CN1246849A - 在吡啶环上带有羧酸取代基的2－甲氧亚氨基－2－(吡啶氧基甲基)苯基乙酰胺杀真菌剂 - Google Patents

在吡啶环上带有羧酸取代基的2－甲氧亚氨基－2－(吡啶氧基甲基)苯基乙酰胺杀真菌剂 Download PDF

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CN1246849A
CN1246849A CN98802270A CN98802270A CN1246849A CN 1246849 A CN1246849 A CN 1246849A CN 98802270 A CN98802270 A CN 98802270A CN 98802270 A CN98802270 A CN 98802270A CN 1246849 A CN1246849 A CN 1246849A
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methoxyimino
alkyl
halo
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CN1126742C (zh
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S·J·毕斯
E·J·卡纳达
D·H·库伯
C·S·高尔卡
N·克尔比
D·G·欧伊米特
D·E·波多莱茨
M·匹克茨科
R·莱扎克
B·J·里德
J·K·斯维泽
V·B·海迪
G·L·桑普森
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Corteva Agriscience LLC
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Abstract

本发明提供一种新颖的在吡啶环上带有羧酸取代基的2－甲氧亚氨基－2－(吡啶氧基甲基)苯基乙酰胺化合物,其作为杀真菌化合物的应用及其在包含至少一种作为活性成份的2－甲氧亚氨基－2－(吡啶氧基甲基)苯基乙酰胺化合物的杀真菌组合物中的应用。

Description

在吡啶环上带有羧酸取代基的2-甲氧亚氨基 -2-(吡啶氧基甲基)苯基乙酰胺杀真菌剂
                    相关申请
此申请的权利要求受益于1997年2月3日申请的美国临时申请No.60/036,858。
                    发明背景
本发明提供新颖的在吡啶环上带有羧酸取代基的2-甲氧亚氨基-2-(吡啶氧基甲基)苯基乙酰胺化合物，其作为杀真菌化合物的应用和在包含作为活性成分的至少一种2-甲氧亚氨基-2-(吡啶氧基甲基)苯基乙酰胺的杀真菌组合物的应用。
                    发明概述
本发明提供新颖的下文式(1)所示的2-甲氧亚氨基-2-(吡啶氧基甲基)苯基乙酰胺化合物
Figure A9880227000071
其中
m是整数0-3；
Y是H、卤素、C1-4-烷基、C1-4-烷氧基或C1-4-烷硫基；
X是H、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷氧基、卤素、硝基、羰基-C1-6-烷氧基、氰基、C1-6-烷硫基或卤代-C1-6-烷硫基；
W或W’独立地是O或S；
R是H、C1-6烷基或C3-7环烷基；它们可任选被卤代-C1-6-烷基、卤代-C1-6-烷氧基、C2-6-链烯基、卤代-C2-6-链烯基、C2-6-炔基、氰基、C1-6-烷氧基、卤素、芳基、取代的芳基或杂芳基取代；和
L是-O-、-CH2-、-SOn-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH＝CH-、-C≡C-、或 ，其中n是整数0-2。
                 本发明详述
在整份文件中，所有的温度均给出的是摄氏度，所有的百分率均是重量百分率，除非另有说明。
术语“卤素”或“卤代”是指F、Cl、I或Br。
术语“烷基”、“链烯基”或“炔基”是指含有指定数目的碳原子的直链或支链碳基团。
术语“烷氧基”是指直链或支链烷氧基。
术语“卤代烷基”是指由一或多个卤原子取代的直链或支链烷基。术语“卤代烷氧基”是指由一或多个卤原子取代的烷氧基。
术语“芳基”或“Ph”是指苯基。术语“取代的芳基”是指由C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷氧基、卤素、硝基、羰基-C1-6-烷氧基或氰基取代的苯基。术语“杂芳基”是指吡啶基、嘧啶基、吡嗪基或哒嗪基。
术语“Me”是指甲基。术语“Et”是指乙基。术语“Pr”是指丙基。术语“Bu”是指丁基。
术语“EtoAc”是指乙酸乙酯。
术语“ppm”是指百万分之几。术语“psi”是指磅/平方英寸。
术语“M.P.”是指熔点。术语“bp”是指沸点。
虽然所有的本发明化合物均具有杀真菌活性，但某些种类的化合物会因为各种原因诸如更有效或易于合成等而更优选。
优选种类的化合物包括下文的式(2)化合物，
Figure A9880227000091
其中取代基如上文式(1)中所定义。更优选的种类包括下文的式(3)化合物
Figure A9880227000092
其中Y是卤素且余下取代基如上文式(1)中所定义。下一组更优选的种类包括下文的式(4)化合物
Figure A9880227000093
其中取代基如上文式(1)中所定义。
下一组更优选的种类包括下文的式(5)化合物
Figure A9880227000101
其中取代基如上文的式(1)中所定义。
下一组更优选的种类包括下文的式(5)化合物，其中X是C1-4烷基、卤素或卤代-C1-4烷基，且R是C1-4烷基，其可任选被链烯基、炔基或烷氧基取代。
本发明的化合物使用已熟知的化学方法制备。所需的起始原料是商业可得的，或利用标准的方法易于制备。
通常，式(1)化合物是通过在惰性溶剂存在下，将大约等摩尔量的相应的吡啶用相应的羟甲基-甲氧亚氨基-苯乙酰胺并加入大约等摩尔量或稍微过量的强碱如氢化钠处理而制备得到。由此产生的式(1)化合物可以任选通过随后的反应来修饰而转化为其它所需的式(1)化合物。
下列实施例进一步例解说明本发明。实施例并非旨在以任何方式限定本发明。
                 实施例
                 实施例1
Figure A9880227000102
用十分钟，向在装备有磁性搅拌器的塑料烧杯中的-5℃下的HF/吡啶(50g)溶液中加入2-氨基-5-溴-3-甲基吡啶(7.55g，40.3mmol)。用15分钟向此反应混合物中加入亚硝酸钠(3.06g，44.4mmol)，温度保持在低于10℃。在搅拌1小时后，将反应混合物倒入冰(100g)中。滤出获得的固体，并用冷水洗涤。干燥的固体溶解于二氯甲烷中，干燥(无水硫酸钠)，过滤并真空浓缩，得到5-溴-2-氟-3-甲基吡啶(7.2g)，为灰白色固体。M.P.64-65℃。
                    实施例2
              3-溴-2-氟-5-甲基吡啶
Figure A9880227000111
利用实施例1中所描述的一般方法，并由2-氨基-3-溴-5-甲基吡啶为起始原料，得到3-溴-2-氟-5-甲基吡啶(5.6g)，为白色固体。
                   实施例3
             6-氟-5-甲基-烟酸甲酯
在-78℃下，向实施例的产物(2.0g，105mmol)在四氢呋喃(THF)(40mL)中的溶液中加入正丁基锂(7.2mL，1.6M己烷溶液)，并将混合物在氮气氛下搅拌15分钟。在-78℃下，将所得的悬浮液经由套管加入到氯甲酸甲酯在THF(20mL)中的溶液中。反应温热至-25℃，并搅拌一小时。在温热到0℃后，加入水，并将混合物用乙醚(3×50mL)萃取，干燥(无水硫酸钠)，过滤并真空浓缩。将粗稠油色谱纯化(硅胶，33％EtOAc/己烷)，得到(2-氟-3-甲基-5-吡啶)甲酸甲酯(0.9g)，为白色片状固体。M.P.99-100℃。
                 实施例4
            6-氟-5-甲基-烟酸叔丁酯
Figure A9880227000121
在-70℃氮气氛下，向叔丁醇(0.19g，2.6mmol)在THF(10mL)中的溶液中加入正丁基锂(1.6mL，1.6M己烷溶液)。向此混合物中缓慢加入实施例3的产物(0.4g，2.4mmol)的溶液，并在-70℃下搅拌一小时。所得的悬浮液温热到25℃，并搅拌16小时，用水(10mL)终止反应(quenched)，并将不同的层分离。水相用乙醚(3×30mL)萃取，干燥(无水硫酸钠)，过滤并真空浓缩，得到(2-氟-3-甲基-5-吡啶)甲酸叔丁酯(0.39g)，为粘稠的黄色油。
                  实施例5
           3-三氟甲基-5-溴-2-吡啶醇
Figure A9880227000122
在搅拌下将3-三氟甲基-2-吡啶酚(5.0g，0.031mol)溶解于甲醇(75mL)中，并在冷却下滴加入溴(5.25g，0.033mol)。将混合物搅拌过夜，然后蒸发至干。残留物溶解于乙酸乙酯(250mL)中，用水和盐水洗涤二次，经硫酸钠干燥后蒸发至干。经硅胶色谱纯化(20％乙酸乙酯∶80％己烷)，得到3-三氟甲基-5-溴-2-吡啶酚(5.2g)，为奶油色固体。M.P.160-162℃。
                   实施例6
          2-氯-3-三氟甲基-5-溴吡啶
将实施例5的产物(11.5g，0.048mol)和苯膦酰基二氯(45mL)在搅拌及135℃下加热四小时，并让之冷却至室温。反应混合物倒入冰(750g)中，放置使其升至室温。混合物用二氯甲烷(150mL)萃取，并过滤。分离出有机相，用水和10％碳酸钠溶液洗涤，经无水硫酸钠干燥后蒸发掉溶剂，得到2-氯-3-三氟甲基-5-溴吡啶(11.6g)，为黄色油。
               实施例7
       2-甲硫基-3-三氟甲基-5-溴吡啶
Figure A9880227000132
在搅拌下，将实施例6的产物(3.0g，0.012mol)溶解于二甲基亚砜(30mL)中，并加入甲硫醇钠(1.2g，0.017mol)。混合物在室温下搅拌过夜，倒入冰-水中，并用己烷(2×50mL)萃取。有机萃取液合并，用水和盐水洗涤，并经无水硫酸钠干燥。减压蒸发掉溶剂，残留物在硅胶上进行色谱纯化(10％乙酸乙酯∶己烷)，得到2-甲硫基-3-三氟甲基-5-溴吡啶(2.2g)，为清澈油状物。
                  实施例8
        6-甲硫基-5-三氟甲基-烟酸异丙酯
在45mL哈斯特洛尹弹式反应器(Hastelloy bomb)中将实施例7的产物(2.0g，7.4mmol)溶解于异丙醇(8mL)和三乙胺(4mL)。加入双(三苯基膦)氯化钯(II)(0.1g)，并在300psi下向容器中通入一氧化碳。反应混合物加热至130℃反应17小时，使之冷却至室温，并释放压力。混合物用乙酸乙酯(25mL)稀释，过滤，并减压蒸发掉溶剂。残留的油状物溶解于乙酸乙酯(50mL)中，并用水和盐水洗涤。在减压下将溶剂蒸发，所得油状物通过硅胶色谱纯化(5％乙酸乙酯∶己烷)，得到6-甲硫基-5-三氟甲基-烟酸异丙酯，为清澈油状物(1.8g)。
                实施例9
      6-甲基磺酰基-5-三氟甲基-烟酸异丙酯
Figure A9880227000141
在搅拌下，将实施例8的产物(1.8g，6.4mmol)溶解于二氯甲烷(100mL)中，并加入间氯过氧苯甲酸(纯度55％，4.4g，0.014mol)。在室温下将混合物搅拌过夜，加入10％碳酸钠溶液(100mL)，并将混合物剧烈搅拌1小时。分液，有机相用2M氢氧化钠溶液(50mL)和盐水洗涤。将其干燥，并在减压下蒸发掉溶剂，得到5-三氟甲基-6-甲基磺酰基-烟酸异丙酯(1.8g)，为清澈油状物，放置固化。
               实施例10
        3，5，6-三氯吡啶甲酸异丙酯
Figure A9880227000142
将3，5，6-三氯吡啶甲酸(3.0g，0.013mol)在亚硫酰氯(20mL)中制成淤浆，并加入二甲基甲酰胺(5滴)。将混合物回流加热三小时，并让之冷却。减压蒸发掉溶剂，给出粗制的酰氯，为黄色油状固体。将之溶解于异丙醇(20mL)中，并加入三乙胺(1.5g，0.015mol)。让混合物在室温下搅拌过夜，倒入水(100mL)中，并用乙酸乙酯(50mL)萃取。分离出有机相，用水和盐水洗涤，并经无水硫酸钠干燥。减压蒸发掉溶剂，给出金色油状物，并使其通过硅胶短柱，用5％乙酸乙酯∶己烷洗脱。减压蒸发掉溶剂，得到3，5，6-三氯吡啶甲酸异丙酯(2.5g)，为清澈油状物。
              实施例11
           2，5，6-三氯烟酸
Figure A9880227000151
将2，5，6-三氯-3-三氯甲基吡啶(22.5g，75mmol)悬浮于100mL85％硫酸中，并加热到125-140℃反应三小时。溶液冷却到室温，并倒入1kg碎冰中。滤出所得的棕黄色固体，并用己烷重结晶，得到2，5，6-三氯烟酸(11.8g)，为棕黄色晶体。
               实施例12
      2，5，6-三氟烟酸叔戊酯
Figure A9880227000152
将实施例11的产物(2.5g，11mmol)在含有二滴无水二甲基甲酰胺(DMF)的亚硫酰氯(30mL)中制成淤浆。将此淤浆加热回流，此时所有的组分均完全溶解入溶液中。将回流再继续三小时。冷却至室温后，真空下去除过量的亚硫酰氯，所得的油状残留物溶于乙醚(20mL)，并在冰浴中冷却至0℃。将叔戊醇(0.88g，10mmol)于乙醚(15mL)中的溶液在干冰浴中冷却至-10℃，并用10分钟滴加入正丁基锂(1.6M己烷溶液，6.5mL，1当量)，同时保持温度低于0℃。将溶液加热到室温，在氮气保护下装入加料漏斗中，并滴加到上面制备的酰氯的氮气清洗的醚溶液中。加毕，将溶液在搅拌下加热至室温过夜。溶液用饱和盐水(3×200ml)洗涤，并将有机物用硫酸钠干燥，过滤，真空去除溶剂，得到2，5，6-三氯烟酸叔戊酯(92.46g)，为橙色油状物。
                 实施例13
        3-氯-6-甲硫基-吡啶甲酸叔丁酯
Figure A9880227000161
将3，6-二氯吡啶甲酸叔丁酯(1.5g，6mmol)溶解于二甲亚砜(DMSO)(20mL)中。用5分钟向此溶液中加入甲硫醇钠(0.63g，9mmol)，保持反应低于30℃。通过色谱进行后处理和纯化，得到所需的产物(0.9g)，为清澈油状物。
                实施例14
       3-氯-6-甲磺酰基吡啶甲酸叔丁酯
Figure A9880227000162
在装备有磁性搅拌棒的50mL圆底烧瓶中装入(0.90g，0.003mol)3-氯-6-甲硫基吡啶甲酸叔丁酯和15mL二氯甲烷。将溶液冷却至0℃，用大约3分钟加入(2.23g，0.06mol)间氯过氧苯甲酸。让反应温热到室温，并搅拌过夜。混合物用35mL二氯甲烷稀释，用每份20mL 2N NaOH洗涤二次，用每份20mL水洗涤三次，之后干燥(硫酸钠)。减压蒸发掉溶剂，给出3-氯-6-甲磺酰基吡啶甲酸叔丁酯(0.9g)，为清澈油。
             实施例15
       (2-氯-6-甲基)异烟酸甲酯
Figure A9880227000171
在氮气氛下，将2-氯-6-甲基-4-吡啶甲酸(0.25g，1.46mmol)溶解于10mL甲醇中，接着经注射器滴加入BF3·MeOH(0.45mL，3当量)。将溶液回流三小时，之后在室温下搅拌过夜。将溶液倒入20mL水中，并用乙醚(2×25mL)萃取。合并有机相，用1.0NNaOH、水洗涤，经硫酸镁干燥，之后浓缩，得到(2-氯-6-甲基)异烟酸甲酸(0.14g)，为桃色固体。
                     实施例16
                 5，6-二氯烟酸异丙酯
Figure A9880227000172
将5，6-二氯烟酸(2.00g，10.4mmol)溶解于50mL异丙醇中，并向其中加入BF3-乙醚复合物(3.84mL，3当量)。将溶液回流过夜。冷却后，将溶液倒入100mL水中，并用乙醚(2×100mL)萃取。合并有机相，用水、盐水、1.0N NaOH洗涤，经硫酸镁干燥，并浓缩，得到5，6-二氯烟酸异丙酯(0.62g)，为乳白色固体。
               实施例17
         5，6-二氯烟酸(二甲基)炔丙酯
将5，6-二氯烟酸(1.92g，10.0mmol)在10mL四氢呋喃中制成淤浆，并向其中加入羰基二咪唑(carbonyldiimidazole)(CDI)(1.78g，11.0mmol)。将混合物在40℃下搅拌一小时，反应体系成均一溶液。经移液管加入2-甲基-3-丁炔-2-醇(1.01g，12.0mmol)，并将溶液回流过夜。将溶液倒入4-5倍体积的水中，并用乙醚萃取(2×100mL)。有机物用2.0N NaOH洗涤，经硫酸镁干燥，浓缩得到1.2g淡黄色油状物。粗制的产物在硅胶(23-400目)中柱上进行色谱纯化，使用由100％石油醚至50/50石油醚/乙酸乙酯的梯度递减溶剂洗脱。浓缩得到5，6-二氯烟酸(二甲基)炔丙酯(0.50g)，为无色油状物。
                   实施例18
             5，6-二氯烟酸里哪酯
Figure A9880227000182
将5，5-二氯烟酸(1.78g，10.0mmol)溶解在10mL四氢呋喃中，并向其中加入羰基二咪唑(CDI)(1.78g，11.0mmol)。所得溶液在室温下搅拌一小时，将1，8-二氮杂双环[5.4.0]-十一碳-7-烯(1.67g，11.0mmol)和里哪醇(1.85g，12.0mmol)一起加入其中。将所得溶液回流三小时，并冷却至室温，将其倒入4-5倍体积的水中，并用乙醚萃取(2×100mL)。有机物经硫酸镁干燥，浓缩得到1.65g琥珀色油状物。粗制的产物在硅胶(230-400目)中柱上进行色谱纯化，使用由100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂洗脱。浓缩得到所需的产物5，6-二氯烟酸里哪酯(0.50g)，为黄色油状物。
                   实施例19
       1-氯-3-氟-2-[(1，1-二甲基乙氧基)甲基]苯
Figure A9880227000191
将200g(1.117mol)2-氯-6-氟苄基氯、118g(1.23mol)叔丁醇钠、2.2mL(11mmol)15-冠-5(15-C-5)和1.2L甲苯的混合物在回流温度下加热4小时。在上反应混合物冷却至45℃后，加入600mL水，接着加入90mL 2N HCl。分离后，将有机相真空浓缩，得到深色油状物。使用5-塔板的Oldershaw柱蒸馏(沙浴至155℃)，得到217.5g1-氯-3-氟-2-[(1，1-二甲基乙氧基)甲基]-苯，为清澈液体(bp60-64℃/0.6mmHg)。
              实施例20
     1，3-二氯-2-[(1，1-二甲基乙氧基)甲基]苯
利用实施例19中描述的一般方法，由2，6-二氯苄基氯为起始原料，得到1，3-二氯-2-[(1，1-二甲基乙氧基)甲基]苯(收率92％，bp74-75℃/0.01mmHg.)。
              实施例21
  3-氟-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯
向73g(3.0摩尔，3当量)镁屑在700mL THF中的混合物中加入40g(0.25mol)1-氯-3-氟-2-[(1，1-二甲基乙氧基)-甲基]苯，接着加入1mL 1，2-二溴乙烷。将反应混合物在回流温度下加热，并将另外的1mL 1，2-二溴乙烷分成二份，在接下来的四小时内加入。此段时间结束后，气相色谱分析表明已经开始形成格氏试剂。用1小时加入余下的177g氟氯苯，并将混合物在回流温度下再加热12小时。所得的浑浊的暗棕色混合物用冰浴冷却至5℃，并经氮气套管加入到163mL(1.2mol)草酸二乙酯在300mL THF中的溶液中。在加入期间，通过干冰/丙酮浴冷却，将温度保持在-60℃至-50℃之间，在45分钟内加料完毕。混合物温热到0℃后，加入100mL 2N HCl，接着加入200mL水，并加入浓盐酸，使pH达到2。真空除去THF，加入乙酸乙酯，并将混合物用水、盐水洗涤，真空浓缩，得到深色液体。使用5-塔板Oldershaw柱蒸馏，得到172g 3-氟-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯，为淡黄色油状物(bp 113-117℃/0.35mmHg.)。
                  实施例22
3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯
Figure A9880227000202
利用实施例21中描述的一般方法，由1，3-二氯-2-[(1，1-二甲基乙氧基)甲基]苯为起始原料，得到3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯(bp 127-130℃/0.1mmHg.)。
              实施例23
 3-氟-2-[(1，1-二甲基乙氧基)甲基]-α-甲氧亚氨基)-苯乙酸乙酯
Figure A9880227000211
向79g(0.28mol)3-氟-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯在300mL乙醇中的溶液中加入100mL甲氧基胺盐酸盐(0.39mol，30％水溶液)，接着加入33g(0.4mol)乙酸钠。之后将混合物在60℃下加热三小时。冷却至室温后，将盐过滤，混合物在真空下浓缩。加入水和乙酸乙酯，分液，有机物用饱和碳酸氢钠、盐水洗涤，并经硫酸镁干燥。过滤后，真空浓缩所得溶液，得到86.1g 3-氟-2-[(1，1-二甲基乙氧基)甲基]-α-(甲氧亚氨基)-苯乙酸乙酯，为淡色油状物，通过气相色谱分析，是比率为1∶2的肟异构体。
               实施例24
3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-(甲氧亚氨基)-苯乙酸乙酯
Figure A9880227000212
利用实施例23中描述的一般方法，由3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-氧代-苯乙酸乙酯为起始原料，得到3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-(甲氧亚氨基)-苯乙酸乙酯。
              实施例25
(E)，(Z)-3-氟-2-(羟甲基)-α-(甲氧亚氨基)-N-甲基-苯乙酰胺
Figure A9880227000221
向84g(270mmol)3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-(甲氧亚氨基)-苯乙酸乙酯在250mL甲苯中的溶液中加入10.3g(54mmol)对甲苯磺酸一水合物，并将混合物加热至回流温度(90℃)。开始剧烈放出气体，并在三小时后，GC检测表明反应完毕。将溶液冷却到室温，并加入30mL(340mmol)40％的甲胺水溶液。反应温度从25℃升到38℃，形成混浊状固体。让混合物在室温下搅拌过夜。滤出固体，用甲苯洗涤，并用真空烘箱在40℃下干燥，得到57.8g(E)，(Z)-3-氟-2-(羟甲基)-α-(甲氧亚氨基)-N-甲基-苯乙酰胺。产物为白色晶状固体，M.P.147-151℃(变软)。
                  实施例26
(E)，(Z)-3-氯-2-(羟甲基)-α-(甲氧亚氨基)-N-甲基-苯乙酰胺
Figure A9880227000222
利用实施例25中描述的一般方法，由3-氯-2-[(1，1-二甲基乙氧基)甲基]-α-(甲氧亚氨基)-苯乙酸乙酯为起始原料，得到(E)，(Z)-3-氯-2-(羟甲基)-α-(甲氧亚氨基)-N-甲基-苯乙酰胺。M.P.141-143℃。
             实施例27α-(甲氧亚氨基)-N-甲基-2-[[[5-氯-6-(叔丁氧基羰基)-2-吡啶基]
              氧基]甲基]-苯乙酰胺
Figure A9880227000231
在装备有磁性搅拌棒和氮气入口管的50mL 3-颈圆底烧瓶中加入(0.55g，0.0024mol)2-羟甲基-α-甲氧亚氨基-N-甲基苯乙酰胺和10mL无水THF。在氮气氛及搅拌下，用20分钟，向反应体系中加入(0.14g，0.003mol)60％NaH。然后向反应体系中加入溶解于8mL无水THF中的3-氯-6-甲磺酰基吡啶甲酸叔丁酯(0.900g，0.003mol)，之后加入2mL DMSO，并在氮气氛及室温下搅拌三小时。之后将混合物用20mL乙酸乙酯和50mL去离子(DI)水稀释，用乙酸乙酯萃取(20ml×4)。合并有机萃取液用去离子(DI)水洗涤(50ml×3)，并用盐水洗涤二次(25ml×2)，色谱纯化后得到产物α-(甲氧亚氨基)-N-甲基-2-[[[5-氯-6-(叔丁氧基羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺，为灰白色油状固体。M.P.103-108℃。
                  实施例28
α-(甲氧亚氨基)-N-甲基-2-[[[5-溴-3-甲基-2-吡啶基]氧基]甲
                     基]-苯乙酰胺
Figure A9880227000232
将氢化钠(60％，0.18g，4.5mmol)加入到2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(1.0g，4.5mmol)在无水THF(25mL)中的溶液中，并在25℃及氮气氛下搅拌10分钟。向此反应混合物中加入实施例1的吡啶产物(0.86g，4.5mmol)，并搅拌16小时。加入水(20mL)，并将所得的混合物用乙醚萃取(3×50mL)，干燥(无水硫酸钠)，过滤并真空浓缩，得到粗制的残留物(1.5g)，将其用乙醚/戊烷研磨，得到α-(甲氧亚氨基)-N-甲基-2-[[[5-溴-3-甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(1.1g)，为白色固体。M.P.115-116℃。
                   实施例29α-(甲氧亚氨基)-N-甲基-2-[[[5-(异丙氧基羰基)-3-甲基-2-吡啶
              基]氧基]甲基]-苯乙酰胺
Figure A9880227000241
将一氧化碳(200psi)通入含有实施例28的产物(2.0g，5.1mmol)、Pd(PPh)3Cl2(0.18g，10mol％)和Et3N(0.57g，5.6mmol)在异丙醇(50mL)中的悬浮液的300mL帕尔反应器(Parr reactor)中。将此混合物在130℃反应16小时，并在160℃下继续加热16小时。冷却后，将混合物过滤并浓缩。所得残留物悬浮在乙醚(50mL)和水(30mL)的混合物中。分液，水层用乙醚(2×50mL)萃取，干燥(无水硫酸钠)，过滤后真空浓缩。将棕色残留物用色谱纯化(硅胶，50％乙酸乙酯/己烷)，得到α-(甲氧亚氨基)-N-甲基-2-[[[5-(异丙氧基羰基)-3-甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(0.7g)，为棕黄色固体。M.P.101-102℃。
              实施例30α-(甲氧亚氨基)-N-甲基-2-[[[3-溴-5-甲基-2-吡啶基]氧基]甲
                   基]-苯乙酰胺
Figure A9880227000251
利用实施例28中描述的一般方法，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-溴-5-甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(9.5g)，为灰白色固体。M.P.104-105℃。
                   实施例31α-(甲氧亚氨基)-N-甲基-2-[[[3-(异丙氧基羰基)-5-甲基-2-吡啶
              基]氧基]甲基]-苯乙酰胺
Figure A9880227000252
利用实施例29中描述的一般方法，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-(异丙氧基羰基)-5-甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(0.49g)，为白色固体。M.P.165-166℃。
                  实施例32α-(甲氧亚氨基)-N-甲基-2-[[[5-(叔丁氧基羰基)-3-甲基-2-吡啶
              基]氧基]甲基]-苯乙酰胺
Figure A9880227000261
利用实施例28中描述的一般方法，但用6-氟-5-甲基烟酸叔丁酯作为起始原料，得到α-(甲氧亚氨基)-N-甲基-2-[[[5-(叔丁氧基羰基)-3-甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(0.49g)，为白色固体。M.P.98-100℃。
                        实施例33α-(甲氧亚氨基)-N-甲基-2-[[[5-(异丙氧基羰基)-3-三氟甲基-2-
            吡啶基]氧基]甲基]-苯乙酰胺
Figure A9880227000262
在搅拌下将2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(1.0g，4.5mmol)溶解于无水THF(30mL)中，并加入氢化钠(60％矿物油分散液，0.25g，6.25mmol)。混合物在室温下搅拌二小时，加入实施例9的产物(1.4g，4.5mmol)在无水THF(5mL)中的溶液。混合物在室温下搅拌过夜，倒入水中，并用乙酸乙酯萃取。有机萃取液用水和盐水洗涤，经无水硫酸钠干燥。减压蒸发掉溶剂，并将残留物用色谱进行纯化(25％乙酸乙酯∶己烷)，得到α-(甲氧亚氨基)-N-甲基-2-[[[5-(异丙氧基羰基)-3-三氟甲基-2-吡啶基]氧基]甲基]-苯乙酰胺(0.65g)，为白色固体。
                        实施例34α-(甲氧亚氨基)-N-甲基-2-[[[3，5-二氯-6-(异丙氧基羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺和α-(甲氧亚氨基)-N-甲基-2-[[[5，6-
二氯-2-(异丙氧基羰基)-3-吡啶基]氧基]甲基]-苯乙酰胺
在搅拌下将2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(1.0g，4.5mmol)溶解于无水THF(30mL)中，并加入氢化钠(60％矿物油分散液，0.25g，6.25mmol)。混合物在室温下搅拌二小时，加入实施例10的产物(1.2g，4.5mmol)在无水THF(5mL)中的溶液。混合物在室温下搅拌过夜，倒入水中，并用乙酸乙酯萃取。有机萃取液用水和盐水洗涤，经无水硫酸钠干燥。减压蒸发掉溶剂，并将残留物用色谱纯化(25％乙酸乙酯∶己烷)，得到α-(甲氧亚氨基)-N-甲基-2-[[[3，5-二氯-6-(异丙氧基羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.74g)，为清亮的胶状物，和α-(甲氧亚氨基)-N-甲基-2-[[[5，6-二氯-2-(异丙氧基羰基)-3-吡啶基]氧基]甲基]-苯乙酰胺(0.52g)，为清亮油状物。
                   实施例35α-(甲氧亚氨基)-N-甲基-2-[[[3，6-二氯-5-(1，1-二甲基-1-丙氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺和α-(甲氧亚氨基)-N-甲基-2-[[[5，6-二氯-3-(1，1-二甲基-1-丙氧羰基)-2-吡啶基]氧基]甲
                   基]-苯乙酰胺
将实施例12的产物(1.8g，6mmol)加入到2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(1.1g，5mmol)和氢化钠(0.25g，6mmol)在无水THF(20mL)中形成的淤浆中。在室温下搅拌1.5小时后，将溶液用去离子水稀释至400mL，并用二氯甲烷(3×75mL)萃取。合并的有机层用水、饱和盐水洗涤，经硫酸钠干燥后，过滤，并浓缩至干。残留物吸附到硅胶上，通过硅胶色谱将区域异构产物分离，用乙酸乙酯/戊烷溶剂进行洗脱。结果得到α-(甲氧亚氨基)-N-甲基-2-[[[5，6-二氯-3-(1，1-二甲基-1-丙氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(130mg)，为粘稠的黄色油状物，和α-(甲氧亚氨基)-N-甲基-2-[[[3，6-二氯-5-(1，1-二甲基-1-异丙氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(1.4g)，为橙色油状物。
                    实施例36α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-6-(3-乙基-3-戊氧羰基)-2-
           吡啶基]氧基]甲基]-苯乙酰胺
Figure A9880227000282
将NaH(60％矿物油分散液，0.24g，6.0mmol)加入到2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(1.11g，5.0mmol)在THF(50mL)中的溶液中。并将5，6-二氯吡啶甲酸3-乙基-3-戊酯(1.68g，5.5mmol)溶解于THF(10mL)中，并经移液管缓慢将其加入此混合物中。当混合物在室温氮气氛下搅拌1小时后，反应混合物转变为深绿色溶液。加入乙酸乙酯使反应体积增加到大约125mL，并用水和盐水洗涤。有机相真空下蒸发，得到粗制的产物，将其在中压LC上进行色谱纯化，使用梯度的增加乙酸乙酯己烷溶液(0-50％)进行洗脱。浓缩色谱馏份，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-6-(3-乙基-3-戊氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.29g)，为黄色油状物。
                        实施例37α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(异丙氧基羰基)-2-吡啶基]
                 氧基]甲基]-苯乙酰胺
将NaH(60％矿物油分散液，0.23g，12.0mmol)用己烷洗涤二次，然后悬浮于THF(10mL)中，并向其中加入2-羟基-α-甲氧亚氨基-N-甲基-苯乙酰胺(0.89g，4.0mmol)的THF溶液。将溶液在室温下搅拌10分钟，此时加入5，6-二氯烟酸异丙酯(1.00g，4.3mmol)的THF溶液。在室温下搅拌15分钟后，将此溶液倒入4-5倍体积的水中，并用乙醚萃取(2×100mL)。有机相经硫酸镁干燥后浓缩得到1.5g棕黄色粘稠的油状物。粗制的产物在硅胶(230-400目)上用从100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂作为流动相进行色谱纯化。洗脱和浓缩，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(异丙氧基羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.72g)，为白色固体。
                  实施例38α-(甲氧亚氨基)-N-甲基-2-[[[(3-氯-5-(羧基)-2-吡啶基]氧基]
                   甲基]-苯乙酰胺
Figure A9880227000301
将利用实施例37中描述的一般方法制备的α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(甲氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(15.8g，40.4mmol)溶解于热甲醇(600mL)中，并向其中加入0.1NNaOH(600mL)。所得溶液在室温下搅拌过夜，之后真空浓缩除去过量的甲醇。残余物用乙醚(200mL)萃取。水层稍微酸化(pH5-6)，得到白色沉淀物。在室温下搅拌30分钟后，收集固体，用水洗涤，并在真空烘箱中干燥，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(羧基)-2-吡啶基]氧基]甲基]-苯乙酰胺(14.9g)。M.P.189-195℃。
                     实施例39α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(2，2.2-三氟乙氧基羰基)-
            2-吡啶基]氧基]甲基]-苯乙酰胺
Figure A9880227000302
实施例38的产物(0.3g，0.79mmol)溶解于THF(10mL)中，并向其中加入羰基二咪唑(0.129g，0.79mmol)。在室温下搅拌一小时，此时加入2，2，2-三氟乙醇(10mL)，在室温下搅拌过夜。将所得溶液倒入4-5倍体积水中，并用乙醚(2×100mL)萃取。有机相经硫酸镁干燥，并浓缩得到黄棕色油状物(0.19g)。粗产物在硅胶(230-400目)上用100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂作为流动相进行色谱纯化。洗脱和浓缩后得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(2，2，2-三氟乙氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.09g)，为绿色油状物。
                    实施例40α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(乙氧羰基二苯基甲氧羰
        基)-2-吡啶基]氧基]甲基]-苯乙酰胺
Figure A9880227000311
将实施例38的产物(0.5g，1.32mmol)溶解于15mL THF中，并向其中加入羰基二咪唑(0.24g，1.48mmol)。所得溶液在室温下搅拌一小时。NaH(60％矿物油分散液，0.08g，3.2mmol)用己烷(2x)洗涤之后悬浮于THF(10mL)中，并向其中加入二苯乙醇酸乙酯(0.40g，3.2mmol)。20分钟后，将咪唑酰胺(imidazolide)中间体滴加到该醇阴离子溶液中，并在室温下继续搅拌过夜。将溶液倒入4-5倍体积水中，并用乙醚(2×100mL)萃取。有机相经硫酸镁干燥后浓缩得到黄色油状物(0.60g)。产物在硅胶(230-400目)中柱上用80/20石油醚/乙酸乙酯作为流动相进行等浓度色谱纯化。洗脱和浓缩后，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(乙氧羰基二苯基甲氧基羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.50g)，为黄色固体。
                   实施例41α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁硫基羰基)-2-吡啶基]
               氧基]甲基]-苯乙酰胺
在0℃及氮气氛下，向10.0ml三甲基铝(2.0M甲苯溶液)在40mL无水二氯甲烷的溶液中加入2.2mL叔丁硫醇。搅拌混合物，放置使其在15-20分钟的时间内温升至室温。将在1mL二氯甲烷中的α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(甲氧羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.23g)加入其中，并将混合物在室温氮气氛下搅拌20小时。向反应体系中加入大约200mL乙醚，小心加入1.0N HCl直到不再放出气体。分离出醚层，用5％NaOH溶液洗涤，接着用水洗涤，最后用盐水洗涤。将醚层干燥，真空除去溶剂，留下浅颜色的油状物。该油状物在于法填充的硅胶(230-400目)柱上用从100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂作为流动相进行色谱纯化。洗脱和浓缩，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁硫基-羰基)-2-吡啶基]氧基]甲基]-苯乙酰胺(0.150g)，为固体物。M.P.114-116℃。
                   实施例42α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]氧基]甲基]-3-氟苯乙酰胺
Figure A9880227000331
将氢化钠(60％，0.15g，3.7mmol)加入3-氟-2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(0.54g，2.25mmol)在无水THF(10mL)中的溶液中，并在25℃及氮气氛下搅拌10分钟。将于2-3mL THF中的5，6-二氟烟酸叔丁酯(0.59g，2.5mmol)加入此反应混合物中，并在25℃下搅拌大约2小时。加入水(40mL)，并将所得混合物用乙醚(2x)萃取，干燥(无水硫酸钠)，过滤并真空浓缩，得到1.2g粗制的油状物。该油状物在干法填充的硅胶(230-400目)上用从100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂作流动相进行色谱纯化。洗脱并浓缩后得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]氧基]甲基]-3-氟-苯乙酰胺(520mg)，为油状物。(98％E型异构体；2％Z型异构体)。
                   实施例43α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]
              氧基]甲基]-3-氯-苯乙酰胺
Figure A9880227000332
将氢化钠(60％，0.12g，3.0mmol)加入到3-氯-2-羟甲基-α-甲氧亚氨基-N-甲基-苯乙酰胺(0.43g，1.68mmol)在无水THF(10mL)中的溶液中，并在25℃及氮气氛下搅拌10分钟。将于2-3mL THF中的5，6-二氯烟酸叔丁酯(0.44g，1.87mmol)加入此反应混合物中，并在25℃下搅拌大约2小时。加入水(40mL)，并将所得的混合物用乙醚(2x)萃取，干燥(无水硫酸钠)，过滤并真空浓缩，得到0.72g粗制的油状物。该油状物在干法填充的硅胶(230-400目)柱上用从100％石油醚至80/20石油醚/乙酸乙酯的梯度递减溶剂作流动相进行色谱分离。洗脱并浓缩，得到α-(甲氧亚氨基)-N-甲基-2-[[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]氧基]甲基]-3-氯-苯乙酰胺(430mg)，为油状物。(95％E型异构体；5％Z型异构体)。
                 实施例44α-(甲氧亚氨基)-N-甲基-2-[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]
                  氧基]-苯乙酰胺
Figure A9880227000341
向装有磁性搅拌器的100mL烧瓶中加入5，6-二氯烟酸叔丁酯(5.0g，0.02mol)、n-甲基吡咯烷酮(n-methylpyrrolidinone)(NMP)(50mL)、二甘醇二甲醚(1mL，内标)和喷雾干燥的KF(5.8g，0.1mol)。所得淤浆加热到120℃并保持三小时。将混合物冷却，并在1，1，2，2-四氯乙烯(30mL)和水间分配。水相用1，1，2，2-四氯乙烯(30mL)萃取，合并有机相，并用1N NaOH萃取，干燥(硫酸钠)，真空去除溶剂，得到3.3g固体产物，经测定为70％的5-氯-6-氟烟酸叔丁酯和30％的5，6-二氯烟酸叔丁酯。将此产物加入到二氯甲烷(10mL)、2-羟基-α-甲氧亚氨基-N-甲基-苯乙酰胺(0.5g，2.4mmol)、碳酸钾粉(0.82g，6.0mmol)和溴化四丁基铵(0.08g，0.25mmol)的混合物中。24小时后，将所得混合物加入到乙醚中，并用稀硫酸、水和1N NaOH萃取。真空去除溶剂，残留物在硅胶上用15％乙腈∶85％二氯甲烷进行色谱分离，得到α-(甲氧亚氨基)-N-甲基-2-[[3-氯-5-(叔丁氧基羰基)-2-吡啶基]氧基]-苯乙酰胺(0.169g)。
下列表格给出一些式(1)化合物，用类似于前述实施例中所述的各种方法制备，其中X或CO2R独立地是如下列化学式中所示的R1、R2、R3或R4：
Figure A9880227000361
  化合物     R1     R2     R3     R4   Y
    1     -H     -H     -CO2CH2Ph   -F   -H
    2     -CO2CH2Ph     -H     -H   -F   -H
    3     -H     -CO2CH3     -H   -Cl   -H
    4     -H     -CO2CH3     -H   -CO2CH3   -H
    5     -H     -Cl     -CO2Et   -H   -H
    6     -H     -H     -H   -CO2CH3   -H
    7     -NO2     -H     -Cl   -CO2CH3   -H
    8     -Cl     -Cl     -Cl   -CO2CH3   -H
    9     -Cl     -H     -CO2iPr   -H   -H
    10     -Cl     -H     -CO2CH3   -H   -H
    11     -H     -H     -CO2iPr   -H   -H
    12     -Cl     -H     -H   -CO2iPr   -H
    13     -Cl     -H     -CO2Et   -H   -H
    14     -Br     -H     -CO2Et   -H   -H
    15     -Cl     -H     -CO2C2H4CH(CH3)2   -H   -H
    16     -Cl     -H     -CO2nPr   -H   -H
    17     -Cl     -H     -CO2tBu   -H   -H
    18     -Cl     -H     -CO2CH2iPr   -H   -H
    19     -Cl     -H     -CO2-环己基   -H   -H
    20     -Cl     -H     -CO2iPr   -H   -H
    21     -CO2CH3     -H     -H   -H   -H
    22     -Cl     -H     -CO2CH2Ph   -H   -H
    23     -Cl     -H     -CO2nBu   -H   -H
    24     -Cl     -H     -CO2Ph   -H   -H
    25     -CO2iPr     -H     -CO2iPr   -H   -H
    26     -F     -H     -CO2iPr   -H   -H
    27     -Br     -H     -CO2iPr   -H   -H
    28     -H     -H     -Cl   -CO2iPr   -H
    29     -Cl     -H     -CO2-2-Et-己基   -H   -H
    30     -CO2iPr     -H     -Cl   -H   -H
    31     -Cl     -H     -CO2sBu   -H   -H
    32     -Cl     -H     -CO2-C(CH3)2CCH   -H   -H
    33     -Cl     -H     -H   -CO2tBu   -H
    34     -CO2iPr     -H     -H   -Cl   -H
    35     -CH3     -H     -CO2iPr   -H   -H
    36     -Cl     -H     -CO2-6-Me-2-庚基   -H   -H
    37     -CO2iPr     -H     -H   -F   -H
    38     -H     -H     -CO2iPr   -F   -H
    39     -H     -H     -CO2iPr   -F   -H
    40     -Cl     -H     -CO2-3-Me-3-戊基   -H   -H
    41     -Cl     -H     -CO2iPr   -Cl   -H
    42     -CO2iPr     -H     -Cl   -Cl   -H
    43     -Cl     -H     -CO2-C(CH3)2CHCH2   -H   -H
    44     -Cl     -H   -CO2-2，4-di-Me-3-戊基   -H   -H
    45     -CO2tBu     -H   -H   -Cl   -H
    46     -H     -H   -H   -CO2iPr   -H
    47     -Cl     -H   -Cl   -CO2iPr   -H
    48     -Cl     -H   -CO2-2，4-di-Me-2-戊基   -H   -H
    49     -Cl     -H   -CO2叔戊基   -H   -H
    50     -Cl     -H   -CO2-3-Et-3-戊基   -H   -H
    51     -CO2-3-Me-3-戊基     -H   -Cl   -Cl   -H
    52     -CO2tBu     -H   -Cl   -Cl   -H
    53     -Cl     -H   -CO2tBu   -Cl   -H
    54     -Cl     -H   -CO2-C(Me)2-t-Bu   -H   -H
    55     -Cl     -H   -CO2-3-Me-3-戊基   -Cl   -H
    56     -CO2-2，4-di-Me-3-戊基     -H   -Cl   -Cl   -H
    57     -Cl     -H   -CO2-2，4-di-Me-3-戊基   -Cl   -H
    58     -Cl     -H   里哪醇酯基   -H   -H
    59     -CO2-2-Et-己基     -H   -Cl   -Cl   -H
    60     -Cl     -H   -CO2-2-Et-己基   -Cl   -H
    61     -Cl     -H   -CO2-C(Me)2-t-Bu   -Cl   -H
    62     -CO2-C(Me)2-t-Bu     -H   -Cl   -Cl   -H
    63     -Br     -H   -CO2-C(Me)2-t-Bu   -H   -H
    64     -CF3     -H   -CO2iPr   -H   -H
    65     -CF3     -H     -CO2tBu   -H   -H
    66     -Cl     -H     -Cl   -CO2tBu   -H
    67     -Cl     -H     -H   -CO2叔戊基   -H
    68     -Cl     -H     -H   -CO2-2，4-di-Me-3-戊基   -H
    69     -Cl     -H     -H   -CO2-2-Et-己基   -H
    70     -Cl     -H     -H   -CO2-C(Me)2-t-Bu   -H
    71     -Cl     -H     -H   -CO2-3-Et-3-戊基   -H
    72     -CF3     -H     -CO2-3-Me-3-戊基   -H   -H
    73     -Br     -H     -CO2-2，4-di-Me-3-戊基   -H   -H
    74     -Br     -H     -CO2-3-Et-3-戊基   -H   -H
    75     -Br     -H     -CO2-3-Me-3-戊基   -H   -H
    76     -Br     -H     -CO2tBu   -H   -H
    77     -Br     -H     -CO2叔戊基   -H   -H
    78     -F     -H     -CO2tBu   -H   -H
    79     -F     -H     -CO2-3-Me-3-戊基   -H   -H
    80     -H     -H     -Cl   -CO2tBu   -H
    81     -Br     -H     -CO2-C(CH3)2CHCH2   -H   -H
    82     -CO2-3-Et-3-戊基     -H     -Cl   -Cl   -H
    83     -Cl     -H     -CO2-3-Et-3-   -Cl   -H
    戊基
    84     -CO2-2-Et-己基     -H     -H     -Cl   -H
    85     -H     -H     -CO2-2-Et-己基     -Cl   -H
    86     -Cl     -H     -COOH     -H   -H
    87     -CO2iPr     -H     -CH3     -H   -H
    88     -CH3     -H     -CO2tBu     -H   -H
    89     -CCl3     -H     -CO2iPr     -H   -H
    90     -CO2叔戊基     -H     -Cl     -Cl   -H
    91     -Cl     -H     -CO2叔戊基     -Cl   -H
    92     -Cl     -H     -CO2-CH2CF3     -H   -H
    93     -H     -H     -H     -CO2tBu   -H
    94     -H     -H     -Cl     -CO2-3-Me-3-戊基   -H
    95     -Cl     -H     葑基     -H   -H
    96     -Cl     -H     -CO2-CH(CF3)2     -H   -H
    97     -CO2iPr     -H     -CF3     -H   -H
    98     -Cl     -H     -CO2-C(CH3)2CN     -H   -H
    99     -Cl     -H     -CO2-CH(CH3)CH2OMe     -H   -H
    100     -Cl     -H     -CO2-C(CH3)2CH2Cl     -H   -H
    101     -Cl     -H     -CO2-C(CH3)2CO2-t-Bu     -H   -H
    102     -Cl     -H     -CO2-C(CH3)2Ph     -H   -H
    103     -Cl     -H     -CO2-C2H4-TMS     -H   -H
    104     -Cl     -H     2-(4-氟苯基)-4，4-二甲基-     -H   -H
   1-戊炔-3-基
    105     -Cl     -H     -CO2-C2H4-OEt     -H   -H
    106     -Cl     -H    -CO2-CH(CH3)C2F5     -H   -H
    107     -Cl     -H    1-乙炔基-环戊基     -H   -H
    108     -Cl     -H    -CO2-环丁基     -H   -H
    109     -Cl     -H    -H     -CO2-3-Me-3-戊基   -H
    110     -Cl     -H    -CO2-(1-Me-环戊基)     -H   -H
    111     -Cl     -H    -CO2-(1-金刚烷基)     -H   -H
    112     -Cl     -H     1，3-二甲基-环戊基     -H   -H
    113     -Cl     -H     2，2-di二甲基-3-(4-甲苯基)-丙基     -H   -H
    114     -Cl     -H     -CO2-2-金刚烷基     -H   -H
    115     -Cl     -H     -CO2-CPh2-CO2Et     -H   -H
    116     -Cl     -H     -CO2-3-Me-4-丁烯-1-基     -H   -H
    117     -Cl     -H     4-氯-3-甲基丁基     -H   -H
    118     Cl      H     CO2t-Bu     H   F
    119     Cl      H     CO2t-Bu     H   Cl
    120     Cl     H     CO2异丙基     H     F
    121     Cl     H     CO2异丙基     H     Cl
    122     H     H     Cl     CO2t-Bu F
    123     H     H     Cl     CO2t-Bu     Cl
    124     CH3     H     CO2t-Bu     H     F
由此产生的式(1)化合物通常获得的是其E和Z型的混合物，如果需要，它们可以通过色谱分离。
式(1)化合物对种类广泛的真菌显示出强的杀真菌活性。下列试验例解释明本发明化合物的杀真菌效力。
                      杀真菌剂应用
已发现本发明化合物可以防治真菌，特别是植物病原菌。当用来处理植物真菌病害时，这些化合物是以病害抑制和植物可接受的量施用于植物。可以在真菌感染植物前或后进行施用。也可以通过处理植物的种子、植物生长的土壤、秧田或用于灌溉的水来进行施用。
如本文中所采用的术语“病害抑制和植物可接受量”是指本发明化合物杀死或抑制植物病害(这点是人们所期望的)，但不对植物产生明显的毒性的量。此量通常是从大约1至1000ppm，优选10至500ppm。所需的确切的化合物浓度随意欲防治的真菌病害、采用的制剂的类型、施用的方法、具体的植物种类、气候条件等因素而变化。适合的施用量一般是大约0.10至大约4磅/英亩(lb/A)。
本发明化合物也可以用来保护贮存的谷物和其它非植物场所不受真菌侵害。
下列实验是在实验室进行的，用以确定本发明化合物的杀真菌效力。
化合物制剂：化合物制剂是通过将工业品溶解于丙酮中，之后用丙酮进行系列稀释从而获得所需的施用比率。根据病原菌的不同，最终处理体积是通过加入九倍体积的0.05％ Tween-20水溶液或Triton X-100而获得的。
小麦白粉病(Erysiphe graminis-ERYSGT)
将小麦(栽培品种：Monon)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到秧苗长到10-20cm高。将这些植物用从病原株收集来的孢子喷粉从而用禾白粉菌(Erysiphe graminis)进行接种。48小时后，将植物用试验化合物以25ppm的浓度喷雾，直到植物湿透，之后将其保持在温室中，直到未处理对照植株开始发病。
小麦叶斑病(Septoria tritici-SEPTTR)
将小麦(栽培品种：Monon)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到秧苗长到10-20cm高。将植株用试验化合物以25ppm的浓度喷雾，直到植株湿透。24小时后，将这些植株用小麦壳针孢(Septoria tritici)的孢子水悬浮液喷雾进行接种。将植株转移到温室中，直到未处理对照植株开始发病。
葡萄霜霉病(Plasmopara viticola-PLASVI)
(24小时保护剂)：将葡萄(栽培品种：Carignane)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到幼苗长到10-20cm高。将植株用试验化合物以100ppm的浓度喷雾，直到植株湿透。24小时后，将这些植株用葡萄生单轴霉菌(Plasmopara viticola)的孢子囊水悬浮液喷雾进行接种。将植株转移到温室中，直到未处理对照植株开始发病。
葡萄霜霉病(Plasmopara viticola-PLASVI)
(96小时保护剂)：将葡萄(栽培品种：Carignane)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到幼苗长到10-20cm高。将植株用试验化合物以100ppm的浓度喷雾，直到植株湿透。96小时后，将这些植株用葡萄生单轴霉菌(Plasmopara viticola)的孢子囊水悬浮液喷雾来进行接种。将植株转移到温室中，直到未处理对照植株开始发病。
葡萄白粉病(Uncinula necator-UNCINE)
将葡萄(栽培品种：Carignane)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到幼苗长到10-20cm高。将植株用试验化合物以100ppm的浓度喷雾，直到植株湿透。168小时后，将这些植株用从病原株收集来的孢子喷粉从而用葡萄钩丝壳霉菌(Uncinulanecator)进行接种。将植株转移到温室中，直到未处理对照植株开始发病。
苹果黑星病(Venturia inaeoualis-VENTIN)
将苹果(栽培品种：RED Delicious)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到幼苗长到10-20cm高。将植株用试验化合物以100ppm的浓度喷雾，直到植物湿透。48小时后，将这些植物用苹果黑星菌(Venturia inaequalis)的孢子水悬浮液喷雾来进行接种。将植株转移到温室中，直到未处理对照植株开始发病。
稻瘟病(Pyricularia oryzae-PYRIOR)
将稻(栽培品种：M9)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到秧苗长到10-20cm高。将植株用试验化合物以25ppm的浓度喷雾，直到植物湿透。96小时后，将这些植物用稻梨孢菌(Pyricularia oryzae)的分生孢子水悬浮液喷雾来进行接种。将植物转移到温室中，直到未处理对照植物开始发病。
稻纹枯病(Rhizoctonia solani-RHIZSO)
将稻(栽培品种：M9)种植在无土泥炭基盆栽混合物(“Metromix”)上，直到秧苗长到10-20cm高。将植株用试验化合物以25ppm的浓度喷雾，直到植物湿透。24小时后，将这些植物用立枯丝核菌(Rhizoctonia solani)侵染的大麦种子进行接种。将植物转移到温室中，直到未处理的对照植株开始发病。
下列表格给出的是在这些实验中评价的本发明典型化合物的活性。试验化合物防治病害的效力使用下列等级表示：空白＝未试验-＝0-24％的植物病害防治率+＝25-74％的植物病害防治率++＝75-100％的植物病害防治率
化合物号 葡萄霜霉病(24小时) 葡萄霜霉病(96小时) 苹果黑星病 葡萄白粉病 稻瘟病 稻纹枯病 小麦白粉病 小麦叶斑病
    1     -     -     -    -   -     -    -
    2     ++     ++     -    -   -     +    +
    3     +     -     -    -   -
    4     +     -     -    -   -     -    +
    5     ++     ++     ++    -   -     +    -
    6     +     -     -    -   -     +    +
    7     ++     ++     -    -   -     ++    +
    8     +     -     +     -     -     +     -
    9     ++     ++     ++     ++     ++     ++     +
    10     ++     -     ++     -     -     ++     +
    11     ++     ++     ++     -     +     ++     ++
    12     ++     ++     ++     ++     ++     ++     ++
    13     ++     +     ++     +     -     ++     +
    14     ++     ++     ++     +     +     ++     +
    15     ++     ++     ++     +     +     ++     +
    16     ++     ++     ++     ++     +     ++     +
    17     ++     ++     ++     ++     ++     ++     ++
    18     ++     ++     ++     ++     -     ++     ++
    19     ++     ++     ++     +     +     ++     ++
    20     ++     ++
    21     -     -     -     -     +
    22     ++     ++     ++     ++     ++
    23     ++     ++     ++     +
    24     +     -     -     -     +
    25     +     -     -     -     +
    26     ++     ++     ++     ++     ++
    27     ++     ++     ++     ++     ++
    28     ++     ++     ++     ++     ++
    29     ++     ++     ++     ++     ++
    30     -     ++     +     -     -
    31     ++     ++     ++     ++     ++
    32     ++     ++     ++     ++     ++
    33     ++     +     ++     ++     +
    34     +     +     +     +     -
    35     ++     ++     ++     ++     ++
    36     ++     ++     ++     ++     ++
    37     ++     ++     ++     ++     +
    38     ++     +     +     +
    39     ++     ++     ++     ++     ++
    40     ++     ++     ++     ++     ++
    41     ++     ++     ++     ++     ++
    42     +     ++     ++     +     +
    43     ++     ++     ++     ++     ++
    44     ++     ++     ++     ++     ++
    45     -     -     +     -     ++
    46     +     ++     ++     ++     +
    47     ++     ++     ++     ++     ++
    48     ++     ++     ++
    49     ++     ++     ++     ++     ++
    50     ++     ++     ++     ++     ++
    51     -     -     +     +     +
    52     ++     ++     ++     +     +
    53     ++     ++     ++     ++     ++
    54     ++     ++     ++     ++     ++
    55     ++     ++     ++     ++     ++
    56     -     +     -     -     +
    57     ++     ++     ++
    58     ++     ++     ++     +     -
    59     -     -     +
    60     ++     ++     ++
    61     ++     ++     ++
    62     -     -
    63     ++     ++     ++     ++     ++
    64     ++     ++     ++     ++     ++
    65     ++     ++     ++
    66     ++     ++     ++     ++     ++
    67     +     +     -
    68     ++     ++     +
    69     +     +     ++
    70     ++     +     +
    71     ++     +     +
    72     ++     ++     ++
    73     ++     ++     ++     ++     ++
    74     ++     ++     ++     ++     ++
    75     ++     ++     ++     ++     ++
    76     ++     ++     ++     ++     ++
    77     ++     ++     ++
    78     ++     ++     ++
    79     ++     ++     ++
    80     ++     ++     ++
    81     ++     ++     ++
    82     -     -     +
    83     ++     ++     ++
    84     +     +     +
    85     ++     ++     ++
    86     -     -     +
    87     ++
    88     ++
    89
    90     ++
    91     ++
    92     ++
    93     ++
    94     ++
    95     ++
    96     ++
    97     +
    98     ++
    99     ++
    100     ++
    101     ++
    102     ++
    103     ++
    104     ++
    105     ++
    106     ++
    107     ++
    108     ++
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    115
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    125
式(1)化合物可以直接施用，或更优选的是以组合物的形式施用，它们是本发明的重要的实施方案，它们包含一或多种式(1)化合物和植物可接受的惰性载体。所述的组合物可以任选地包含杀真菌组合物，该组合物包含至少1％的一种或多种式(1)化合物和其它的杀真菌剂、除草剂和/或杀虫剂。
本发明组合物或是浓缩制剂，该制剂施用时要分散于水中，或是粉剂或颗粒剂，它无需进一步处理而直接施用。可根据农业化学领域常规方法制备所述的组合物。但是这些组合物是新颖和重要的，因为其中含有本发明化合物。然而，下文中仍将对组合物的制剂作一些描述，以确保农业化学工作者易于制备出所需的组合物。
化合物施用的分散液最通常是由化合物的浓缩制剂制备的悬浮液或乳液。水溶性、水可悬浮性或乳剂或是固体(通常称作可湿性粉剂)或是液体(通常称作乳油或水悬浮制剂)。可湿性粉剂可以被压实从而形成水可分散性颗粒剂，它包含活性化合物、惰性载体和表面活性剂。活性化合物的浓度通常是大约10至90％。惰性载体通常选自硅镁土、蒙脱石、硅藻土或纯化的硅酸盐。有效的表面活性剂，其量为可湿性粉剂的大约0.5％至大约10％，它可选自磺化的木质素、萘磺酸盐、烷基苯磺酸盐、烷基硫酸盐，和非离子表面活性剂如烷基酚的环氧乙烷加成物。
化合物的乳油包含适宜浓度，如液体量的大约10％至大约50％的化合物，化合物溶解于惰性载体(该载体或是与水可混溶的溶剂或是与水不可混溶的有机溶剂的混合物)和乳化剂中。可用的有机溶剂包括芳族化合物，特别是石油的高沸点萘和烯属馏分如重芳烃石脑油。也可以使用其它有机溶剂，例如萜烯溶剂，包括松香衍生物，脂族酮类，如环己酮和复杂的醇，如2-乙氧基乙醇。适合用于乳油的乳化剂选自常规的非离子表面活性剂，如上面提到的那些。
水悬剂包括本发明的水不溶性化合物的悬浮液，这些化合物以大约5％至大约50％的浓度分散在含水载体中。悬浮液通过将化合物精细研磨，并将其剧烈混入包含水和选自与上面讨论的类型相同的表面活性剂的载体中。也可以加入惰性成分，如无机盐和合成或天然胶，来增加含水载体的密度和粘度。通常最有效的是将混合物在制备含水混合物时的同时研磨和混合，并将其在装置如砂磨、球磨或活塞型均化器中均化。
化合物也可以以颗粒组合物形式施用，特别是施用于土壤中。颗粒组合物通常含有大约0.5％至大约10％的本发明化合物，分散于惰性载体中，该载体由大部分的粘土或类似的低廉物质组成。这些组合物通常是通过将化合物溶解于适合的溶剂，并将其涂到预先成形成适合颗粒大小(大约0.5至3mm)的颗粒载体上制备的。这些组合物还可以通过制成载体和化合物的湿团或糊状物，然后压碎和干燥从而获得所需的颗粒剂。
含有本发明化合物的粉剂是通过简单地将粉末状化合物与合适的粉状农业载体如高岭土、研碎的火山岩等紧密混合而制备。粉剂可以适合地含有大约1％至10％的本发明化合物。

Claims (17)

1.式(1)所示的化合物
Figure A9880227000021
其中
m是整数0-3；
Y是H、卤素、C1-4-烷基、C1-4-烷氧基或C1-4-烷硫基；
X是H、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷氧基、卤素、硝基、羰基-C1-6-烷氧基、氰基、C1-6-烷硫基或卤代-C1-6-烷硫基；
W或W’独立地是O或S；
R是H、C1-6烷基或C3-7环烷基；它们可任选地被卤代-C1-6-烷基、卤代-C1-6-烷氧基、C2-6-链烯基、卤代-C2-6-链烯基、C2-6-炔基、氰基、C1-6-烷氧基、卤素、芳基、取代的芳基或杂芳基取代；和
L是-O-、-CH2-、-SOn-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH＝CH-、-C≡C-、或
Figure A9880227000022
，其中n是整数0-2。
2.下式所示的权利要求1的化合物
Figure A9880227000031
其中取代基如权利要求1中所定义。
3.下式所示的权利要求2的化合物其中Y是卤素且余下的取代基如权利要求2中所定义。
4.下式所示的权利要求3的化合物其中Y是卤素且余下的取代基如权利要求3中所定义。
5.下式所示的权利要求4的化合物其中取代基如权利要求4中所定义。
6.权利要求5的化合物，其中X是C1-4-烷基、卤素或卤代-C1-4-烷基，且R是C1-4-烷基，它可任选被链烯基、炔基或烷氧基取代。
7.权利要求5的化合物，其中X是氯，m是0，W是O，W’是O，且R是异丙基。
8.权利要求5的化合物，其中X是氯，m是0，W是O，W’是O，且R是叔丁基。
9.权利要求5的化合物，其中X是甲基，m是0，W是O，W’是O，且R是异丙基。
10.权利要求5的化合物，其中X是甲基，m是0，W是O，W’是O，且R是叔丁基。
11.权利要求5的化合物，其中X是三氟甲基，m是0，W是O，W’是O，且R是叔丁基。
12.权利要求5的化合物，其中X是氯，m是0，W是O，W’是O，且R是叔戊基。
13.下式所示的权利要求4的化合物
Figure A9880227000042
其中取代基如权利要求4中所定义。
14.权利要求13的化合物，其中X是氯，m是0，W是O，W’是O，且R是叔丁基。
15.下式所示的化合物
Figure A9880227000051
其中Y是氯或氟。
16.制备下面式(a)所示的化合物的方法：
Figure A9880227000052
其中Y是氯或氟；该方法包括：使式(b)所示的化合物与对甲苯磺酸反应，从而得到式(a)所示的化合物。
17.一种杀真菌方法，该方法包括将杀真菌有效量的式(1)所示的化合物施用到意欲处理的场所
Figure A9880227000054
其中
m是整数0-3；
Y是H、卤素、C1-4-烷基、C1-4-烷氧基或C1-4-烷硫基；
X是H、C1-6-烷基、C1-6-烷氧基、卤代-C1-6-烷基、卤代-C1-6-烷氧基、卤素、硝基、羰基-C1-6-烷氧基、氰基、C1-6-烷硫基或卤代-C1-6-烷硫基；
W或W’独立地是O或S；
R是H、C1-6烷基或C3-7环烷基；它们可任选地被卤代-C1-6-烷基、卤代-C1-6-烷氧基、C2-6-链烯基、卤代-C2-6-链烯基、C2-6-炔基、氰基、C1-6-烷氧基、卤素、芳基、取代的芳基或杂芳基取代；和
L是-O-、-CH2-、-SOn-、-CH2O-、-OCH2-、-CH2S-、-SCH2-、-CH＝CH-、-C≡C-、或
Figure A9880227000061
，其中n是整数0-2。
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AU6254398A (en) 1998-08-25
CA2278851A1 (en) 1998-08-06
AU729160B2 (en) 2001-01-25
CN1126742C (zh) 2003-11-05
BR9807145B1 (pt) 2010-06-29
CA2278851C (en) 2009-04-07
KR100514941B1 (ko) 2005-09-15
KR20000070702A (ko) 2000-11-25
BR9807145A (pt) 2000-03-14
HUP0001957A3 (en) 2000-12-28
EP0961771A1 (en) 1999-12-08

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