含哌啶噻唑结构的乙酰氨基衍生物的合成及杀菌活性


农药学学报 2019, Vol. 21 Issue (3): 372-377	PDF

引用本文

丁成荣, 殷许, 潘亚运, 张国富, 魏军, 谭成侠. 含哌啶噻唑结构的乙酰氨基衍生物的合成及杀菌活性[J]. 农药学学报, 2019, 21(3): 372-377, doi: 10.16801/j.issn.1008-7303.2019.0045

DING Chengrong, YIN Xu, PAN Yayun, ZHANG Guofu, WEI Jun, TAN Chengxia. Synthesis and fungicidal activity of acetamido derivatives containing piperidine thiazole moiety[J]. Chinese Journal of Pesticide Science, 2019, 21(3): 372-377, doi: 10.16801/j.issn.1008-7303.2019.0045

含哌啶噻唑结构的乙酰氨基衍生物的合成及杀菌活性

丁成荣, 殷许, 潘亚运, 张国富, 魏军, 谭成侠

浙江工业大学化学工程学院，杭州 310014

收稿日期: 2019-02-18 录用日期: 2019-04-11

基金项目: 浙江省绿色农药2011协同创新中心开放基金资助项目

作者简介: 丁成荣，男，教授级高级工程师，主要从事农药、医药中间体的合成，E-mail：dingcr@zjut.edu.cn.

谭成侠，通信作者 (Author for correspondence)，男，研究员，主要从事新农药创制工作，E-mail：tanchengxia@zjut.edu.cn.

摘要: 为了寻找高效的杀菌活性物质，以哌啶噻唑结构为母体，甘氨酸为连接基团，通过重氮化、氯化、成环和缩合等步骤合成了14个含哌啶噻唑结构的乙酰氨基衍生物，通过核磁共振氢谱 (¹H NMR)、碳谱(¹³C NMR)及高分辨质谱 (HRMS)对化合物的结构进行确证。初步杀菌活性测定结果表明：甘氨酸作为连接基团对化合物杀菌活性的提高具有积极影响，其中，化合物7a、7c和7g在25 mg/L剂量下对黄瓜灰霉病菌的抑制率为68.7%、71.6%和67.2%，化合物7a、7g和7i对马铃薯晚疫病菌的抑制率分别为50.8%、61.9% 和55.8%。

关键词: 哌啶噻唑乙酰氨基衍生物杀菌活性新农药创制

Synthesis and fungicidal activity of acetamido derivatives containing piperidine thiazole moiety

DING Chengrong, YIN Xu, PAN Yayun, ZHANG Guofu, WEI Jun, TAN Chengxia

College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China

Abstract: In order to find novel compounds with high fungicidal activities, a series of acetamido derivatives containing piperidine thiazole moiety were designed and synthesized by the procedure of diazotization, chlorination, cyclization and condensation. Their structures were characterized by ¹H NMR, ¹³C NMR and HRMS. Preliminary bioassay indicated that some title compounds showed good fungicidal activities and the introduction of acetamido group had positive effect on the fungicidal activity. At the concentration of 25 mg/L, compounds 7a, 7c and 7g possessed fungicidal activities against Botrytis cinereal with the inhibition rates of 68.7%, 71.6% and 67.2%, respectively. In addition, compounds 7a, 7g and 7i showed good fungicidal activities against Phytophthora infestans (Mont.) de Bary with the inhibition rate of 50.8%, 61.9% and 55.8%, respectively.

Key words: piperidine thiazole acetamido derivatives fungicidal activity new agrochemical

哌啶噻唑类化合物是一类新颖的具有良好杀菌活性的化合物，起初应用于医药领域^[1]。杜邦公司最早发现该类化合物具有杀菌活性^[2-3]，并于2012年推出第一个含哌啶噻唑结构的农药品种—氟噻唑吡乙酮 (oxathiapiprolin)，其对黄瓜霜霉病、番茄晚疫病和葡萄霜霉病等都有显著的防治效果，尤其对马铃薯和番茄晚疫病的致病疫霉Phytophthora infestans高效^[4]。之后，研究人员对哌啶噻唑结构进行改造修饰，发现了许多具有杀菌活性的哌啶噻唑类化合物^[5-7]，拜耳公司也推出了结构与氟噻唑吡乙酮相似的新品种fluoxapiprolin^[8-9]。此外，甘氨酸常作为药效基团的连接部分出现在农药结构中，以提高农药的生物活性^[10-14]。在前期研究中，笔者发现当哌啶环上连接磺酰胺及杂环酰胺时，化合物表现出良好的杀虫、杀菌活性，而连接苯基或取代苯基时却几乎无杀菌活性^[15-16]。鉴于此，本研究以哌啶噻唑结构作为母体，以甘氨酸作为纽带连接基团R和哌啶基，设计并合成了一系列含哌啶噻唑结构的乙酰氨基衍生物，对其化学结构进行了鉴定，并初步测定了所有目标化合物对几种常见植物病原真菌的杀菌活性，目标化合物的设计及合成路线见图式1和图式2。

图式1 目标化合物设计 Scheme1 Design of title compounds

图式2 目标化合物合成路线 Scheme2 Synthesis route of title compounds

1 实验部分 1.1 仪器与试剂

SHZ-III型循环水式真空泵 (郑州长城)；Ry-1G熔点仪(温度计未校正，天津光学仪器厂) AVANCE Ⅲ 500MHz核磁共振仪 (TMS为内标，以CDCl₃为溶剂，Bruker)；Hei-VAP Value旋转蒸发仪(德国Heidolph)；Daltonics Bio-TOF-Q III型质谱仪(Bruker)柱层析硅胶为H型 (青岛海洋化工厂，48~75 μm)。所用试剂和溶剂均为分析纯。97%多菌灵 (carbendazim) 原药 (上海阿拉丁生化科技股份有限公司)；98%噻呋酰胺 (thifluzamide) 原药 (上海麦克林生化科技有限公司)。

1.2 化合物的合成 1.2.1 化合物1~4的合成

化合物1和2参照文献[17]方法合成；化合物3和4分别参照文献[18]和[16]方法合成。

1.2.2 4-(4-(3-甲基苯基)-5-甲基噻唑-2-基) 哌啶-1-甲酸叔丁酯 (5) 的合成

参照文献[16]的方法合成。在250 mL三口瓶中加入10.0g中间体4 (0.04 mol)、7.3 g中间体3 (0.04 mol)、6.6 g无水乙酸钠 (0.08 mol) 和乙酸100 mL，80 ℃下搅拌反应12 h。过滤，滤液旋转蒸发至干。所得产物用50 mL乙酸乙酯溶解后加入到100 mL水中，静置分层。取有机相，水相再用乙酸乙酯萃取3次，每次50 mL。合并萃取液，旋转蒸发脱去溶剂，得黄色油状物11 g，收率76%。¹H NMR (500 MHz, CDCl₃)，δ：7.31 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.5 Hz, 1H), 4.25 (s, 2H), 3.14 (t, J = 11.3 Hz, 1H), 2.88 (s, 2H), 2.48 (s, 3H), 2.40 (s, 3H), 2.12 (d, J = 14.7 Hz, 2H), 1.80~1.69 (m, 2H), 1.49 (s, 9H)。HRMS (ESI):计算值C₂₁H₂₈N₂O₂S [M+H]⁺ 373.194 9；测定值373.195 2。

1.2.3 (2(4-(4-甲基-5-(3-甲基苯基) 噻唑-2-基) 哌啶-1-基)-2-氧代乙基) 氨基甲酸叔丁酯 (6) 的合成

在250 mL三口瓶中加入10.0 g (26.8 mmol) 中间体5，再加入4 mol/L的盐酸二氧六环溶液50 mL，室温下搅拌4 h。过滤，滤饼烘干后得白色盐酸盐固体。不经提纯，直接进行下一步反应。

参照文献[19]方法进行缩合反应。取100 mL二氯甲烷置于冰浴中，加入8.0 g (26.0 mmol) 上述盐酸盐和4.6 g (26.0 mmol) N-Boc-甘氨酸，搅拌后依次加入5.4 g (28.6 mmol) 1-乙基-(3-二甲基氨基丙基) 碳酰二亚胺盐酸盐 (EDCI)、6.8 g (52.0 mmol) N,N-二异丙基乙胺 (DIPEA) 和3.8 g (28.6 mmol) 1-羟基苯并三唑 (HOBt)，于室温下反应24 h。反应液先用30 mL 5%的盐酸溶液洗涤2次，再用30 mL 5% 碳酸氢钠溶液洗涤2次，最后用30 mL饱和氯化钠水溶液洗涤2次，无水硫酸钠干燥，旋转蒸发至干，得淡黄色油状物8.8 g，收率79%。¹H NMR (500 MHz, CDCl₃), δ: 7.30 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 5.56 (s, 1H), 4.64 (d, J = 13.5 Hz, 1H), 4.00 (s, 2H), 3.82 (d, J = 13.5 Hz, 1H), 3.35~3.14 (m, 2H), 2.85 (t, J = 12.6 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.18 (t, J = 13.3 Hz, 2H), 1.85~1.71 (m, 2H), 1.46 (s, 9H)。HRMS (ESI)：计算值C₂₃H₃₁N₃O₃S [M+H]⁺ 430.215 9；测定值430.216 6。

1.2.4 目标化合物7的合成

在100 mL三口瓶中加入8 g (18.6 mmol) 中间体6和4 mol/L的盐酸二氧六环溶液20 mL，室温下搅拌4 h。旋转蒸发至干，得黄色盐酸盐固体，不经提纯，直接进行下一步缩合反应。

取上步盐酸盐1.0 mmol和羧酸1.0 mmol于20 mL二氯甲烷中，温度控制在0 ℃左右，依次加入1.1 mmol EDCI、2.0 mmol DIPEA和1.1 mmol HOBt，于室温下搅拌反应过夜。反应液依次经10 mL 5% 的盐酸溶液洗涤2次，10 mL 5%的碳酸氢钠溶液洗涤2次，10 mL饱和氯化钠水溶液洗涤2次后，无水硫酸钠干燥，旋转蒸发脱去溶剂。粗产物经硅胶柱层析分离得产物7(7a~7n)，其中7a~7j、7n的洗脱剂为V (石油醚): V (乙酸乙酯) = 6: 1，7k、7l、7m流动相为 V (石油醚): V (乙酸乙酯) = 4: 1。

1.3 杀菌活性测定

供试菌株：水稻纹枯病菌Rhizoctonia solani、黄瓜灰霉病菌Botrytis cinerea和马铃薯晚疫病菌Phytophthora infestans (Mont.) de Bary均由浙江省化工研究院有限公司提供。

采用菌丝生长率法^[20]测定。以多菌灵和噻呋酰胺为对照药剂，含溶剂的无菌水为空白对照。准确称取0.05 g (精确至0.000 1 g) 样品，用0.20 mL N, N-二甲基甲酰胺 (DMF) 溶解，加入含体积分数为0.1% Tween-80的无菌水溶液98.8 mL，配制成化合物质量浓度为500 mg/L的药液。取各药液2 mL，加入到38 mL冷却至45 ℃的马铃薯葡萄糖琼脂 (PDA) 培养基中，制成终浓度为25 mg/L的含药培养基平板。从培养好供试病原菌菌落边缘打取直径6.0 mm的菌丝块，移至含药培养基上。每处理4次重复。置于28 ℃的恒温生化培养箱中培养，4 d后测量菌落直径，计算菌生长抑制率。

2 结果与分析 2.1 化合物的合成

以间甲基苯胺为原料，经重氮化反应制成氟硼酸重氮盐固体1，再在Cu₂O催化下与乙酸异丙烯酯反应，生成1-(间甲苯基)-2-丙酮 (2) ；化合物2与磺酰氯发生氯化反应，得到关键中间体3。由于中间体3在氯化过程中易生成二氯取代产物，因此需控制磺酰氯用量和反应时间，投料时磺酰氯与化合物2物质的量之比为1.1: 1.0, 反应时间以40 min为最佳。化合物3与4在80 ℃下, 以乙酸作溶剂、乙酸钠作缚酸剂条件下形成噻唑环，得化合物5。文献中报道，在合成噻唑环时通常使用乙醇、DMF和丙酮^[21-23]等作溶剂，但收率低，产物难以分离纯化，而采用乙酸作溶剂，收率可达85%以上，后处理方便。化合物5经过脱Boc保护后，以EDCI作为缩合剂经缩合反应得到一系列目标产物7a~7n。其熔点、收率及高分辨质谱数据见表1，核磁共振氢谱 (¹H NMR) 及核磁共振碳谱 (¹³C NMR) 见表2。

表 1 目标化合物7a~7n的理化数据及高分辨质谱 Table 1 Physical properties, HRMS of compounds 7a-7n

化合物 Compd.	外观 Apperance	熔点 m.p./℃	分子式 Formula	收率 Yield/%	高分辨质谱 HRMS[M+H]⁺
化合物 Compd.	外观 Apperance	熔点 m.p./℃	分子式 Formula	收率 Yield/%	计算值 Calcd.	测定值 Found
7a	白色固体 White solid	105~106	C₂₅H₂₇N₃O₂S	67	434.1897	434.1904
7b	白色固体 White solid	113~114	C₂₆H₂₆F₃N₃O₂S	63	502.1815	502.1799
7c	白色固体 White solid	109~110	C₂₅H₂₆FN₃O₂S	65	452.1803	452.1803
7d	白色固体 White solid	135~136	C₂₅H₂₅Cl₂N₃O₂S	68	502.1117	502.1112
7e	白色固体 White solid	92~93	C₂₅H₂₅F₂N₃O₂S	63	470.1708	470.1708
7f	白色固体 White solid	124~125	C₂₇H₃₁N₃O₂S	62	462.2210	462.2213
7g	白色固体 White solid	130~131	C₂₅H₂₆BrN₃O₂S	71	512.1002	512.0989
7h	白色固体 White solid	118~119	C₂₆H₂₉N₃O₃S	68	464.2002	464.2012
7i	黄色固体 Yollow solid	89~90	C₂₅H₂₃F₄N₃O₂S	62	506.1520	506.1524
7j	黄色固体 Yollow solid	83~84	C₂₅H₂₄F₃N₃O₂S	63	488.1614	488.1602
7k	黄色固体 Yollow solid	95~96	C₂₅H₂₅F₃N₄O₂S	56	503.1723	503.1729
7l	黄色固体 Yollow solid	90~91	C₂₄H₂₅ClN₄O₂S	59	469.1460	469.1468
7m	白色固体 White solid	102~103	C₂₅H₂₈F₃N₅O₂S	66	520.1989	520.1990
7n	白色固体 White solid	81~82	C₂₀H₂₅N₃O₂S	62	372.1740	372.1742

表 1 目标化合物7a~7n的理化数据及高分辨质谱 Table 1 Physical properties, HRMS of compounds 7a-7n

表 2 目标化合物7a~7n的 ¹H NMR和 ¹³C NMR数据 Table 2 The ¹H NMR and ¹³C NMR data of compounds 7a-7n

化合物 Compd.	¹H NMR (CDCl₃, 500 MHz, TMS), δ	¹³C NMR (CDCl₃, 126 MHz, TMS), δ
7a	7.86 (d, J = 7.8 Hz, 2H), 7.52 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.40 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.4 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 4.68 (d, J = 13.5 Hz, 1H), 4.30 (t, J = 3.6 Hz, 2H), 3.93 (d, J = 13.7 Hz, 1H), 3.35~3.20 (m, 2H), 2.92 (t, J = 12.7 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.30~2.17 (m, 2H), 1.90~1.76 (m, 2H).	171.9, 167.2, 166.4, 145.1, 138.7, 133.9, 132.0, 131.6, 130.6, 129.8, 129.3, 128.8, 128.5, 127.1, 126.2, 44.2, 41. 9, 41.7, 39.6, 32.6, 32.0, 21.4, 15.2.

7b	8.14 (s, 1H), 8.03 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.59 (t, J = 7.8 Hz, 1H), 7.50 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.5 Hz, 2H), 7.17 (d, J = 7.8 Hz, 1H), 4.68 (d, J = 13.5 Hz, 1H), 4.31 (t, J = 3.6 Hz, 2H), 3.94 (d, J = 13.9 Hz, 1H), 3.35~3.22 (m, 2H), 3.00~2.87 (m, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.31~2.18 (m, 2H), 1.89~1.78 (m, 2H).	170.2, 166.1, 165.7, 147.1, 138.4, 134.7, 131.9, 131.2, 131.2 (q, 2J_FC = 32.8 Hz), 130.2, 129.9, 129.2, 128.6, 128.2 (q, 3J_FC = 3.7 Hz), 126.2, 124.3 (q, 3J_FC = 3.8 Hz), 123.7 (q, 1J_FC = 272.6 Hz, CF₃), 44.3, 42.1, 41.8, 40.3, 32.5, 32.0, 21.4, 16.1.

7c	7.64~7.56 (m, 2H), 7.45~7.41 (m, 1H), 7.40 (s, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.23~7.19 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 4.68 (d, J = 13.5 Hz, 1H), 4.29 (t, J = 3.7 Hz, 2H), 3.92 (d, J = 13.9 Hz, 1H), 3.36~3.18 (m, 2H), 2.94 (t, J = 12.7 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.31~2.16 (m, 2H), 1.93~1.76 (m, 2H).	170.2, 166.1, 165.8, 162.8 (d, J = 247.6 Hz), 147.1, 138.4, 136.2 (d, J = 6.9 Hz), 131.9, 131.2, 130.2 (d, J = 7.8 Hz), 129.9, 128.6, 126.2, 122.5, 118.6 (d, J = 21.3 Hz), 114.6 (d, J = 22.9 Hz), 44.3, 42.1, 41.8, 40.3, 32.5, 32.0, 21.4, 16.1.

7d	7.72 (d, J = 1.9 Hz, 2H), 7.49 (t, J = 1.9 Hz, 1H), 7.44 (s, 1H), 7.32 (t, J = 7.7 Hz, 1H), 7.22 (d, J = 7.2 Hz, 2H), 7.18 (d, J = 7.7 Hz, 1H), 4.69 (d, J = 13.5 Hz, 1H), 4.27 (dd, J = 10.3, 3.9 Hz, 2H), 3.92 (d, J = 13.8 Hz, 1H), 3.36 (t, J = 11.3 Hz, 1H), 3.28 (t, J = 12.9 Hz, 1H), 2.94 (t, J = 12.7 Hz, 1H), 2.50 (s, 3H), 2.40 (s, 3H), 2.33~2.21 (m, 2H), 1.91~1.76 (m, 2H).	170.7, 166.0, 164.5, 146.4, 138.5, 136.7, 135.4, 131.6, 131.5, 131.4, 129.8, 128.8, 128.7, 126.2, 125.8, 44.2, 42.1, 41.8, 40.0, 32.5, 31.9, 21.4, 15.8.

7e	7.41~7.35 (m, 1H), 7.31 (t, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 7.5 Hz, 1H), 6.96 (t, J = 8.1 Hz, 2H), 4.66 (d, J = 13.5 Hz, 1H), 4.37~4.28 (m, 2H), 3.90 (d, J = 13.8 Hz, 1H), 3.31~3.21 (m, 2H), 2.92 (t, J = 12.7 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.29~2.16 (m, 2H), 1.90~1.76 (m, 2H).	170.3, 165.6, 160.3, 160.1 (dd, J = 252.9, 6.9 Hz), 147.1, 138.4, 132.0, 131.8 (t, J = 10.2 Hz), 131.2, 129.9, 128.5, 126.2, 113.9 (t, J = 19.7 Hz), 112.1 (d, J = 4.5 Hz), 111.9 (d, J = 4.5 Hz), 44.3, 42.1, 41.8, 40.3, 32.5, 32.0, 21.4, 16.1.

7f	7.46 (s, 2H), 7.34 (s, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.18~7.13 (m, 2H), 4.69 (d, J = 13.5 Hz, 1H), 4.29 (t, J = 3.6 Hz, 2H), 3.94 (d, J = 13.9 Hz, 1H), 3.30~3.21 (m, 2H), 2.93 (t, J = 12.7 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.36 (s, 6H), 2.28~2.18 (m, 2H), 1.89~1.78 (m, 2H).	170.3, 167.5, 166.4, 147.1, 138.4, 138.2, 133.9, 133.2, 132.0, 131.2, 129.9, 128.5, 128.5, 126.2, 124.8, 44.2, 42.0, 41.7, 40.4, 32.5, 32.0, 21.4, 21.2, 16.1.

7g	8.02 (s, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 7.39 (s, 1H), 7.31 (q, J = 7.5 Hz, 2H), 7.22 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 4.67 (d, J = 13.5 Hz, 1H), 4.28 (t, J = 3.6 Hz, 2H), 3.92 (d, J = 13.8 Hz, 1H), 3.26 (t, J = 11.4 Hz, 2H), 2.94 (t, J = 11.4 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.29~2.18 (m, 5H), 1.88~1.80 (m, 2H).	170.2, 166.1, 165.7, 147.2, 138.4, 135.9, 134.6, 132.0, 131.2, 130.4, 130.1, 129.9, 128.6, 126.2, 125.6, 122.8, 44.3, 42.1, 41.8, 40.3, 32.5, 32.0, 21.4, 16.1.

7h	7.83 (d, J = 8.8 Hz, 2H), 7.30 (dd, J = 15.5, 7.5 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 4.68 (d, J = 13.4 Hz, 1H), 4.28 (t, J = 3.8 Hz, 2H), 3.94 (d, J = 13.7 Hz, 1H), 3.85 (s, 3H), 3.31~3.21 (m, 2H), 2.93 (t, J = 13.8 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.27~2.18 (m, 2H), 1.89~1.78 (m, 2H).	170.4, 166.7, 166.6, 162.3, 147.0, 138.4, 131.9, 131.3, 129.9, 128.9, 128.6, 126.3, 126.2, 113.8, 55.4, 44.3, 42.0, 41.7, 40.3, 32.5, 32.0, 21.4, 16.0.

7i	7.37 (s, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 7.8 Hz, 2H), 7.19~7.12 (m, 2H), 4.63 (d, J = 13.5 Hz, 1H), 4.32 (dd, J = 3.6, 1.8 Hz, 2H), 3.88 (d, J = 14.1 Hz, 1H), 3.26 (t, J = 11.4 Hz, 2H), 2.93 (t, J = 11.4 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.28~2.17 (m, 2H), 1.90~1.76 (m, 2H).	170.2, 165.2, 158.0, 147.1, 146.0 (dd, J = 245.6, 4.1 Hz), 143.7 (dd, J = 252.2, 14.3 Hz), 138.4, 132.0, 131.3, 129.9, 128.6, 126.2, 116.7 (t, J = 18.3 Hz), 107.6 (t, J = 22.4 Hz), 44.3, 42.1, 41.9, 40.2, 32.5, 31.9, 21.4, 16.1.

7j	7.99~7.89 (m, 2H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.8 Hz, 2H), 7.16 (d, J = 7.7 Hz, 1H), 7.03 (td, J = 10.1, 6.1 Hz, 1H), 4.67 (d, J = 13.5 Hz, 1H), 4.31 (t, J = 2.7 Hz, 2H), 3.90 (d, J = 13.8 Hz, 1H), 3.32~3.17 (m, 2H), 3.01~2.87 (m, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.28~2.18 (m, 2H), 1.90~1.74 (m, 2H).	170.2, 165.8, 161.1, 156.1 (dd, J = 258.4, 2.3 Hz), 147.1, 147.1 (dd, J = 234.3, 2.8 Hz), 138.4, 132.0, 131.3, 129.9, 128.6, 126.2, 119.8 (d, J = 21.3 Hz), 117.6 (d, J = 15.5 Hz), 106.3 (dd, J = 30.9, 21.4 Hz), 44.3, 42.1, 40.3, 32.5, 32.0, 21.4, 16.1.

7k	8.89 (s, 1H), 8.87 (d, J = 5.1 Hz, 1H), 7.60 (d, J = 5.1 Hz, 1H), 7.31 (t, J = 7.5 Hz, 1H), 7.26 (s, 1H), 7.22 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 4.62 (d, J = 13.5 Hz, 1H), 4.31 (d, J = 3.9 Hz, 2H), 3.89 (d, J = 13.8 Hz, 1H), 3.33~3.20 (m, 2H), 2.92 (t, J = 12.6 Hz, 1H), 2.47 (s, 3H), 2.40 (s, 3H), 2.29~2.16 (m, 2H), 1.90~1.76 (m, 2H).	170.1, 165.4, 164.9, 151.9, 149.6, 147.2, 138.4, 135.3 (q, 2J_FC = 33.9 Hz), 133.7 (q, 3J_FC = 3.9 Hz), 132.0, 131.2, 129.9, 128.6, 126.2, 122.3 (q, 1J_FC = 274.4 Hz, CF₃), 119.8 (d, 3J_FC = 4.4 Hz), 44.3, 42.1, 42.0, 40.2, 32.4, 31.9, 21.4, 16.1.

7l	8.47 (dd, J = 4.7, 2.0 Hz, 1H), 8.11 (dd, J = 7.6, 2.0 Hz, 1H), 7.77 (s, 1H), 7.34 (dd, J = 7.6, 4.8 Hz, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.3 Hz, 1H), 4.65 (d, J = 13.5 Hz, 1H), 4.39~4.27 (m, 2H), 3.90 (d, J = 13.7 Hz, 1H), 3.34~3.19 (m, 2H), 2.93 (t, J = 12.0 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.28~2.18 (m, 2H), 1.90~1.77 (m, 2H).	170.2, 165.6, 164.4, 151.0, 147.7, 147.1, 139.5, 138.4, 131.9, 131.2, 130.8, 129.9, 128.5, 126.2, 122.5, 44.3, 42.1, 41.9, 40.2, 32.5, 31.9, 21.4, 16.1.

7m	7.30 (t, J = 7.6 Hz, 1H), 7.21 (d, J = 7.7 Hz, 2H), 7.16 (d, J = 7.5 Hz, 1H), 6.85 (s, 1H), 6.39 (s, 1H), 4.87 (s, 2H), 4.59 (d, J = 13.4 Hz, 1H), 4.17~4.04 (m, 2H), 3.81 (d, J = 13.7 Hz, 1H), 3.21 (q, J = 12.8, 12.1 Hz, 2H), 2.87 (t, J = 11.6 Hz, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.35 (s, 3H), 2.27~2.11 (m, 2H), 1.85~1.71 (m, 2H).	170.1, 165.4, 164.9, 151.9, 149.6, 147.2, 138.4, 135.3 (q, 2J_FC = 33.9 Hz), 132.0, 131.2, 129.9, 129.6, 128.6, 126.2, 122.3 (q, 1J_FC = 274.4 Hz, CF₃), 119.8 (q, 3J_FC = 4.4 Hz), 52.7, 44.3, 42.1, 42.0, 40.2, 32.4, 31.9, 21.4, 16.1.

7n	7.30 (t, J = 7.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 7.8 Hz, 1H), 6.70 (s, 1H), 4.64 (d, J = 13.6 Hz, 1H), 4.09 (t, J = 3.8 Hz, 2H), 3.86 (d, J = 14.0 Hz, 1H), 3.26~3.14 (m, 2H), 2.90~2.82 (m, 1H), 2.46 (s, 3H), 2.39 (s, 3H), 2.24~2.15 (m, 2H), 2.06 (s, 3H), 1.84~1.72 (m, 2H).	170.4, 170.2, 166.3, 147.0, 138.4, 131.9, 131.3, 129.9, 128.6, 128.6, 126.2, 44.3, 42.0, 41.4, 40.3, 32.5, 32.0, 23.0, 21.4, 16.0.

表 2 目标化合物7a~7n的 ¹H NMR和 ¹³C NMR数据 Table 2 The ¹H NMR and ¹³C NMR data of compounds 7a-7n

以目标化合物7k为例。在 ¹H NMR谱图中：δ 7.31、7.22和7.16处为芳环上的质子信号；-CONH-基团含有活泼氢，且位于低场区，在δ 7.26处呈宽单峰；吡啶的氢与苯环氢相比处于低场，化学位移较大，其中与N原子相邻碳上的氢的化学位移更偏于低场，δ 8.89处的单峰和δ 8.87处的双峰为吡啶基N原子邻位质子，δ 7.60处的双峰为吡啶基N原子间位的质子；甲基上的质子在δ 2.47 和2.40处，且为单峰。

2.2 杀菌活性

测试结果 (表3) 表明，在25 mg/L剂量下，部分目标化合物对黄瓜灰霉病菌具有较好的抑菌效果，其中化合物7a、7c和7g对黄瓜灰霉病菌的抑制率在70%左右；化合物7a、7g、7i 对马铃薯晚疫病菌也有中等抑制作用。从化合物结构上看：当R为苯基、间溴苯基和间氟苯基时，化合物对黄瓜灰霉病菌表现出良好的杀菌活性，且当R为间溴苯基时，对马铃薯晚疫病菌也有良好的抑制作用；而对于含氟化合物, 当R为间氟苯基时，对黄瓜灰霉病菌的杀菌效果最好，其他含氟化合物杀菌活性一般。与前期报道^[15-16]相比，引入甘氨酸作为连接基团，部分化合物生物活性有了一定程度提高，其中化合物7a、7c、7g和7i的杀菌活性较好，可以对其进一步优化以提高活性。

表 3 25 mg/L下目标化合物7a~7n对3种植物病原菌的抑菌活性 Table 3 Fungicidal activities of compounds 7a-7n against 3 fungi at 25 mg/L

化合物 Compd.	抑制率 Inhibition rate/%
化合物 Compd.	水稻纹枯病菌 Rhizoctonia solani	黄瓜灰霉病菌 Botrytis cinerea	马铃薯晚疫病菌 Phytophthora infestans
7a	0	68.7	50.8
7b	0	20.4	0
7c	5.90	71.6	20.4
7d	0	40.8	18.6
7e	0	30.6	10.2
7f	0	40.8	10.2
7g	14.3	67.2	61.9
7h	0	58.9	10.2
7i	11.9	42.6	55.8
7j	0	40.8	14.3
7k	0	30.6	20.4
7l	0	42.8	35.5
7m	0	30.6	6.12
7n	0	40.8	16.3
噻呋酰胺 thifluzamide	95.2	32.6	75.5
多菌灵 carbendazim	100	91.5	93.7
空白对照 CK	0	0	0

表 3 25 mg/L下目标化合物7a~7n对3种植物病原菌的抑菌活性 Table 3 Fungicidal activities of compounds 7a-7n against 3 fungi at 25 mg/L

3 结论

以哌啶噻唑结构为母体，设计并合成了14个未见报道的含哌啶噻唑结构的乙酰氨基衍生物，所有化合物的结构均经过 ¹H NMR、¹³C NMR和HRMS确证。杀菌活性测试结果表明，部分目标化合物在25 mg/L下对黄瓜灰霉病和马铃薯晚疫病表现出良好的杀菌活性。其中化合物7a、7c和7g对黄瓜灰霉病菌的杀菌效果显著，抑制率在70%左右；7a、7g和7i对马铃薯晚疫病菌也有中等程度的杀菌效果，抑制率在50%以上。总体而言，化合物7a、7c、7g和7i的杀菌活性较好，具有进一步研究的价值。

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