CN104994733B - 制备4‑氨基‑5‑氟‑3‑氯‑6‑(取代的)吡啶甲酸酯的方法 - Google Patents

制备4‑氨基‑5‑氟‑3‑氯‑6‑(取代的)吡啶甲酸酯的方法 Download PDF

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CN104994733B
CN104994733B CN201380064521.7A CN201380064521A CN104994733B CN 104994733 B CN104994733 B CN 104994733B CN 201380064521 A CN201380064521 A CN 201380064521A CN 104994733 B CN104994733 B CN 104994733B
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J·M·伦加
G·T·惠特克
P·L·约翰逊
C·加利福德
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Abstract

4‑氨基‑5‑氟‑3‑氯‑6‑(取代的)吡啶甲酸酯由三氟乙酸、对‑甲氧基苯胺、3,3‑二烷氧基丙‑1‑炔和取代的亚甲基胺通过一系列步骤制备。具体地，本申请提供无需金属辅助的偶联且无需用昂贵的氟化剂进行氟化的情况下，由非吡啶来源制备4‑氨基‑5‑氟‑3‑氯‑6‑(取代的)吡啶甲酸酯的方法。这些吡啶甲酸酯可用作除草剂。

Description

制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯的方法
相关申请的交叉引用
本申请要求2012年12月13日提交的美国临时专利申请61/736,835的优先权，其公开内容通过参考明确并入本申请。
技术领域
本申请提供了制备4-氨基-5-氟-3-卤代-6-(取代的)吡啶甲酸酯的方法。更特别地，本申请提供了由非吡啶来源制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯的方法。
背景技术
美国专利6,784,137 B2和7,314,849 B2特别描述了某些4-氨基-3-氯-5-氟-6-(芳基)吡啶甲酸酯化合物以及它们作为除草剂的用途。美国专利7,432,227 B2特别描述了某些4-氨基-3-氯-5-氟-6-(烷基)吡啶甲酸酯化合物以及它们作为除草剂的用途。这些专利的每一篇均描述了如下制备4-氨基3-氯-5-氟-吡啶甲酸酯起始原料：用1-(氯甲基)-4-氟-1,4-重氮双环[2.2.2]辛烷二(四氟硼酸酯)将相应的5-未取代的吡啶氟化。这些专利的每一篇也均描述了由偶联反应制备6-(芳基)-4-氨基吡啶甲酸酯，所述偶联反应包括具有容易离去的基团的甲基吡啶或其在甲基吡啶环的6位的金属衍生物。有利的是，不依赖于金属辅助的偶联来制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯。有利的是，由非吡啶来源有效和高收率地制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯。也有利的是，不依赖于用昂贵的氟化剂如1-(氯甲基)-4-氟-1,4-重氮双环[2.2.2]辛烷二(四氟硼酸酯)在吡啶环的5位进行直接氟化来制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯。
发明内容
本申请提供了由非吡啶来源无需金属辅助的偶联且无需用昂贵的氟化剂如1-(氯甲基)-4-氟-1,4-重氮双环[2.2.2]辛烷二(四氟硼酸酯)氟化即可制备4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯的方法。更特别地，本申请提供了制备式I的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯的方法
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R2表示C1-C12烷基，或未取代或取代的C7-C11芳基烷基，
所述方法包括以下步骤：
a)使三氟乙酸与对-甲氧基苯胺在三芳基膦和三烷基胺碱的存在下在四氯化碳溶剂中接触，从而制备式A的亚氨代乙酰氯
b)使式A的亚氨代乙酰氯与3,3-二烷氧基丙-1-炔(式B)在碘化亚铜(I)、碱金属碘化物和碱金属磷酸盐的存在下在极性非质子溶剂中接触，从而制备式C的(亚氨基)戊-2-炔二烷基缩醛
其中R3表示C1-C4烷基，
其中R3如前限定；
c)使式C的(亚氨基)戊-2-炔二烷基缩醛与式D的胺在无机碱金属碱的存在下在极性非质子溶剂中在约环境温度至约100℃的温度环化，从而制备式E的4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛
其中R1如前限定，
其中R1和R3如前限定；
d)用1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(式F)在极性溶剂中使式E的4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛氯化，从而制备式G的保护的4-氨基-5-氟-3-氯-6-(取代的)吡啶-2-二烷基缩醛
其中R1和R3如前限定；
e)用无机酸在极性溶剂中使式G的保护的4-氨基-5-氟-3-氯-6-(取代的)吡啶-2-二烷基缩醛脱保护和水解，从而制备式H的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛
其中R1如前限定；
f)用碱金属亚氯酸盐在无机酸和次氯酸清除剂的存在下在含水醇溶剂中将式H的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛氧化，从而制备式J的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸
其中R1如前限定；和
g)用式R2X的化合物使式J的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯化，从而制备式I的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯
R2X
其中
X表示OH，Cl，Br，或I，和
R2如前限定。
另一种实施方式是式C的化合物
其中R3表示C1-C4烷基。
另一种实施方式是式E的化合物
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R3表示C1-C4烷基。
另一种实施方式是式G的化合物
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R3表示C1-C4烷基。
另一种实施方式是式H的化合物
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基。
具体实施方式
本申请使用的术语“烷基”和“链烯基”及派生术语例如“烷氧基”包括它们范围内的直链或支链部分。
本申请使用的术语“芳基烷基”是指苯基取代的烷基(其总共具有7至11个碳原子)，例如苄基(–CH2C6H5)，2-甲基萘基(–CH2C10H7)和1-苯乙基或2-苯乙基(–CH2CH2C6H5或–CH(CH3)C6H5)。苯基本身可以是未取代的或取代有一个或多个取代基，所述取代基独立地选自卤素、硝基、氰基、C1-C6烷基、C1-C6烷氧基、卤代C1-C6烷基、卤代C1-C6烷氧基、C1-C6烷基硫基、C(O)OC1-C6烷基，或者其中两个邻近的取代基共同作为–O(CH2)nO–，其中n＝1或2，条件是所述取代基是空间相容的并且满足化学键接和应变能量的规则。
除非另有明确限制，否则术语“卤素”以及派生术语例如“卤代”是指氟，氯，溴和碘。
取代有1至4个独立选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基的苯基可以具有任何选择方向，但是4-取代的苯基、2,4-二取代的苯基、2,3,4-三取代的苯基、2,4,5-三取代的苯基、和2,3,4,6-四取代的苯基异构体是优选的。
4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯由三氟乙酸、对-甲氧基苯胺、3,3-二烷氧基丙-1-炔和取代的亚甲基胺通过一系列步骤制备。
在步骤a)中，三氟乙酸与对-甲氧基苯胺和四氯化碳在三芳基膦和三烷基胺碱的存在下反应，制得2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯。尽管对于每当量三氟乙酸需要一当量的对-甲氧基苯胺，但是通常便利的是使用过量的苯胺，通常过量10至20％。类似地，过量的三烷基胺碱也是优选的。通常方便的是，使用远远过量的三芳基膦，通常过量2至4倍。四氯化碳虽然用作反应物，但是其也便利地用作初始反应的溶剂。反应是放热的，因此便利的是如下控制放热：外部冷却，以及控制向三氟乙酸、三烷基胺和三芳基膦在四氯化碳中的混合物添加对-甲氧基苯胺的四氯化碳溶液。在初始的放热减弱之后，通常将反应混合物加热至回流，直到完成转化。
在典型的反应中，将约3当量三苯基膦和三氟乙酸在四氯化碳中的混合物在冰浴中冷却至约0℃，添加20％过量的三乙胺。继续冷却，缓慢添加约20％过量的对-甲氧基苯胺在四氯化碳中的溶液。在完成添加之后，将混合物加热至约70℃并保持几小时。在冷却之后，用己烷萃取反应混合物，将溶剂蒸发，得到粗制的2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯。
在步骤b)中，2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯与3,3-二烷氧基丙-1-炔在碘化亚铜(I)、碱金属碘化物和碱金属磷酸盐的存在下在极性非质子溶剂中偶联，制得N-(5,5-二烷氧基-1,1,1-三氟戊-3-炔-2-亚基)-4-甲氧基苯胺。尽管对于每当量亚氨代乙酰氯需要一当量的3,3-二烷氧基丙-1-炔，但是通常便利地使用过量的3,3-二烷氧基丙-1-炔，通常为过量10至20％。类似地，10至20％摩尔过量的碱金属碘化物和碱金属磷酸盐通常是优选的。反应是在碘化亚铜(I)中的催化反应，通常使用约0.1至约0.3当量的碘化亚铜(I)。偶联反应在极性非质子溶剂中在约40℃至约100℃的温度进行。优选的极性非质子溶剂包括：醚，例如四氢呋喃；酯，例如乙酸乙酯；腈，例如乙腈；酰胺，例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮；和亚砜，例如二甲基亚砜。无水溶剂是优选的，其中尤其优选无水乙腈。
在典型的反应中，将2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯和稍微过量的3,3-二乙氧基丙-1-炔与约0.3当量的碘化亚铜(I)和稍微过量的磷酸钾和碘化钾在无水乙腈中混合。将混合物在氮气气氛下在约60℃加热，直到反应完成。冷却之后，将萃取溶剂例如卤化烃与水一起添加到混合物中。回收有机层，用盐水洗涤，并干燥。将溶剂蒸发，得到粗制的N-(5,5-二乙氧基-1,1,1-三氟-戊-3-炔-2-亚基)-4-甲氧基苯胺。
在步骤c)中，N-(5,5-二乙氧基-1,1,1-三氟-戊-3-炔-2-亚基)-4-甲氧基苯胺与取代有烷基、环丙基、链烯基或(取代的)苯基的亚甲基胺在无机碱金属碱的存在下在极性非质子溶剂中反应，制得4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛。尽管对于每当量N-(5,5-二乙氧基-1,1,1-三氟-戊-3-炔-2-亚基)-4-甲氧基苯胺需要一当量取代的亚甲基胺，但是通常便利地使用过量的取代的亚甲基胺，通常为2至4倍过量。适宜的无机碱金属碱包括锂、钠、钾和铯的氢氧化物、碳酸盐和磷酸盐。碳酸铯是特别优选的。通常，方便的是，使用2至4倍过量的无机碱金属碱。优选的极性非质子溶剂包括：醚，例如四氢呋喃；酯，例如乙酸乙酯；腈，例如乙腈；酰胺，例如N,N-二甲基甲酰胺和N-甲基吡咯烷酮；和亚砜，例如二甲基亚砜。无水溶剂是优选的，其中尤其优选无水四氢呋喃和二甲基亚砜。反应通常在从约环境温度至约100℃的温度进行。
在典型的反应中，将N-(5,5-二乙氧基-1,1,1-三氟-戊-3-炔-2-亚基)-4-甲氧基苯胺与约2.5至3倍过量的对-氯苄胺和约2.5至3倍过量的碳酸铯在无水四氢呋喃中混合。将混合物在约80℃加热，直到反应完成。冷却之后，将萃取溶剂例如卤化烃与水一起添加到混合物中。回收有机层，用盐水洗涤，并干燥。将溶剂蒸发，得到粗制的2-(4-氯苯基)-6-(二乙氧基甲基)-3-氟-N-(4-甲氧基苯基)吡啶-4-胺。
在步骤d)中，用1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮在极性溶剂中在约环境温度至约100℃的温度将4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛氯化，制得4-((3-氯-6-(取代的)-2-(二烷氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮。尽管对于每当量4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛需要一当量的1,3-二氯-5,5-二甲基-咪唑烷-2,4-二酮，但是通常便利地使用过量的取代的1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮，通常为2至4倍过量。氯化反应便利地在极性溶剂例如乙腈与水的混合物中进行。
在典型的反应中，用2当量1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮在乙腈/水混合物中处理粗制的2-(4-氯苯基)-6-(二乙氧基甲基)-3-氟-N-(4-甲氧基苯基)吡啶-4-胺。将混合物在环境温度搅拌，直到反应完成。通过过滤收集固体产物，用另外的乙腈/水混合物洗涤并干燥，得到粗制的4-((3-氯-6-(4-氯苯基)-2-(二乙氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮。
在步骤e)中，在极性溶剂中在从约环境温度至约100℃的温度用无机酸处理4-((3-氯-6-(取代的)-2-(二烷氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮，制得4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛。适宜的无机酸包括硫酸和磷酸，其中硫酸是优选的。无机酸通常作为水溶液使用。需要约一当量的无机酸，但是优选过量10至30％。脱保护/水解便利地在极性溶剂例如乙腈与水的混合物中进行。
在典型的反应中，在乙腈/水的混合物中用1M(摩尔浓度)硫酸溶液处理4-((3-氯-6-(4-氯苯基)-2-(二乙氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮。将混合物在回流温度加热，直到反应完成。将混合物添加到二氯甲烷中，分离有机层，用盐水洗涤，并干燥。将溶剂蒸发，得到粗制的4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲醛。
在步骤f)中，用碱金属亚氯酸盐在无机酸和次氯酸清除剂的存在下在含水醇溶剂中将4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛氧化，制得4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸。尽管对于将醛氧化为羧酸需要一当量的亚氯酸钠，但是通常便利地使用2-8当量。在水与无机溶剂例如乙腈或叔丁醇的混合物中在稍酸性条件(pH 3–5)下进行氧化反应，所述稍酸性条件通过添加2-10当量的无机酸盐例如磷酸氢二钠实现。为避免由在氧化过程中形成的次氯酸发生不期望的反应，添加2-30当量的清除剂，例如2-甲基-2-丁烯、间苯二酚或氨基磺酸。
在典型的反应中，用过量的亚氯酸钠、20-30当量的2-甲基-2-丁烯和约5当量的磷酸氢二钠在叔丁醇/水混合物中将4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲醛氧化。将混合物在约80℃加热，直到反应完成。冷却之后，用稀盐酸处理混合物，并用乙酸乙酯萃取。将有机层分离并干燥。蒸发溶剂，得到粗制的4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸。
在步骤g)中，将4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯化。吡啶甲酸的酯如下制备：使用任何数目的适当活化剂例如用于肽偶联的那些例如二环己基碳二亚胺(DCC)或羰基二咪唑(CDI)使吡啶甲酸与醇偶联；或者使相应的酸与适当的芳基烷基醇在酸催化剂的存在下反应。或者，酯可以如下制备：使吡啶甲酸与烷基卤化物或芳基烷基卤化物在碱的存在下反应。这些过程是有机化学工作者熟知的，并且描述于，例如，每个专利申请公开2012/0190551 A1。
在典型的反应中，4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸与稍微过量的苄基溴和约2当量碳酸钾在极性非质子溶剂例如二甲基亚砜或N,N-二甲基甲酰胺中反应。4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸苄基酯如下回收：使反应混合物在乙酸乙酯和水之间分配，分离，并干燥有机层，蒸发溶剂。
通过这些过程任一种获得的产物可以通过常规方法(例如蒸发或萃取)回收，并且可以通过标准过程(例如重结晶或色谱法)纯化。
所述实施方式和以下实施例的目的是说明，并不意图限制所附权利要求的范围。在不背离要求保护的主题内容的精神和范围的情况下，关于本申请所述组合物的其它修改、用途、或组合对于本领域技术人员而言是显而易见的。
实施例
实施例1 2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯
将三苯基膦(34.6克(g)，132.0毫摩尔(mmol))、2,2,2-三氟乙酸(3.37毫升(mL)，44mmol)、三乙胺(7.38mL，53.0mmol)和四氯化碳(21.33mL，220.0mmol)的混合物磁力搅拌，同时用冰浴冷却。在10分钟(min)之后，缓慢添加(放热)溶解于四氯化碳(21.33mL，220.0mmol)的对-甲氧基苯胺(6.53g，53.0mmol)。移走冰浴，将反应混合物在回流温度搅拌4小时(h)。在冷却至室温之后，用己烷(3x 100mL)洗涤反应混合物。使用旋转蒸发仪移除溶剂，得到9.8g橙色油状物。蒸馏得到作为浅黄色液体的2,2,2-三氟-N-(4-甲氧基苯基)亚氨代乙酰氯(9.31g，39.2mmol，89％收率)：bp 75-77℃/0.3mmHg；1H NMR(400MHz，CDCl3)δ7.31(m，2H)，6.96(m，2H)，3.84(s，3H)；13C NMR(101MHz，CDCl3)δ159.56(s)，135.45(s)，127.98(q)，124.35(s)，117.05(q)，114.25(s)，55.50(s)。
实施例2 N-(5,5-二乙氧基-1,1,1-三氟戊-3-炔-2-亚基)-4-甲氧基苯胺
向2,2,2-三氟-N-(4-甲氧基苯基)-亚氨代乙酰氯(2.376g，10.00mmol)和3,3-二乙氧基丙-1-炔(1.538g，12.00mmol)在乙腈(20mL)中的磁力搅拌的溶液添加碘化亚铜(I)(0.571g，3.00mmol)、磷酸钾(2.55g，12.0mmol)和碘化钾(1.660g，10.00mmol)的磨碎的混合物。在60℃在氮气下加热16h之后，将反应混合物加入到二氯甲烷(CH2Cl2；100mL)和水(50mL)中。将有机层用氯化钠(NaCl)的饱和溶液洗涤，并干燥(硫酸镁；MgSO4)，移除溶剂，留下3.35g黄色液体。在用5％乙酸乙酯(EtOAc)/己烷洗脱的硅胶上进行快速色谱法，得到作为黄色液体的N-(5,5-二乙氧基-1,1,1-三氟戊-3-炔-2-亚基)-4-甲氧基苯胺(2.75g，8.18mmol，82％收率)：1H NMR(400MHz，CDCl3)δ7.46(m，2H)，6.93(m，2H)，5.41(s，1H)，3.84(s，3H)，3.63(m，4H)，1.22(m，6H)；13C NMR(101MHz，CDCl3)δ160.00(s)，139.55(s)，134.98(s)，134.59(s)，124.65(s)，113.98(s)，94.64(s)，91.21(s)，74.83(s)，61.55(s)，55.50(s)，15.00(s)；19F NMR(376MHz，CDCl3)δ-70.91(s)；HRMS-ESI(m/z)[M+H]+，对于C16H18F3NO3，计算值为329.1239；实测值为329.1225。
实施例3 2-(4-氯苯基)-6-(二乙氧基甲基)-3-氟-N-(4-甲氧基苯基)吡啶-4-胺
将N-(5,5-二乙氧基-1,1,1-三氟戊-3-炔-2-亚基)-4-甲氧基苯胺(0.659g，2mmol)、对-氯苄胺(0.850g，6.00mmol)和碳酸铯(1.629g，5.00mmol)在无水四氢呋喃(THF；10mL)的磁力搅拌的溶液在微波炉中在100℃加热8h。将反应混合物添加到醚(100mL)和水(50mL)中。将有机层用NaCl的饱和溶液洗涤，并干燥(MgSO4)，移除溶剂，留下1.42g黄色固体。在用10％EtOAc/己烷洗脱的硅胶上进行快速色谱法，得到作为灰白色固体的2-(4-氯苯基)-6-(二乙氧基甲基)-3-氟-N-(4-甲氧基苯基)吡啶-4-胺(0.689g，1.600mmol，80％收率)：mp 110-111℃；1H NMR(400MHz，CDCl3)δ7.90(dd，J＝8.5，1.4Hz，2H)，7.43(m，2H)，7.18(m，2H)，7.13(d，J＝6.2Hz，1H)，6.94(m，2H)，6.19(d，J＝3.7Hz，1H)，5.31(br s，1H)，3.84(s，3H)，3.73(m，2H)，3.57(m，2H)，1.22(t，J＝7.1Hz，6H)；19F NMR(376MHz，CDCl3)δ-150.95；HRMS-ESI(m/z)[M+H]+，对于C23H24ClFN2O3，计算值为430.1459；实测值为430.1457。
实施例4. 4-((3-氯-6-(4-氯苯基)-2-(二乙氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮
将2-(4-氯苯基)-6-(二乙氧基甲基)-3-氟-N-(4-甲氧基-苯基)吡啶-4-胺(0.862g，2mmol)和1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(0.788g，4.00mmol)在1:1乙腈/水(20mL)中的混合物在室温搅拌。在2h之后，通过过滤收集橙色固体，用1:1乙腈/水(5mL)洗涤，在室温干燥，从醚/己烷重结晶。分离作为橙色晶体的4-((3-氯-6-(4-氯苯基)-2-(二乙氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮(0.272g，30％收率)：mp 134-136℃；1H NMR(400MHz，CDCl3)δ7.96(m，2H)，7.44(m，3H)，6.76(m，2H)，6.58(dd，J＝10.2，2.1Hz，1H)，5.79(s，1H)，3.90(m，2H)，3.72(m，2H)，1.31(t，J＝7.1Hz，6H)；19F NMR(376MHz，CDCl3)δ-134.18；HRMS-ESI(m/z)[M+H]+，对于C22H19Cl2FN2O3，计算值为448.0757；实测值为448.0761。
实施例5 4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲醛
将在乙腈/水的1:1混合物(4mL)中的4-((3-氯-6-(4-氯苯基)-2-(二乙氧基甲基)-5-氟吡啶-4-基)亚氨基)环己-2,5-二烯酮(180毫克(mg)，0.401mmol)和0.1摩尔浓度(M)硫酸(H2SO4；0.5mL)的混合物加热至80℃并保持1h。在室温搅拌2h之后，将反应混合物添加到CH2Cl2(20mL)中。将有机层用NaCl的饱和溶液洗涤，并干燥(MgSO4)，移除溶剂，留下作为灰白色固体的4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲醛(82mg，0.273mmol，68％收率)：mp166-169℃；1H NMR(400MHz，CDCl3)δ10.12(s，1H)，7.96(m，2H)，7.48(m，2H)，4.99(s，2H)；19F NMR(376MHz，CDCl3)δ-137.68；ESIMS m/z 285.64([M+H]+)。
实施例6 4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸
将4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲醛(105mg，0.37mmol)溶解于叔丁醇(2.2mL)。将水(800μL)、2-甲基-2丁烯(1.0mL，700mg，10mmol)、磷酸氢二钠(Na2HPO4；276mg，2mmol)和亚氯酸钠(106mg，1.2mmol)添加到压盖式密封微波瓶中。混合反应物，将反应容器密封，加热至80℃并保持16h。然后将反应混合物冷却至环境温度，用1当量浓度(N)盐酸(HCl；5mL)和EtOAc(10mL)稀释混合物。搅拌5min之后，将各层分离，水层用EtOAc(4x 5mL)萃取。将合并的有机层干燥(硫酸钠；Na2SO4)，并蒸发至干燥，得到95mg油状棕色固体。将固体溶解于最少量的1N氢氧化钠(NaOH)水溶液，用4N HCl水溶液缓慢中和，直到出现白色/棕色沉淀物。收集沉淀物，并干燥，得到4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸(78mg，72％收率)：1H NMR(400MHz，CDCl3)δ8.5(br s，1H)，7.96-7.86(m，2H)，7.59-7.75(m，2H)，6.1(br s，2H)；19F NMR(376MHz，DMSO-d6)δ-141.07；ESIMS m/z 299.4([M-H]-)。
实施例8 4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸苄基酯
将4-氨基-3-氯-6-(4-氯苯基)-5-氟吡啶甲酸(23.1mg，0.080mmol)溶解于压盖式密封微波瓶中的二甲基亚砜(800μL)。添加碳酸钾(23.4mg，0.166mmol)与苄基溴(10μL，14.4mg，0.084mmol)。将反应容器密封，将反应混合物在室温剧烈搅拌16h。然后将反应混合物在水(10mL)和EtOAc(10mL)之间分配。分离各层，将水层用另外的EtOAc(3mL)萃取。将合并的有机层用水(3x 4mL)洗涤，用盐水(2mL)洗涤，干燥(Na2SO4)，并蒸发至干燥，得到26.1mg白色固体。粗产物使用快速柱色谱法使用用梯度为0-100％的EtOAc/己烷历时6min洗脱的4g ISCO硅胶柱纯化。用最少量的二氯甲烷将粗产物装载柱上。获得的4-氨基-3-氯-6-(4-氯苯基)-5-氟-吡啶甲酸苄基酯(8.3mg，25％收率)为浅色蜡状油状物：1H NMR(400MHz，CDCl3)δ7.93-7.91(s，J＝7.3Hz，2H)，7.53-7.35(m，7H)，5.46(s，2H)，4.94-4.87(br m，2H)；19F NMR(376MHz，DMSO)δ-144.88；ESIMS m/z 391.4([M+H]+)。

Claims (5)

1.制备式I的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯的方法
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R2表示C1-C12烷基，或未取代或取代的C7-C11芳基烷基，
所述方法包括以下步骤：
a)使三氟乙酸与对-甲氧基苯胺在三芳基膦和三烷基胺碱的存在下在四氯化碳溶剂中接触，从而制备式A的亚氨代乙酰氯
b)使式A的亚氨代乙酰氯与3,3-二烷氧基丙-1-炔(式B)在碘化亚铜(I)、碱金属碘化物和碱金属磷酸盐的存在下在极性非质子溶剂中接触，从而制备式C的(亚氨基)戊-2-炔二烷基缩醛
其中R3表示C1-C4烷基，
其中R3如前限定；
c)使式C的(亚氨基)戊-2-炔二烷基缩醛与式D的胺在无机碱金属碱的存在下在极性非质子溶剂中在环境温度至100℃的温度环化，从而制备式E的4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛
其中R1如前限定，
其中R1和R3如前限定；
d)用1,3-二氯-5,5-二甲基咪唑烷-2,4-二酮(式F)在极性溶剂中使式E的4-(4-甲氧基苯基)氨基-5-氟-6-(取代的)吡啶-2-二烷基缩醛氯化，从而制备式G的保护的4-氨基-5-氟-3-氯-6-(取代的)吡啶-2-二烷基缩醛
其中R1和R3如前限定；
e)用无机酸在极性溶剂中使式G的保护的4-氨基-5-氟-3-氯-6-(取代的)吡啶-2-二烷基缩醛脱保护和水解，从而制备式H的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛
其中R1如前限定；
f)用碱金属亚氯酸盐在无机酸和次氯酸清除剂的存在下在含水醇溶剂中将式H的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲醛氧化，从而制备式J的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸
其中R1如前限定；和
g)用式R2X的化合物使式J的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯化，从而制备式I的4-氨基-5-氟-3-氯-6-(取代的)吡啶甲酸酯
其中
X表示OH，Cl，Br，或I，和
R2如前限定。
2.式C的化合物
其中
R3表示C1-C4烷基。
3.式E的化合物
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R3表示C1-C4烷基。
4.式G的化合物
其中
R1表示C1-C4烷基，环丙基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基，和
R3表示C1-C4烷基。
5.式H的化合物
其中
R1表示C1-C4烷基，C2-C4链烯基，或取代有1至4个取代基的苯基，所述取代基独立地选自卤素、C1-C4烷基、C1-C4卤代烷基、C1-C4烷氧基或C1-C4卤代烷氧基。
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US10259789B2 (en) * 2016-01-22 2019-04-16 Dow Agrosciences Llc Process for the preparation of 4-alkoxy-3-acetoxypicolinic acids
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764646A (zh) * 2003-04-02 2006-04-26 美国陶氏益农公司 6－烷基或烯基－4－氨基吡啶甲酸酯及其作为除草剂的应用

Family Cites Families (10)

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SU680613A3 (ru) * 1971-12-07 1979-08-15 Циба-Гейги Аг (Фирма) Средство борьбы с насекомыми и клещами
MXPA02006933A (es) * 2000-01-14 2003-01-28 Dow Agrosciences Llc 4-aminopicolinatos y su uso como herbicidas.
AR037228A1 (es) 2001-07-30 2004-11-03 Dow Agrosciences Llc Compuestos del acido 6-(aril o heteroaril)-4-aminopicolinico, composicion herbicida que los comprende y metodo para controlar vegetacion no deseada
TW200307669A (en) * 2002-04-15 2003-12-16 Nippon Soda Co Novel oxime o-ether compound, production process thereof, and agricultural or horticultural bactericide
WO2006062979A1 (en) * 2004-12-06 2006-06-15 E.I. Dupont De Nemours And Company Herbicidal 6-cyclopropyl-substitute 4-aminopicolinic acid derivatives
CN102731381B (zh) 2006-01-13 2016-08-17 美国陶氏益农公司 6-（多取代芳基）-4-氨基吡啶甲酸酯及其作为除草剂的用途
WO2012041873A1 (en) * 2010-09-29 2012-04-05 Intervet International B.V. N-heteroaryl compounds
TWI596088B (zh) 2011-01-25 2017-08-21 陶氏農業科學公司 ４－胺基－６－（經取代的苯基）吡啶甲酸酯及６－胺基－２－（經取代的苯基）－４－嘧啶羧酸酯之芳烷酯以及其等作為除草劑之用途
TWI529163B (zh) * 2011-01-25 2016-04-11 陶氏農業科學公司 用於製備４－胺基－５－氟－３－鹵素－６－（經取代之）吡啶甲酸酯的方法
CA2895180A1 (en) * 2012-12-13 2014-06-19 Dow Agrosciences Llc Process for the preparation of 4-amino-5-fluoro-3-chloro-6-(substituted)picolinates

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1764646A (zh) * 2003-04-02 2006-04-26 美国陶氏益农公司 6－烷基或烯基－4－氨基吡啶甲酸酯及其作为除草剂的应用
US7432227B2 (en) * 2003-04-02 2008-10-07 Dow Agrosciences Llc 6-alkyl or alkenyl-4-aminopicolinates and their use as herbicides

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