CN114380740A - A kind of synthetic method of polysubstituted pyridine-2-oxy ether compounds - Google Patents
A kind of synthetic method of polysubstituted pyridine-2-oxy ether compounds Download PDFInfo
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- CN114380740A CN114380740A CN202111594242.4A CN202111594242A CN114380740A CN 114380740 A CN114380740 A CN 114380740A CN 202111594242 A CN202111594242 A CN 202111594242A CN 114380740 A CN114380740 A CN 114380740A
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- RDAMCMXHPYETRL-UHFFFAOYSA-N 2-pyridin-2-yloxyperoxypyridine Chemical class C=1C=CC=NC=1OOOC1=CC=CC=N1 RDAMCMXHPYETRL-UHFFFAOYSA-N 0.000 title claims description 12
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 238000004821 distillation Methods 0.000 claims abstract description 47
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 20
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims abstract description 17
- 150000003222 pyridines Chemical class 0.000 claims abstract description 13
- 238000006266 etherification reaction Methods 0.000 claims abstract description 10
- 238000001035 drying Methods 0.000 claims abstract description 5
- 238000001816 cooling Methods 0.000 claims abstract description 4
- 238000001914 filtration Methods 0.000 claims abstract description 4
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 39
- -1 polysubstituted pyridine-2-oxy ether compound Chemical class 0.000 claims description 32
- 230000018044 dehydration Effects 0.000 claims description 27
- 238000006297 dehydration reaction Methods 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 22
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 17
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 16
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims description 16
- 230000002194 synthesizing effect Effects 0.000 claims description 15
- 239000002994 raw material Substances 0.000 claims description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000005070 sampling Methods 0.000 claims description 2
- 239000000463 material Substances 0.000 claims 1
- 238000010025 steaming Methods 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 6
- 150000003839 salts Chemical class 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 5
- 239000002351 wastewater Substances 0.000 abstract description 5
- 239000003513 alkali Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract 4
- 229910052760 oxygen Inorganic materials 0.000 abstract 4
- 239000001301 oxygen Substances 0.000 abstract 4
- 238000001308 synthesis method Methods 0.000 abstract 3
- 238000002156 mixing Methods 0.000 abstract 1
- AQIHDXGKQHFBNW-UHFFFAOYSA-N 2-(4-hydroxyphenoxy)propanoic acid Chemical compound OC(=O)C(C)OC1=CC=C(O)C=C1 AQIHDXGKQHFBNW-UHFFFAOYSA-N 0.000 description 6
- QUKGYYKBILRGFE-UHFFFAOYSA-N benzyl acetate Chemical compound CC(=O)OCC1=CC=CC=C1 QUKGYYKBILRGFE-UHFFFAOYSA-N 0.000 description 6
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 6
- 150000001408 amides Chemical group 0.000 description 4
- MYGAJZBZLONIBZ-UHFFFAOYSA-N methyl 2-chloropyridine-3-carboxylate Chemical compound COC(=O)C1=CC=CN=C1Cl MYGAJZBZLONIBZ-UHFFFAOYSA-N 0.000 description 4
- MVIVCWMMSVVJNT-UHFFFAOYSA-N 2-[2-chloro-4-(trifluoromethyl)phenoxy]pyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1OC1=CC=C(C(F)(F)F)C=C1Cl MVIVCWMMSVVJNT-UHFFFAOYSA-N 0.000 description 3
- YNWKEXMSQQUMEL-UHFFFAOYSA-N 2-chloro-4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1Cl YNWKEXMSQQUMEL-UHFFFAOYSA-N 0.000 description 3
- VXHSATAEEHCPFE-UHFFFAOYSA-N 2-chloro-n-(2,4-difluorophenyl)pyridine-3-carboxamide Chemical compound FC1=CC(F)=CC=C1NC(=O)C1=CC=CN=C1Cl VXHSATAEEHCPFE-UHFFFAOYSA-N 0.000 description 3
- UGEJOEBBMPOJMT-UHFFFAOYSA-N 3-(trifluoromethyl)phenol Chemical compound OC1=CC=CC(C(F)(F)F)=C1 UGEJOEBBMPOJMT-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940007550 benzyl acetate Drugs 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical group 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000011570 nicotinamide Substances 0.000 description 3
- 229960003966 nicotinamide Drugs 0.000 description 3
- ADVQMCQMDHBTHJ-UHFFFAOYSA-N 2-chloro-6-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC=CC(Cl)=N1 ADVQMCQMDHBTHJ-UHFFFAOYSA-N 0.000 description 2
- IBRSSZOHCGUTHI-UHFFFAOYSA-N 2-chloropyridine-3-carboxylic acid Chemical compound OC(=O)C1=CC=CN=C1Cl IBRSSZOHCGUTHI-UHFFFAOYSA-N 0.000 description 2
- RJUFJBKOKNCXHH-UHFFFAOYSA-N Methyl propionate Chemical compound CCC(=O)OC RJUFJBKOKNCXHH-UHFFFAOYSA-N 0.000 description 2
- PVNIIMVLHYAWGP-UHFFFAOYSA-N Niacin Chemical compound OC(=O)C1=CC=CN=C1 PVNIIMVLHYAWGP-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical group 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 2
- 229940017219 methyl propionate Drugs 0.000 description 2
- 239000000575 pesticide Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 229910052700 potassium Inorganic materials 0.000 description 2
- 239000011591 potassium Substances 0.000 description 2
- RXIDMPWPFKWGRZ-UHFFFAOYSA-N 3-chloro-2,5-bis(trifluoromethyl)pyridine Chemical compound FC(F)(F)c1cnc(c(Cl)c1)C(F)(F)F RXIDMPWPFKWGRZ-UHFFFAOYSA-N 0.000 description 1
- BAYGVMXZJBFEMB-UHFFFAOYSA-N 4-(trifluoromethyl)phenol Chemical compound OC1=CC=C(C(F)(F)F)C=C1 BAYGVMXZJBFEMB-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 239000000417 fungicide Substances 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 239000004009 herbicide Substances 0.000 description 1
- CUEDLSLTSIRGCF-VQHVLOKHSA-N methyl (e)-2-(2-hydroxyphenyl)-3-methoxyprop-2-enoate Chemical compound CO\C=C(\C(=O)OC)C1=CC=CC=C1O CUEDLSLTSIRGCF-VQHVLOKHSA-N 0.000 description 1
- BTTXESIFAHCXMK-UHFFFAOYSA-N methyl 2-methoxyprop-2-enoate Chemical compound COC(=C)C(=O)OC BTTXESIFAHCXMK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229960001238 methylnicotinate Drugs 0.000 description 1
- 239000011664 nicotinic acid Substances 0.000 description 1
- 235000001968 nicotinic acid Nutrition 0.000 description 1
- 229960003512 nicotinic acid Drugs 0.000 description 1
- 238000010534 nucleophilic substitution reaction Methods 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- NESLWCLHZZISNB-UHFFFAOYSA-M sodium phenolate Chemical class [Na+].[O-]C1=CC=CC=C1 NESLWCLHZZISNB-UHFFFAOYSA-M 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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
- C07D213/78—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
- C07D213/82—Amides; Imides in position 3
-
- 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
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
-
- 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
-
- 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
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
Description
技术领域technical field
本发明属于农药生产技术领域，具体涉及一种多取代吡啶-2-氧醚类化合物的合成方法。The invention belongs to the technical field of pesticide production, in particular to a method for synthesizing a polysubstituted pyridine-2-oxyether compound.
背景技术Background technique
多取代吡啶-2-氧醚类化合物多用于杀菌剂和除草剂，广泛应用于农药领域。多取代吡啶-2-氧醚类化合物合成路线一般为：在相转移催化剂作用下，氢氧化钾或氢氧化钠与酚反应得到酚钾/钠盐，再与吡啶杂环2号位卤原子发生亲核取代反应得到多取代吡啶-2-氧醚类化合物，反应原理如下：Polysubstituted pyridine-2-oxyether compounds are mostly used in fungicides and herbicides, and are widely used in the field of pesticides. The synthetic route of polysubstituted pyridine-2-oxyether compounds is generally as follows: under the action of a phase transfer catalyst, potassium hydroxide or sodium hydroxide reacts with phenol to obtain potassium/sodium phenate salt, which is then reacted with the halogen atom at position 2 of the pyridine heterocycle. Nucleophilic substitution reaction obtains polysubstituted pyridine-2-oxyether compounds, and the reaction principle is as follows:
其中：R1为羧酸、酯、酰胺或取代类酰胺；Wherein: R1 is carboxylic acid, ester, amide or substituted amide;
R4为苯基或其衍生物；R4 is phenyl or its derivative;
X为卤素；X is halogen;
M为钠、钾。M is sodium and potassium.
但上述合成路线在生产中会产生大量废水和废盐，带来环保压力。因此，如何减少合成过程中废水和废盐是本领域技术人员一直研究的问题。However, the above synthetic route will generate a large amount of waste water and waste salt during production, which brings environmental pressure. Therefore, how to reduce waste water and waste salts in the synthesis process is a problem that those skilled in the art have been studying.
发明内容SUMMARY OF THE INVENTION
本发明的目的是提供一种多取代吡啶-2-氧醚类化合物的合成方法，具有工艺过程简单，无废水废盐产生，环保压力小。The purpose of the present invention is to provide a method for synthesizing a polysubstituted pyridine-2-oxyether compound, which has the advantages of simple technological process, no waste water and waste salt generation, and low environmental protection pressure.
本发明解决上述问题所采用的技术方案为：一种多取代吡啶-2-氧醚类化合物的合成方法，将多取代吡啶衍生物与酚直接混合反应得到多取代吡啶-2-氧醚类化合物。The technical solution adopted by the present invention to solve the above problems is: a method for synthesizing a polysubstituted pyridine-2-oxyether compound, wherein the polysubstituted pyridine derivative and phenol are directly mixed and reacted to obtain a polysubstituted pyridine-2-oxyether compound .
反应原理如下：The reaction principle is as follows:
其中：R1为羧酸、酯、酰胺或取代类酰胺；Wherein: R1 is carboxylic acid, ester, amide or substituted amide;
R2，R3为H、卤素、烷基或烷基衍生物；R2, R3 are H, halogen, alkyl or alkyl derivatives;
R4为苯基或其衍生物；R4 is phenyl or its derivative;
X为卤素。X is halogen.
优选的，一种多取代吡啶-2-氧醚类化合物的合成方法，包括以下步骤：Preferably, a kind of synthetic method of polysubstituted pyridine-2-oxy ether compound, comprises the following steps:
（1）将吡啶衍生物加入有机溶剂中进行蒸馏脱水；(1) adding the pyridine derivative to the organic solvent for distillation and dehydration;
（2）将酚加入有机溶剂中进行蒸馏脱水；(2) adding phenol into an organic solvent for distillation and dehydration;
（3）将步骤（2）得到的溶液连续滴加至步骤（1）中，滴加结束，升温回流进行醚化反应，得到反应液；(3) The solution obtained in step (2) is continuously added dropwise to step (1), the dropwise addition is completed, the temperature is raised and refluxed to carry out etherification reaction to obtain a reaction solution;
（4）将步骤（3）中反应液负压蒸馏回收多余的酚；(4) negative pressure distillation of the reaction solution in step (3) is used to reclaim excess phenol;
（5）将步骤（4）中蒸馏残液中加入有机溶剂升温溶解，再经冷却、过滤、干燥得到多取代吡啶-2-氧醚化合物。(5) adding an organic solvent to the distillation residue in step (4), heating up and dissolving, and then cooling, filtering and drying to obtain a polysubstituted pyridine-2-oxyether compound.
更优选的，步骤（1）、步骤（2）、步骤（5）中所述有机溶剂为甲苯、二甲苯、环己烷、庚烷或氯苯。More preferably, the organic solvent in step (1), step (2) and step (5) is toluene, xylene, cyclohexane, heptane or chlorobenzene.
更优选的，所述步骤（1）具体为：0-160℃温度下将吡啶衍生物加入有机溶剂中进行蒸馏脱水，吡啶衍生物与有机溶剂质量比为10:1~1:50，所述蒸馏脱水温度为100-150℃。More preferably, the step (1) is as follows: adding the pyridine derivative into the organic solvent for distillation and dehydration at a temperature of 0-160°C, and the mass ratio of the pyridine derivative to the organic solvent is 10:1 to 1:50. The temperature of distillation and dehydration is 100-150°C.
更更优选的，步骤（1）中多取代吡啶衍生物与有机溶剂质量比为2:1~1:5。More preferably, in step (1), the mass ratio of the polysubstituted pyridine derivative to the organic solvent is 2:1 to 1:5.
更优选的，所述步骤（2）具体为：0-160℃温度下将酚加入有机溶剂中进行蒸馏脱水，酚与有机溶剂质量比为10:1~1:50，所述蒸馏脱水温度为100-150℃。More preferably, the step (2) is specifically as follows: adding phenol into an organic solvent for distillation and dehydration at a temperature of 0-160°C, the mass ratio of phenol to the organic solvent is 10:1 to 1:50, and the distillation and dehydration temperature is 100-150℃.
更更优选的，步骤（2）中酚与有机溶剂质量比为2:1~1:3。More preferably, in step (2), the mass ratio of phenol to organic solvent is 2:1 to 1:3.
更优选的，所述步骤（3）具体为：将步骤（2）得到的溶液连续滴加至步骤（1）中，滴加结束，升温回流进行醚化反应，通过蒸出有机溶剂或补加新鲜有机溶剂控制反应体系温度90~200℃，反应时间1-25h，取样中控，原料多取代吡啶衍生物含量＜0.5%。More preferably, the step (3) is specifically as follows: the solution obtained in the step (2) is continuously added dropwise to the step (1); The fresh organic solvent controls the temperature of the reaction system to 90~200℃, the reaction time is 1-25h, the sampling is controlled, and the content of the multi-substituted pyridine derivatives of the raw materials is less than 0.5%.
更更优选的，步骤（3）中醚化温度为125-160℃。More preferably, the etherification temperature in step (3) is 125-160°C.
更优选的，所述步骤（4）具体为：将步骤（3）中反应液负压蒸馏回收多余的酚，蒸馏温度为80-180℃，真空-0.04~-0.1Mpa。More preferably, the step (4) is specifically as follows: the excess phenol is recovered by negative pressure distillation of the reaction solution in the step (3), the distillation temperature is 80-180°C, and the vacuum is -0.04~-0.1Mpa.
更更优选的，步骤（4）中蒸馏温度为115-165℃。More preferably, the distillation temperature in step (4) is 115-165°C.
更优选的，所述步骤（5）具体为：将步骤（4）中蒸馏残液中加入有机溶剂升温溶解，再依次在0-30℃冷却、过滤、在40-140℃干燥得到多取代吡啶-2-氧醚化合物。More preferably, the step (5) is specifically as follows: adding an organic solvent to the distillation residue in the step (4) for heating and dissolving, and then sequentially cooling at 0-30°C, filtering, and drying at 40-140°C to obtain the polysubstituted pyridine -2-Oxyether compounds.
与现有技术相比，本发明的优点在于：Compared with the prior art, the advantages of the present invention are:
本发明的多取代吡啶-2-氧醚类化合物的合成方法中无碱参与，酚与多取代吡啶衍生物直接发生醚化反应而制得多取代吡啶-2-氧醚化合物，避免废水和废盐的产生，后处理过程简化，为环保友好型技术路线。In the method for synthesizing the polysubstituted pyridine-2-oxyether compounds of the present invention, no alkali is involved, and the phenol and the polysubstituted pyridine derivatives are directly etherified to obtain the polysubstituted pyridine-2-oxyether compounds, thereby avoiding waste water and waste. The production of salt and the simplification of the post-processing process are environmentally friendly technical routes.
具体实施方式Detailed ways
以下结合实施例对本发明作进一步详细描述。The present invention will be described in further detail below in conjunction with the embodiments.
实施例1Example 1
一种多取代吡啶-2-氧醚类化合物N-(2,4-二氟苯基)-2-[(3-三氟甲基)苯氧基]-3-吡啶甲酰胺的合成方法，包括以下步骤：A method for synthesizing a polysubstituted pyridine-2-oxyether compound N-(2,4-difluorophenyl)-2-[(3-trifluoromethyl)phenoxy]-3-pyridinecarboxamide, Include the following steps:
将N-(2,4-二氟苯基)-2-氯-3-吡啶甲酰胺溶解于溶剂环己烷中进行蒸馏脱水得到N-(2,4-二氟苯基)-2-氯-3-吡啶甲酰胺环己烷溶液，N-(2,4-二氟苯基)-2-氯-3-吡啶甲酰胺与环己烷质量比为1:1，蒸馏脱水温度为145℃；将间三氟甲基苯酚溶解于环己烷中进行蒸馏脱水得到间三氟甲基苯酚环己烷溶液，间三氟甲基苯酚与环己烷质量比为2:1，蒸馏脱水温度为140℃；将间三氟甲基苯酚环己烷溶液滴加至N-(2,4-二氟苯基)-2-氯-3-吡啶甲酰胺环己烷溶液中，升温至145-155℃进行醚化反应，并保持温度145-155℃，若体系温度低于145℃则蒸出部分环己烷以维持温度在145-155℃之间，若体系温度高于155℃则补加部分环己烷以维持温度在145-155℃之间，直至原料N-(2,4-二氟苯基)-2-氯-3-吡啶甲酰胺含量＜0.5%停止反应，反应8小时；在温度135℃，压力-0.095Mpa条件下，蒸馏回收间三氟甲基苯酚并得到蒸馏残余物；蒸馏残余物中加入N-(2,4-二氟苯基)-2-[(3-三氟甲基)苯氧基]-3-吡啶甲酰胺理论产量3倍的环己烷，升温溶解，后5℃冷却、过滤和120℃干燥后得N-(2,4-二氟苯基)-2-[(3-三氟甲基)苯氧基]-3-吡啶甲酰胺产品。The N-(2,4-difluorophenyl)-2-chloro-3-pyridinecarboxamide was dissolved in the solvent cyclohexane for distillation and dehydration to obtain N-(2,4-difluorophenyl)-2-chloro -3-pyridinecarboxamide cyclohexane solution, the mass ratio of N-(2,4-difluorophenyl)-2-chloro-3-pyridinecarboxamide and cyclohexane is 1:1, and the distillation dehydration temperature is 145℃ ; m-trifluoromethylphenol is dissolved in cyclohexane and carries out distillation dehydration to obtain m-trifluoromethylphenol cyclohexane solution, m-trifluoromethylphenol and cyclohexane mass ratio are 2:1, and the distillation dehydration temperature is 140°C; m-trifluoromethylphenol cyclohexane solution was added dropwise to N-(2,4-difluorophenyl)-2-chloro-3-pyridinecarboxamide cyclohexane solution, and the temperature was raised to 145-155 ℃ ℃ to carry out etherification reaction, and keep the temperature at 145-155 ℃, if the system temperature is lower than 145 ℃, then steam part of cyclohexane to maintain the temperature between 145-155 ℃, if the system temperature is higher than 155 ℃, add part The cyclohexane was maintained at a temperature of 145-155 ° C until the content of the raw material N-(2,4-difluorophenyl)-2-chloro-3-pyridinecarboxamide was less than 0.5% to stop the reaction, and the reaction was carried out for 8 hours; At a temperature of 135°C and a pressure of -0.095Mpa, m-trifluoromethylphenol was recovered by distillation and a distillation residue was obtained; N-(2,4-difluorophenyl)-2-[(3-trifluorophenyl) was added to the distillation residue. Fluoromethyl)phenoxy]-3-pyridinecarboxamide yields 3 times the theoretical yield of cyclohexane, dissolve at elevated temperature, cool at 5°C, filter and dry at 120°C to obtain N-(2,4-difluorophenyl) -2-[(3-Trifluoromethyl)phenoxy]-3-pyridinecarboxamide product.
实施例2Example 2
一种多取代吡啶-2-氧醚类化合物2-[4-(3-氯-5三氟甲基吡啶基-2-基)苯氧基]丙酸甲酯的合成方法，包括以下步骤：A method for synthesizing methyl 2-[4-(3-chloro-5 trifluoromethylpyridyl-2-yl) phenoxy] propionate, a polysubstituted pyridine-2-oxyether compound, comprises the following steps:
将2-（4-羟基苯氧基）丙酸溶解于溶剂甲苯中进行蒸馏脱水得到2-（4-羟基苯氧基）丙酸甲苯溶液，2-（4-羟基苯氧基）丙酸与甲苯质量比为1:2.5，蒸馏脱水温度为112℃；将3-氯-2，5-双三氟甲基吡啶溶解于甲苯中进行蒸馏脱水得到3-氯-2，5-双三氟甲基吡啶甲苯溶液，3-氯-2，5-双三氟甲基吡啶与甲苯质量比为2:1；将3-氯-2，5-双三氟甲基吡啶甲苯溶液滴加至2-（4-羟基苯氧基）丙酸甲苯溶液中，升温进行醚化反应，保持温度在140-145℃，若体系温度低于140℃则蒸出部分甲苯以维持温度在140-150℃之间，若体系温度高于150℃则补加部分甲苯以维持温度在140-150℃之间，直至原料2-（4-羟基苯氧基）丙酸含量＜0.5%反应停止，反应6小时；在温度165℃，压力-0.095Mpa条件下，蒸馏2-（4-羟基苯氧基）丙酸；蒸馏残渣中加入2-[4-(3-氯-5三氟甲基吡啶基-2-基)苯氧基]丙酸甲酯理论产量5倍的甲苯，升温溶解，后5℃冷却、过滤和100℃干燥后得2-[4-(3-氯-5三氟甲基吡啶基-2-基)苯氧基]丙酸甲酯产品。Dissolve 2-(4-hydroxyphenoxy)propionic acid in solvent toluene and perform distillation and dehydration to obtain a toluene solution of 2-(4-hydroxyphenoxy)propionic acid, 2-(4-hydroxyphenoxy)propionic acid and The mass ratio of toluene is 1:2.5, and the temperature of distillation and dehydration is 112 °C; pyridine solution in toluene, the mass ratio of 3-chloro-2,5-bistrifluoromethylpyridine to toluene is 2:1; add 3-chloro-2,5-bistrifluoromethylpyridine toluene solution dropwise to 2- (4-Hydroxyphenoxy)propionic acid in toluene solution, heat up to carry out etherification reaction, keep the temperature at 140-145 °C, if the system temperature is lower than 140 °C, steam out part of the toluene to maintain the temperature between 140-150 °C , if the system temperature is higher than 150 ℃, add some toluene to maintain the temperature between 140-150 ℃, until the raw material 2-(4-hydroxyphenoxy) propionic acid content <0.5%, the reaction stops, and the reaction is stopped for 6 hours; 2-(4-hydroxyphenoxy)propionic acid was distilled at a temperature of 165°C and a pressure of -0.095Mpa; 2-[4-(3-chloro-5-trifluoromethylpyridyl-2-yl was added to the distillation residue) ) phenoxy] methyl propionate yield 5 times the theoretical yield of toluene, dissolve at temperature, then cool at 5°C, filter and dry at 100°C to obtain 2-[4-(3-chloro-5trifluoromethylpyridyl-2 -yl)phenoxy]methyl propionate product.
实施例3Example 3
一种多取代吡啶-2-氧醚类化合物(E)-Α-甲氧基亚甲基-2-(3-三氟甲基-2-吡啶氧甲基)乙酸苯甲酯的合成方法，包括以下步骤：A method for synthesizing a polysubstituted pyridine-2-oxyether compound (E)-α-methoxymethylene-2-(3-trifluoromethyl-2-pyridyloxymethyl) benzyl acetate, Include the following steps:
将(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯溶解于溶剂氯苯中进行蒸馏脱水得到(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯氯苯溶液，(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯与氯苯质量比为1:3，蒸馏脱水温度为144℃；将2-氯-6(三氟甲基)吡啶溶解于氯苯中进行蒸馏脱水得到2-氯-6(三氟甲基)吡啶氯苯溶液，2-氯-6(三氟甲基)吡啶与环己烷质量比为2:1，蒸馏脱水温度为140℃；将2-氯-6(三氟甲基)吡啶氯苯溶液滴加至(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯溶液中，升温进行醚化反应，保持温度在170-175℃，若体系温度低于170℃则蒸出部分氯苯以维持温度在170-175℃之间，若体系温度高于175℃则补加部分氯苯以维持温度在170-175℃之间，直至原料(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯含量＜0.5%停止反应，反应7小时；在温度165℃，压力-0.095Mpa条件下，蒸馏(E)-2-(2-羟基苯基)-3-甲氧基丙烯酸甲酯；蒸馏残渣中加入(E)-Α-甲氧基亚甲基-2-(3-三氟甲基-2-吡啶氧甲基)乙酸苯甲酯理论产量5倍的甲苯，升温溶解，后5℃冷却、过滤、100℃干燥后得(E)-Α-甲氧基亚甲基-2-(3-三氟甲基-2-吡啶氧甲基)乙酸苯甲酯产品。(E)-2-(2-hydroxyphenyl)-3-methoxymethyl acrylate is dissolved in the solvent chlorobenzene and subjected to distillation and dehydration to obtain (E)-2-(2-hydroxyphenyl)-3-methyl Methyl oxyacrylate chlorobenzene solution, the mass ratio of (E)-2-(2-hydroxyphenyl)-3-methoxymethyl acrylate and chlorobenzene is 1:3, and the distillation dehydration temperature is 144°C; 2 - Chloro-6 (trifluoromethyl) pyridine is dissolved in chlorobenzene for distillation and dehydration to obtain 2-chloro-6 (trifluoromethyl) pyridine chlorobenzene solution, 2-chloro-6 (trifluoromethyl) pyridine and ring The mass ratio of hexane is 2:1, and the temperature of distillation and dehydration is 140 °C; 2-chloro-6(trifluoromethyl)pyridinechlorobenzene solution is added dropwise to (E)-2-(2-hydroxyphenyl)-3 -In the methyl methoxyacrylate solution, the temperature is raised to carry out the etherification reaction, and the temperature is kept at 170-175°C. If the system temperature is lower than 170°C, part of the chlorobenzene is evaporated to maintain the temperature between 170-175°C. If the temperature is higher than 175℃, add some chlorobenzene to maintain the temperature between 170-175℃, until the content of the raw material (E)-2-(2-hydroxyphenyl)-3-methoxymethyl acrylate <0.5% Stop the reaction and react for 7 hours; under the conditions of temperature 165°C and pressure -0.095Mpa, distill (E)-methyl 2-(2-hydroxyphenyl)-3-methoxyacrylate; add (E) to the distillation residue -α-Methoxymethylene-2-(3-trifluoromethyl-2-pyridyloxymethyl)benzyl acetate yields 5 times the theoretical yield of toluene, dissolves at the temperature, and cools at 5°C, filters, and dissolves at 100°C After drying, (E)-α-methoxymethylene-2-(3-trifluoromethyl-2-pyridyloxymethyl) benzyl acetate product is obtained.
实施例4Example 4
一种多取代吡啶-2-氧醚类化合物2-（2-氯-4-（三氟甲基）苯氧基）烟酸的合成方法，包括以下步骤：A method for synthesizing polysubstituted pyridine-2-oxyether compound 2-(2-chloro-4-(trifluoromethyl)phenoxy)nicotinic acid, comprising the following steps:
将2-氯烟酸溶解于溶剂庚烷中进行蒸馏脱水得到2-氯烟酸庚烷溶液，2-氯烟酸与庚烷质量比为1:1，蒸馏脱水温度为82℃；将2-氯-4-（三氟甲基）苯酚溶解于庚烷中进行蒸馏脱水得到2-氯-4-（三氟甲基）苯酚庚烷溶液，2-氯-4-（三氟甲基）苯酚与庚烷质量比为2:1；将2-氯-4-（三氟甲基）苯酚庚烷溶液滴加至2-氯烟酸庚烷溶液中，升温进行醚化反应，保持温度在155-165℃，若体系温度低于155℃则蒸出部分庚烷以维持温度在155-165℃之间，若体系温度高于165℃则补加部分庚烷以维持温度在155-165℃之间，直至原料2-氯烟酸含量＜0.5%停止反应，反应8小时；在温度145℃，压力-0.095Mpa条件下，蒸馏回收2-氯-4-（三氟甲基）苯酚；蒸馏残余物中加入2-（2-氯-4-（三氟甲基）苯氧基）烟酸理论产量3倍的庚烷，升温溶解，后5℃冷却、过滤、120℃干燥后得2-（2-氯-4-（三氟甲基）苯氧基）烟酸产品。The 2-chloronicotinic acid is dissolved in the solvent heptane and subjected to distillation and dehydration to obtain a 2-chloronicotinic acid heptane solution. Chloro-4-(trifluoromethyl)phenol was dissolved in heptane for distillation and dehydration to obtain 2-chloro-4-(trifluoromethyl)phenol heptane solution, 2-chloro-4-(trifluoromethyl)phenol The mass ratio with heptane is 2:1; the 2-chloro-4-(trifluoromethyl)phenol heptane solution is added dropwise to the 2-chloronicotinic acid heptane solution, and the temperature is raised to carry out etherification reaction, keeping the temperature at 155 ℃ -165°C, if the system temperature is lower than 155°C, part of heptane is distilled to maintain the temperature between 155-165°C; if the system temperature is higher than 165°C, part of heptane is added to maintain the temperature between 155-165°C The reaction was stopped for 8 hours until the content of 2-chloronicotinic acid in the raw material was less than 0.5%, and the reaction was carried out for 8 hours; 2-chloro-4-(trifluoromethyl)phenol was recovered by distillation at a temperature of 145°C and a pressure of -0.095Mpa; the distillation residue Add 2-(2-chloro-4-(trifluoromethyl)phenoxy) nicotinic acid to heptane with 3 times the theoretical yield of nicotinic acid, heat up to dissolve, then cool at 5°C, filter, and dry at 120°C to obtain 2-( 2-Chloro-4-(trifluoromethyl)phenoxy)nicotinic acid product.
实施例5Example 5
一种多取代吡啶-2-氧醚类化合物2-（4-（三氟甲基）苯氧基）烟酸甲酯的合成方法，包括以下步骤：A method for synthesizing methyl 2-(4-(trifluoromethyl)phenoxy)nicotinate of a polysubstituted pyridine-2-oxyether compound, comprising the following steps:
将2-氯烟酸甲酯溶解于溶剂环己烷中进行蒸馏脱水得到2-氯烟酸甲酯环己烷溶液，2-氯烟酸甲酯与环己烷质量比为1:1，蒸馏脱水温度为140℃；将4-（三氟甲基）苯酚溶解于环己烷中进行蒸馏脱水得到4-（三氟甲基）苯酚环己烷溶液，4-（三氟甲基）苯酚与环己烷质量比为2:1；将4-（三氟甲基）苯酚环己烷溶液滴加至2-氯烟酸甲酯环己烷溶液中，升温进行醚化反应，保持温度在145-155℃，若体系温度低于145℃则蒸出部分环己烷以维持温度在145-155℃，若体系温度高于155℃则补加部分环己烷以维持温度在145-155℃，直至原料2-氯烟酸甲酯含量＜0.5%停止反应，反应6小时；在温度140℃，压力-0.095Mpa条件下，蒸馏回收间4-（三氟甲基）苯酚；蒸馏残余物中加入2-（4-（三氟甲基）苯氧基）烟酸甲酯理论产量3倍的环己烷，升温溶解，后5℃冷却、过滤和120℃干燥后得2-（4-（三氟甲基）苯氧基）烟酸甲酯产品。The methyl 2-chloronicotinate is dissolved in the solvent cyclohexane and subjected to distillation and dehydration to obtain a solution of methyl 2-chloronicotinate in cyclohexane. The mass ratio of methyl 2-chloronicotinate to cyclohexane is 1:1, and the distillation The dehydration temperature is 140°C; 4-(trifluoromethyl)phenol is dissolved in cyclohexane and subjected to distillation and dehydration to obtain a 4-(trifluoromethyl)phenol cyclohexane solution. The mass ratio of cyclohexane is 2:1; the 4-(trifluoromethyl)phenol cyclohexane solution is added dropwise to the 2-chloronicotinic acid methyl ester cyclohexane solution, and the temperature is raised to carry out etherification reaction, keeping the temperature at 145 ℃ -155°C, if the system temperature is lower than 145°C, part of the cyclohexane is distilled to maintain the temperature at 145-155°C; if the system temperature is higher than 155°C, part of the cyclohexane is added to maintain the temperature at 145-155°C, The reaction was stopped until the content of methyl 2-chloronicotinate in the raw material was less than 0.5%, and the reaction was carried out for 6 hours; under the conditions of temperature 140 ° C and pressure -0.095 Mpa, m-4-(trifluoromethyl) phenol was recovered by distillation; The theoretical yield of methyl 2-(4-(trifluoromethyl)phenoxy)nicotinate was 3 times the theoretical yield of cyclohexane, which was dissolved at elevated temperature, cooled at 5°C, filtered and dried at 120°C to obtain 2-(4-(tri Fluoromethyl)phenoxy)methyl nicotinate product.
除上述实施例外，本发明还包括有其他实施方式，凡采用等同变换或者等效替换方式形成的技术方案，均应落入本发明权利要求的保护范围之内。In addition to the above-mentioned embodiments, the present invention also includes other embodiments, and all technical solutions formed by equivalent transformation or equivalent replacement shall fall within the protection scope of the claims of the present invention.
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| CN101198590A (en) * | 2005-08-24 | 2008-06-11 | 卫材R&D管理有限公司 | Novel Pyridine Derivatives and Pyrimidine Derivatives (3) |
| CN101209992A (en) * | 2006-12-28 | 2008-07-02 | 张月亮 | Preparation method of biological anthelmintic fluazuron |
| CN102459180A (en) * | 2009-06-09 | 2012-05-16 | 江苏迈度药物研发有限公司 | Urea derivatives as kinase inhibitors |
| CN110894188A (en) * | 2018-09-13 | 2020-03-20 | 江苏丰山集团股份有限公司 | Preparation method of 2-substituted halogenated pyridine compound |
| CN110684013A (en) * | 2019-11-18 | 2020-01-14 | 辽宁大学 | 4-phenoxypyridine derivatives containing 3-pyridazinone, 4-pyridazinone and 1,2,4-triazinone structures and their applications |
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