CN109053559B - 5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法 - Google Patents

5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法 Download PDF

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CN109053559B
CN109053559B CN201810718395.7A CN201810718395A CN109053559B CN 109053559 B CN109053559 B CN 109053559B CN 201810718395 A CN201810718395 A CN 201810718395A CN 109053559 B CN109053559 B CN 109053559B
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methoxymethyl
dimethyl
pyridinedicarboxylate
sodium methoxide
thionyl chloride
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CN109053559A (zh
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孙永辉
张元元
刘晓佳
高建红
万里红
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Nanjing Gaoheng Biotechnology Co ltd
Jiangsu Agrochem Laboratory 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
    • C07D213/803—Processes of preparation
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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
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    • C07D213/80—Acids; Esters in position 3

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Abstract

本发明公开了一种5‑甲氧甲基‑2,3‑吡啶二甲酸二甲酯的制备方法，包括：①[(5,6‑二羧基‑3‑吡啶基)‑甲基]三甲基溴化铵二甲酯与甲醇钠在甲醇存在下的甲氧化反应；②向反应后的体系中加入氯化亚砜的酰氯化+酯化反应。季铵盐与甲醇钠的摩尔比为1∶1～1∶2，季铵盐与氯化亚砜的摩尔比为1∶1～1∶2，酰氯化+酯化反应时间为10～20h，酰氯化+酯化反应温度为回流。本发明的方法有效降低了副产物，提高了反应收率，最终能够得到纯度在97%以上的目标产物，反应收率可达90%以上。

Description

5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法
技术领域
本发明属于除草剂中间体制备技术领域，具体涉及一种甲氧咪草烟中间体5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法。
背景技术
甲氧咪草烟是咪唑啉酮类除草剂品种，通过叶片吸收、传导并积累于分生组织，抑制AHAS的活性，导致支链氨基酸-撷氨酸、亮氨酸与异亮氨酸生物合成停止，干扰DNA合成及细胞有丝分裂与植物生长，最终造成植株死亡。
5-甲氧甲基-2,3-吡啶二甲酸二甲酯则是合成甲氧咪草烟的重要中间体，而现有制备5-甲氧甲基-2,3-吡啶二甲酸二甲酯的方法基本都是以5-甲基-2,3-吡啶二甲酸二甲酯为起始原料，先经卤代反应得到5-卤代甲基-2,3-吡啶二甲酸二甲酯，再与三烷基胺反应得到[(5,6-二羧基-3-吡啶基)-甲基]三烷基卤化铵二甲酯，最后再与甲醇钠/甲醇体系反应得到5-甲氧甲基-2,3-吡啶二甲酸二甲酯（参见文献1～文献4）。
对于上述最后一步反应，现有技术存在的最大问题在于：产物纯度和收率均不理想；文献1的实施例7显示收率只有70%左右，文献3的实施例显示收率更是只有50%左右。
文献1：美国专利文献US5288866A，公开日1994年2月22日。
文献2：中国专利文献CN102245575A，公开日2011年11月16日。
文献3：中国专利文献CN103613535A，公开日2014年3月5日。
文献4：中国专利文献CN105732492A，公开日2016年7月6日。
发明内容
本发明的目的在于解决上述问题，提供一种产物纯度和收率均较高的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法。
实现本发明目的的技术方案是：一种5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，包括：
①[(5,6-二羧基-3-吡啶基)-甲基]三甲基溴化铵二甲酯【以下均简称为季铵盐】与甲醇钠在甲醇存在下的甲氧化反应；以及
②向反应后的体系中加入氯化亚砜的酰氯化+酯化反应。
申请人经过大量试验分析发现：导致上述反应收率和产物纯度不理想的根本原因在于产物5-甲氧甲基-2,3-吡啶二甲酸二甲酯在甲醇钠/甲醇体系中容易水解成不易分离的副产物单甲酸和二甲酸，反应式如下：
Figure 859289DEST_PATH_IMAGE001
。
所述季铵盐与所述甲醇钠的摩尔比为1∶1～1∶2，优选为1∶1.2～1∶1.4。
所述季铵盐与所述氯化亚砜的摩尔比为1∶1～1∶2，优选为1∶1.1～1∶1.2。
所述甲醇钠的加入温度为0～50℃，优选为15～20℃。
所述甲氧化反应时间为1～10h，优选为5h。
所述甲氧化反应温度优选为回流条件下进行。
所述氯化亚砜的加入温度为0～50℃，优选为10～15℃。
所述酰氯化+酯化反应时间为10～20h，优选为17h。
所述酰氯化+酯化反应温度优选为回流条件下进行。
本发明具有的积极效果：本发明的方法有效降低了副产物，提高了反应收率，最终能够得到纯度在97%以上的目标产物，反应收率可达90%以上。
具体实施方式
（实施例1）
本实施例的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法如下：
①向反应瓶中加入68g的季铵盐（0.196mol）和150g的甲醇，搅拌均匀后，控温15～20℃滴加47g浓度为27wt%的甲醇钠甲醇溶液（0.235mol），滴完升温至回流，反应5h。
②反应结束后，降温至15℃以下，控温10～15℃滴加26g的氯化亚砜（0.219mol），滴完先在15℃搅拌1h，然后升温至回流，反应17h。
③反应结束后，先减压回收甲醇，然后加水，搅拌均匀，接着用二氯乙烷萃取两次，合并二氯乙烷层，最后经水洗、脱溶，得到45.0g的5-甲氧甲基-2,3-吡啶二甲酸二甲酯，收率为96.1%，纯度为97.5%（HPLC）。
（实施例2～实施例5）
各实施例的制备方法与实施例1基本相同，不同之处见表1。
表1
实施例1 实施例2 实施例3 实施例4 实施例5
季铵盐 68g 68g 68g 68g 136g
27wt%的甲醇钠甲醇溶液 47g 55g 47g 47g 94g
氯化亚砜 26g 26g 28g 26g 52g
反应时间 17h 17h 17h 20h 17h
产量 45.0g 43.4g 44.2g 43.7g 89.2g
收率 96.1% 92.7% 94.4% 93.3% 95.2%
纯度 97.5% 97.7% 97.4% 97.5% 97.3%
（对比例1）
本对比例与实施例1的区别在于：不含步骤②。
最终得到35.0g的5-甲氧甲基-2,3-吡啶二甲酸二甲酯，收率为74.7%，纯度为85.5%（HPLC）。

Claims (9)

1.一种5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于包括：
①[(5,6-二羧基-3-吡啶基)-甲基]三甲基溴化铵二甲酯与甲醇钠在甲醇存在下的甲氧化反应；以及
②向反应后的体系中加入氯化亚砜的酰氯化+酯化反应。
2.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述[(5,6-二羧基-3-吡啶基)-甲基]三甲基溴化铵二甲酯与所述甲醇钠的摩尔比为1∶1～1∶2。
3.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述[(5,6-二羧基-3-吡啶基)-甲基]三甲基溴化铵二甲酯与所述氯化亚砜的摩尔比为1∶1～1∶2。
4.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述甲醇钠的加入温度为0～50℃。
5.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述甲氧化反应时间为1～10h。
6.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述甲氧化反应温度为回流条件下进行。
7.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述氯化亚砜的加入温度为0～50℃。
8.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述酰氯化+酯化反应时间为10～20h。
9.根据权利要求1所述的5-甲氧甲基-2,3-吡啶二甲酸二甲酯的制备方法，其特征在于：所述酰氯化+酯化反应温度为回流条件下进行。
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CN113620928A (zh) * 2021-08-16 2021-11-09 辽宁先达农业科学有限公司 一种甲氧咪草烟钠盐的合成方法

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