JOCR Journal of Organic Chemistry Research 2330-5231 Scientific Research Publishing 10.12677/JOCR.2018.64013 JOCR-27753 JOCR20180400000_84905676.pdf 化学与材料 2,7-二氨基取代噻吩并嘧啶酮衍生物的合成与生物活性研究 Studies on Synthesis and Biological Activities of 2,7-Diamino Substituted Thienopyrimidinone Derivatives 徐 硕星 2 1 徐 胜臻 2 * 华中农业大学理学院，湖北 武汉 null 27 11 2018 06 04 87 94 © Copyright 2014 by authors and Scientific Research Publishing Inc. 2014 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

噻吩并嘧啶酮类衍生物由于其良好的生物活性和药理活性，在医学和农用化学领域有很广阔的应用前景。利用三组分aza-Wittig反应，用3,4-二乙氧羰基-2,5-双三苯基膦亚胺噻吩、芳基异氰酸酯、亲核试剂胺或水合肼以54%~64%的收率合成了12个未见文献报道的化合物，通过IR，1H NMR，LC-MS对化合物进行了表征。进一步探究了化合物的抑菌活性，结果表明部分化合物对茶树生赤霉菌和茶树生茎点霉有良好的抑菌活性。 Thienopyrimidinone derivatives have wide application prospect in the field of medicine and agri-cultural chemical due to their good biological and pharmacological activities. 12 new compounds which have not been reported in the literature were synthesized in 54% - 64% yields via aza-Wittig reaction of 3,4-diethoxy-2,5-bis(triphenylphosphine)phosphinimine thiophene with aromatic iso-cyanate and nucleophile amine or hydrazine hydrate; the new compounds were confirmed by IR, 1H NMR, LC-MS. Their antibacterial activities were tested and some of the compounds showed good antibacterial activity to gibberella of tea and phoma of tea.

噻吩并嘧啶酮衍生物，Aza-Wittig反应，合成，抑菌活性, Thienopyrimidinone Derivatives Aza-Wittig Reaction Synthesis Antibacterial Activity 2,7-二氨基取代噻吩并嘧啶酮衍生物的合成与生物活性研究<sup> </sup>

徐硕星，徐胜臻*

华中农业大学理学院，湖北 武汉

收稿日期：2018年11月5日；录用日期：2018年11月20日；发布日期：2018年11月27日

 摘 要

噻吩并嘧啶酮类衍生物由于其良好的生物活性和药理活性，在医学和农用化学领域有很广阔的应用前景。利用三组分aza-Wittig反应，用3,4-二乙氧羰基-2,5-双三苯基膦亚胺噻吩、芳基异氰酸酯、亲核试剂胺或水合肼以54%~64%的收率合成了12个未见文献报道的化合物，通过IR，1H NMR，LC-MS对化合物进行了表征。进一步探究了化合物的抑菌活性，结果表明部分化合物对茶树生赤霉菌和茶树生茎点霉有良好的抑菌活性。

关键词 :噻吩并嘧啶酮衍生物，Aza-Wittig反应，合成，抑菌活性

Copyright © 2018 by authors and beplay安卓登录

This work is licensed under the Creative Commons Attribution International License (CC BY).

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 1. 引言

作为一类具有广谱高效低毒的生物活性的稠环化合物，含氮杂环化合物因其在杀菌、杀虫、除草、消炎、抗病毒、抗肿瘤等方面都有很好的活性 [ 1 ] [ 2 ] [ 3 ] [ 4 ] [ 5 ] ，从而引起了人们对此类杂环化合物的重视。而大多数含氮杂环化合物对病菌和害虫具有高选择性的杀灭作用，相对来说，对温血动物、鸟类、鱼类的毒性较低 [ 6 ] [ 7 ] [ 8 ] ，由于这些特性使得含氮杂环化合物在医学和农药学领域的应用日渐广泛。含嘧啶类氮杂环化合物是氮杂环大家庭中的重要一个成员，自然界内许多重要的生物碱、天然产物的骨架结构均为嘧啶环类衍生物，这类衍生物在动植物体内的新陈代谢过程中起着重要作用 [ 9 ] [ 10 ] ，而噻吩并嘧啶衍生物是一类将噻吩环嵌入到嘧啶环上得到的稠环化合物，从噻吩并嘧啶酮的构造上来分析，噻吩并嘧啶酮与人体中DNA，RNA的基本构成物嘌呤构造相似，从而有可能成为人体核酸代谢拮抗物的替代物，相关文献也证明了此类化合物具有杀虫、杀菌、抗病毒、抗肿瘤、除草等生物活性 [ 11 ] - [ 16 ] ，近年来利用原料易得、反应条件温和、产率较高的aza-Wittig反应来合成取代含氮杂环和稠杂环成为热门，另外，该方法易于在环上变换官能团，有利于对药物的构效关系研究 [ 17 ] [ 18 ] [ 19 ] 。本文致力于利用三组分串联aza-Wittig反应设计和合成新型噻吩并嘧啶酮衍生物，对所合成的物质进行生物活性测试，并希望能找到具有研究前的化合物。合成路线见图1和表1。

 2. 结果与讨论 2.1. 结构表征

目标化合物的IR图谱中，所有特征基团均有明显的吸收，氨基峰在3481 cm−1~3411 cm−1有较为明显的伸缩振动，芳环在2854 cm−1~2952 cm−1有明显的伸缩振动，羰基峰在1710 cm−1附近有明显的伸缩振动，C=N双键的振动峰出现在1500 cm−1左右出现的强伸缩振动峰，在1350 cm−1~1550 cm−1出现的强弱不等的伸缩振动峰为C=C双键的振动峰。化合物的1H NMR图谱，化合物的各个出峰均得到了验证。两个芳环在δ7.42 ppm~6.96 ppm表现为一组多峰，六位与七位的仲胺和伯胺两个活泼氢分别在δ8.56 ppm左右和δ4.83 ppm左右表现出一组单峰，有时伯胺的氢无法顺利出峰，当为吗啡啉取代基的4组氢表现为两组峰，与O相连的两组CH2在δ3.37 ppm左右表现为一组三重峰，与N相连的两组δCH2在3.00 ppm 左右表现为一组三重峰；若为哌啶取代基5组CH2表现为三组峰，与N相连的两组δCH2在3.00左右表现为一组三重峰，其余三组CH2在1.43 ppm~1.19 ppm表现出两组多峰；若为二乙胺取代4组CH2变现为两组峰，与N相连的两组CH2在δ3.00 ppm 左右表现为一组四重峰，另外两组CH2在δ0.76 ppm左右表现出一组三重峰。目标化合物的LC-MS图中所有目标化合物都出现[M + H]峰，部分化合物出现[M + Na]和[2M + H]峰。

图1. 化合物5的合成路径

Synthesis of Compound
Product Ar Y Ar1 Yield/%
5a Ph morpholin-4-yl 4-Me-Ph 54
5b Ph piperidin-1-yl 4-Me-Ph 62
5c Ph NEt2 Ph 59
5d Ph NEt2 4-Me-Ph 56
5e Ph NEt2 4-CF3O-Ph 60
5f Ph NEt2 4-CF3-Ph 58
5g 4-Me-Ph morpholin-4-yl Ph 54
5h 4-Me-Ph morpholin-4-yl 4-Me-Ph 59
5i 4-Me-Ph morpholin-4-yl 4-Me-O-Ph 62
5j 4-Me-Ph morpholin-4-yl 4-Cl-Ph 64
5k 4-Me-Ph piperidin-1-yl 4-Me-Ph 62
5l 4-Me-Ph NEt2 4-CF3CO-Ph 59

表1. 化合物5的合成

 2.2. 化合物的抑菌活性

菌种茶树生赤霉菌(Pyrenomycctes)、蔷薇生链格孢(Alternariaalternata)、茶树炭疽菌(Gloeosporiumtheaesinensis miyake)和茶树生茎点霉(Phomaadianticola)四种菌由华中农业大学植物科学技术学院提供。

抑菌活性试验采用含毒介质法。在PDA培养基中按100 mg/L (有效含量)加入定量乳化剂吐温−80，待培养基冷却后接种直径为5 mm的供试菌片，菌丝面朝下，置于培养箱(25˚C)培养，48 h后调查抑制率。结果见表2。从表中数据来看，有如下规律：1) 大多数化合物对四种受试菌种的抑菌效果在41%~89%之间，对茶树生赤霉菌和茶树生茎点霉的抑制活性较好；2) 其中化合物5h对茶树生赤霉菌和茶树生茎点霉的抑制活性分别为80%和81%，5i对茶树生茎点霉属的抑制活性为80%，5j对茶树生赤霉菌和茶树生茎点霉的抑制活性分别为89%和83%的，5a对蔷薇生链格孢和茶树炭疽菌的抑制活性为71%；3) 从表中可以看出化合物5h，5i，5j的活性较高，而化合物5h，5i，5j七位均为吗啡啉取代，六位为Ph-Me-P取代，活性高于七，六位的其他取代基团，说明二位引入吗啡啉环，六位引入Ph-Me-P比引入其他取代基更加有利于化合物的杀菌活性。

Antibacterial activity of compounds 5 (Inhibition at 100 mg/L%
化合物 茶树生赤霉菌 蔷薇生链格孢 茶树炭疽菌 茶树生茎点霉
5a 72 71 71 58
5b 50 59 62 47
5c 41 74 58 46
5d 33 53 42 37
5e 51 52 46 35
5f 62 50 66 50
5g 39 64 73 69
5h 80 47 52 81
5i 32 56 42 80
5j 89 70 46 83
5k 32 54 69 77
5l 63 50 62 54

表2. 化合物5的抑菌活性(抑制率%)

 3. 结论

利用aza-Wittig反应设计并合成了一系列新型噻吩并双嘧啶二酮衍生物，通过IR，1H NMR，LC-MS等方法对所合成化合物进行了结构表征，采用含毒介质离体平皿法对茶树生赤霉菌，蔷薇生链格孢，茶树炭疽菌，茶树生茎点霉等4种菌进行了初步的杀菌活性测试。目标化合物对测试的4种菌均有一定的杀菌活性，特别是对茶树生赤霉菌和茶树生茎点霉属的抑制活性较高，其中5h，5i，5j的活性相对较好。

 4. 实验部分 4.1. 仪器与试剂

RY-2型熔点仪(天津市分析仪器厂)；AM-600MHz氢核磁共振潜仪(德国Bruker公司)；AVAIAR330型红外光谱仪(美国Nieolet公司)；紫外灯(波长254 nm，ZF-7)；Agilent 6100系列单四极杆质谱仪(美国Agilent公司)。

异氰酸酯购自于安耐吉药业有限公司，氘代试剂购自于百灵威试剂有限公司，其他试剂购置于国药集团化学试剂有限公司。溶剂都需要经过严格的干燥处理，乙腈、三乙胺加入活化的4A分子筛除水，无水乙醚加入钠丝干燥，二氯甲烷加入干燥的氯化钙干燥，乙醇重蒸。

 4.2. 中间体1，2，3的制备

中间体1，2，3的制备参见文献 [ 20 ] [ 21 ] [ 22 ] [ 23 ] 。

 4.3. 目标化合物5的制备

称取干燥膦亚胺3 2 mmol加入到100mL圆底烧瓶，加入10 mL二氯甲烷溶解，用注射器称取2 mmol芳基异氰酸酯快速注入烧瓶中密闭于0~5˚C密闭8 h~12 h，减压脱去大部分溶剂，加入V (乙醚)：V (石油醚) = 2:1 (20 mL)过滤以除去三苯氧磷，滤液脱去溶剂加入无水乙醇溶解，将其转入另一个干燥的100 mL圆底烧瓶中并配备磁力搅拌，向其中滴加两当量的水合肼的乙醇溶液，滴完，继续搅拌1 h，过程中会析出大量白色沉淀，过滤，柱层析分离得白色固体。

2-(4-甲苯氨基)-3-氨基-6-苯基-7-(吗啡啉-4-基)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5a)

White crystals (yield 57%). m.p. 277˚C~278˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.56 (s, 1H, N-H), 7.42~6.96 (m, 9H, Ar-H), 4.83 (s, 2H, NH2), 3.36 (t, J = 4.8Hz, 4H, 2OCH2), 3.01 (t, J = 4.4Hz, 4H, 2NCH2), 2.41 (s, 3H, CH3). IR (KBr) 3487, 3408 (NH2), 1701 (C=O), 1536, 1486, 1359, 950 cm−1. LC-MS m/z 502.1 [M + 1].

2-(4-甲苯氨基)-3-氨基-6-苯基-7-(哌啶-1-基) 噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5b)

White crystals (yield 62%). m.p. >300˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.47 (s, 1H, N-H), 7.41~7.04 (m, 9H, Ar-H), 4.74 (s, 2H, NH2), 3.08~2.98 (t, J = 4.8Hz, 4H, 2NCH2), 2.36 (s, 3H, CH3), 1.42~1.40 (m, 2H, CH2), 1.38~1.17 (m, 4H, 2CH2). IR (KBr) 3420, 3311 (NH2), 1701 (C=O), 1530, 1495, 1468, 944, 753 cm−1. LC-MS m/z 500.1 [M + 1].

2-(苯氨基)-3-氨基-6-苯基-7-(二乙胺)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5c)

White crystals (yield 59%). m.p. 269˚C~271˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.59 (s, 1H, N-H), 7.53~7.07 (m, 10H, Ar-H), 4.87 (s, 2H, NH2), 3.02~2.97 (q, J = 7.2Hz, 4H, 2NCH2), 0.79~0.76 (t, J = 6.8Hz, 6H, 2CH3). IR (KBr) 3455, 3311 (NH2), 1704 (C=O), 1539, 1489, 1465, 932 cm−1. LC-MS m/z 474.1 [M + 1].

2-(4-甲苯氨基)-3-氨基-6-苯基-7-(二乙胺)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5d)

White crystals (yield 56%). m.p. 271˚C~273˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.50 (s, 1H, N-H), 7.45~7.17 (m, 9H, Ar-H), 4.76 (s, 2H, NH2), 3.07~3.02 (q, J = 7.2Hz, 4H, 2NCH2), 2.35 (s, 3H, CH3), 0.82~0.78 (t, J = 7.2Hz, 6H, 2CH3). IR (KBr) 3414, 3308 (NH2), 1701 (C=O), 1530, 1468, 1377, 938 cm−1. LC-MS m/z 488.1 [M + 1].

2-(4-三氟甲氧基苯氨基)-3-氨基-6-苯基-7-(二乙胺)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5e)

White crystals (yield 60%). m.p. 274˚C~276˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.67 (s, 1H, N-H), 7.59~7.08 (m, 9H, Ar-H), 4.87 (s, 2H, NH2), 3.05~3.00 (q, J = 7.2Hz, 4H, 2NCH2), 0.81~0.77 (t, J = 6.8Hz, 6H, 2CH3). IR (KBr) 3487, 3408 (NH2), 1704 (C=O), 1533, 1495, 1468, 1159 cm−1. LC-MS m/z 558.1 [M + 1].

2-(4-三氟甲基-苯氨基)-3-氨基-6-苯基-7-(二乙胺)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5f)

White crystals (yield 58%). m.p. 277˚C~279˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.87 (s, 1H, N-H), 7.80~7.22 (m, 9H, Ar-H), 4.83 (s, 2H, NH2), 3.11~3.06 (q, J = 7.2Hz, 4H, 2NCH2), 0.84~0.81 (t, J = 7.2Hz, 6H, 2CH3). IR (KBr) 3420, 3340 (NH2), 1689 (C=O), 1533, 1471, 1324, 943 cm−1. LC-MS m/z 542.1 [M + 1].

2-(苯氨基)-3-氨基-6-(4-甲苯基)-7-(吗啡啉-4-基) 噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5g)

White crystals (yield 54%). m.p. 263˚C~265˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.61 (s, 1H, N-H), 7.54~6.97 (m, 9H, Ar-H), 4.83 (s, 2H, NH2), 3.38 (t, J = 4.8Hz, 4H, 2OCH2), 3.05 (t, J = 4.4Hz, 4H, 2NCH2), 2.38 (s, 3H, CH3). IR (KBr) 3478, 3304 (NH2), 1709 (C=O), 1542, 1495, 1468, 997 cm−1. LC-MS m/z 502.1 [M + 1].

2-(4-甲苯氨基)-3-氨基-6-(4-甲苯基)-7-(吗啡啉-4-基)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5 (3H,6H)-二酮(5h)

White crystals (yield 59%).m.p. 258˚C~260˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.49 (s, 1H, N-H), 7.38~6.90 (m, 8H, Ar-H), 4.86 (s, 2H, NH2), 3.36 (t, J = 4.8Hz, 4H, 2OCH2), 3.01 (t, J = 4.4Hz, 4H, 2NCH2), 2.38 (d, 6H, 2CH3). IR (KBr) 3411, 3328 (NH2), 1704 (C=O), 1540, 1497, 1456, 951 cm−1. LC-MS m/z 516.1 [M + 1].

2-(4-甲氧基-苯氨基)-3-氨基-6-(4-甲苯基)-7-(吗啡啉-4-基)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5i)

White crystals (yield 62%). m.p. 262˚C~264˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.43 (s, 1H, N-H), 7.46~6.92 (m, 8H, Ar-H), 4.77 (s, 2H, NH2), 3.83 (s, 3H, OCH3), 3.38 (t, J = 4.8Hz, 4H, 2OCH2), 3.07 (t, J = 4.4Hz, 4H, 2NCH2), 2.39 (s, 3H, CH3). IR (KBr) 3414, 3320 (NH2), 1701 (C=O), 1562, 1497, 1386, 1109, 753 cm−1. LC-MS m/z 532.1[M + 1].

2-(4-氯苯氨基)-3-氨基-6-(4-甲苯基)-7-(吗啡啉-4-基)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5 (3H,6H)-二酮(5j)

White crystals (yield 64%). m.p. >300˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.63 (s, 1H, N-H), 7.56~7.06 (m, 8H, Ar-H), 4.77 (s, 2H, NH2), 3.42 (t, J = 4.8Hz, 4H, 2OCH2), 3.08 (t, J = 4.8Hz, 4H, 2NCH2), 2.39 (s, 3H, CH3). IR (KBr) 3417, 3325 (NH2), 1701 (C=O), 1539, 1486, 1439, 950 cm−1. LC-MS m/z 536.1 [M + 1].

2-(4-甲苯氨基)-3-氨基-6-(4-甲苯基)-7-(哌啶-1-基) 噻吩并[2,3-d:5,4-d’]双嘧啶-4,5 (3H,6H)-二酮(5k)

White crystals (yield 62%). m.p. >300˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm)：8.47 (s, 1H, N-H), 7.41~6.94 (m, 8H, Ar-H), 4.82 (s, 2H, NH2), 3.03 (t, J = 5.2Hz, 4H, 2NCH2), 2.38 (d, J = 6.8Hz, 6H, 2CH3), 1.43~1.18 (m, 6H, 3CH2). IR (KBr) 3467, 3304 (NH2), 1701 (C=O), 1530, 1495, 1368, 944 cm−1. LC-MS m/z 514.1 [M + 1].

2-(4-三氟甲氧基-苯氨基)-3-氨基-6-(4-甲苯基)-7-(二乙胺)噻吩并[2,3-d:5,4-d’]双嘧啶-4,5(3H,6H)-二酮(5l)

White crystals (yield 59%). m.p. >300˚C. 1H NMR (CDCl3, 400 MHZ) δ (ppm) 8.67 (s, 1H, N-H), 7.66~7.04 (m, 8H, Ar-H), 4.81 (s, 2H, NH2), 3.09-3.04 (q, J = 7.2Hz, 4H, 2NCH2), 2.38 (s, 3H, CH3), 0.85~0.81 (t, J = 6.8Hz, 6H, 2CH3). IR (KBr) 3484, 3414 (NH2), 1704 (C=O), 1533, 1506, 1471, 935 cm−1. LC-MS m/z 572.1 [M + 1].

 基金项目

中央高校基础科研业务费(Fundamental Research Funds for Central Universities (2662016PY122))。

 文章引用

徐硕星,徐胜臻. 2,7-二氨基取代噻吩并嘧啶酮衍生物的合成与生物活性研究Studies on Synthesis and Biological Activities of 2,7-Diamino Substituted Thienopyrimidinone Derivatives[J]. 有机化学研究, 2018, 06(04): 87-94. https://doi.org/10.12677/JOCR.2018.64013

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