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CN106279012B - 一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法 - Google Patents

一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法 Download PDF

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CN106279012B
CN106279012B CN201510311767.0A CN201510311767A CN106279012B CN 106279012 B CN106279012 B CN 106279012B CN 201510311767 A CN201510311767 A CN 201510311767A CN 106279012 B CN106279012 B CN 106279012B
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晏三军
任杰
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Lier Chemical Co Ltd
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    • 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
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    • 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

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Abstract

本发明公开了一种3,4,6‑三氯吡啶‑2‑甲酸及其酯的制备方法，目的在于解决目前3,4,6‑三氯吡啶‑2‑甲酸及其甲酯的制备方法存在合成线路长、收率低、生产成本高的问题。本发明3,4,6‑三氯吡啶‑2‑甲酸的制备方法包括如下步骤：在‑10～10℃下将3，6‑二氯‑4氨基‑2‑吡啶甲酸与盐酸、亚硝酸钠混合，混合完毕后将反应液升温，得到3,4,6‑三氯吡啶‑2‑甲酸。本发明的制备方法操作步骤简单，流程短，收率高达74%以上，纯度达98%，显著优于现有技术，具有较好的应用前景。同时，本发明合成线路短，原料成本低，能够有效降低3,4,6‑三氯吡啶‑2‑甲酸及其酯的生产成本，满足工业化大规模生产的需要，对于促进3,4,6‑三氯吡啶‑2‑甲酸及其酯的应用和发展具有重要的意义。

Description

一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法
技术领域
本发明涉及化工领域，尤其是合成领域，具体为一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法，即涉及3,4,6-三氯吡啶-2-甲酸的制备方法和3,4,6-三氯吡啶-2-甲酸酯的制备方法，进一步包括3,4,6-三氯吡啶-2-甲酸甲酯的制备方法。
背景技术
氯代砒啶羧酸衍生物是一类重要的化工中间体，广泛应用于农药、医药合成等领域。其中，3,4,6-三氯吡啶-2-甲酸及其相应的酯是多氯代砒啶羧酸衍生物中比较重要的化合物。
3,4,6-三氯吡啶-2-甲酸及其相应的酯作为一种有用的精细化工中间体，其在合成除草剂方面的用途已被专利WO2010149956(中国同族专利：201080027838.X，4-氨基吡啶甲酸酯和它们作为除草剂的应用)所公开。同时，该专利中还具体公开了3,4,6-三氯吡啶-2-甲酸甲酯的如下合成路线：
然而，该方法也存在如下缺点:(1)合成路线长；(2)收率低，据文献报道，该法的收率不高于30％，且分离纯化困难；(3)该方法中需要采用三氟乙酸酐等昂贵的试剂，生产成本高。上述缺点导致该方法难以满足工业化大规模生产的需要，限制了3,4,6-三氯吡啶-2-甲酸及其酯的应用和发展。
因此，目前迫切需要一种新的方法，以解决上述问题。
发明内容
本发明的发明目的在于：针对目前3,4,6-三氯吡啶-2-甲酸及其甲酯的制备方法存在合成线路长、收率低、生产成本高的问题，提供一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法。本发明的制备方法收率高达74％以上，纯度可达98％，显著优于现有技术。同时，本发明合成线路短，原料成本低，能够有效降低3,4,6-三氯吡啶-2-甲酸及其酯的生产成本，满足工业化大规模生产的需要，对于促进3,4,6-三氯吡啶-2-甲酸及其酯的应用和发展具有重要的意义。
为了实现上述目的，本发明采用如下技术方案：
一种3,4,6-三氯吡啶-2-甲酸的制备方法，包括如下步骤：在-10～10℃下将3，6-二氯-4氨基-2-吡啶甲酸与盐酸、亚硝酸钠混合，混合完毕后将反应液升温，得到3,4,6-三氯吡啶-2-甲酸。
盐酸与3，6-二氯-4氨基-2-吡啶甲酸的摩尔比为1.5～3：1。
亚硝酸钠与3，6-二氯-4氨基-2-吡啶甲酸的摩尔比为1～1.5：1。
将反应液升温至60～100℃，保温0.5～10h，得到3,4,6-三氯吡啶-2-甲酸。
将反应液升温至75～80℃，保温0.5～10h，得到3,4,6-三氯吡啶-2-甲酸。
在-10～10℃条件下，将盐酸加入反应器内，再在搅拌条件下，向反应器中加入3，6-二氯-4氨基-2-吡啶甲酸，然后加入亚硝酸钠的水溶液，保温搅拌至3，6-二氯-4氨基-2-吡啶甲酸完全溶解后，将反应液升温至75～80℃，保温2～4h，得到3,4,6-三氯吡啶-2-甲酸。
采用如下方式进行后处理，将制备的含3,4,6-三氯吡啶-2-甲酸的产物冷却至室温后，用有机溶剂进行萃取，将萃取液减压浓缩结晶，得到3,4,6-三氯吡啶-2-甲酸结晶物。
以前述方法制备的3,4,6-三氯吡啶-2-甲酸为原料制备其酯的方法，包括如下步骤：3,4,6-三氯吡啶-2-甲酸在硫酸作用下，与醇剂反应，得到3,4,6-三氯吡啶-2-甲酸酯。
将3,4,6-三氯吡啶-2-甲酸、醇剂、浓硫酸加入反应器中，升温回流10～30h，收集-0.098Mpa条件下155-160℃的馏分，向馏分中加入馏分质量2～5倍的甲醇进行加热回流，回流完成后，冷却至0℃，减压抽滤，得到3,4,6-三氯吡啶-2-甲酸酯。
所述醇剂为甲醇或乙醇。
本发明提供一种3,4,6-三氯吡啶-2-甲酸及其酯的制备方法，本发明以3，6-二氯-4氨基-2-吡啶甲酸为起始原料，通过重氮化反应制备3,4,6-三氯吡啶-2-甲酸，然后再与醇剂酯化，得到目标产物。以制备3,4,6-三氯吡啶-2-甲酸甲酯为例，其反应路线如下：
本发明步骤简单，操作简便，无需使用昂贵、安全性差、腐蚀性强的三氟乙酸酐、三氯氧磷等物质，生产成本低，收率高，能够满足工业化大规模生产的需要。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
本说明书中公开的任一特征，除非特别叙述，均可被其他等效或具有类似目的的替代特征加以替换。即，除非特别叙述，每个特征只是一系列等效或类似特征中的一个例子而已。
实施例1 制备3,4,6-三氯吡啶-2-甲酸
向1L反应瓶中加入240ml水、90ml浓盐酸，在搅拌下，向反应瓶中加入3，6-二氯-4氨基-2-吡啶甲酸108.68g(0.525mol)，再在0℃下，缓慢滴加亚硝酸钠溶液(该亚硝酸钠溶液含51g(0.6mol)亚硝酸钠和90ml水)，滴加完毕后，保温搅拌至3，6-二氯-4氨基-2-吡啶甲酸消失，得到反应溶液。将反应溶液缓慢加热至60℃～100℃，优选75℃～80℃，保温反应3h后，降至室温，再用乙酸乙酯萃取三次，每次乙酸乙酯的用量为120mL，合并有机相。将有机相水洗、浓缩后，经重结晶得到3,4,6-三氯吡啶-2-甲酸，含量为98％。
在其他反应条件不变的情况下，对滴加温度筛选的结果见下表1所示。
表1 不同滴加温度下的测定结果
序号 滴加温度/℃ 收率/％
1 -10 80
2 0 81
3 5 80
4 10 74
实施例2 制备3,4,6-三氯吡啶-2-甲酸酯
向100mL反应瓶中加入10g(0.0444mol)3,4,6-三氯吡啶-2-甲酸，再加入20g甲醇和1g浓硫酸，升温回流反应16h，反应完毕后，减压蒸出甲醇，然后再收集-0.098MPa条件下155-160℃的馏分。向馏分中加入馏分质量三倍甲醇进行加热回流，冷却至0℃，减压抽滤，得母液。将母液旋干后，再用甲醇热打浆后，冷却、抽滤，得到白色固体3,4,6-三氯吡啶-2-甲酸甲酯9.5g。
经测定：制备的白色固体的mp(melting point，简称：熔点)为60-63℃，1H NMR(400MHz,CDCl3)δ7.58(s,1H)，4.01(s,3H)ppm。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的组合。

Claims (7)

1.一种3,4,6-三氯吡啶-2-甲酸的制备方法，其特征在于，包括如下步骤：在-10～10℃条件下，将盐酸加入反应器内，再在搅拌条件下，向反应器中加入3，6-二氯-4氨基-2-吡啶甲酸，然后加入亚硝酸钠的水溶液，保温搅拌至3，6-二氯-4氨基-2-吡啶甲酸完全溶解后，将反应液升温至75～80℃，保温2～4h，得到3,4,6-三氯吡啶-2-甲酸。
2.根据权利要求1所述3,4,6-三氯吡啶-2-甲酸的制备方法，其特征在于，盐酸与3，6-二氯-4氨基-2-吡啶甲酸的摩尔比为1.5～3：1。
3.根据权利要求1或2所述3,4,6-三氯吡啶-2-甲酸的制备方法，其特征在于，亚硝酸钠与3，6-二氯-4氨基-2-吡啶甲酸的摩尔比为1～1.5：1。
4.根据权利要求1所述3,4,6-三氯吡啶-2-甲酸的制备方法，其特征在于，采用如下方式进行后处理，将反应液冷却至室温后，用有机溶剂进行萃取，将萃取液减压浓缩结晶，得到3,4,6-三氯吡啶-2-甲酸结晶物。
5.采用权利要求1-4任一项制得的所述3,4,6-三氯吡啶-2-甲酸制备其酯的方法，其特征在于，包括如下步骤：3,4,6-三氯吡啶-2-甲酸在硫酸作用下，与醇剂反应，得到3,4,6-三氯吡啶-2-甲酸酯。
6.根据权利要求5所述的方法，其特征在于，将3,4,6-三氯吡啶-2-甲酸、醇剂、浓硫酸加入反应器中，升温回流10～30h，收集-0.098Mpa条件下155-160℃的馏分，向馏分中加入馏分质量2～5倍的甲醇进行加热回流，回流完成后，冷却至0℃，减压抽滤，得到3,4,6-三氯吡啶-2-甲酸酯。
7.根据权利要求5或6所述的方法，其特征在于，所述醇剂为甲醇或乙醇。
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CN1416419A (zh) * 2000-01-14 2003-05-07 美国陶氏益农公司 4－氨基吡啶甲酸酯和它们作为除草剂的应用

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CN1416419A (zh) * 2000-01-14 2003-05-07 美国陶氏益农公司 4－氨基吡啶甲酸酯和它们作为除草剂的应用

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