CN1072217C - 生产2－取代－3,4－稠合杂环苯甲酸的方法 - Google Patents

生产2－取代－3,4－稠合杂环苯甲酸的方法 Download PDF

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CN1072217C
CN1072217C CN97118446A CN97118446A CN1072217C CN 1072217 C CN1072217 C CN 1072217C CN 97118446 A CN97118446 A CN 97118446A CN 97118446 A CN97118446 A CN 97118446A CN 1072217 C CN1072217 C CN 1072217C
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tert
butylhydrazine
methylbenzoyl
methoxy
och
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CN1176251A (zh
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Z·利德特
D·P·李
R·E·霍曼
T·R·奥比
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Corteva Agriscience LLC
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Rohm and Haas Co
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Abstract

本发明涉及式N-(2-Ra-3-Rb-4-Rb-苯甲酰基)-N′-(2-Rc-3-Rd-4-Re-5-R5-苯甲酰基)-N′-R9-肼的杀虫化合物，以及包括农药上可接受的载体和杀虫有效量的上述化合物的杀虫组合物，使用这类化合物或组合物的方法。
本发明还涉及化合物及其中间体的生产方法，包括在酸性条件下将3-氨基-2-取代苯甲酸、亚硝酸钠和甲醇进行混合，或者混合3.4-稠合杂环苯甲酸和烷基锂试剂，接着再与亲电子试剂进行反应。

Description

生产2-取代-3,4-稠合杂环苯甲酸的方法
本发明涉及可用作杀虫剂的N′-取代-N,N′-二酰肼，含有这些化合物的组合物及其使用方法。本发明也涉及可用于生产这些化合物的中间产物的方法。
由于对具有较高活性、较好选择性、较低的对环境的不利影响、较低的生产和销售成本以及对许多已知杀虫剂具有抗性的昆虫有较强的有效性的化合物需要，人们一直未停止研究，以期找到既具有良好杀虫活性又具有较低的毒性的化合物。
对于作为生产部分本发明N′-取代-N,N′-二酰肼的中间体的3-烷氧基-2-烷基苯甲酸的生产，现有技术中的方法是以由2-烷基-3-氨基苯甲酸的盐酸盐生产3-羟基-2-烷基苯甲酸作为起始步骤。这种放热的苯铵盐酸盐反应存在着反应安全性和物质稳定性方面的问题，并且需要进行受控冷却。这些不利因素造成了在有利中间体生产过程中安全性和成本方面的负担增加。
另外，在可用作生产一些本发明其它N′-取代-N,N′-二酰肼中间体的2-烷基-3,4-亚烷基二氧基苯甲酸的生产中，现有技术的方法涉及到利用活化/保护基代替羧基，并需要额外步骤以将其转化为苯甲酸。
人们一直希望开发出杀虫性质和如上所述的生产方法均得到改善的杀虫化合物，也一直希望开发出用于生产可用于该方法中的中间体的较为安全的方法。本发明提供了经过改进的N′-取代的N,N′-二酰肼，它具有意想不到的高活性，还提供了一种可用于它们的生产的中间体的较为安全的生产方法。将较高的活性、较经济的制备方法和较安全的生产方法结合在一起，使得本发明的应用具有经济方面和环境方面的优越性。
按照本发明，提供了具有式N-(2-Ra-3-Rb-4-Rb-苯甲酰基)-N′-(2-Rc-3-Rd-4-Re-5-Rf-苯甲酰基)-N′-Rg-肼的杀虫化合物，它具有如下所示结构式：其中Ra为卤素或低级烷基；Rb为低级烷氧基，它可任意被卤素(优选氟)取代；Rc选自氢、卤素、低级烷基、低级烷氧基、低级烷氧基低级烷基和硝基；Rd、Re和Rf分别选自氢、溴、氯、氟、低级烷基、低级烷氧基和低级烷氧基低级烷基；Rg为支链C4-6烷基；Rh为氢、低级烷氧基、低级烷基。或与Rb共同形成亚甲基二氧基(-OCH2O-)、1,2-亚乙基氧基(-CH2CH2O-)或1,3-亚丙基氧基(-CH2CH2CH2O-)，其中氧原子位于Rb位；且当取代基Rc和Rd或Rd和Re或Re和Rf一起时，可为亚甲基二氧基或1,2-亚乙基二氧基。
本发明也提供了包含农亚上可接受的载体和杀虫有效量的上述化合物的组合物。本发明化合物和组合物对鳞翅目昆虫具有杀虫活性，其中部分化合物和组合物的不同在于它们既对鳞翅目昆虫又对同翅目昆虫具有杀虫活性。
本发明还提供了较为安全和较为直接地生产上述化合物及其中间体的改进方法，该方法包括将3-氨基-2-(取代)苯甲酸、亚硝酸钠和醇在酸性条件下有效混合，以产生主要含3-烷氧基-2-(取代)苯甲酸的反应产物。
另外还叙述了更直接地产生某些2-烷基-3,4-稠合杂环苯甲酸和2-卤代-3,4-稠合杂环苯甲酸的改进方法，这些化合物是这里所述的某些杀虫化合物的中间体。该方法包括将3,4-稠合杂环苯甲酸和烷基锂试剂混合，然后再与亲电子试剂反应。
卤素为氯、氟、溴或碘。
低级烷基为直链或支链C1-6烷基，如甲基、乙基、正戊基、异戊基、新戊基、正己基、异己基、甲基新戊基(3,3-二甲基-2-丁基)等。
低级烷氧基为直链或直链C1-4烷氧基，可被卤素任意取代，如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、三氟甲氧基、二氟甲氧基等。
低级烷氧基低级烷基以C1-4烷氧基C1-3烷基，如甲氧甲基、乙氧甲基、2-甲氧乙基、2-乙氧乙基等。
本发明的一个具体实施方案是式N′-(2-Ra-3-Rb-4-Rh-苯甲酰基)-N′-(2-Rc-3-Rd-4-Re-5-Rf-苯甲酰基)-N′-Rg-肼的杀虫化合物，其中Ra为卤素，优选溴或氯，或低级烷基，优选C1-3)烷基，更优选甲基或乙基；Rb为低级烷氧基，优选C1-4烷氧基，更优选甲氧基、三氟甲氧基或乙氧基，最优选甲氧基或乙氧；Rc选自氢、溴、氯、氟、低级烷基(优选C1-3烷基，更优选甲基)、低级烷氧基(优选C1-4烷氧基，更优选甲氧基)、C1-2烷氧基C1-2烷基(优选甲氧基甲基)和硝基；Rd、Re和Rs分别选自氢、溴、氯、氟、低级烷基(优选C1-3烷基，更优选甲基)、低级烷氧基(优选C1-4烷氧基，更优选甲氧基)和C1-2烷氧基C1-2烷基(优选甲氧基甲基)；Ra为C4-6烷基，优选叔丁基、新戊基或甲基新戊基，更优选叔丁基；Rh为氢、低级烷氧基(优选C1-2烷氧基)、低级烷基(优选C1-2烷基)，或与Rb-起共同形成亚甲基二氧基、1,2-亚乙基二氧基、1,2-亚乙基氧基或1,3-亚丙基氧基，其中氧原子位于Rb位；且当取代基Rc和Rd或Rd和Re或Re和Rf一起时可共同形成亚甲基二氧基或1,2-亚乙基二氧基。
该实施方案化合物可用结构式表示如下：
Figure C9711844600071
优选其中Rb为甲氧基，Rh为氢，或Rb和Rh共同形成亚甲基二氧基或1,2-亚乙基二氧基，且Rg为叔丁基的杀虫化合物。更优选其中Ra为甲基、乙基、氯或溴，Rb为甲氧基且Rh为氢，或Rb和Rh共同形成亚甲基二氧基或1,2-亚乙基二氧基，Rg为叔丁基，且其中Rc、Rd、Re和Rf中不超过三个取代基是选自溴、氟和氯的同一原子或基因或Rd、Re和Rf中不多于两个的取代基为甲氧基的杀虫化合物。更优选的化合物是其中Rc、Rd、Re和Rf中不多于三个的取代基独自选自氯、氟、甲基和甲氧基，而其余的Rc、Rd、Re和Rf为氢的化合物。最优选Rd和Rf独自选自氯、甲基和甲氧基，且Rc和Re均为氢。
因其高活性和/或低生产成本而优选的化合物包括：
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2,4-二甲氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-苯甲酰基-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4,5-三氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3，甲氧基-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3，甲氧基-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯-3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯-2-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-5-氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2-甲氧基-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-乙氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-甲基-3-三氟甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氟-3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-乙基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2,5-二-4-氟苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2,5-二氟苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二氯苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-甲基-3,4-亚甲二氧基甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-乙氧基-2-乙基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3,4-(1,2-亚乙二氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3,4-(1,2-亚乙二氧基苯甲酰基))-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
优选的其中Rg为C5-6烷基的杀虫化合物中，是其中Rg为新戊基或取代的新戊基的化合物，优选未取代的新戊基或甲基新戊基，优选的新戊基化合物是N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-新戊基肼，N-(3-甲氧基-2-甲基苯甲酰基)-N′(3,5-二甲基苯甲酰基)-N′-(甲基新戊基)肼，N-(3-甲氧基-2-乙基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-(新戊基肼和N′-(3-甲氧基-2-乙基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′(甲基新戊基)肼。
因其对鳞翅目昆虫优良的杀虫活性而更优选的化合物及其组合物包括：
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲氧基-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲氧基-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯-3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯-2-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-5-氯苯甲酰基)-N′-叔丁基肼，
N-(2-甲基-3-甲氧基苯甲酰基)-N′-(3,5-二氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2-甲氧基-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(2,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-乙氧基-2-甲基苯甲酰基)-N′-(3,5-二甲苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3-乙氧基苯甲酰基)-N′-(3,5-二甲苯甲酰基)-N′-叔丁基肼，
N-(2-甲基-3-三氟甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-溴-4-氟苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氟-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-4-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4,5-三氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-乙基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二氯-4-氟苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二氟苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二氯苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2-氯-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-甲基-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-3,4-亚甲二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3,4(1,2-亚乙二氧基)-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3,4-(1,2-亚乙二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
因其对鳞翅目昆虫超常的杀虫活性而尤其优选的化合物及其组合物包括：
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-氯-5-苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,4-二氯苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-乙氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3-甲氧基-5-甲基苯甲酰基)-N′-叔丁基肼，
N-(3-甲氧基-2-甲基苯甲酰基)-N′-(4-氟苯甲酰基)-N′-叔丁基肼，
N-(2-氯-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-溴-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(3,4-(1,2-亚乙二氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3,4-(1,2-亚乙二氧基)苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
因其对同翅目昆虫的杀虫活性而更优选的化合物及其组合物包括：
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-氯-5甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲氧基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2-甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(2-氯苯甲酰基)-N′-叔丁基肼，
N-(3-乙氧基-2-乙基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，
N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3-甲基苯甲酰基)-N′-叔丁基肼，
N-(3,4-(1,2-亚乙二氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼，和
N-(2-乙基-3,4-(1,2-亚乙二氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼。
许多本发明的化合物及与其相关的中间体可利用类似于制备N′-取代的N,N′-二酰肼的已知方法制备。本领域普遍技术人员在了解这里所公开的内容后能够利用或改进这些方法，以调节本发明中间体和化合物中的许多取代基Rc、Rd、Re和Rf。
本发明人已发现一种生产某些中间体的新方法，这些中间体是生产本发明取代基Ra和Rb所需的。该方法在产物及本发明反应的安全性方面达到意想不到的效果，本发明也提供一种简化和经济的方法。该方法包括将3-氨基-2-(取代的)苯甲酸、亚硝酸钠和醇(优选甲醇或乙醇)或水与醇的混合物(优选仅含醇)在酸性条件下有效混合，产生含3-烷氧基-2-(取代)苯甲酸，优选3-甲氧基-2-(取代)苯甲酸或3-乙氧基-2-(取代)苯甲酸的反应基质。
因此，本发明的一个方法实施方案包括混合：
(a)由包括以下成分的组合物：
(ⅰ)3-氨基-2-(取代)苯甲酸或其酯；
(ⅱ)醇或醇与水的混合物，优选甲醇或乙醇；
(b)有效量的无机酸；
(c)亚硝酸钠。总的反应流程可表示如下：
Figure C9711844600211
R3、R4、R5和R6分别为氢、直链或支链C1-10烷基、直链或支链卤代C1-10烷基、直链或支链C1-10烷氧基、直链或支链卤代C1-10烷氧基或卤素取代基。优选R2为与所需化合物取代一致的取代基。优选的3-氨基-2-(取代)苯甲酸为3-氨基-2-甲基苯甲酸或3-氨基-2-乙基苯甲酸。优选的卤素取代基是溴、氯和氟。优选的卤代C1-10烷基是三氟甲基。R3为烷基，优选低级烷基，更优选甲基或乙基，它产生于反应过程所使用的式R3OH的醇。
R7可为氢、直链或支链C1-10烷基或直链或支链卤代C1-10烷基。直链或支链C1-10烷基的非限制性例子可以是作为C4烷基的正丁基，作为支链C4烷基的仲丁基或异丁基。卤代烷基可被一个或多个相同或不同的卤素取代。优选R7为氢或(C1-C4)烷基，更优选氢。对目的产物中R7进行某些取代常常发生，从而产生酸和酯的产物混合物。
酸性条件可通过利用氢溴酸、盐酸、磷酸或硫酸(优选硫酸)创造。酸的量是与所用水或甲醇结合后产生大量所需烷氧化产物的有效量。酸的用量范围从约0.5约5摩尔当量，优选约1-4摩尔当量，更优选约1.5-2.5摩尔当量。
反应基质中所产生的烷氧化产物的量优选至少约为60％(重量)，更优选至少约80％(重量)。
反应基质可包含附加产物，由在3-位具有羟基(OH)的羟基化产物(如“苯酚类化合物”)组成(如3-羟基-2-甲基苯甲酸)。优选的是反应基质中羟基化副产物的含量低于10％(重量)，更优选低于约5％(重量)，最优选基本上不含羟基化产物。
反应基质中也可包含与3-氨基苯甲酸中羧基上“羟基”氧原子结合的取代残基的附加化合物[如， ，其中R3可以是所用醇的烷基部分，如甲基]。
反应温度为从室温至反应混合物的沸点，虽然可以冷却，但并不需要。优选的温度是约0°-100℃，更优选约25℃-75℃，最优选约45℃-65℃。
由于该反应可能产生某些酚类副产物，因此可根据需要采用一附加步骤以转化反应中所产生的任何酚类副产物，它包括随后将含有这类酚类化合物的反应基质与以下物质混合：
(a)有效量的碱，优选氢氧化钠、氢氧化钾、碳酸钠或碳酸钾，更优选氢氧化钠和氢氧化钾，和
(b)有效量的甲基化试剂，优选碳酸二甲酯、甲基、甲基碘或硫酸二甲酯，以便将大量的(优选几乎所有的)酚类化合物转化为3-甲氧苯甲酸或3-甲氧基苯甲酸酯衍生化合物。
碱的用量可优选为约4-6当量，甲基化试剂的用量可优选为约2-4当量。
与具有潜在爆炸危险的现有方法相比，上述方法出人意料地导致了一种更安全且一步直接生产出3-甲氧基苯甲酸的方法。安全性的提高是由于避免了重氮中间体在反应过程中的积累。
本发明还发现了一种用于生产某种中间体的新方法，而这些中间体是在某些稠合至Rb和Rh位的杂环存在的情况产生R2取代基所需的。该方法在产物以及所涉及反应的简便等方面具有意想不到的效果，并且提供的是一种简便、经济的方法。该方法包括在低温下将3,4-稠合的杂环苯甲酸与烷基锂试剂有效混合，然后加入亲电子剂，产生出含有2-取代的3,4-稠合的杂环苯甲酸的反应基质。因此，该反应允许在羧基存在的情况下对某些苯甲酸衍生物进行部位直接锂化，避免使用其它激活/保护基来代替羧基。
相应地，本发明的第二个方法实施方案包括在-90℃至-20℃将下列(a)、(b)、(c)混合约1-4小时：
(a)含有以下成分的组合物
(ⅰ)3,4-稠合的杂环苯甲酸和
(ⅱ )非质子传递溶剂，和
(b)含有以下成分的组合物
(ⅰ)烷基锂试剂和
(ⅱ )非质子传递溶剂，接着于-90℃至室温与以下成分混合：
(c)亲电子试剂
总的反应流程可表示如下：
Figure C9711844600241
R8和R9可各自为氢、直链或支链C1-10烷基或直链或支链C1-10烷氧基。优选R8和R9为氢。X可为亚甲基(CH2)、氧(O)、硫(S)或N-R12，其中R12可为直链或支链C1-10烷基。Y可为氧、硫或N(当N与相连碳原子形成双键时)。优选X为O或CH2且Y为O。由n代表的亚甲基链的长度可为1-3，优选1或2。
锂化试剂R10Li可以是正丁基锂、仲丁基锂、叔丁基锂或苯基锂，优选正丁基锂。
非质子传递反应溶剂可以是四氢呋喃、乙醚、1,4-二恶烷、乙烷或它们的混合物，优选四氢呋喃。
反应混合物也可含有附加的锂螯合剂，如四甲基亚乙基二胺(TMEDA)。
亲电子剂由式R11Z表示，其中R11为低级烷基，优选甲基或乙基、全卤烷基，或为氯、溴或碘等卤素，Z为卤素(如氯、溴或碘)、烷基卤基(如乙酰基或丙酰基)、烷基羰氧基(如乙酰氧基)或甲酰基。更优选的亲电子剂是低基烷基碘化物，如碘代甲烷或碘代乙烷。
邻位-锂化的反应温度可为约-90℃至约-20℃，优选约-50℃至约-80℃。
邻位锂化的反应时间可为约1-4小时，优选约2小时。
亲电子试剂反应的反应温度可为约-90℃至约室温。优选于约-65℃加入亲电子试剂，且反应混合物被允许在不另外加热的情况下温热至室温。
亲电子试剂反应的反应时间可为约30分钟至约2小时。
该方法意想不到地导致了一种简单的一步生产2-取代的苯甲酸的方法，该化合物也在3和4位带有稠合杂环。该方法尽量减少了导致产生不希望有的二苯酮的烷基锂试剂与羰基的反应，并且不需要其它活化/保护基来代替羧基。
可利用与用作杀虫剂的N′-取代的N,N′-二酰肼有关的现有技术中的已知成盐方法，合成出本发明杀虫化合物的农药上可接受的盐。
本发明化合物在作为杀虫剂使用时显示出意想不到的良好结果。本领域熟练技术人员将能够测定出给定化合物对于给定昆虫的活性以及获得意想不到的良好杀虫效果所需的剂量。对于具体情况下的具体剂量可按常规方式确定，用于该目的的组合物和配方以及所需的附加成分(如农业上可接受的载体、稀释剂、补充剂和杀虫组合物中常用的其它添加剂)也可按已知方式确定。
相应地，另一个实施方案是一种杀虫组合物，它包含一种或多种具有式N-(2-Ra-3-Rb-4-Rh-苯甲酰基)-N′-(2-Rc-3-Rd-4-Re-5-Rf-苯甲酰基)-N′-Rg-肼的化合物，其中Ra为为卤素或低级烷基；Rb为低级烷氧基，它可被卤素(优选氟)任意取代；Rc选自氢、溴、氯、氟、低级烷基、低级烷氧基、低级烷氧基低级烷基和硝基；Rd、Ra和Rf各自独自选自氢、溴、氯、氟、低级烷基、低级烷氧基和低级烷氧基低级烷基；Rg为C4-6烷基；Rh为氢、低级烷氧基、低级烷基或与Rb一起形成亚甲二氧基(-OCH2O-)、1,2-亚乙二氧基(-OCH2CH2O-)、1,2-亚乙氧基(-CH2CH2O-)或1,3-亚丙氧基(-CH2CH2CH2O-)，其中氧原子位于Rb位；且当取代基Rc和Rd或Rd和Re或Re和Rf结合在一起时可为亚甲二氧基或1,2-亚乙二氧基。优选的组合物具有如上提出的优选化合物。
另外还实施了一种控制昆虫的方法，包括将昆虫与杀虫有效量的式N-(2-Ra-3-Rb-4-Rh-苯甲酰基)-N′-(2-Rc-3-Rd-4-Re-5-Rf-苯甲酰基)-N′-R3-肼化合物接触，其中Ra为卤素或低级烷基；Rb为低级烷氧基，它可被卤素(优选氟)任意取代；Rc选自氢、溴、氯、氟、低级烷基、低级烷氧基、低级烷氧基低级烷和硝基；Rd、Re和Rf各自独立选自氢、溴、氯、氟、低级烷基、低级烷氧基和低级烷氧基低级烷基；Rg为C4-6烷基；Rh为氢、低级烷氧基、低级烷基或与Rb共同形成亚甲二氧基(-OCH2O-)、1,2-亚乙二氧基(-OCH2CH2O-)、1,2-亚乙氧基(-CH2CH2O-)，其中氧代原子位于Rb位；且当取代基Rc和Rd或Rd和Re或Re和Rf结合在-起时可为亚甲氧基或1,2-亚乙二氧基、优选的方法将利用上面所述的优选化合物。在一优选的方法中，Ra为甲基、乙基、氯或溴，Rb为甲氧基且Rh为氢或当R6和Rh结合在一起时为亚甲二氧基或1,2-亚乙二氧基，R为叔丁基，且其中Rc、Rd、Re和Rf中不多于三个的取代基是选自溴、氟和氯的相同成分，或Rd、Re和Rf中不多于两个的取代基为甲氧基。
以下实施例说明了3-烷氧基-2-烷基苯甲酸、3,4-稠合的杂环苯甲酸、中间体以及本发明代表性化合物的制备方法。实施例1:3-甲氧基-2-甲基苯甲酸的制备
将3-氨基-2-甲基苯甲酸(140.3g,0.93mole)分四部分在5.7质量当量的甲醇中反应，用1.5摩尔当量的浓硫酸处理。加热该混合物至55℃，并在30-45分钟内，将溶于两倍于其质量的水中1.05摩尔当量的亚硝酸钠加入其中，并维持温度在55-65℃。然后于50-60℃，在半小时内加入4.5摩尔当量25％氢氧化钠水溶液，接着在半小时内加入2摩尔当量硫酸二甲酯。半小时后通过气相色谱(GC)检测反应混合物。分批加入额外的氢氧化钠和硫酸二甲酯，直至观察到完全的转化。真空除去剩余的醇，残余物在乙酸乙酯和水(用硫酸使其成酸性)之间分配。真空下除去乙酸乙酯，将溶于350g热甲醇中的合并残余物(152.8g)倒入298g浓硫酸和1升水的混合物中。过滤收集所产生的沉淀，水洗并真空干燥，得到135.8g产物，经GC测得其纯度为96％。实施例2:3-氯-5-甲基苯甲酸的制备
将含有3,5-二甲基氯苯(25g,180mmol)、四水合乙酸钴(Ⅱ)(1.1g,4.5mmol)和溴化钠(0.46g,4.5mmol)及50ml乙酸的混合物加热至85℃，同时鼓入空气泡，55小时后，通过GC测定反应是否完全。冷却至室温，过滤反应混合物。将滤液在水(500ml)和乙酸乙酯(200ml)间分配。用2×100ml乙酸乙酯萃取水相。水洗合并后的有机相，然后用4％氢氧化钠水溶液(3×200ml)萃取。用冰冷却碱性水相，并用浓盐酸酸化。通过真空过滤收集所产生的白色沉淀并干燥，得到15.5g白色固体(mp175-177℃)，通讨NMR和GC测得它与3-氯-5-甲基苯甲酸结构一致。实施例3:3-氨基-2-甲基苯甲酸的制备
于55Lb/Psi下将2-甲基-3-硝基苯甲酸(m.p.182-184℃，22g,0.12mole)于400ml甲醇中的溶液在氧化铂(100mg)上氢化45分钟，然后在Celite(50g)床上过滤掉催化剂，并减压蒸发溶剂，得到3-氨基-2-甲基苯甲酸(mp.178-181℃)产率为18.3g。实施例4:3-甲氧基-2-甲基苯甲酸的制备
在装有机械搅拌器和温度计的1L三颈圆底烧瓶中，将磨碎的3-氨基-2-甲基苯甲酸(17g,0.11mole)与甲醇(120ml)混合。搅拌下向该混合物中滴加15.5ml浓硫酸。加毕，混合物的温度升至50℃。加入时间为2分钟。加毕。将烧瓶置于预热过的油溶中，并维持烧瓶内部温度在50-55℃。然后开始滴加亚硝酸钠溶液(8.1g于17ml水)。温度达到62℃后，关掉油溶下的加热。l0分钟后，温度降至55℃，此时在30分钟内滴加用水(55ml)稀释的氢氧化钠(50％,55g)，然后在30分钟内将水(55ml)一次性和硫酸二甲酯(25ml)分两次(15ml和10ml)加入，时间间隙为20分钟。混合物冷却至室温后倒入用水(360ml)稀释的浓硫酸(40ml)，过滤收集产物并真空干燥24小时，得到3-甲氧基-2-甲基苯甲酸(12g)。1H-NMR(CDCl3)ppm2.50(S,3H),3.85(S,3H),7.03(d,1H,Ar),7.22(dd,1H,C-5),7.59(d,1H,Ar)。实施例5:3-甲氧基-2-甲基苯甲酰氯的制备
于65℃，在6小时内向含有20g二甲基甲酰胺的1300ml氯仿中的3-甲氧基-2-甲基苯甲酸(454g,2.73mole)中滴加亚硫酰氯(390g)，然后减压蒸发掉溶剂，于110℃ 1-2mmHg下蒸馏残余物(512g)后得到3-甲氧基-2-甲基苯甲酰氯(435g)。实施例6:N-(3,5-二甲基苯甲酰基)-N-叔丁基肼的制备
将叔丁基肼(290g,2.33moles)于甲苯(830ml)中的悬浮液在冰浴中冷却至5℃。在30分钟内缓慢加入与冰(180g)混合的氢氧化钠(50％；180g,2.25moles)。2小时内向其中加入碳酸二叔丁酯(500g,2.29moles)，并将反应温度保持在接近5℃，之后，加热反应至室温并搅拌过夜。用水和盐水洗涤有机层，于硫酸镁上干燥，过滤并汽提。粗产物经已烷重结晶后得到一固体(338.7g，其熔点为83-86℃)。于7℃以使反应混合物维持在5-9℃的速率，向该固体(320g,1.69mol)的甲苯(11)溶液中连续加入3,5-二甲基苯甲酰氯(268g,159mol)和氢氧化钠(50％水溶液，127.23g,1.59mol)。加完后(2h)，并过滤产物。通过用水和盐水洗涤滤液有机部分，蒸发溶剂和用已烷研磨后得到附加产物。将合并后的滤饼(470g,1.5mol)悬浮在甲醇(1500ml)中，并以使温度维持在35℃以下的速率用37％盐酸(357ml,3.62mol)处理，于冰上冷却。加毕，搅拌反应混合物72小时。再加入另一部分盐酸(50ml)，并轻微搅拌，然后用碳酸氢钠中和。过滤产物，水洗并干燥，得到256gN-(3,5-二甲基苯甲酰基)-N-叔丁基肼。1H-NMRppm1.47(s,9H,t-Bu)2.31(s,6H),3.73(s,2H,NH2),7.00(s,1H,C-4),7.05(S,2H,Ar-C-2和6)。实施例7：由实施例4和6的产物制备N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼。
将3-甲氧基-2-甲基苯甲酸(1.5g,0.01mole)于亚硫酰氯(10ml)中的溶液回流45分钟，然后减压汽提残余物溶于二氯甲烷(50ml)中，并在冷却至0℃的情况下滴加至N-N-(3,5-二甲苯甲酰基)-N-叔丁基肼(4.4g,0.02mole)的二氯甲烷(50ml)溶液中。加毕，于室温下过夜搅拌溶液，并过滤。滤饼用水和乙醚充分洗涤，然后真空干燥，得到2.1gN-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲苯甲酰基)-N′-叔丁基肼，熔点为204-204.5℃。1H-NNRδppm1.5(S,9H,tert-Bu),1.63(S,3H,Ar-CH3),2.25(S,6H,di-CH3),3.75(s,3H,OCH3),6.26(d,1H,Ar),6.93-7.20(m,5H,Ar)。实施例8：由实施例5产物制备N-(3-甲氧基-2-甲基苯甲酰基)-N′-叔丁基肼
 于0℃向叔丁基肼盐酸盐(397g,3.27mole)于二氯甲烷(2l)的搅拌悬浮液中加入用水(400ml)稀释的氢氧化钠(50％水溶液，260g)。然后于-20℃同时加入3-甲氧基-2-甲基苯甲酰氯(140g,0.78mole)的二氯甲烷(1l)溶液和用水(400ml)稀释过的氢氧化钠(50％水溶液，80g)。加毕，加热反应混合物至室温，30分钟后水洗(4×500ml)有机层，再经硫酸镁干燥和汽提后得到N-(3-甲氧基-2-甲基苯甲酰基)-N′-叔丁基肼(177g)。1H-NMR(CDCl3)δppm1.19(s,9H,t-Bu),2.29(s,3H,CH3),3.87(s,3H,OCH3),6.90(d,1H,C-4或6),6.95(d,1H,C-4或6)7.19(dd,1H,C-5)。实施例9：由实施例8产物制备N-(3-甲氧基-2-甲基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼。
于5℃以使混合物的温度不超过10℃的速率，向N-(3-甲氧基-2-甲基苯甲酰基)-N′-叔丁基肼(506g,2.14mole)的二氯甲烷(1.51)搅拌溶液中同时加入3.5-二甲基苯甲酰氯(360g,2.14mole)的二氯甲烷(500ml)溶液和用水(400ml)稀释的氢氧化钠(50％水溶液，171.2g,2.14mole)、加毕，使反应混合物达至室温，并连续搅拌1小时，然后用二氯甲烷(121)稀释反应混合物，经水洗、硫酸镁干燥、过液和汽提后，得到N-(3-甲氧基-2-甲基苯酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼(663g)，熔点204-204.5℃。实施例10:2-(3-甲氧苯基)-5,5-二甲基噁唑啉的制备
向装有温度计、冷凝管、加料漏斗和磁力搅拌器的500ml三颈圆底烧瓶中加入43.2g(253mmole)间-茴香酰氯的500ml二氯甲烷溶液。于冰上冷却溶液，并在搅拌下缓慢加入2-甲基-氨基丙醇(56.4g,60.4ml,633mmole)的50ml二氯甲烷溶液。将混合物温热至室温并搅拌过夜。过液掉固体，并真空除去溶剂。在冰冷下向剩下的油状物中加入亚硫酰氯(90.8g,55.7ml,763mmoles)，于室温搅拌混合物1小时，倒入1l乙醚中，弃掉乙醚，并在冰冷下将剩余油小心倒入100ml20％氢氧化钠中。经乙醚数次萃取后，合并有机相，于硫酸镁上干燥，并真空除去溶剂，得到粘性黄色油状物。经柱色谱(1∶1乙醚、己烷)或蒸馏(5mmHg,b,p·=150℃)纯化该粗品后得到一低熔点固体。实施例11:2-乙基-3-甲氧基苯甲酸的制备
将装有加料漏斗、顶端搅拌器和氮气出口的5L四颈圆底烧瓶干燥，并加入128g(623mmole)2-(3-甲氧苯基)-5,5-二甲基恶唑啉的2.5l四氢呋喃溶液。混合物于干冰，异丙醇浴上冷却至-65℃，并缓慢加入450ml 1.6N正丁基锂，加毕，于-45℃-30℃搅拌混合物1.5小时。冷却至-45℃后，加入碘代乙烷(80ml,1mole)。将温度维持在-45℃20分钟后温热至室温，并过夜搅拌。在冰冷却下加入饱和氯化铵，混合物用乙醚数次萃取。合并有机萃取物，于硫酸钠上干燥，并经真空除去溶剂后得到油状固体。将固体溶于1L6N盐酸于3∶1水∶甲醇中的溶液中，回流加热15小时。通过1HNMR监测水解并显示出75％水解完全。再加入酸(200ml于3∶1水∶甲醇中的6N盐酸)，再次回流加热混合物8小时，于冰上冷却混合物，收集固体，溶于10％氢氧化钠水溶液/二氯甲烷。除去水层，酸化并过滤后得到褐色固体，将其于室温下风干(53g)。通过进一步酸水解二氯甲烷萃取物后得到另外23g产物，所需酸的熔点为100-101℃。实施例12:N-(2-乙基-3-甲氧基苯甲酰基)-N′-(3,5-二甲基苯甲酰基)-N′-叔丁基肼的制备
将2-乙基-3-甲氧基苯甲酰氯(0.52g,2.9mmol)和2ml亚硫酰氯加入-25ml的圆底烧瓶中，混合物加热回流2小时，真空除去剩余的亚硫酰氯，得到2-乙基-3-甲氧基苯甲酰氯，为褐色固体。
将此酰氯和0.60g(2.72mmol)N-叔丁基-N-3,5-二甲基苯甲酰基肼溶于5ml二氯甲烷，在一冰浴中冷却，再加入碳酸钾(0.83g,6.0mmol)于2ml水中的溶液，将此混合物在0℃下缓慢搅拌几小时，然后再在室温下搅拌过夜。移出二氯甲烷层，混合物再用二氯甲烷提取一次。合并有机相，用硫酸镁干燥，蒸发掉溶剂。得到的固体用乙醚/正己烷(1∶1)洗涤几次，然后在70℃干燥1小时，得到10g标题化合物，m.p.146℃。实施例13:2-乙基-3-甲氧基-4-甲基苯甲酸的制备
将按实施例10类似方法合成的2(2-乙基-3-甲氧基-4-甲氧基)-5,5-二甲基噁唑啉(2.7g,13.1mmol)和2.2ml(35.3mmol)甲基碘溶于4ml二甲亚砜，此混合物在室温下搅拌18小时，加入4.2g氢氧化钾于35ml水中的溶液后，回流加热8小时。加入40g冰后用乙醚提取。水层在冰上冷却后用5％的盐酸酸化。过滤出所得的沉淀并经空气干燥，得到1.69g产品。1H NMR(200MHz,CDCl3)δ=7.72(1H,d,8Hz),7.1(1H,d,8Hz),3.77(3H,S),3.06(2H,q,7Hz),2.36(3H,S),1.22(3H,t,7Hz)ppm。实施例14:2-甲基胡椒基酸的制备
将装有吹氮装置、隔片入口和磁性搅拌器的250ml圆底烧瓶经氮气氛下干燥，然后加入2.5g(15mmol)胡椒基酸和100ml四氢呋喃，将此溶液冷却至-70℃，加入正丁锂(1.6M,22ml,35.2mmol)。混合物在-70℃下搅拌2小时。在≤-65℃下加入甲基碘(3ml,48.2mmol)，于-70℃下搅拌1小时，此后让溶液温热至0℃。反应用饱和氯化铵溶液终止，分出有机层，用稀盐酸酸化，得到1.37g产品。水相和有机相的酸化共得到2.67g黄色粉状固体。1H NMR(200MHz,DMSO-db)δ=7.5(1H,d,8Hz),6.83(1H,d,8Hz),6.08(2H,s),2.37(3H,s)ppm。实施例15:2-异丙基-3-甲氧基苯甲酸的制备
将装有吹氮装置、隔片入口和磁性搅拌的500ml圆底烧瓶经氮气氛干燥后加入5g(21.2mmol)2(2,3-二甲氧基苯基)-5,5-二甲基噁唑啉(按实施例10类似方法合成)和100ml四氢呋喃。此溶液经冷却至10℃后加入58ml的2N氯化异丙镁/乙醚。在室温下将此混合物搅拌过夜，倾入饱和氯化铵/冰(1∶1)的混合物中，然后用乙醚提取2次。合并有机层，以硫酸镁干燥，真空除去溶剂，得到5.3g黄色油状物。将油状物溶于200ml的6N盐酸中，加热回流8.5小时。用乙醚提取几次，合并的有机相以硫酸钠干燥，真空除去溶剂，得到4.6g油状物，静置后结晶。1H NMR(200MHz,CDCL3)δ=7.29(1H,dd,1.5,7.5Hz),7.21(1H,t,7.5Hz),7.01(1H,dd,1.5.7Hz),3.85(3H,s),3.65(1H,m),1.37(6H,d,7Hz)ppm。实施例16:1,4-苯并二噁烷-6-羧酸的制备
将1,4-苯并二噁烷-6-羧甲醛(8.87g,54mmol)、19.68g甲醇、50.3wt％氢氧化钠(5.99g)和30％过氧化氢水溶液(5.30g,46.8mmol)在-250ml的圆底瓶中于油浴温度39-52℃下加热17分钟，然后于52-58℃下加热18分钟。在不激烈的泡沫消退后，加入30％的过氧化氢水溶液(13.54g,119mmol)，加入是在58-66℃下分成约相等的三份，历时22分钟。12分钟后，再加入2份30％的过氧化氢溶液(分别为4.24g和5.25g；共加入了28.33g或250mmol)，间隔时间20分钟。每次加入都放出缓和的瞬时氧。混合物于67-47℃下加热搅拌55分钟。溶液经冷却后加23.62g去离子水。用二氯甲烷(其10.1g)将中性油(2.12g，主要是未反应的原料)提取四次弃除。提取后的水层用37％的盐酸水溶液酸化，将得到的膏浆摇匀。过滤物用水洗涤3次，每次20g，干燥后得到1,4-苯并二噁烷-6-羧酸白色晶体(6.97g),m.p.134.2-136.7℃。实施例17:5-乙基-1,4-苯并二噁烷-6-羧酸的制备
将1,4-苯并二噁烷-6-羧酸(6.59,36.6mmol)于96.5g干(0.02％水份)四氢呋喃中的溶液在-装有磁性搅拌器、酒精温度计和用大直径注射器针连于氮气管的橡胶隔片柱塞的300ml烧瓶中搅拌并冷却。混合物冷却至-71℃(干冰/异丙醇浴)时，在约1分钟的时间内加入2.5mol正丁锂于正己烷中的溶液(16.7ml)，此时放热，温度升至-28℃。保持冷却16分钟后，于-70至-61℃用5次增量再加正丁锂溶液(共计35ml)。这些正丁锂的加入溶解了原溶液冷却后沉淀出的微小固体。6分钟后，加入16.3g四氢呋喃以期溶解剩余的固体。在最后一次加入正丁锂后于-62至-72℃下将悬浮液进行搅拌，总计4.2小时。然后在-65℃下加入99％的碘乙烷(7.17g,46.0mmol)，此时有微弱放热，在约-60℃经19分钟后，混合物经89分钟温热至14℃，又另经16小时温热至室温。然后加入50.6g去离子水，分离出得到的强碱性水层(67.4g)，有机层用15.3g去离子水/0.85g的50.3％氢氧化钠水溶液洗涤，弃去有机层(含约3.1g中性胶质副产物)。水层和洗涤液经酸化后用正己烷/乙醚提取，得到的粗产物含61％(面积)原料酸和26％5-乙基-1.4-二噁烷-6-羧酸(气相色谱法分析)。
将粗产物溶于乙醚/正己烷(约14g)中，经八级部分中和/提取入氢氧化钠稀水溶液进行纯化(存留在有机相中的主要是乙基化的酸)，得到5-2基-1.4-苯并二噁烷-6-羧酸(0.54g)。经气相色谱分析，其纯度约为88％．m.p.148-176℃。质子核磁共振图谱显示乙基化和未乙基化1,4-苯并二噁烷-6-羧酸的重量比为92∶8。生物试验法
采用下述试验步骤评定本发明化合物的杀虫活性。
将本发明的化合物溶于1∶1的丙酮/甲醇溶液制成600ppm的试验溶液，然后加水得到5∶5∶90的丙酮/甲醇/水溶液，最后加表面活性剂，其量相当于每100加仑试验溶液1盎司表面活性剂。
叶面杀虫活性的评定是以-种或两种下述昆虫进行的：南方粘虫(SAW)-Spodoptera eridania和蚕豆微叶蝉(PLH)-Empoasca fabae。整株试验
整体植物的南方粘虫试验是将各盆栽利马豆植物phaseolus limensis var.Henderson用De Vilbiss No.52型手摇喷雾器喷洒试验溶液至滴流(每公顷100加仑)。干后，将两片植物叶子取下置于陪氏培养皿(100×20mm)中的湿润滤纸上。培养皿以10只南方粘虫三令幼虫感染，然后加盖。如果幼虫在处理或三天存活，则置换滤纸，加入新的未处理的豆叶，所有的处均保持在75-80°F的通风良好的有荧光灯的室内。百分死亡率的测定是在处理后三天和六天。
整体植物的蚕豆微叶蝉试验是用De Vilbiss No.152型手摇喷雾器将试验溶液喷洒在盆栽的fava豆植物Vicia faba varLong Pod上，直至滴流(每公顷100加仑)，经干燥后，取下雨片植物叶置于两个陪提氏培养皿(50×9mm)中的湿润滤垫上，每皿一叶。每皿以5只马铃薯三令蛹感染，然后加盖盖严。所有处理保持在75-80°F有荧光灯的通风良好的室内。处理后三天测定百分死亡率。分离叶试验
分离叶的南方粘虫试验是将单个的利马豆Phaseolus limensis Var.Woods′Prolific叶置于陪提氏培养皿(100×20mm)中的湿润滤纸上。用旋转盘喷雾器将试验溶液喷在叶片上并让其滴干，培养皿以10只南方粘虫三令幼虫感染，然后加盖。如幼虫在处理后两天存活，则加入新的未处理的豆叶。所有处理保持在75-80°F有荧光灯的通风良好的室内。处理后两天和四天测定其百分死亡率。
下面的表中例举出(但不限于此)本发明的优先选择的化合物。
在表ⅠA、ⅠB和ⅠC中，SAW(6天)一栏是本发明化合物的两种不同浓度(10和25ppm)以及在整体植物试验中在该浓度下6天后观察到的南方粘虫幼虫的百分死亡率，除非另外指明。
                   表ⅠA-化合物1-72
                                             SAW(6天)化合物号  Ra   Rb   Rc   Rd   Re   Rf  10ppm    2.5ppm1     CH3  OCH3  H     CH3  H     CH3 100      1002     CH3  OCH3  H     CH3  H     H    NT(1)    1003     CH3  OCH3  H     H     H     H    100       1004     CH3  OCH3  Cl    H     Cl    H    NT        1005     CH3  OCH3  Cl    H     H     CH3 NT        1006     CH3  OCH3  Cl    H     H     H    100       107     CH3  OCH3  H     H     F     H    100       1008     CH3  OCH3  H     H     Cl    H    NT        1009     CH3  OCH3  Br    H     H     H    100       010    CH3  OCH3  Cl    H     F     H    100       9011    CH3  OCH3  H     Cl    Cl    H    100       10012    CH3  OCH3  H     Cl    H     Cl   100       10013    CH3  OCH3  H     OCH3 H     H    100       10014    CH3  OCH3  F     H     F     H    100       2015    CH3  OCH3  OCH3 H     H     H    100       3016    CH3  OCH3  H     H     CH3  H    100       10017    CH3  OCH3  H     Cl    H     H    100       10018    CH3  OCH3  H     CH3  CH3  H    NT        10019    CH3  OCH3  H     F     H     F    100       10020    CH3  OCH3  H     Br    H     H    100        6021    CH3  OCH3  H     Cl    H     CH3 NT        10022    CH3  OCH3  H     OCH3 H     CH3 NT        10023    CH3  OCH3  H     OCH3 CH3  H    100       10024    CH3  OCH3  H     CH3  Cl    H    100       10025    CH3  OCH3  OCH3 H     Cl    H    100       10026    CH3  OCH3  H     Br    H     CH3 NT        10027    CH3  OCH3  H     Br    H     Cl   100       10028    CH3  OCH3  H     Cl    F     H    100       10029    CH3  OCH3  H     F     H     H    100       10030    CH3  OCH3  H     F     F     H    100       100
                                               SAW(6天)化合物号  Ra     Rb    Rc   Rd     Re     Rf   10ppm   2.5ppm31     CH3   OCH3   OCH3 H       CH3     H       NT      10032     CH3   OCH3    H     Cl      Cl       Cl      100     10033     CH3   OCH3    H     F       F        F       100     10034     CH3   OCH3    H     OCH3   CH3   OCH3    100     10035     CH3   OCH3   OCH3  H        H      CH3    100      036     Br     OCH3    H     CH3     H      CH3     NT      10037     Cl     OCH3    H     CH3     H      CH3     NT      10038     CH3   OCF3    H     CH3     H      CH3     NT      10039     CH3   OC2H5  H     CH3     H      CH3     NT      10040     CH3   OCH3    H    -OCH2O-  H      100      1041     CH3   OCH3    OCH3 H        H      CH3    100       7042     CH3   OCH3    NO2  H        H      H        100      1043     CH3   OCH3    H     OCH3    H      OCH3    100      10044     CH3   OCH3    OCH3 H        H      Cl       100      1045     CH3   OCH3    CH3  H        CH3   H        100      5046     CH3   OCH3    H     Br        F      H        NT      10047     CH3   OCH3    H     F         CH3   H        NT      10048     CH3   OCH3    H     Br        OCH3  Br       100     NT49     CH3   OCH3    F     F         F       H       100     1050     CH3   OCH3    H     Cl        CH3   H        NT      10051     CH3   OCH3    H     Cl        OCH3  H        100     10052     CH3   OCH3    H     C2H5   H       H       100     10053     CH3   OCH3    H     Cl        F       Cl      100     10054     C2H5 OCH3    H     CH3      H      CH3    100     10055     C2H5 OCH3    H     Cl        H      CH3    100     10056     C2H5 OCH3    OCH3 H         H      H        100     8057     C2H5 OCH3    H     F         H       F       100     10058     C2H5 OCH3    H     OCH3     H       H       100     10059     C2H5 OCH3    H     CH3      H       H       100     10060     C2H5 OCH3    Cl    H         H       H       100      5061     C2H5 OCH3    H     Cl        H       Cl      100      10062     CH3   OCH3    H     CH2OCH3 H       CH3   100      10
                                            SAW(6天)化合物号  Ra     Rb   Rc  Rd   Re  Rf    10ppm   2.5ppm63     C2H5 OCH3 Cl    H     Cl    H      100      10064     CH3   OCH3 H     OC2H5H    H      100      1065     C2H5 OCH3 Cl    H     H     CH3   100      10066     CH3   OCH3 NO2  H     H     CH3   100      9067     Cl     OCH3 H     CH3  H     H       NT       100(2)68     Cl     OCH3 H     H     H     H       NT       80(2)69     Cl     OCH3 Cl    H     Cl    H       NT       70(2)70     Cl     OCH3 Cl    H     H     CH3   100      1071     Cl     OCH3 CH3  H     CH3  H      100      10072     C2H5OC2H5H    CH3  H     CH3   100      401NT指化合物在该指定浓度下未经试验2用分离叶法试验，4天后进行观察
                  表ⅠB-化合物73-78
                               SAW(6天)化合物号      Ra       n       10ppm   2.5ppm73            CH3      1        100      10074            C2H5    1        100      10075            Cl        1        100      10076            Br        1        100      10077            CH3      2        100      10078(2)        C2H5    2        100      100(2)用分离叶法试验，4天后进行观察表ⅠC-化合物79
Figure C9711844600432
SAW(6天)10ppm  2.5ppm100      100
表Ⅱ的PLH(3天)一栏是用浓度为10ppm的本发明化合物处理后的蚕豆微叶蝉观察死亡率表Ⅱ-对蚕豆微叶蝉的试验结果化合物号              PLH(3天)at10ppm54                       10055                       10056                       10058                        8059                       10060                        9072                        6077                        9078                        90
应知道，本发明说明书和实施例是为了说明而不是给予限制，各种变型和改变都不离开本发明的精神和范围，如所附权利要求所限定。

Claims (5)

1．一种生产2-烷基-3,4-稠合杂环苯甲酸或2-卤-3,4-稠合杂环苯甲酸的方法，包括在-90℃至-20℃的温度下混合3,4-稠合杂环苯甲酸和一烷基锂试剂，接着再在-90℃至室温的温度下进行与亲电子试剂的反应。
2．权利要求1的方法，它生产的化合物是2-烷基-3,4-稠合杂环苯甲酸。
3．权利要求2的方法，其中3,4-稠合杂环苯甲酸具有通式
Figure C9711844600021
其中，R8和R9各自独立地为氢，直链或支链C1-C10烷基，或者是直链或支链的C1-C10烷氧基，
X为亚甲基，氧，硫或N-R12，其中R12为直链或支链C1-C10烷基，
Y为氧，硫，或N、当N与相连碳原子形成双键时，和
n为1-3。
4．权利要求3的方法，其中亲电子试剂是甲基碘或乙基碘。
5．权利要求4的方法，其中2-烷基-3；4-稠合杂环苯甲酸是具有以下通式的2-甲基-1,4-稠合杂环苯甲酸或2-乙基-3,4-稠合杂环苯甲酸，
Figure C9711844600022
其中，R8和R9各自独立地为氢，直链或支链C1-C10烷基，或者是直链或支链的C1-C10烷氧基，
X为亚甲基，氧，硫或N-R12，其中R12为直链或支链C1-C10烷基，
R11为甲基或乙基，
Y为氧，硫，或N、当N与相连碳原子形成双键时，和
n为1-3。
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DE69324552T2 (de) 1999-12-23
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US5530028A (en) 1996-06-25
AU5063593A (en) 1994-06-02
CA2103110A1 (en) 1994-05-24
CN1176251A (zh) 1998-03-18
CN1038673C (zh) 1998-06-10
KR940011414A (ko) 1994-06-21
EP0602794A2 (en) 1994-06-22
NZ280487A (en) 1998-02-26
DE69324552D1 (de) 1999-05-27
NZ250170A (en) 1997-08-22
PH31254A (en) 1998-06-18
IL107533A0 (en) 1994-02-27
AU683224B2 (en) 1997-11-06
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CA2103110C (en) 2004-09-14
GR3030029T3 (en) 1999-07-30
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KR100317793B1 (ko) 2002-11-27
CN1116271C (zh) 2003-07-30
CN1176245A (zh) 1998-03-18
EP0729934A3 (en) 1997-02-26
HRP931427A2 (en) 1996-06-30
IL107533A (en) 1999-01-26
EP0729953A3 (en) 1997-02-26
ATE179166T1 (de) 1999-05-15
EP0729934A2 (en) 1996-09-04
EP0729953A2 (en) 1996-09-04
HUT75039A (en) 1997-03-28
EP0602794B1 (en) 1999-04-21
DE69324552T4 (de) 2006-05-04
BR9304789A (pt) 1994-07-05
BG98232A (en) 1995-02-28
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CN1182075A (zh) 1998-05-20

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