CN114644565A - 一种咪唑啉酮类化合物关键中间体的合成方法 - Google Patents
一种咪唑啉酮类化合物关键中间体的合成方法 Download PDFInfo
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- CN114644565A CN114644565A CN202011498188.9A CN202011498188A CN114644565A CN 114644565 A CN114644565 A CN 114644565A CN 202011498188 A CN202011498188 A CN 202011498188A CN 114644565 A CN114644565 A CN 114644565A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/04—Formation of amino groups in compounds containing carboxyl groups
- C07C227/10—Formation of amino groups in compounds containing carboxyl groups with simultaneously increasing the number of carbon atoms in the carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/30—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- 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
- C07D213/80—Acids; Esters in position 3
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- 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
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Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
本发明涉及农药化学领域，具体涉及一种咪唑啉酮类化合物关键中间体的合成方法，包括如下步骤：将化合物Ⅱ与化合物Ⅲ溶于有机溶剂中，搅拌下反应，反应完成后蒸除溶剂即得到中间体I；将中间体I溶于有机溶剂，加入氨源、催化剂和化合物Ⅳ，热处理反应，即得到化合物Ⅴ。本发明提供的咪唑啉酮类化合物关键中间体的合成方法反应步骤短、原料易得、反应温和，提高了产物的收率和纯度，降低生产成本，适合工业化生产。
Description
技术领域
本发明涉及农药化学领域，尤其涉及咪唑啉酮类化合物关键中间体吡啶-2,3-二羧酸酯的合成方法。
背景技术
咪唑啉酮类化合物作为高效性除草剂，作用机制主要抑制乙酸羟酸合成酶(AHAs)的活性,影响3种支链氨基酸——缬氨酸、亮氨酸与异亮氨酸的生物合成,最终破坏蛋白质的合成,干扰DNA合成及细胞分裂和生长。而甲氧咪草烟，甲基咪草烟，乙基咪草烟是咪唑啉酮类除草剂的重要组成部分。
美国专利US4948896A和US5047542A公开了通过马来酸二烷基酯衍生物合成吡啶-2,3-二羧酸酯的方法，但其收率仅有66～88％，纯度仅有69～93％，总体较低，同时生产过程中还有有机三废高的问题，难以解决。
中国发明专利CN1062724A、CN1057456A分别公开了由氯代马来酸酯、二氯代马来酸二烷基酯制备吡啶-2,3-二羧酸二烷基酯的方法，其原料简单易得，但是转化率低，而且氯代马来酸酯遇到高热和碱性物质会发生分解，中间体稳定性较差，反应时间长达16～72小时，一定程度上增加工业化的难度。
美国专利US4816588A和US5597924A公开了用喹啉衍生物经过过氧化物氧化得到产品，氧化本身属于危险工艺，具有较高的危险性，而且收率很低仅为48～69％，原子利用率差。
美国专利US5334576A和US4798619A公开了以苯胺类衍生物为原料制备吡啶-2,3-二羧酸酯的方法，收率较低且危险。
中国发明专利CN104447527A公开了一种吡啶-2,3-二羧酸二烷基酯的方法，收率虽然能做到82～96％，但是需要用到危险的催化剂氨基钠、钠氢或三苯甲基钠，不利于工业化生产，另外反应温度高，引起副反应多，并且不易控制反应，工艺复杂。
因此，作为咪唑啉酮类化合物合成的重要中间体，现有的吡啶-2,3-二羧酸酯合成方法均不够理想，亟需一种反应步骤短、原料易得、反应温和、产品收率和纯度较高的吡啶-2,3-二羧酸酯合成方法合成方法。
发明内容
本发明要解决的技术问题是：提供一种反应步骤短、原料易得、反应温和，提高了产物的收率和纯度，降低生产成本，适合工业化生产的咪唑啉酮类化合物关键中间体的合成方法。
本发明的第一目的在于提供一种咪唑啉酮类化合物关键中间体的合成方法，其特征在于包括如下步骤：
(1)将化合物Ⅱ与化合物Ⅲ溶于有机溶剂中，搅拌下反应，反应完成后蒸除溶剂即得到中间体I；
(2)将中间体I溶于有机溶剂，加入氨源、催化剂和化合物Ⅳ，热处理反应，即得到通式Ⅴ；具体反应式如下：
其中，R1和R2各自独立的选自C1～6烷基；
R3和R4各自独立的选自C1～6烷基；
X选自氢、卤素、被0个、1个或多个卤素、羟基、C1～6的烷氧基或C1～6的烷硫基取代的C1～6烷基，C1～6的烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基。
优选的，R1和R2各自独立的选自C1～4烷基；
R3和R4各自独立的选自C1～4烷基；
X选自氢、卤素、被0个、1个或多个卤素、羟基、C1～4的烷氧基或C1～4的烷硫基取代的C1～4烷基，C1～4的烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基。
优选的，所述步骤(1)中的有机溶剂为卤代烷类，如二氯甲烷，二氯乙烷，氯仿；芳烃类，如甲苯或二甲苯等，所述二甲苯包括邻二甲苯、对二甲苯或间二甲苯。
优选的，所述步骤(1)中的反应温度为0～100℃，进一步的10～50℃。
优选的，所述步骤(1)中的化合物Ⅱ与化合物Ⅲ的摩尔比为1:1.0～3.0，进一步的，所述步骤(1)中的化合物Ⅱ与化合物Ⅲ的摩尔比为1：1.0～1.5；更进一步的，所述步骤(1)中的化合物Ⅱ与化合物Ⅲ的摩尔比为1：1.0～1.3。
优选的，所述步骤(2)中的有机溶剂为链烷醇类，如甲醇，乙醇，异丙醇；腈类，如乙腈；酰胺类，如N,N-二甲基甲酰胺；亚砜类，如二甲基亚砜等；进一步的有机溶剂为甲醇，乙醇等。
优选的，所述步骤(2)中氨源为氨基磺酸铵，磺酰胺，氨基磺酸，碳酸铵，乙酸铵，碳酸氢铵，氯化铵或甲酸铵等；进一步优选的氨源为氨基磺酸铵，氨基磺酸等酸性氨源。
优选的，所述步骤(2)中的催化剂为有机或无机酸，可以是盐酸，硫酸，甲酸，乙酸，三氟醋酸等，进一步的催化剂为硫酸。
优选的，所述步骤(2)中反应温度为20～120℃，进一步的40～80℃。
优选的，所述步骤(2)中所述步骤(2)中中间体I、氨源、催化剂与化合物Ⅳ的投料摩尔比为1：1～5.0：0.001～3.0：1～3.0；进一步的，中间体I、氨源、催化剂与化合物Ⅳ的投料摩尔比为1：1～1.5：0.01～1.0：1～2.0；更进一步的，中间体I、氨源、催化剂与化合物Ⅳ的投料摩尔比为1：1～1.3：0.01～0.5：1.05～1.5。
本发明的第二目的在于提供一种咪唑啉酮类化合物关键中间体，其结构如式I所示：
其中，R1和R2各自独立的选自C1～6烷基；R4选自C1～6的烷基。
优选的，如式I所示的中间体，其中R1和R2各自独立的选自C1～4烷基；R4选自C1～4的烷基。
本发明提供的咪唑啉酮类化合物关键中间体的合成方法反应步骤短、原料易得、反应温和，提高了产物的收率和纯度，降低生产成本，适合工业化生产。
具体实施方式
以下结合实例说明本发明，但不限制本发明。在本领域内，技术人员对本发明所做的简单替换或改进均属于本发明所保护的技术方案内。
实施例1：
(E)-二甲基2-(二甲氨基亚甲基)-3-氧代丁二酸酯的制备：
将160.13g(1mol)草酰乙酸二甲酯和119.16g(1mol)N,N-二甲基甲酰胺二甲缩醛混合溶解在二氯甲烷中，室温搅拌反应1h，反应完毕后减压蒸除溶剂得到油状物213.05g，定性含量98％，重量收率99％，1H NMR(400MHz,DMSO)δ7.96(d,J＝5.5Hz,1H),3.70(s,3H),3.59(s,3H),3.40(s,3H),2.94(s,3H).
实施例2：
5-甲基吡啶-2,3二羧酸甲酯的制备：
将213.05g纯度为98％的(E)-二甲基2-(二甲氨基亚甲基)-3-氧代丁二酸酯(0.97mol)和143.93g的氨基磺酸铵(1.26mol)溶于450g甲醇，加入0.98g浓硫酸(0.01mol)，升温至50℃，滴加61.98g丙醛(1.07mol)进入反应体系，滴加用时3h，滴加完毕后保温搅拌5h，反应跟踪结束后蒸出溶剂，加入水，二氯乙烷萃取分层，脱干溶剂得到黄色固体192.81g，定性含量98％，重量收率95％，1H NMR(400MHz,DMSO)δ8.67–8.62(m,1H),8.11(dd,J＝1.9,0.7Hz,1H),3.85(s,6H),2.41(s,3H).
实施例3：
5-乙基吡啶-2,3二羧酸甲酯的制备：
将213.05g纯度为98％的(E)-二甲基2-(二甲氨基亚甲基)-3-氧代丁二酸酯(0.97mol)和132.86g的氨基磺酸铵(1.16mol)溶于600g乙醇，加入2.94g浓硫酸(0.03mol)，升温至回流，滴加73.25g丁醛(1.02mol)进入反应体系，滴加用时2h，滴加完毕后保温搅拌3h，反应跟踪结束后蒸出溶剂，加入水，甲苯萃取分层，脱干溶剂得到黄色固体184.69g，定性含量96％，重量收率91％。
实施例4：
5-甲氧甲基吡啶-2,3二羧酸甲酯的制备：
将213.05g纯度为98％的(E)-二甲基2-(二甲氨基亚甲基)-3-氧代丁二酸酯(0.97mol)和94.2g的氨基磺酸(0.97mol)溶于320g乙醇，加入47.54g浓硫酸(0.49mol)，升温至回流，滴加128.22g甲氧基丙醛(1.46mol)进入反应体系，滴加用时5h，滴加完毕后保温搅拌10h，反应跟踪结束后蒸出溶剂，加入水，二氯甲烷萃取分层，脱干溶剂得到黄色固体182.66g，定性含量95％，重量收率90％。1H NMR(400MHz,DMSO)δ8.79(d,J＝1.9Hz,1H),8.24(d,J＝1.9Hz,1H),4.60(s,2H),3.94(d,J＝9.8Hz,6H),3.40(s,3H).
实施例5：
(E)-二乙基2-(二甲氨基亚甲基)-3-氧代丁二酸酯的制备：
将188.18g草酰乙酸二乙酯(1mol)和154.91g N,N-二甲基甲酰胺二甲缩醛(1.3mol)混合溶解在二氯乙烷中，室温搅拌反应2h，反应完毕后减压蒸除溶剂得到油状物243.20g，定性含量97％，重量收率99％。
实施例6：
5-甲氧甲基吡啶-2,3二羧酸乙酯的制备：
将243.20g纯度为97％的(E)-二乙基2-(二甲氨基亚甲基)-3-氧代丁二酸酯(1.1mol)和122.40g的氨基磺酸(1.26mol)溶于486g乙醇，加入13.72g浓硫酸(0.14mol)，升温至回流，滴加132.31g甲氧基丙醛(1.50mol)进入反应体系，滴加用时5h，滴加完毕后保温搅拌8h，反应跟踪结束后蒸出溶剂，加入水，二氯甲烷萃取分层，脱干溶剂得到黄色固体238.46g，定性含量95％，重量收率92％。
以上所述的仅是本发明的优选实施方式，应当指出，对于本领域的普通技术人员来说，在不脱离本发明创造构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。
Claims (10)
1.一种咪唑啉酮类化合物关键中间体的合成方法，其特征在于包括如下步骤：
(1)将化合物Ⅱ与化合物Ⅲ溶于有机溶剂中，搅拌下反应，反应完成后蒸除溶剂即得到中间体I；
(2)将中间体I溶于有机溶剂，加入氨源、催化剂和化合物Ⅳ，热处理反应，即得到通式Ⅴ；具体反应式如下：
其中，R1和R2各自独立的选自C1～6烷基；
R3和R4各自独立的选自C1～6烷基；
X选自氢、卤素、被0个、1个或多个卤素、羟基、C1～6的烷氧基或C1～6的烷硫基取代的C1～6烷基，C1～6的烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基。
2.如权利要求1所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，
R1和R2各自独立的选自C1～4烷基；
R3和R4各自独立的选自C1～4烷基；
X选自氢、卤素、被0个、1个或多个卤素、羟基、C1～4的烷氧基或C1～4的烷硫基取代的C1～4烷基，C1～4的烷氧羰基，氨基羰基，苯硫基，苯氧基或苯基。
3.如权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(1)中的有机溶剂选自二氯甲烷、二氯乙烷、氯仿、甲苯或二甲苯。
4.如权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(1)中的化合物Ⅱ与化合物Ⅲ的摩尔比为1:1.0～3.0。
5.如权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(2)中有机溶剂选自甲醇、乙醇、异丙醇、乙腈、N,N-二甲基甲酰胺或二甲基亚砜。
6.权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(2)中的氨源为氨基磺酸铵，磺酰胺，氨基磺酸，碳酸铵，乙酸铵，甲酸铵，碳酸氢铵或氯化铵。
7.如权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(2)中的催化剂选自盐酸、硫酸、甲酸、乙酸或三氟醋酸。
8.如权利要求1～2任一项所述的咪唑啉酮类化合物关键中间体的合成方法，其特征在于，所述步骤(2)中中间体I、氨源、催化剂与通式Ⅳ的投料摩尔比为1：1～5.0：0.001～3.0：1～2.0。
9.一种咪唑啉酮类化合物关键中间体，其结构如式I所示：
其中，R1和R2各自独立的选自C1～6烷基；R4选自C1～6的烷基。
10.如权利要求9所述的咪唑啉酮类化合物关键中间体，其特征在于，所述R1和R2各自独立的选自C1～4烷基；R4选自C1～4的烷基。
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