CN105669541B - 2-酰胺基环烷基磺酰胺化合物及制备方法和作为杀菌、除草剂的用途 - Google Patents

2-酰胺基环烷基磺酰胺化合物及制备方法和作为杀菌、除草剂的用途 Download PDF

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CN105669541B
CN105669541B CN201610014075.4A CN201610014075A CN105669541B CN 105669541 B CN105669541 B CN 105669541B CN 201610014075 A CN201610014075 A CN 201610014075A CN 105669541 B CN105669541 B CN 105669541B
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pyridin
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李兴海
陈小员
纪明山
祁之秋
谷祖敏
张杨
李修伟
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Huate Western Shaanxi Science And Technology Industrial Co ltd
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Abstract

一种2‑酰胺基环烷基磺酰胺化合物及制备方法和作为杀菌、除草剂的用途，将2‑氧代环烷基磺酰胺(I)在四异丙氧基钛+氨气+硼氢化钠条件下还原胺化，得到2‑氨基环烷基磺酰胺(II)，进一步与合成得到的各种不同取代类型酰氯对接合成新的2‑酰胺基环烷基磺酰胺(III)系列化合物。化合物III对蔬菜、农作物、水果等病原菌有病害的防治作用；对单双子叶杂草具有防治作用。具体结构通式I，II，III如下：

Description

2-酰胺基环烷基磺酰胺化合物及制备方法和作为杀菌、除草 剂的用途
技术领域
本发明涉及的含有N-(2-三氟甲基-4-氯苯基)-2-取代酰胺基环烷基磺酰胺类化合物的合成和作为杀菌剂与除草剂，属农用化学品领域。
背景技术
新型环烷基磺酰胺类化合物在农用杀菌剂中的应用起源于王道全研究组于1997年报道的2-氧代环十二烷基磺酰胺类化合物(汪晓平,等.高等学校化学学报,1997,18(6):889-893)，其对小麦赤霉病菌Gibberllazeae和梨黑星病菌Venturianashicola具有较好抑制活性。在随后的研究基础上，候选创制杀菌剂——环己磺菌胺A(开发代号CAUWL-2004-L-13)被开发出来(CN1900059A；CN101720764A)，可用于防治番茄灰霉病、油菜菌核病、黄瓜褐斑病及黑星病等病害。
为了进一步获得杀菌活性优异的新化合物，在原有羰基基础上进行结构衍生，2-羟基环烷基磺酰胺类化合物被合成出来(Li Xing-hai,et al.J Agr Food Chem,2010,58(21):11384–11389)，盆栽试验表明羰基还原成羟基后，活性明显增强，其中N-(2-三氟甲基-4-氯苯基)-2-羟基环己烷基磺酰胺B对番茄灰霉病菌Botrytis cinerea的EC50为3.37μg/mL。
继续进行结构优化，引入酯键这一活性基团，合成得到2-酰氧基环己烷基磺酰胺类化合物(Li Xing-hai,et al.Int J MolSci,2013,14(11):22544-22557)，经菌丝生长速率法筛选出对番茄灰霉病菌具高活性的化合物N-(2-三氟甲基-4-氯苯基)-2-乙氧基乙酰氧基环己烷基磺酰胺C，EC50和EC80分别为4.17μg/mL，17.15μg/mL，优于对照药剂腐霉利(4.46μg/mL，35.02μg/mL)。
在六元环基础上进行结构衍生，1-氧代四氢萘基-2-磺酰胺类化合物被合成出来(CN101503381)，其中N-(2-三氟甲基-4-氯苯基)-1-氧代四氢萘基-2-磺酰胺D在50μg/mL下对立枯丝核菌、灰霉病菌、芦笋茎枯病菌、菌核病菌、稻瘟病菌等具有广谱的杀菌效果。在六元环上引入醚键，5-烃氧基-2-氧代环己烷基磺酰胺类化合物被合成出来(CN104151209)，如N-(2-三氟甲基-4-氯苯基)-5-苄氧基-2-氧代环己烷基磺酰胺E在50μg/mL下对油菜菌核病菌、番茄灰霉病菌、辣椒疫霉病菌、稻瘟病菌的抑制效果均在90％以上。将六元环变为三元环，以1-氯环丙基乙酮为原料，1-氯环丙基羰基甲磺酰胺类化合物被合成出来(CN104211621)，其中以N-(2-三氟甲基-4-氯苯基)-2-(1-氯环丙基)-2-氧代乙磺酰胺F效果最为明显，在50μg/mL下对油菜菌核病菌、番茄灰霉病菌、辣椒疫霉病菌、稻瘟病菌、棉花立枯病菌、芦笋茎枯病菌六种病菌的抑制率均在100％左右。
以上所涉及化合物A，B，C，D，E，F之间的优化及官能团转换如下：
发明内容
本发明的目的是在上述研究的基础上，将环烷基磺酰胺(I)还原胺化，得到2-氨基环烷基磺酰胺(II)，进一步与合成得到的各种不同取代类型酰氯对接合成新的2-酰胺基环烷基磺酰胺(III)系列化合物。化合物III除了具有良好的杀菌活性外，还具有除草活性。
其具体结构通式I，II，III如下：
式中I-1,II-1:n＝2,R1＝H；I-2,II-2:n＝1,R1＝H；I-3,II-3:n＝3,R1＝H；I-4,II-4:n＝4,R1＝H；I-5,II-5:n＝2,R1＝3-CH3；I-6,II-6:n＝2,R1＝4-CH3；I-7,II-7:n＝2,R1＝5-CH3；I-8,II-8:n＝2,R1＝5-C2H5；I-9,II-9:n＝2,R1＝5-n-C3H7；I-10,II-10:n＝2,R1＝5-n-C5H11；I-11,II-11:n＝2,R1＝5-C(CH3)3。
R2＝取代苯基:2-CH3OC6H4-,4-CH3OC6H4-,2-CH3C6H4-,3-CH3C6H4-,4-CH3C6H4-,2,3-(CH3)2C6H3-,2,4-(CH3)2C6H3-,2,5-(CH3)2C6H3-,3,5-(CH3)2C6H3-,2-FC6H4-,3-FC6H4-,2-ClC6H4-,3-ClC6H4-,4-ClC6H4-,2,4-Cl2C6H3-,2,5-Cl2C6H3-,2,6-Cl2C6H3-,3,4-Cl2C6H3-,3,5-Cl2C6H3-,2-CF3C6H4-,3-CF3C6H4-,2-CH3O-5-ClC6H3-；烷基:CH3-,CH3CH2-,CH3(CH2)2-,CH3(CH2)3-,CH3(CH2)4-,CH3(CH2)5-,CH3(CH2)6-；卤代烷基:ClCH2-,Cl2CH-,CH3ClCH-,ClCH2CH2-,Cl3C-,BrCH2-,CH3BrCH-,BrCH2CH2-；2-烷氧基烷基:CH3OCH2-,C2H5OCH2-；2-烷硫基烷基:CH3SCH2,C2H5SCH2-,(CH3)2CHSCH2-；取代吡啶基:2-Cl-pyridine-3-yl,6-Cl-pyridine-3-yl,5-Br-pyridine-3-yl,5-F-pyridine-3-yl,6-F-pyridine-3-yl,2,6-Cl2-pyridine-3-yl,2,6-Cl2-pyridine-3-yl,5-Br-2-Cl-pyridine-3-yl,4-C5H4N-,2-(3-CF3-C6H4NH)-pyridine-3-yl,2-OH-pyridine-3-yl,5-OH-pyridine-3-yl,4-CH3-2-OH-pyridine-3-yl,6-OH-pyridine-2-yl,6-OH-pyridine-3-yl。
合成路线如下：
化合物III对番茄灰霉、水稻纹枯、水稻稻瘟、玉米大斑、瓜果腐霉、黄瓜镰刀、辣椒疫霉等病原菌的菌丝生长有抑制作用，用于其病害的防治；化合物III对反枝苋、苘麻、稗草、马唐等单双子叶杂草具有抑制生长的作用。
本发明的积极效果：将环烷基磺酰胺(I)还原胺化，得到2-氨基环烷基磺酰胺(II)，进一步与合成得到的各种不同取代类型酰氯对接合成新的2-酰胺基环烷基磺酰胺(III)系列化合物；化合物III除了具有良好的杀菌活性外，还具有除草活性。
具体实施方式
实例1.N-(2-三氟甲基-4-氯苯基)-2-氨基环烷基磺酰胺(II)的制备
首先连接气路，通入N2以赶走反应瓶中的空气，保持通入N2。在室温下，将10.67g(30mmol)I-1、150mL无水乙醇加入250mL圆底烧瓶中，搅拌溶解后用移液枪移取17mL(60mmol)四异丙氧基钛加入到烧瓶中，关闭N2通入阀，改为向反应系统中通入氨气，再将反应容器密闭，持续通入氨气，并将反应装置连接到U型水银压力计上，维持氨气的压力在20mmHg左右。搅拌反应12h，TLC监测(乙酸乙酯-石油醚-甲醇(V:V:V＝10:10:3))反应完全后，撤去氨气和U型水银压力计。加入1.7g(45mmol)还原剂硼氢化钠，反应液中产生大量气泡，继续反应3h。加入120mL(2mol/L)氨水使反应猝灭，抽滤后，滤液减压浓缩除去乙醇，滤饼用150mL乙酸乙酯洗涤，乙酸乙酯与浓缩后的滤液合并再次抽滤，分液后水层用乙酸乙酯200mL×2萃取，合并有机层，用饱和食盐水300mL洗涤，经无水硫酸钠干燥后抽滤浓缩得产物，经甲醇重结晶得II-1的白色粉末状固体7.8g。收率：72.9％；m.p.252-254℃；状态：无色晶体；1H NMR(DMSO-d6,400MHz),δ(ppm)：1.32-2.00(m,8H,4CH2),2.89(dt,J＝12.5,3.2Hz,1H,CH-N),3.79(d,J＝2.1Hz,1H,CH-SO2),7.27-7.42(m,3H,Ph-H),8.21(s,3H,NH2+NH)；IR,(ν,cm-1)：3516(NH),2947,2866(CH2),1321,1190(S＝O)；MS(z/e)：357(M+),175,162,98,81.
参考文献：Miriyala B,Bhattacharyya S,Johh S.Chemoselective reductivealkylation of ammonia with carbonyl compounds:synthesis of primary andsymmetrical secondary amines.Tetrahedron,2004,60:1463-1471.
按照上述的方法合成得到其它的N-(2-三氟甲基-4-氯苯基)-2-氨基环烷基磺酰胺，共11个。化合物的理化数据见表1，波谱数据见表2。
表1化合物(II)的理化性质及收率
表2化合物(II)的核磁共振氢谱(1H NMR)、红外光谱(IR)、质谱(MS)数据
实例2.N-(2-三氟甲基-4-氯苯基)-2-取代酰胺基环烷基磺酰胺(III)的合成通法
N2保护，室温，将N-(2-三氟甲基-4-氯苯基)-2-氨基环烷基磺酰胺1.5mmol，干燥的三乙胺251μL(1.8mmol)和干燥的二氯甲烷20mL加入100mL的三口圆底烧瓶中，搅拌，待固体完全溶解后，加入对应酰氯1.5mmol，搅拌反应2h。抽滤，滤饼用20mL二氯甲烷洗涤，将反应液转入分液漏斗，先后用15mL的3mol/L盐酸，15mL饱和碳酸氢钠，20mL饱和食盐水洗涤，所得二氯甲烷层用无水硫酸钠干燥，抽滤，滤液减压浓缩得粗产物，用丙酮+石油醚重结晶得产物。
按照上述方法合成得到的N-(2-三氟甲基-4-氯苯基)-2-取代酰胺基环烷基磺酰胺，共67个。化合物的理化数据见表3，波谱数据见表4。
表3化合物(III)的理化性质及收率
表4化合物(III)的核磁共振氢谱(1H NMR)、红外光谱(IR)数据
实例3.化合物(III-1～III-67)对灰霉病菌的杀菌活性
参照农药室内生物测定试验准则，采用平皿法(抑制菌丝生长实验)，用浓度为50mg/L的含药培养基，测定目标化合物(III)对采制不同地区的多种番茄灰霉病菌Botrytis cinerea的杀菌活性。以环己磺菌胺和腐霉利为对照药剂，设置丙酮溶剂为空白对照，每个处理重复三次。待空白对照中的菌落充分生长后，以十字
交叉法测量各处理的菌落直径，取其平均值，用以下公式计算抑制率：
抑制率(％)＝(空白对照菌落直径_含药介质菌落直径)/(空白对照菌落直径-菌饼直径)×100％
灰霉病菌Botrytis cinerea存在着多个生理小种，因为生存环境和用药水平的不同，采制不同地区的菌株对新化合物的敏感性也是不同的。首先测定了所有新化合物对SY-10(采制辽宁沈阳)和DD-15(采制辽宁丹东)2种番茄灰霉病菌Botrytis cinerea的抑制活性，试验结果见表5。新化合物对2个灰霉菌株表现出了非常高的杀菌活性，普遍高于对照药剂环己磺菌胺与腐霉利，其中抑制率大于80％的高活性化合物有17个，分别为：III-2，III-4，III-8，III-11，III-13，III-16，III-18，III-20，III-21，III-27，III-28，III-30，III-31，III-34，III-36，III-39，III-41。
表5化合物(III-1～III-67)对番茄灰霉病菌Botrytis cinerea菌株SY-10和DD-15的抑制率(50mg/L)
实例4.化合物(III)对灰霉病菌的精密毒力测定
参照农药室内生物测定试验准则，采用平皿法(抑制菌丝生长实验)，将样品化合物分别用丙酮制成5000,1250,312.5,78.25mg/L 4个原始浓度。无菌状态下，用PDA(马铃薯葡萄糖培养基)稀释100倍得到50,12.5,3.125,0.7825mg/L 4个浓度的含药培养基。接种直径5mm的菌块，在23℃左右培养3-5天。测量菌落直径(十字交叉法)。利用EXCEL软件按照文献(刘霞，等，2009)的统计方法计算EC50值，比较药毒力大小。8个2-酰胺基环己烷基磺酰胺类化合物对6种灰霉病菌Botrytis cinerea的毒力测定的EC50见表6，菌株代号分别为AS-12(采制辽宁鞍山)、CY-07(采制辽宁朝阳)、DD-04(采制辽宁丹东)、DL-12(采制辽宁大连)、FS-06(采制辽宁抚顺)、HLD-16(采制辽宁葫芦岛)。11个2-三氯乙酰胺基环烷基磺酰胺类化合物对5种灰霉病菌的毒力测定的EC50见表7，菌株代号分别为AS-11(采制辽宁鞍山)、CY-09(采制辽宁朝阳)、DL-11(采制辽宁大连)、FS-11(采制辽宁抚顺)、HLD-15(采制辽宁葫芦岛)。
试验结果表明8个2-酰胺基环己烷基磺酰胺类化合物对6种病原菌都有很高的杀菌活性。从EC50值看，III-34对6种病原菌的活性均高于对照药剂环己磺菌胺与腐霉利，III-31对5种病原菌的活性高于环己磺菌胺与腐霉利，III-32与III-39对4种病原菌的活性高于腐霉利。不同的灰霉病原菌菌株对相同的化合物的敏感性存在差异，以III-34为例，其对6种病原菌的EC50在0.37～7.56之间，而对照药剂环己磺菌胺的EC50在8.07～29.41之间，腐霉利的EC50在2.49～75.84之间。
试验结果表明以三氯乙酰氯与不同的2-氨基环烷基磺酰胺(II)对接合成的2-三氯乙酰胺基环烷基磺酰胺类化合物化合物(III)也有着非常高的杀菌活性，普遍高于对照药剂环己磺菌胺与腐霉利。从III-34与III-43～III-45的杀菌活性可以看出环烷基的大小对杀菌活性有着较大的影响，5,6,7,8员环化合物的活性普遍较高，其中6员环类化合物的活性最高，其对5种菌的EC50在0.15～3.64之间，而5,7,8员环类化合物的EC50分别在0.66～11.68,0.38～8.33,0.82～9.49之间。从III-46～III-52的杀菌活性可以看出环己烷基上的取代烷基对杀菌活性有着明显的影响，随着烷基基团的增大化合物的杀菌活性明显降低。烷基的位置对活性影响较大，从III-46,III-47,III-48的杀菌活性看，甲基所在位置与杀菌活性之间的对应关系是4-位>5-位>3-位。综合来看III-34与III-43表现出了更优异的杀菌活性。
表6化合物(III)对6种灰霉病菌的毒力(EC50)
表7化合物(III-34与III-43～III-52)对5种灰霉病菌的毒力测定(EC50)
实例5.化合物(III)对6种植物病原真菌的杀菌活性
参照农药室内生物测定试验准则，采用平皿法(抑制菌丝生长实验)，用浓度为50mg/L的含药培养基，测定目标化合物(III)对水稻纹枯病菌、水稻稻瘟病菌、玉米大斑病菌、瓜果腐霉病菌、黄瓜镰刀病菌、辣椒疫霉病菌的杀菌活性。以环己磺菌胺和百菌清为对照药剂，设置丙酮溶剂为空白对照，每个处理重复三次。待空白对照中的菌落充分生长后，以十字交叉法测量各处理的菌落直径，取其平均值，用以下公式计算抑制率：
抑制率(％)＝(空白对照菌落直径_含药介质菌落直径)/(空白对照菌落直径-菌饼直径)×100％
试验结果见表8。结果表明该系列化合物对这6种病原菌都有杀菌活性，其中化合物III-43、III-44、III-45对水稻纹枯病菌的活性高于环己磺菌胺和百菌清；有25个化合物对水稻稻瘟病菌的活性高于环己磺菌胺和百菌清，其中化合物III-34、III-43、III-45、III-47、III-49表现出了更优异的活性；多数化合物对玉米大斑病菌的活性高于环己磺菌胺，其中III-34、III-47与百菌清的活性接近；多数化合物对瓜果腐霉病菌的活性高于环己磺菌胺，其中III-27、III-28、III-43、III-45、III-47的活性高于百菌清；化合物III-27、III-44、III-46、III-47、III-48、III-49、III-50、III-52、III-58、III-59对黄瓜镰刀病菌的活性高于环己磺菌胺，并且接近百菌清；化合物III-2、III-20、III-31、III-32、III-34、III-43、III-45、III-47、III-48、III-54对辣椒疫霉病菌的活性高于对照药剂环己磺菌胺和百菌清。
表8化合物(III)对6种病原菌的抑制活性(50mg/L)
实例6.化合物(III)的除草活性测定
参照农药室内生物测定试验准则(农业部农药检定所，2008)，将新化合物配制成浓度为1000μg/mL的丙酮溶液，吸取0.5mL药液加入铺有滤纸的10cm培养皿中，待丙酮挥发干后，加入5mL 0.05％吐温80水溶液，稀释得到100μg/mL的水溶液，然后将刚刚萌发的种子整齐地排列在培养皿中，放在23～26℃的环境中培养，以0.05％吐温80水溶液为空白对照，每处理3个重复。3～6天后，分别测量单子叶杂草稗草、马唐(以等浓度乙草胺为对照药剂)和双子叶杂草反枝苋、苘麻(以等浓度莠去津为对照药剂)的芽长及根长，计算除草活性，公式如下：
抑制率(％)＝(空白对照长度-处理长度)/空白对照长度×100％
化合物(III)的除草活性实验结果见表9。化合物III-43、III-44、III-45、III-47可明显抑制稗草的芽长生长，活性高于乙草胺，III-34、III-43、III-44、III-45、III-47、III-48可明显抑制稗草的根长生长，活性优于乙草胺。化合物III-44和III-48可明显抑制马唐的芽长生长，化合物III-30、III-31、III-34、III-43、III-44、III-45、III-47、III-48可明显抑制马唐的根长生长，效果均优于乙草胺。该系列化合物可用于防除单子叶杂草如稗草、马唐等。
试验结果表明，除草活性实验筛选出III-28、III-31、III-34、III-43、III-47可明显抑制反枝苋的芽与根的生长，效果均优于莠去津；大部分化合物对苘麻的芽和根生长均表现出了良好的抑制效果，化合物III-1、III-2、III-4、III-9、III-11、III-12、III-13、III-15、III-18、III-22、III-23、III-24、III-29、III-31、III-32、III-34、III-37、III-38、III-39、III-40、III-41、III-43、III-44、III-45、III-47、III-48对苘麻的根与芽的生长抑制活性均优于莠去津。该系列化合物可用于防除双子叶杂草如反枝苋、苘麻等。
表9化合物(I，II，III)的除草活性(100μg/mL)

Claims (4)

1.一种2-酰胺基环烷基磺酰胺化合物，其特征在于下述通式所示的系列化合物II与III
式中
II-1:n＝2,R1＝H；II-2:n＝1,R1＝H；II-3:n＝3,R1＝H；II-4:n＝4,R1＝H；II-5:n＝2,R1＝3-CH3；II-6:n＝2,R1＝4-CH3；II-7:n＝2,R1＝5-CH3；II-8:n＝2,R1＝5-C2H5；II-9:n＝2,R1＝5-n-C3H7；II-10:n＝2,R1＝5-n-C5H11；II-11:n＝2,R1＝5-C(CH3)3；
R2＝取代苯基:2-CH3OC6H4-,4-CH3OC6H4-,2-CH3C6H4-,3-CH3C6H4-,4-CH3C6H4-,2,3-(CH3)2C6H3-,2,4-(CH3)2C6H3-,2,5-(CH3)2C6H3-,3,5-(CH3)2C6H3-,2-FC6H4-,3-FC6H4-,2-ClC6H4-,3-ClC6H4-,4-ClC6H4-,2,4-Cl2C6H3-,2,5-Cl2C6H3-,2,6-Cl2C6H3-,3,4-Cl2C6H3-,3,5-Cl2C6H3-,2-CF3C6H4-,3-CF3C6H4-,2-CH3O-5-ClC6H3-；
烷基:CH3-,CH3CH2-,CH3(CH2)2-,CH3(CH2)3-,CH3(CH2)4-,CH3(CH2)5-,CH3(CH2)6-；
卤代烷基:ClCH2-,Cl2CH-,CH3ClCH-,ClCH2CH2-,Cl3C-,BrCH2-,CH3BrCH-,BrCH2CH2-；
2-烷氧基烷基:CH3OCH2-,C2H5OCH2-；
2-烷硫基烷基:CH3SCH2,C2H5SCH2-,(CH3)2CHSCH2-；
取代吡啶基:2-Cl-吡啶-3-基,6-Cl-吡啶-3-基,5-Br-吡啶-3-基,5-F-吡啶-3-基,6-F-吡啶-3-基,2,6-Cl2-吡啶-3-基,2,6-Cl2-吡啶-3-基,5-Br-2-Cl-吡啶-3-基,4-C5H4N-,2-(3-CF3-C6H4NH)-吡啶-3-基,2-OH-吡啶-3-基,5-OH-吡啶-3-基,4-CH3-2-OH-吡啶-3-基,6-OH-吡啶-2-基,6-OH-吡啶-3-基。
2.一种如权利要求1所述2-酰胺基环烷基磺酰胺化合物的制备方法，其特征在于化合物中所示化合物II与III的合成路线为
式中R1和R2的含义同权利要求1，将环烷基磺酰胺(I)在四异丙氧基钛+氨气+硼氢化钠条件下还原胺化，得到2-氨基环烷基磺酰胺(II)，进一步与合成得到的各种不同取代类型酰氯对接合成新的2-酰胺基环烷基磺酰胺(III)系列化合物。
3.一种如权利要求1所述2-酰胺基环烷基磺酰胺化合物的用途，其特征在于化合物III作为农用杀菌剂，用于番茄灰霉、水稻纹枯、水稻稻瘟、玉米大斑、瓜果腐霉、黄瓜镰刀、辣椒疫霉的农业植物病害的防治。
4.一种如权利要求1所述2-酰胺基环烷基磺酰胺化合物的用途，其特征在于化合物III作为农用除草剂，用于单子叶和双子叶杂草的防治。
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