟基-2-取代吡唑并[1,5-a]吡啶类化合物的新型制备方法。
背景技术
吡唑并[1,5-a]吡啶作为吲哚的电子等排体，近年来受到药物化学领域的广泛关注。此类化合物具有抗疱疹病毒活性, 黄嘌呤腺苷A1受体的拮抗活性,P38致活酶的抑制活性,多巴胺D2、D3、D4受体拮抗活性等。
吡唑并[1, 5-a]吡啶类化合物的合成，主要方法是通过1-氨基吡啶正离子与取代炔的1, 3-偶极环加成反应，此反应有很好的区域选择性，但对于2, 6位无取代的非对称的氨基吡啶盐来说，此反应产生4位和6位取代的异构体。同时此反应需要较长反应时间，且产率很低。另外一种较为重要的方法是通过氮宾的重排得到。此环化反应非常有效，但是通过热分解得到氮宾的前体化合物叠氮化物却较难制备。因此，寻找原料便宜易得，反应条件温和，操作简单的吡唑并[1,5-a]吡啶类化合物的新型合成方法就变得尤为迫切。
发明内容
针对现有技术的不足，本发明的目的在于提供一种4-羟基-2-取代吡唑并[1,5-a]吡啶-5-甲酸乙酯类化合物的新型合成方法。
本发明的4-羟基-2-取代吡唑并[1,5-a]吡啶-5-甲酸乙酯类化合物的制备方法如下：
Figure 780434DEST_PATH_IMAGE001
其中，R为甲基、苯基、对甲基苯基、对氟苯基、对氯苯基、对溴苯基。
以多种3-取代吡唑-5-甲酸乙酯为原料，在碱的催化条件下，和4-溴代巴豆酸乙酯在溶剂中反应8-12小时，通过串联反应一步得到4-羟基-2-取代吡唑并[1,5-a]吡啶-5-甲酸乙酯。
3-取代吡唑-5-甲酸乙酯、碱和4-溴代巴豆酸乙酯加入溶剂中，78度反应8-12小时，后处理得到4-羟基-2-取代吡唑并[1,5-a]吡啶-5-甲酸乙酯。其中，碱是碳酸钾，碳酸铯，吡啶或三乙胺，优选碳酸钾；溶剂是乙醇、甲醇、乙腈、DMF或丙酮，优选乙醇。
3-取代吡唑-5-甲酸乙酯与碳酸钾的摩尔比为1：3。
3-取代吡唑-5-甲酸乙酯与4-溴代巴豆酸乙酯的摩尔比为1：3。
具体实施方式
实施例1：4-羟基-2-甲基吡唑并[1,5-a]吡啶-5-甲酸乙酯
Figure 461687DEST_PATH_IMAGE002
在25 mL圆底烧瓶中依次加入0.15g（1.00 mmol）3-甲基吡唑-5-甲酸乙酯，0.42g（3.00 mmol）碳酸钾，0.58g（3.00 mmol）4-溴代巴豆酸乙酯和15 mL乙醇，78度下回流反应8-12小时，浓缩，柱层析得0.09g无色固体产品，产率42 %。1H NMR (400 MHz, CDCl3): δ11.77 (s, 1H), 7.89 (d, J = 8 Hz, 1H), 6.96 (d, J = 8 Hz, 1H), 6.67 (s, 1H),4.42 (q, J = 8 Hz, 2H), 2.49 (s, 3H), 1.43 (t, d, J = 4 Hz, 3H); 13C NMR (100MHz, CDCl3): δ 169.9, 155.4, 151.3, 134.5, 120.0, 108.4, 102.0, 98.6, 61.7,14.2, 13.8; HRMS: m/z calcd for C11H13N2O3 [M+H]+ 221.0926, found 221.0923.
实施例2：
参照例1制备4-羟基-2-苯基吡唑并[1,5-a]吡啶-5-甲酸乙酯，产率60%。
1H NMR (400 MHz, CDCl3): δ 11.85 (s, 1H), 7.98 (m, 3H), 7.40 (m, 4H),7.04 (d, J = 4 Hz, 1H), 4.44 (q, J = 8 Hz, 2H), 1.43 (t, d, J = 4 Hz, 3H); 13CNMR (100 MHz, CDCl3): δ 169.8, 155.7, 153.3, 135.1, 132.5, 128.8, 128.6,126.3, 120.3, 109.3, 102.2, 96.1, 61.8, 14.2; HRMS: m/z calcd for C16H15N2O3 [M+H]+ 283.1083, found 283.1088.
实施例3：
参照例1制备4-羟基-2-（4-甲基）苯基吡唑并[1,5-a]吡啶-5-甲酸乙酯，产率48%。
1H NMR (400 MHz, CDCl3): δ 11.84 (s, 1H), 7.99 (d, J = 8 Hz, 1H),7.85 (d, J = 8 Hz, 2H), 7.24 (d, J = 8 Hz, 2H), 7.16 (s, 1H), 7.03 (d, J = 8Hz, 1H), 4.44 (q, J = 8 Hz, 2H), 2.40 (s, 3H), 1.44 (t, d, J = 4 Hz, 3H); 13CNMR (100 MHz, CDCl3): δ 169.9, 155.7, 153.4, 138.4, 135.1, 129.7, 129.5,126.2, 120.3, 109.2, 102.1, 95.8, 61.8, 21.4, 14.2; HRMS: m/z calcd forC17H17N2O3 [M+H]+ 297.1239, found 297.1231.
实施例4：
参照例1制备4-羟基-2-（4-氟）苯基吡唑并[1,5-a]吡啶-5-甲酸乙酯。产率44%。
1H NMR (400 MHz, CDCl3): δ 11.85 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.94(m, 2H), 7.14 (m, 3H), 7.06 (d, J = 8 Hz, 1H), 4.45 (q, J = 8 Hz, 2H), 1.45(t, d, J = 4 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 169.8, 164.3, 155.7, 152.4,128.1, 128.0, 120.3, 115.9, 115.6, 109.4, 107.9, 102.3, 95.8, 61.8, 14.2;HRMS: m/z calcd for C16H14FN2O3 [M+H]+ 301.0988, found 301.0996.
实施例5：
参照例1制备4-羟基-2-（4-氯）苯基吡唑并[1,5-a]吡啶-5-甲酸乙酯，产率53%。
1H NMR (400 MHz, CDCl3): δ 11.85 (s, 1H), 7.99 (d, J = 4 Hz, 1H),7.89 (d, J = 8 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 7.16 (s, 1H), 7.07 (d, J = 4Hz, 1H), 4.45 (q, J = 8 Hz, 2H), 1.44 (t, d, J = 4 Hz, 3H); 13C NMR (100 MHz,CDCl3): δ 169.8, 155.8, 152.2, 135.3, 134.5, 131.1, 129.0, 127.6, 120.3,109.7, 102.4, 96.1, 61.9, 14.2; HRMS: m/z calcd for C16H14ClN2O3 [M+H]+317.0693, found 317.0684.
实施例6：
参照例1制备4-羟基-2-（4-溴）苯基吡唑并[1,5-a]吡啶-5-甲酸乙酯，产率50%。
1H NMR (400 MHz, CDCl3): δ 11.85 (s, 1H), 7.99 (d, J = 8 Hz, 1H), 7.83(d, J = 8 Hz, 2H), 7.58 (d, J = 8 Hz, 2H), 7.17 (s, 1H), 7.07 (d, J = 8 Hz,1H), 4.45 (q, J = 8 Hz, 2H), 1.44 (t, d, J = 4 Hz, 3H); 13C NMR (100 MHz,CDCl3): δ 169.8, 155.8, 152.2, 135.3, 132.0, 131.6, 127.9, 122.7, 120.3,109.7, 102.4, 96.1, 61.9, 14.2; HRMS: m/z calcd for C16H14BrN2O3 [M+H]+361.0188, found 361.0187.
以上所述，仅为本发明较佳的具体实施方式，但本发明的保护范围并不局限于此，任何熟悉本技术领域的技术人员，在本发明披露的技术范围内，根据本发明的技术方案及其发明构思加以等同替换或改变，都应该涵盖在本发明的保护范围之内。

Claims (8)

1.一种4-羟基-2-取代吡唑并[1,5-a]吡啶类化合物的合成方法，其特征在于，反应方程式为：
Figure 620693DEST_PATH_IMAGE001
其中，R为甲基、苯基、对甲基苯基、对氟苯基、对氯苯基、对溴苯基；
以3-取代吡唑-5-甲酸乙酯为原料，在碱的催化条件下，和4-溴代巴豆酸乙酯在溶剂中反应8-12小时，通过串联反应一步得到4-羟基-2-取代吡唑并[1,5-a]吡啶-5-甲酸乙酯。
2.如权利要求1所述的合成方法，其特征在于，所选用的碱是碳酸钾，碳酸铯，吡啶，三乙胺。
3.如权利要求1所述的合成方法，其特征在于，所选用的碱是碳酸钾。
4.如权利要求1所述的合成方法，其特征在于，反应温度为78摄氏度。
5.如权利要求3所述的合成方法，其特征在于，3-取代吡唑-5-甲酸乙酯与碳酸钾的摩尔比为1：3。
6.如权利要求1所述的合成方法，其特征在于，3-取代吡唑-5-甲酸乙酯与4-溴代巴豆酸乙酯的摩尔比为1：3。
7.如权利要求1所述的合成方法，其特征在于，所选溶剂为乙醇、甲醇、乙腈、DMF、丙酮。
8.如权利要求1所述的合成方法，其特征在于，所选溶剂为乙醇。
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