CN103874685A - 4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法 - Google Patents

4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法 Download PDF

Info

Publication number
CN103874685A
CN103874685A CN201280014336.2A CN201280014336A CN103874685A CN 103874685 A CN103874685 A CN 103874685A CN 201280014336 A CN201280014336 A CN 201280014336A CN 103874685 A CN103874685 A CN 103874685A
Authority
CN
China
Prior art keywords
chloro
pyridine
fluoro
formonitrile hcn
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201280014336.2A
Other languages
English (en)
Other versions
CN103874685B (zh
Inventor
K.E.阿恩特
J.M.伦加
朱远明
G.T.惠特克
C.T.罗威
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Corteva Agriscience LLC
Original Assignee
Dow AgroSciences LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dow AgroSciences LLC filed Critical Dow AgroSciences LLC
Priority to CN201510105205.0A priority Critical patent/CN104788368B/zh
Publication of CN103874685A publication Critical patent/CN103874685A/zh
Application granted granted Critical
Publication of CN103874685B publication Critical patent/CN103874685B/zh
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
    • A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
    • A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/803—Processes of preparation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Agronomy & Crop Science (AREA)
  • Pest Control & Pesticides (AREA)
  • Plant Pathology (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Environmental Sciences (AREA)
  • Pyridine Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯是通过一系列步骤方便地从3,4,5,6-四氯吡啶-2-甲腈制备的，所述步骤包括氟交换、胺化、卤素交换和水解、酯化和过渡金属辅助的偶联。

Description

4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
技术领域
本发明涉及4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法。更具体而言，本发明涉及其中5-氟取代基是在方法方案早期通过卤素交换引入的4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法。
背景技术
美国专利6,297,197B1特别地描述了某些4-氨基-3-氯-5-氟-6-(烷氧基或芳基氧基)吡啶-2-甲酸酯化合物及其作为除草剂的用途。美国专利6,784,137B2和7,314,849B2特别地描述了某些4-氨基-3-氯-5-氟-6-(芳基)吡啶-2-甲酸酯化合物及其作为除草剂的用途。美国专利7,432,227B2特别地描述了某些4-氨基-3-氯-5-氟-6-(烷基)吡啶-2-甲酸酯化合物及其作为除草剂的用途。这些专利中每个都描述了通过使得相应的5-(未取代的)吡啶-2-甲酸酯与1-(氯甲基)-4-氟-1,4-二氮鎓二环[2.2.2]辛烷二(四氟硼酸盐)的氟化来制造4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯起始物质。不必依赖于用昂贵的氟化剂如1-(氯甲基)-4-氟-1,4-二氮鎓二环[2.2.2]辛烷二(四氟硼酸盐)对吡啶-2-甲酸酯的5-位进行直接氟化对生成4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯而言将会是有利的。
发明内容
本发明涉及从3,4,5,6-四氯吡啶-2-甲腈制备4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的方法。更具体而言，本发明涉及式I的4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
Figure BDA0000384981220000011
其中
R表示C1-C4烷基、环丙基、C2-C4烯基或苯基，所述苯基被1至4个取代基所取代，所述取代基独立地选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基或卤代C1-C4烷氧基；
R1表示C1-C12烷基或者未取代的或取代的C7-C11芳基烷基；
其包括下列步骤：
a)用氟离子源氟化3,4,5,6-四氯吡啶-2-甲腈(式A)
Figure BDA0000384981220000021
以生成3-氯-4,5,6-三氟吡啶-2-甲腈(式B)
b)用氨胺化3-氯-4,5,6-三氟-吡啶-2-甲腈(式B)以生成4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(式C)
c)用溴化氢(HBr)、氯化氢(HCl)或碘化氢(HI)交换4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(式C)的6-位的氟取代基并水解腈以生成式D的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酰胺
Figure BDA0000384981220000024
其中L是Br、Cl或I；
d)用强酸和醇(R1OH)酯化式D的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酰胺以生成式E的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酸酯
Figure BDA0000384981220000025
其中L和R1如先前所定义；和
e)将式E的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酸酯与式F的芳基金属化合物、烷基金属化合物或烯基金属化合物在过渡金属催化剂存在下偶联以生成式I的4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯，所述式F为：
R-Met           F
其中R如先前所定义且Met表示Zn-卤化物、Zn-R、三-(C1-C4烷基)锡、铜或B(OR2)(OR3)，其中R2和R3彼此独立地是氢、C1-C4烷基或一起形成亚乙基或亚丙基。
a)到e)的步骤典型地如方案I中所描述的进行。
方案I
Figure BDA0000384981220000031
本发明的另一个方面是本方法过程中生成的新型中间体，即，下式的化合物：
a)
Figure BDA0000384981220000032
其中X和Y独立地表示F或Cl；
b)
Figure BDA0000384981220000033
其中X和Y独立地表示F或Cl，但须X和Y中至少一个是F；
c)
Figure BDA0000384981220000041
其中W1表示F、Cl、Br或I；
d)
Figure BDA0000384981220000042
其中W2表示Cl、Br或I；或
e)
Figure BDA0000384981220000043
其中R1表示C1-C12烷基或者未取代的或取代的C7-C11芳基烷基且W3是Br或I。
具体实施方式
如本申请所用，术语“烷基”、“烯基”和“炔基”以及衍生术语例如“烷氧基”、“酰基”、“烷基硫基”和“烷基磺酰基”，在其范围之内包括直链、支链和环状部分。除非另有具体说明，每个可以是未取代的或者被一个或多个取代基所取代的，所述取代基选自但不限于卤素、羟基、烷氧基、烷基硫基、C1-C6酰基、甲酰基、氰基、芳基氧基或芳基，只要所述取代基是空间上相容的且满足化学键合和应变能规则。术语“烯基”和“炔基”意在包括一个或多个不饱和键。
如本申请所用，术语“芳基烷基”指具有总计7至11个碳原子的苯基取代的烷基，例如苄基(–CH2C6H5)、2-甲基萘基(–CH2C10H7)和1-或2-苯乙基(–CH2CH2C6H5或–CH(CH3)C6H5)。所述苯基自身可以是未取代的或者被一个或多个取代基所取代的，所述取代基选自卤素、硝基、氰基、C1-C6烷基、C1-C6烷氧基、卤代的C1-C6烷基、卤代的C1-C6烷氧基、C1-C6烷基硫基、C(O)OC1-C6烷基或者其中两个相邻取代基一起成为–O(CH2)nO–(其中n=1或2)，只要所述取代基是空间上相容的且满足化学键合和应变能规则。
除非另有具体限定，术语“卤素”以及衍生术语例如“卤代”，指氟、氯、溴和碘。
被1至4个独立地选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基或卤代C1-C4烷氧基的取代基所取代的苯基可以具有任何定位，但是优选4-取代的苯基异构体、2,4-二取代的苯基异构体、2,3,4-三取代的苯基异构体、2,4,5-三取代的苯基异构体和2,3,4,6-四取代的苯基异构体。
4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯是通过一系列步骤从3,4,5,6-四氯吡啶-2-甲腈制备的，所述步骤包括氟交换、胺化、与HCl、HBr或HI的反应、水解、酯化和过渡金属辅助的偶联。个别步骤可以以不同的顺序来进行。
3,4,5,6-四氯吡啶-2-甲腈起始物质是已知的化合物且是可商购的。
在氟化物交换反应中，氟化的吡啶-2-甲腈是通过使得相应的氯化吡啶-2-甲腈与对于所要交换的每个环氯取代基而言大约一个当量的氟离子源反应来制备的。
Figure BDA0000384981220000051
典型的氟离子源是碱金属氟化物，其包括氟化钠(NaF)、氟化钾(KF)和氟化铯(CsF)，优选KF和CsF。烷基的或芳基的季铵或季鏻氟化物也可以作为氟化物源或作为添加剂来使用。优选地，所述反应在极性非质子性溶剂或反应介质中进行，例如二甲基亚砜(DMSO)、N-甲基吡咯烷酮(NMP)、N,N-二甲基甲酰胺(DMF)、六甲基磷酰胺(HMPA)或二氧噻吩烷。反应进行的温度不是决定性的但通常是在60℃至180℃且优选地在70℃至80℃。取决于具体反应中所用的溶剂，最适温度将会改变。一般而言，温度越低反应将会进行得越慢。本反应典型地在剧烈搅拌下进行，所述搅拌足以保持基本上均一分散的反应物的混合物。
在进行氟化反应中，反应物的比率和加入次序都不是决定性的。通常，在向反应混合物加入氯化吡啶-2-甲腈之前将溶剂与碱金属氟化物混合。典型的反应一般需要2至100小时，优选地需要3至6小时且通常在环境大气压进行。
尽管反应物的精确量不是决定性的，但是优选使用将供给基于起始物质中所要交换氯原子的数目而言至少等摩尔量氟原子的量的碱金属氟化物，即，至少等摩尔量的碱金属氟化物。反应完成后，通过使用标准的分离和纯化技术例如蒸馏、结晶或色谱法重新得到期望的产物。
在典型的氟化物交换中，获得产物的混合物，其包括显著量的过度氟化的副产物3,4,5,6-四氟吡啶-2-甲腈(式H)。
Figure BDA0000384981220000061
期望的3-氯-4,5,6-三氟吡啶-2-甲腈的最终产率可通过以下方法来提高：分离过度氟化的副产物3,4,5,6-四氟吡啶-2-甲腈并将其重复利用以生成可经受氟化物交换反应的中间体。这可以在若干天内完成。3,4,5,6-四氟吡啶-2-甲腈与LiCl的反应或3,4,5,6-四氟吡啶-2-甲腈与过量3,4,5,6-四氯吡啶-2-甲腈的反应或两者的组合，在含有或不含有溶剂的情况下，都产生氯代-氟代吡啶-2-甲腈，其中3-氯代异构体可用作形成期望产物的起始物质。因此3,4,5,6-四氟吡啶-2-甲腈可以与过量LiCl加热以生成主要是3,4,5-三氯-6-氟吡啶-2-甲腈和3,4,5,6-四氯吡啶-2-甲腈的混合物。在另一技术中，在相转移催化剂存在下，使得分离出的3,4,5,6-四氟吡啶-2-甲腈与过量3,4,5,6-四氯吡啶-2-甲腈的反应，生成主要由一氟-三氯吡啶-2-甲腈和二氟-二氯吡啶-2-甲腈组成的混合物。最后，在相转移催化剂存在下，分离出的3,4,5,6-四氟吡啶-2-甲腈与3,4,5,6-四氯吡啶-2-甲腈的等量混合物和1至3当量的LiCl生成主要是3,4,5-三氯-6-氟吡啶-2-甲腈和3,4,5,6-四氯吡啶-2-甲腈的混合物。这些主要由一氟-三氯吡啶-2-甲腈和/或二氟-二氯吡啶-2-甲腈组成的混合物，在使用碱金属氟化物的氟化反应中是有用的，以由3,4,5,6-四氟吡啶-2-甲腈制备3-氯-4,5,6-三氟吡啶-2-甲腈。
在逆向卤素交换反应中，将3,4,5,6-四氟吡啶-2-甲腈与5至10当量的LiCl加热，优选与6当量的LiCl加热以生成4,5-二氯-3,6-二氟吡啶-2-甲腈(3,6-F2-PN)、6-氟-3,4,5-三氯吡啶-2-甲腈(6-F-PN)和3,4,5,6-四氯吡啶-2-甲腈(Cl4-PN)的混合物。所述反应可无溶剂或在极性非质子性溶剂或反应介质中进行，例如DMSO、NMP、DMF、HMPA或二氧噻吩烷。在溶剂中进行反应往往是方便的。反应进行的温度不是决定性的但通常是在80℃至200℃且优选100℃至150℃。
Figure BDA0000384981220000071
通过经氟交换反应重复利用混合物，90%或更多的混合物对形成3-氯-4,5,6-三氟吡啶-2-甲腈而言是有用的。
在氟和氯基团互换的置换反应中，使得3,4,5,6-四氟吡啶-2-甲腈与1至3当量的3,4,5,6-四氯吡啶-2-甲腈反应，优选与2当量的3,4,5,6-四氯吡啶-2-甲腈反应。所述反应可无溶剂或在极性非质子性溶剂或反应介质中进行，例如DMSO、NMP、DMF、HMPA或二氧噻吩烷。不用溶剂进行反应往往是方便的。所述置换反应在添加剂存在下进行。添加剂包括(a)含10个或更多碳原子的季鏻盐和(b)通常称作冠醚的大环聚醚。适合的冠醚催化剂包括，但不限于，18-冠-6；二环己烷-18-冠-6；二苯并-18-冠-6；15-冠-5。适合的季鏻盐包括特别优选的四正烷基鏻盐。反应进行的温度不是决定性的但通常是在80℃至200℃且优选150℃至180℃。
在典型的置换反应中，例如，其中允许1当量的3,4,5,6-四氟吡啶-2-甲腈与2当量的3,4,5,6-四氯吡啶-2-甲腈反应，获得下列异构体的混合物：3,4,5,6-四氯吡啶-2-甲腈(Cl4-PN)、3,5-二氯-4,6-二氟吡啶-2-甲腈(4,6-F2-PN)、3,4-二氯-5,6-二氟吡啶-2-甲腈(5,6-F2-PN)、4,5-二氯-3,6-二氟吡啶-2-甲腈(3,6-F2-PN)、6-氟-3,4,5-三氯吡啶-2-甲腈(6-F-PN)和4-氟-3,5,6-三氯吡啶-2-甲腈(4-F-PN)。
Figure BDA0000384981220000081
通过经氟交换反应重复利用混合物，80%的混合物对形成3-氯-4,5,6-三氟吡啶-2-甲腈而言是有用的。
在逆向卤素交换反应和置换反应的组合中，允许3,4,5,6-四氟吡啶-2-甲腈与1至3当量的3,4,5,6-四氯吡啶-2-甲腈反应，优选与1当量的3,4,5,6-四氯-吡啶-2-甲腈反应，并与1至4当量的LiCl反应，优选与1.5至2.5当量的LiCl反应。所述反应可无溶剂或在极性非质子性溶剂或反应介质中进行，例如DMSO、NMP、DMF、HMPA或二氧噻吩烷。不用溶剂进行反应往往是方便的。所述置换反应在添加剂存在下进行。添加剂包括(a)含10个或更多碳原子的季鏻盐和(b)通常称作冠醚的大环聚醚。适合的冠醚催化剂包括，但不限于，18-冠-6；二环己烷-18-冠-6；二苯并-18-冠-6；15-冠-5。适合的季鏻盐包括特别优选的四正烷基鏻盐。反应进行的温度不是决定性的但通常是在80℃至200℃且优选150℃至180℃。
在逆向卤素交换和置换反应的典型组合中，例如，允许1当量的3,4,5,6-四氟吡啶-2-甲腈与1当量的3,4,5,6-四氯吡啶-2-甲腈及1.5当量的LiCl反应，并获得下列异构体的混合物：
Figure BDA0000384981220000082
通过经氟交换反应重复利用混合物，92%的混合物对形成3-氯-4,5,6-三氟吡啶-2-甲腈而言是有用的。
在胺化反应中，允许4-氟吡啶-2-甲腈与氨反应以用氨基替换氟原子。
Figure BDA0000384981220000091
尽管仅需要化学量的氨，但使用大量过量的氨往往是方便的。使用氨既作为反应物又作为中和反应生成的氟化氢(HF)的碱往往是方便的。可替换地，氨可以是溶液形式，例如氢氧化铵的水溶液。所述反应不用溶剂或在惰性溶剂中进行。如果使用溶剂，惰性溶剂包括，但不限于，醇、醚、酯、酮、DMSO和芳族溶剂。反应进行的温度不是决定性的但通常是在0℃至45℃且优选10℃至30℃。
典型的反应一般需要0.5至5小时且通常在环境大气压进行。通过使用标准的分离和纯化技术重新得到期望的产物。
在卤素交换和水解反应中，6-卤代吡啶-2-甲酰胺式通过使得相应的6-氟吡啶-2-甲腈与至少两个当量的卤化氢反应来制备的。
Figure BDA0000384981220000092
尽管仅需要两个当量的卤化氢，但使用大量过量的卤化氢往往是方便的。所述反应在惰性溶剂中进行，特别优选C1-C4链烷酸。反应进行的温度不是决定性的但通常是在75℃至150℃且优选100℃至130℃。所述卤素交换方便地在密封管中加压进行。
在进行卤化和水解反应中，可将6-氟吡啶-2-甲腈与卤化氢和链烷酸溶剂在密封的反应器中加热。典型的反应一般需要0.5至24小时。通过使用标准的分离和纯化技术重新得到期望的产物。
在酯化反应中，在布朗斯台德酸或路易斯酸存在下使得2-吡啶-2-甲酰胺与醇反应。
Figure BDA0000384981220000101
布朗斯台德酸包括但不限于酸例如盐酸、硫酸和磷酸。路易斯酸包括三氟化硼、四卤化钛、四醇钛、卤化锌、卤化锡及五氟化磷和五氟化锑。典型地使用化学量的酸例如硫酸或磷酸。所述反应在期望的酯的C1-C12烷基醇或者未取代的或取代的C7-C11芳基烷基醇中进行。如果反应温度在醇溶剂的沸腾温度以上，反应可方便地在密封反应器中进行。
在进行酯化中，将吡啶-2-甲酰胺或吡啶-2-甲腈加入到醇和酸的混合物中。虽然反应的温度不是决定性的，但往往从80℃加热至140℃且保持2至24小时，优选从100℃加热至120℃且保持6至8小时。通过使用标准的分离和纯化技术重新得到期望的产物。
有时与卤素交换步骤的后处理联合进行酯化步骤是方便的。
在偶联反应中，使得6-卤代吡啶-2-甲酸酯与芳基金属化合物、烷基金属化合物或烯基金属化合物在过渡金属催化剂存在下反应，其中所述金属是Zn-卤化物、Zn-R、三-(C1-C4烷基)锡、铜或B(OR2)(OR3)，其中R2和R3彼此独立地是氢、C1-C4烷基或一起形成亚乙基或亚丙基。
Figure BDA0000384981220000102
“催化剂”是过渡金属催化剂，具体而言是钯催化剂例如乙酸钯(II)或二(三苯基膦)二氯化钯(II)，或者是镍催化剂例如乙酰丙酮镍(II)或二(三苯基膦)二氯化镍(II)。除此之外，催化剂可以从金属盐和配体原位制备，例如乙酸钯(II)和三苯基膦或者二氯化镍(II)和三苯基膦。这些原位催化剂可以通过先前的金属盐和配体的反应来制备，其后是加入到反应混合物中，或是直接向反应混合物中分开加入金属盐和配体。
典型地，在没有氧的条件下使用惰性气体进行偶联反应，例如氮气或氩气。用来从偶联反应混合物中排除氧的技术，例如用惰性气体鼓泡，是本领域的技术人员所熟知的。这些技术的实例在The Manipulation of Air-SensitiveCompounds,2nd ed.,D.F.Shriver,M.A.Drezdzon,Eds.;Wiley-Interscience,1986中有描述。使用亚化学量的催化剂，典型地是0.0001当量至0.1当量。可以任选地加入另外量的配体以增加催化剂稳定性和活性。除此之外，典型地向偶联反应中加入添加剂例如碳酸钠、碳酸钾、氟化钾、氟化铯和氟化钠。所述偶联反应一般需要1至5当量这种添加剂，优选地是1至2当量。可以任选地向偶联反应中加入水以增加这些添加剂的可溶性。所述偶联反应一般需要1至3当量的芳基金属化合物、烷基金属化合物或烯基金属化合物，优选地是1至1.5当量。反应在惰性溶剂中进行，例如甲苯、THF、二噁烷或乙腈。进行反应的温度不是决定性的但通常是在25℃至150℃并优选地在50℃至125℃。典型的反应一般需要0.5至24小时。典型地加入反应物不需要特定的次序。往往操作上较为简单的是：组合除催化剂之外的所有反应物然后使反应溶液脱氧。脱氧之后，加入催化剂以开始偶联反应。
当芳基金属化合物、烷基金属化合物或烯基金属化合物的Met部分是Zn-卤化物、Zn-R或铜时，反应官能团的保护可能是必要的。例如，如果存在氨基取代基(-NHR或–NH2)，可能需要这些反应基团的保护。多种用于保护氨基免于与有机金属试剂反应的基团是本领域中已知的。这些保护基团的实例在Protective Groups in Organic Synthesis,3rd ed.,T.W.Greene,P.G.M.Wuts,Eds.;Wiley-Interscience,1999中有描述。R-Met中使用的金属的选择受多种因素影响，例如成本、稳定性、反应性和保护反应官能团的需要。
通过这些方法中的任意一个获得的产物，可通过常规手段重新得到，例如蒸发或萃取，并可通过标准操作步骤纯化，例如通过重结晶或色谱法。
提出下列实施例以示例说明本发明。
实施例
氟交换
实施例1a3-氯-4,5,6-三氟吡啶-2-甲腈
Figure BDA0000384981220000111
氮气下将DMSO(3820毫升(mL))、粉末状的碳酸钾(K2CO3；42克(g))和细磨的氟化铯(CsF；1510g)装入5-升(L)机械搅拌的烧瓶中。通过在75-80℃(3.5mmHg,0.46kPa)蒸馏除去DMSO(大约1L)。在细磨的3,4,5,6-四氯吡啶-2-甲腈(685g)加入之前，在氮气下将淤浆冷却至55℃。加入历时15分钟同时冷却，保持反应温度在74℃以下。在慢的氮气流下将温度控制在65-70℃且保持4小时(h)。将反应混合物冷却至40-50℃并将其倾入冰水(H2O;15L)和乙醚(Et2O;3L)混合物中。分离有机相后，用Et2O(2x2L)萃取水相。合并有机萃取物，以硫酸镁(MgSO4)干燥，过滤并通过在大气压蒸馏浓缩，得到粗产物混合物(469g)，其为浅棕色油。该油与类似制备的另外的物质合并，得到总计1669g粗产物。使用30板(tray)Oldershaw柱在80-90℃温度范围将该油真空蒸馏得到63、13和2mm Hg(8.4,1.7和0.27kPa)收集的馏分。在13mm收集物质，得到457克(22%产率)作为两种一氯三氟吡啶-2-甲腈的93/7混合物的固体。将该固体在5℃从己烷(420g)和Et2O的混合物中重结晶，得到3-氯-4,5,6-三氟吡啶-2-甲腈(354克,98%纯度)，其为白色细针状物。将少量样品第二次重结晶得到经气相色谱法(GC)的99.7%纯度:mp41.5–43℃;19F NMR(376MHz,CDCl3)δ-78.1(t,JF-F=23.1Hz,F6),-114.2(dd,JF-F=18.5,22.5Hz,F4),-149.3(dd,JF-F=18.2,22.6Hz,F5);13C{1H}NMR(101MHz,CDCl3)δ154.5(ddd,JF-C=270,11,7Hz,C4),151.3(ddd,JF-C=247,13,5Hz,C6),138.0(ddd,JF-C=279,31,13Hz,C5),124.7(ddd,JF-C=16,6,2Hz,C3),124.4(ddd,JF-C=16,7,2Hz,C2),112.2(s,CN);EIMS m/z192([M]+)。C6ClF3N2的分析计算值:C,37.43;N,14.55。实测值：C,36.91;N;14.25.
蒸馏的第一部分(63mm Hg,8.4kPa)得到纯的3,4,5,6-四氟-吡啶-2-甲腈(525g,24%)，其为无色油:19F NMR(376MHz,CDCl3)δ-77.6(t,JF-F=23.8Hz,F6),-133.7(q,JF-F=18.8Hz,F4),-134.2(ddd,JF-F=24.2,18.6,10.1Hz,F3),-145.3(ddd,JF-F=24.1,18.2,10.2Hz,F5);13C{1H}NMR(101MHz,CDCl3)δ150.4(dm,JF-C=272Hz,C3),148.5(ddd,JF-C=245,12,4Hz,C6),147.3(dm,JF-C=270Hz,C4),138.6(ddd,JF-C=280,33,11Hz,C5),113.4(m,C2),110.20(s,CN).
蒸馏的第三部分(2mm Hg,0.27kPa)得到3,5-二氯-4,6-二氟-吡啶-2-甲腈(48g,98%纯度)，其为白色固体:mp78-79℃;19F NMR(376MHz,CDCl3)δ-63.65(d,JF-F=18.7Hz,F6),-92.52(d,JF-F=18.5Hz,F4);13C{1H}NMR(101MHz,CDCl3)δ162.6(dd,JF-C=269,6Hz,C4),157.8(dd,JF-C=245,5Hz,C6),127.6(dd,JF-C=17,3Hz,C3),123.5(dd,JF-C=18,6Hz,C2),112.4(dd,JF-C=36,21Hz,C5),112.3(CN).
实施例1b3,4,5,6-四氟吡啶-2-甲腈与氯化锂的逆向卤素交换反应
Figure BDA0000384981220000131
将3,4,5,6-四氟吡啶-2-甲腈(17g,0.1摩尔(mol))与无水LiCl(25.4g,0.6mol)的混合物在无水DMSO(200mL)中加热。通过GC分析从H2O中萃取至Et2O中的等分试样来监测反应。最初将反应混合物加热至120℃且所有LiCl溶解。在120℃保持5分钟后，消耗所有的起始物质和一氯三氟-PN异构体，得到3,6-F2-PN(83%)和6-F-PN(14%)的混合物。将反应温度升高至135℃并在总计75分钟后通过GC进行分析。测得所述混合物是3,6-F2-PN/6-F-PN/Cl4-PN的8:80:12混合物。
实施例1ca3,4,5,6-四氟吡啶-2-甲腈的置换
Figure BDA0000384981220000132
氮气下将3,4,5,6-四氯吡啶-2-甲腈(16.1g,66毫摩尔(mmol))和3,4,5,6-四氟吡啶-2-甲腈(5.9g,33mmol)的混合物加热至160℃，形成溶液。向该搅拌的溶液中加入四丁基氯化鏻(Bu4PCl;0.36g,1.2mmol)，且将该溶液控制在160℃且保持1h。将等分试样溶于二氯甲烷(CH2Cl2)并在GC分析之前经过短的硅胶垫。卤代的吡啶-2-甲腈的特征是:11.2%Cl4-PN;11.3%4,6-F2-PN;2.3%5,6-F2-PN;19%3,6-F2-PN;52.6%6-F-PN和3.6%4-F-PN。80%的混合物在生成3-氯-4,5,6-三氟吡啶-2-甲腈的卤素交换反应中是有用的。
实施例1cb从3,4,5,6-四氟吡啶-2-甲腈置换的重复利用
将细磨的CsF(35.1g,0.23mol)和无水DMSO(175mL)装入配备有短程蒸馏头的反应烧瓶中。将反应器搅拌并在真空(0.1mm)加热至70-75℃直至蒸去DMSO(75mL)。将该淤浆在氮气下冷却至50℃，并加入来自上面反应的热反应混合物(21.7g)。良好搅拌下将反应混合物加热至70℃且保持2.5h。将加到水中的等分试样的乙醚萃取物经GC检测发现其含有：61%3,4,5,6-四氟吡啶-2-甲腈；31%3-氯-4,5,6-三氟吡啶-2-甲腈；3.4%5-氯-3,5,6-三氟吡啶-2-甲腈和4.8%3,5-二氯-4,6-二氟吡啶-2-甲腈。这可有利地与当类似的反应用纯的3,4,5,6-四氯吡啶-2-甲腈起始时典型的38-42%的粗略GC纯度相比。
实施例1d3,4,5,6-四氟吡啶-2-甲腈的LiCl辅助置换
Figure BDA0000384981220000141
氮气下将3,4,5,6-四氯吡啶-2-甲腈(12.2g,50mmol)和3,4,5,6-四氟吡啶-2-甲腈(8.8g,50mmol)的混合物加热至160℃，得到澄清溶液。向该溶液中加入Bu4PCl(0.36g,1.2mmol)。在加入无水LiCl(4.2g,0.1mol)之前将反应溶液控制在160℃且保持15分钟。60分钟后加入更多的LiCl(2.2g,50mmol)，并将反应混合物搅拌11h。来自水的醚萃取物的GC分析显示是3,6-F2-PN/6-F-PN/Cl4-PN的8:75:17混合物。
胺化
实施例24-氨基-3-氯-5,6-二氟吡啶-2-甲腈
Figure BDA0000384981220000142
将3-氯-4,5,6-三氟吡啶-2-甲腈(200g)在乙酸乙酯中的溶液(EtOAc;3L)冷却至10℃。向该溶液中慢慢加入14%氢氧化铵水溶液(NH4OH;1296g)并保持温度在18-23℃。将水溶液从有机溶液中分离。依次用饱和NaCl水溶液与水的50/50溶液(500mL)及饱和NaCl水溶液(250mL)洗涤有机相。在50℃将有机相真空浓缩至500mL体积同时产物结晶出来。向该淤浆中加入庚烷(1L)，并真空除去剩余的EtOAc，得到最终淤浆。经由过滤收集固体。将该固体用戊烷洗涤并真空干燥，得到4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(173.8g,90%,99.6%纯度)，其为白色结晶状固体:mp190–191.5℃;13C{1H}NMR(101MHz,DMSO-d6)δ150.03(dd,J=232.4,12.5Hz,C6),144.29(dd,J=11.4,6.9Hz,C4),133.72(dd,J=257.9,30.8Hz,C5),122.14(dd,J=19.6,4.9Hz,C2),119.31(s,C3),114.25(s,CN);19F NMR(376MHz,DMSO-d6)δ-91.24(d,J=24.2Hz),-154.97(d,J=24.2Hz);EIMS m/z189([M]+)。C6H2ClF2N3的分析计算值:C,38.02;H,1.06;N,22.17。实测值：C.37.91;H.1.00;22.02.
卤素交换、水解和酯化
实施例34-氨基-6-溴-3-氯-5-氟吡啶-2-甲酰胺和4-氨基-6-溴-3-氯-5- 氟吡啶-2-甲酸甲酯
Figure BDA0000384981220000151
将密封的、搅拌反应管中的4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(70g,0.37mol)和33%HBr乙酸溶液(700mL)的混合物加热至120℃且保持2h。冷却至室温后，从大量黄褐色固体中分离出上清液并将其真空浓缩，得到粘的深色残留物。将该残留物溶于甲醇(600mL)并加回到仍在压力反应器中的黄褐色固体中。向该混合物中慢慢加入浓硫酸(H2SO4;40g,0.41mol)，将反应器再次密封并加热至110℃且保持6h。将冷却的反应混合物慢慢倾入饱和碳酸钠水溶液(2L)和Et2O(1L)中。将醚萃取物以MgSO4干燥，过滤并浓缩成黄褐色固体。该固体经柱色谱纯化得到4-氨基-6-溴-3-氯-5-氟吡啶甲酸甲酯(78g,75%)，其为白色细晶体:mp119–120℃;1H NMR(400MHz,CDCl3)δ3.97;13C{1H}NMR(101MHz,DMSO-d6)δ163.54(s,C=O),144.63(d,J=256.3Hz,C5),142.60(d,J=4.9Hz,C2),140.55(d,J=13.6Hz,C4),125.61(d,J=21.0Hz,C6),116.65(s,C3),53.2(s,OMe);19F NMR(376MHz,CDCl3)δ-128.86;EIMS m/z284([M]+)。C7H5BrClFN2O2的分析计算值:C,29.66;H,1.78;N,9.88。实测值：C,30.03;H,1.80;N,9.91.
经柱色谱还分离出4-氨基-6-溴-3-氯-5-氟吡啶-2-甲酰胺(200mg)，其为浅黄褐色固体:mp215℃ dec;13C{1H}NMR(101MHz,DMSO-d6)δ165.64(s,C=O),148.02(d,J=4.8Hz,C2),142.31(d,J=233.2Hz,C5),141.86(d,J=14.0Hz,C4),124.13(d,J=19.9Hz,C6),112.55(d,J=2.1Hz,C3);19F NMR(376MHz,DMSO-d6)δ-131.56;EIMS m/z269([M]+)。C6H4BrClFN3O的分析计算值:C,26.84;H,1.50;N,15.65。实测值：C,26.95;H,1.52;N,15.16.
偶联
实施例44-氨基-3-氯-5-氟-6-(4-氯-2-氟-3-甲氧基-苯基)吡啶-2-甲酸 甲酯
Figure BDA0000384981220000161
使氮气流通过4-氨基-6-溴-3-氯-5-氟吡啶-2-甲酸甲酯(2.8g,10mmol)和2-(4-氯-2-氟-3-甲氧基苯基)-1,3,2-二氧杂环戊硼烷(3.2g,13mmol)在乙腈(CH3CN;40mL)中的溶液和KF(1.7g,30mmol)在H2O(20mL)中的溶液的无色混合物同时将其加热至50℃(20-30分钟)。加入二(三苯基膦)二氯化钯(II)(PdCl2(PPh3)2;140mg,0.2mmol)，并将该混合物加热至65℃。反应经HPLC监测并在5h后完成。将反应混合物经短的硅藻土垫趁热过滤然后用H2O(20mL)稀释并使其冷却。经由过滤收集产物。真空干燥浅黄褐色固体得到4-氨基-3-氯-6-(4-氯-2-氟-3-甲氧基苯基)-5-氟吡啶-2-甲酸甲酯(2.6g,72%):mp169–170.5℃;1H NMR(400MHz,DMSO-d6)δ7.48(d,J=8.4Hz,1H),7.32(t,J=7.7Hz,1H),7.15(s,2H),3.96(s,3H),3.90(s,3H);13C{1H}NMR(101MHz,DMSO-d6)δ164.85(s),153.11(d,J=252.5Hz),146.29(s),144.52(d,J=4.3Hz),143.74(s),142.75(dd,J=227.1,14.0Hz),136.38(d,J=13.4Hz),128.58(d,J=3.2Hz),125.87(s),125.54(d,J=3.5Hz),122.89(dd,J=13.8,4.0Hz),113.01(d,J=3.0Hz),61.61(d,J=4.2Hz),52.70(s);ESIMS m/z364([M+H]+)。C14H10Cl2F2N2O3的分析计算值:C,46.30;H,2.78;N,7.71。实测值：C,46.60;H,2.68;N,7.51.

Claims (2)

1.式I的4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
Figure FDA0000384981210000011
其中
R表示C1-C4烷基、环丙基、C2-C4烯基或苯基，所述苯基被1至4个取代基所取代，所述取代基独立地选自卤素、C1-C4烷基、卤代C1-C4烷基、C1-C4烷氧基或卤代C1-C4烷氧基；
R1表示C1-C12烷基或者未取代的或取代的C7-C11芳基烷基；
所述方法包括下列步骤：
a)用氟离子源氟化3,4,5,6-四氯吡啶-2-甲腈(式A)
以生成3-氯-4,5,6-三氟吡啶-2-甲腈(式B)
Figure FDA0000384981210000013
b)用氨胺化3-氯-4,5,6-三氟-吡啶-2-甲腈(式B)以生成4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(式C)
Figure FDA0000384981210000014
c)用溴化氢(HBr)、氯化氢(HCl)或碘化氢(HI)交换4-氨基-3-氯-5,6-二氟吡啶-2-甲腈(式C)的6-位的氟取代基并水解腈以生成式D的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酰胺，
Figure FDA0000384981210000021
其中L是Br、Cl或I；
d)用强酸和醇(R1OH)酯化式D的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酰胺以生成式E的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酸酯
其中L和R1如先前所定义；和
e)将式E的4-氨基-3-氯-5-氟-6-卤代吡啶-2-甲酸酯与式F的芳基金属化合物、烷基金属化合物或烯基金属化合物在过渡金属催化剂存在下偶联以生成式I的4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯，所述式F为：
R-Met            F
其中R如先前所定义且Met表示Zn-卤化物、Zn-R、三-(C1-C4烷基)锡、铜或B(OR2)(OR3)，其中R2和R3彼此独立地是氢、C1-C4烷基或一起形成亚乙基或亚丙基。
2.下式的化合物：
a)
Figure FDA0000384981210000023
其中X和Y独立地表示F或Cl；
b)
Figure FDA0000384981210000024
其中X和Y独立地表示F或Cl，但条件是X和Y中至少一个是F；
c)
Figure FDA0000384981210000031
其中W1表示F、Cl、Br或I；
d)
Figure FDA0000384981210000032
其中W2表示Cl、Br或I；或
e)
Figure FDA0000384981210000033
其中R1表示C1-C12烷基或者未取代的或取代的C7-C11芳基烷基且W3是Br或I。
CN201280014336.2A 2011-01-25 2012-01-24 4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法 Expired - Fee Related CN103874685B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510105205.0A CN104788368B (zh) 2011-01-25 2012-01-24 4‑氨基‑3‑氯‑5‑氟‑6‑(取代的)吡啶‑2‑甲酸酯的制备方法

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US201161435966P 2011-01-25 2011-01-25
US61/435,966 2011-01-25
PCT/US2012/022285 WO2012103041A2 (en) 2011-01-25 2012-01-24 Process for the preparation of 4-amino-3-chloro-5-fluoro-6-(substituted) picolinates

Related Child Applications (1)

Application Number Title Priority Date Filing Date
CN201510105205.0A Division CN104788368B (zh) 2011-01-25 2012-01-24 4‑氨基‑3‑氯‑5‑氟‑6‑(取代的)吡啶‑2‑甲酸酯的制备方法

Publications (2)

Publication Number Publication Date
CN103874685A true CN103874685A (zh) 2014-06-18
CN103874685B CN103874685B (zh) 2016-02-03

Family

ID=46544648

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201280014336.2A Expired - Fee Related CN103874685B (zh) 2011-01-25 2012-01-24 4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
CN201510105205.0A Expired - Fee Related CN104788368B (zh) 2011-01-25 2012-01-24 4‑氨基‑3‑氯‑5‑氟‑6‑(取代的)吡啶‑2‑甲酸酯的制备方法

Family Applications After (1)

Application Number Title Priority Date Filing Date
CN201510105205.0A Expired - Fee Related CN104788368B (zh) 2011-01-25 2012-01-24 4‑氨基‑3‑氯‑5‑氟‑6‑(取代的)吡啶‑2‑甲酸酯的制备方法

Country Status (20)

Country Link
US (3) US20120190857A1 (zh)
EP (1) EP2668163B1 (zh)
JP (1) JP5739018B2 (zh)
KR (1) KR101537879B1 (zh)
CN (2) CN103874685B (zh)
AR (1) AR085022A1 (zh)
AU (1) AU2012209277B2 (zh)
BR (2) BR112013019025A2 (zh)
CA (1) CA2825475C (zh)
CO (1) CO6731125A2 (zh)
HK (2) HK1213875A1 (zh)
IL (1) IL227646A (zh)
MX (1) MX342328B (zh)
PL (1) PL2668163T3 (zh)
RU (1) RU2545021C1 (zh)
SG (1) SG192093A1 (zh)
TW (1) TWI592401B (zh)
UA (1) UA106945C2 (zh)
WO (1) WO2012103041A2 (zh)
ZA (1) ZA201305577B (zh)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI592401B (zh) 2011-01-25 2017-07-21 陶氏農業科學公司 用於製備４－胺基－３－氯－５－氟－６－（經取代的）吡啶甲酸酯的方法（一）
CN105208859A (zh) 2013-03-15 2015-12-30 美国陶氏益农公司 作为除草剂的新型的4-氨基吡啶和6-氨基嘧啶羧酸酯
US9113629B2 (en) 2013-03-15 2015-08-25 Dow Agrosciences Llc 4-amino-6-(4-substituted-phenyl)-picolinates and 6-amino-2-(4-substituted-phenyl)-pyrimidine-4-carboxylates and their use as herbicides
KR102305436B1 (ko) 2013-03-15 2021-09-27 코르테바 애그리사이언스 엘엘씨 4-아미노-6-(헤테로시클릭)피콜리네이트 및 6-아미노-2-(헤테로시클릭)피리미딘-4-카르복실레이트 및 제초제로서의 그의 용도
US9637505B2 (en) 2013-03-15 2017-05-02 Dow Agrosciences Llc 4-amino-6-(heterocyclic)picolinates and 6-amino-2-(heterocyclic)pyrimidine-4-carboxylates and their use as herbicides
TW201609651A (zh) 2013-11-12 2016-03-16 陶氏農業科學公司 用於氟化化合物之過程（一）
TW201524956A (zh) * 2013-11-12 2015-07-01 Dow Agrosciences Llc 用於氟化化合物之過程（二）
BR102014028162A2 (pt) 2013-11-12 2015-09-08 Dow Agrosciences Llc processo para fluoração de compostos
TWI726900B (zh) 2015-08-04 2021-05-11 美商陶氏農業科學公司 用於氟化化合物之過程
AU2017268424B2 (en) 2016-05-19 2021-07-15 Corteva Agriscience Llc Synthesis of 6-aryl-4-aminopicolinates and 2-aryl-6-aminopyrimidine-4-carboxylates by direct suzuki coupling
CN107954925A (zh) * 2016-10-18 2018-04-24 内蒙古佳瑞米精细化工有限公司 一种2,3-二氯-5-三氟甲基吡啶前杂的去除方法
WO2020061146A1 (en) 2018-09-19 2020-03-26 Dow Agrosciences Llc Preparation of halogen analogs of picloram
CN115279737A (zh) 2020-03-18 2022-11-01 科迪华农业科技有限责任公司 4-氨基-6-(杂环)吡啶甲酸酯的改进合成
EP4121416A1 (en) 2020-03-18 2023-01-25 Corteva Agriscience LLC Improved synthesis of 6-aryl-4-aminopicolinates

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3629424A (en) * 1967-12-26 1971-12-21 Dow Chemical Co Cyanofluoropyridines and fungicidal compositions and methods for using the same
US3803159A (en) * 1967-12-26 1974-04-09 Dow Chemical Co Fluorine containing cyanopyridines
US4336384A (en) * 1981-04-23 1982-06-22 The Dow Chemical Company Preparation of 4-amino-3,5,6-trichloropicolinic acid
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
CN101360713A (zh) * 2006-01-13 2009-02-04 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

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3285925A (en) * 1962-03-06 1966-11-15 Dow Chemical Co Amino-trichloropicolinic acid compounds
US5710106A (en) * 1996-02-22 1998-01-20 American Cyanamid Company Substituted pyridine herbicidal agents
FR2803592A1 (fr) * 2000-01-06 2001-07-13 Aventis Cropscience Sa Nouveaux derives de l'acide 3-hydroxypicolinique, leur procede de preparation et compositions fongicides les contenant.
ES2279817T3 (es) * 2000-01-14 2007-09-01 Dow Agrosciences Llc 4-aminopicolinatos y su uso como herbicidas.
US6297197B1 (en) 2000-01-14 2001-10-02 Dow Agrosciences Llc 4-aminopicolinates and their use as herbicides
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
MX2010003464A (es) * 2007-10-02 2010-04-27 Dow Agrosciences Llc Acidos 2-substituido-6-amino-5-alquilo, alquenilo o alquinilo-4-pirimidinacarboxilico y acidos picolinicos 6-substituido-4-amino-3-alquilo, alquenilo o alquinilo y su uso como herbicidas.
US8252938B2 (en) * 2009-06-08 2012-08-28 Dow Agrosciences, Llc. Process for the preparation of 6-(aryl)-4-aminopicolinates
GB0910766D0 (en) * 2009-06-22 2009-08-05 Syngenta Ltd Chemical compounds
GB201008290D0 (en) * 2010-05-18 2010-06-30 Syngenta Ltd Chemical compounds
TWI592401B (zh) 2011-01-25 2017-07-21 陶氏農業科學公司 用於製備４－胺基－３－氯－５－氟－６－（經取代的）吡啶甲酸酯的方法（一）

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3629424A (en) * 1967-12-26 1971-12-21 Dow Chemical Co Cyanofluoropyridines and fungicidal compositions and methods for using the same
US3803159A (en) * 1967-12-26 1974-04-09 Dow Chemical Co Fluorine containing cyanopyridines
US4336384A (en) * 1981-04-23 1982-06-22 The Dow Chemical Company Preparation of 4-amino-3,5,6-trichloropicolinic acid
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
CN101360713A (zh) * 2006-01-13 2009-02-04 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

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
STEPHEN C. FIELDS等: "Electrophilic fluorination: the aminopyridine dilemma", 《TETRAHEDRON LETTERS》 *

Also Published As

Publication number Publication date
CN104788368B (zh) 2017-09-26
JP2014515725A (ja) 2014-07-03
CN103874685B (zh) 2016-02-03
EP2668163A2 (en) 2013-12-04
IL227646A (en) 2016-10-31
KR101537879B1 (ko) 2015-07-17
CN104788368A (zh) 2015-07-22
BR102012001636A2 (pt) 2015-07-28
AU2012209277B2 (en) 2015-09-17
UA106945C2 (uk) 2014-10-27
US9067890B2 (en) 2015-06-30
CO6731125A2 (es) 2013-08-15
HK1199245A1 (zh) 2015-06-26
PL2668163T3 (pl) 2017-10-31
EP2668163A4 (en) 2015-03-11
US9452984B2 (en) 2016-09-27
WO2012103041A3 (en) 2014-05-01
AR085022A1 (es) 2013-08-07
SG192093A1 (en) 2013-08-30
US20120190857A1 (en) 2012-07-26
MX342328B (es) 2016-09-22
EP2668163B1 (en) 2017-05-10
MX2013008603A (es) 2013-08-12
HK1213875A1 (zh) 2016-07-15
JP5739018B2 (ja) 2015-06-24
KR20130121950A (ko) 2013-11-06
CA2825475A1 (en) 2012-08-02
WO2012103041A2 (en) 2012-08-02
IL227646A0 (en) 2013-09-30
TWI592401B (zh) 2017-07-21
TW201309649A (zh) 2013-03-01
US20150274669A1 (en) 2015-10-01
CA2825475C (en) 2017-08-22
RU2013139300A (ru) 2015-04-10
RU2545021C1 (ru) 2015-03-27
BR112013019025A2 (pt) 2016-07-12
ZA201305577B (en) 2014-09-25
US20140142317A1 (en) 2014-05-22

Similar Documents

Publication Publication Date Title
CN103874685B (zh) 4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
CN103429082B (zh) 4-氨基-3-氯-5-氟-6-(取代的)吡啶-2-甲酸酯的制备方法
CN103458689A (zh) 4-氨基-5-氟-3-卤代-6-(取代的)吡啶-2-甲酸酯的制备方法
AU2012209277A1 (en) Process for the preparation of 4-amino-3-chloro-5-fluoro-6-(substituted) picolinates
US7939697B2 (en) Fluorinating agent and method for producing fluorine-containing compound using the same
JP6547087B1 (ja) 光学活性な２，３−ビスホスフィノピラジン誘導体、その製造方法、遷移金属錯体及び有機ホウ素化合物の製造方法
JP5045989B2 (ja) トリフルオロメタンスルホン酸無水物の製造方法。
JP6682703B2 (ja) 光学活性な２，３−ビスホスフィノピラジン誘導体の製造方法及び光学活性なホスフィン遷移金属錯体の製造方法
JP3409603B2 (ja) ジアリールカーボネートの製造方法
JPH07278047A (ja) アリールオキシプロピオン酸の製造法
JP2009013118A (ja) アルカン化合物の製造方法
JP2006143606A (ja) １−ハロ−３−アリール−２−プロパノン類の製造法

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
REG Reference to a national code

Ref country code: HK

Ref legal event code: DE

Ref document number: 1199245

Country of ref document: HK

C14 Grant of patent or utility model
GR01 Patent grant
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20160203

Termination date: 20200124

CF01 Termination of patent right due to non-payment of annual fee
REG Reference to a national code

Ref country code: HK

Ref legal event code: WD

Ref document number: 1199245

Country of ref document: HK