CN115215795A - Synthesis method of flonicamid - Google Patents
Synthesis method of flonicamid Download PDFInfo
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- CN115215795A CN115215795A CN202110431024.2A CN202110431024A CN115215795A CN 115215795 A CN115215795 A CN 115215795A CN 202110431024 A CN202110431024 A CN 202110431024A CN 115215795 A CN115215795 A CN 115215795A
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- flonicamid
- aminoacetonitrile
- nicotinic acid
- chloride
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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
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
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Abstract
The invention provides a synthetic method of flonicamid, which takes 4-trifluoromethyl nicotinic acid or metal salt thereof as a raw material to generate an intermediate with a structure shown in a formula (I) or a formula (II), and the intermediate reacts with aminoacetonitrile salt to obtain the flonicamid;
Description
Technical Field
The invention relates to the technical field of organic synthesis, in particular to a synthetic method of flonicamid.
Background
Flonicamid is on the market in 2003, shows extremely high biological activity to aphids through a unique mechanism action, is a specific drug for preventing and treating aphids at present, has no cross resistance with other insecticides on the market at present, and is a product for market competition due to the characteristic of bee friendliness, so that market shares of neonicotinoids, flonicamid, fluopicolide and the like are expected to be gradually seized in the future.
According to the available patent literature, the current methods for preparing flonicamid from 4-trifluoromethyl nicotinic acid or 4-trifluoromethyl nicotinate can be roughly classified into direct methods and indirect methods: the direct method is represented by a method for preparing flonicamid by taking 4-trifluoromethyl nicotinic acid, thionyl chloride and aminoacetonitrile sulfate as raw materials and triethylamine as an acid-binding agent, and comprises the following steps: JP2007210923A, because 4-trifluoromethyl nicotinoyl chloride has too high activity, the sulfoxaflor can continue to react with 4-trifluoromethyl nicotinoyl chloride while generating flonicamid, so as to obtain a by-product of N-cyanomethyl bis (trifluoromethyl) nicotinamide; n-cyanomethyl bis (trifluoromethyl) nicotinamide can be converted to flonicamid, such as CN107417606A; 4-trifluoromethyl nicotinic acid, aminoacetonitrile hydrochloride and phosgene are taken as raw materials, such as: CN103951616A. The indirect method is represented by a method for preparing flonicamid by taking 4-trifluoromethyl nicotinic acid and 1,3, 5-tricyanomethylhexahydro-s-triazine as raw materials to prepare N-chloromethyl-N-cyanomethyl-4- (trifluoromethyl) nicotinamide firstly, then preparing N-hydroxymethyl-N-cyanomethyl-4- (trifluoromethyl) nicotinamide under the action of hydrochloric acid and finally preparing flonicamid under the action of sodium carbonate. However, both the direct method and the indirect method have the defects of low yield, high production cost, unfavorable wide popularization and application and the like. Furthermore, the flonicamid is prepared by using methylsulfonyl chloride as an activating reagent, so that the preparation of high-activity 4-trifluoromethyl nicotinoyl chloride is avoided, and the flonicamid can be further efficiently prepared, such as CN109851552A. Although this process results in solid waste and is cost prohibitive, it has been directed to finding suitable reagents for the preparation of intermediates with low activity relative to 4-trifluoromethylnicotinoyl chloride, which makes it possible to produce flonicamid efficiently and economically.
Therefore, the method is obtained by carrying out intensive research on the synthetic method of flonicamid.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for synthesizing flonicamid, which can effectively improve the yield and the purity of flonicamid, is simple, convenient, safe and environment-friendly, and is suitable for large-scale industrial production.
In order to achieve the purpose, the invention adopts the technical scheme that:
a synthetic method of flonicamid takes 4-trifluoromethyl nicotinic acid or metal salt thereof as a starting material to generate an intermediate with a structure shown in a formula (I) or a formula (II), and the intermediate and aminoacetonitrile salt are subjected to substitution reaction to obtain the flonicamid;
the metal salt of 4-trifluoromethyl nicotinic acid is sodium salt, potassium salt, magnesium salt, etc. of 4-trifluoromethyl nicotinic acid, preferably sodium salt and potassium salt.
The inventor finds through a large number of experiments that the structural compound shown in the formula (I) or the formula (II) has lower activity compared with 4-trifluoromethyl nicotinoyl chloride, and has good reaction selectivity, less byproducts and high yield of target products when the structural compound is subjected to substitution reaction with aminoacetonitrile salt.
Specifically, the synthetic method of flonicamid comprises the following steps: 4-trifluoromethyl nicotinic acid or metal salt thereof and vilsmeier reagent are used as raw materials to generate the compound shown in the formula (I) through addition reaction.
Further, the vilsmeier reagent is prepared by chlorination of an N, N-disubstituted amide with an acid chloride. Preferably, the N, N-disubstituted amide is N, N-dimethylformamide; the acyl chloride is POCl 3 Thionyl chloride, oxalyl chloride or phthaloyl chloride, preferably thionyl chloride.
Further, the molar ratio of the 4-trifluoromethyl nicotinic acid or the metal salt thereof, the aminoacetonitrile salt and the vilsmeier reagent is 1: (1-2): (1 to 3), preferably 1:1.1:1.1.
further, the temperature of the addition reaction is-80-50 ℃, preferably-20-0 ℃;
further, the temperature of the substitution reaction is-20 to 150 ℃, preferably 0 to 25 ℃.
The other synthetic method of the flonicamid comprises the following steps: 4-trifluoromethyl nicotinic acid or metal salt thereof and acyl chloride reagent are taken as raw materials, and the generated acyl chloride product and 4-dimethylamino pyridine undergo electrophilic substitution reaction to generate the compound shown in the formula (II).
Further, the acyl chlorination reagent is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosgene, preferably thionyl chloride.
Further, the mol ratio of the 4-trifluoromethyl nicotinic acid or the metal salt thereof, the acyl chloride reagent, the 4-dimethylamino pyridine and the aminoacetonitrile salt is 1: (1-2): (1-2): (1-2), preferably 1:1.1:1.1:1.1.
further, the process is carried out at a temperature of-10 to 150 ℃, preferably 0 to 25 ℃.
In the two methods for synthesizing flonicamid, the method is carried out in a solvent, wherein the solvent is one or more of dichloromethane, dichloroethane, dioxane, methyl tert-butyl ether, tetrahydrofuran toluene, ethyl acetate and acetonitrile, and dichloromethane is preferred;
further, the weight of the solvent is 3 to 8 times, preferably 3 to 5 times that of the 4-trifluoromethylnicotinic acid or the metal salt thereof.
Further, the process is carried out in the presence or absence of a base. Preferably, the base is selected from one or more of pyridine, piperidine, triethylamine, 4-dimethylaminopyridine, sodium carbonate and potassium carbonate, and further preferably pyridine or no base is added.
Further, the aminoacetonitrile salt is aminoacetonitrile hydrochloride or aminoacetonitrile sulfate, preferably aminoacetonitrile hydrochloride.
In some specific embodiments, the flonicamid is synthesized by the following route:
adding dichloromethane and 4-trifluoromethyl nicotinic acid (compound 1, R = H) into a reaction bottle with a thermometer and a stirring paddle, stirring and reducing the temperature to 0 ℃, slowly dripping vilsmeier reagent (compound 2), preserving heat for 1 hour, adding aminoacetonitrile hydrochloride (compound 3), raising the temperature to room temperature, preserving heat for 2-3 hours, after sampling and controlling the reaction, adding a proper amount of ammonium chloride aqueous solution to wash once, and desolventizing an organic phase to obtain a product (compound 4).
In other specific embodiments, the synthetic route for flonicamid is as follows:
adding dichloromethane and 4-trifluoromethyl nicotinic acid (compound 1, R = H) into a reaction bottle with a thermometer and a stirring paddle, stirring and reducing the temperature to 0 ℃, slowly dripping thionyl chloride (compound 5), preserving heat for 1 hour, adding 4-dimethylamino pyridine (compound 6), preserving heat for 1 hour, adding aminoacetonitrile hydrochloride (compound 3), raising the temperature to room temperature, preserving heat for 2-3 hours, after sampling and controlling the reaction to be finished, adding a proper amount of ammonium chloride aqueous solution, washing once, and performing organic phase desolventization and recrystallization to obtain a product (compound 4).
In the method of the present invention, the reaction time is not particularly limited, and those skilled in the art can preferably stop the reaction when the conversion of the starting material, 4-trifluoromethylnicotinic acid or its metal salt, reaches 99.0% or more by performing detection analysis by a conventional method such as GC, HPLC.
The invention has the following beneficial effects:
(1) The yield and the purity of the obtained flonicamid product are high;
(2) The used raw materials are safer for human bodies;
(3) The whole process is safer, simpler and more convenient and has low cost;
(4) And part of reaction materials can be recycled and reused, so that the cost is further reduced, and the method is more environment-friendly.
The invention adopts the following two new methods: firstly, 4-trifluoromethyl nicotinic acid or 4-trifluoromethyl nicotinate, a vilsmeier reagent and aminoacetonitrile hydrochloride are taken as raw materials; secondly, 4-trifluoromethyl nicotinic acid or 4-trifluoromethyl nicotinate, thionyl chloride, 4-dimethylamino pyridine and aminoacetonitrile hydrochloride are used as raw materials, and dichloromethane is used as a solvent, so that the flonicamid can be safely, economically and efficiently industrially prepared at room temperature.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products available from regular distributors, not indicated by the manufacturer. In the case where no particular description is given, commercially available products are used as the starting materials.
Preparation of vilsmeier reagent: adding N, N-dimethylformamide into a reaction bottle with a thermometer and a stirring paddle, cooling to 5-10 ℃, slowly dropwise adding equivalent thionyl chloride, heating to 50 ℃, and reacting for 1-2 hours to obtain a vilsmeier reagent for later use.
Example 1
450g of dichloromethane and 95.54g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ under stirring, 69.86g of vilsmeier reagent is slowly dripped, the temperature is kept for 1 hour, 50.90g of aminoacetonitrile hydrochloride is added, the temperature is raised to room temperature, the temperature is kept for 2 hours, after sampling and controlled reaction, a proper amount of ammonium chloride aqueous solution is added for washing once, and the organic phase is desolventized to obtain 115.39g, the purity is 95.54 percent, and the yield is 96.21 percent.
Example 2
450g of dichloromethane and 95.57g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ by stirring, 69.88g of vilsmeier reagent is slowly dropped into the reaction bottle, the reaction bottle is kept for 1 hour, 50.89g of aminoacetonitrile hydrochloride is added, the reaction bottle is heated to room temperature and kept for 2 hours, after sampling and controlled reaction, a proper amount of ammonium chloride aqueous solution is added to wash once, and the organic phase is desolventized to obtain 115.26g with the purity of 96.27 percent and the yield of 96.81 percent.
Example 3
450g of dichloromethane and 95.58g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ under stirring, 69.83g of vilsmeier reagent is slowly dripped, the temperature is kept for 1 hour, 50.87g of aminoacetonitrile hydrochloride is added, the temperature is raised to room temperature, the temperature is kept for 2 hours, after sampling and controlled reaction, a proper amount of ammonium chloride aqueous solution is added for washing once, 113.57g of organic phase is obtained after desolventization, the quantification is 96.13%, and the yield is 95.24%.
Example 4
450g of dichloromethane and 95.55g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ by stirring, 65.40g of thionyl chloride is slowly dropped, the temperature is kept for 1 hour, 67.17g of 4-dimethylamino pyridine is added, the temperature is kept for 1 hour, 50.89g of aminoacetonitrile hydrochloride is added, the temperature is raised to room temperature and kept for 2 hours, after sampling and controlling the reaction, a proper amount of ammonium chloride aqueous solution is added for washing once, and the organic phase is desolventized and recrystallized to obtain 116.70g, the purity is 96.54 percent, and the yield is 98.31 percent.
Example 5
Adding 450g of dichloromethane and 95.59g of 4-trifluoromethyl nicotinic acid into a reaction bottle with a thermometer and a stirring paddle, stirring and reducing the temperature to 0 ℃, slowly and dropwise adding 65.42g of thionyl chloride, preserving heat for 1 hour, adding 67.19g of 4-dimethylaminopyridine, preserving heat for 1 hour, adding 50.91g of aminoacetonitrile hydrochloride, raising the temperature to room temperature, preserving heat for 2 hours, after sampling and controlling the reaction, adding a proper amount of ammonium chloride aqueous solution to wash once, and performing desolventizing recrystallization on an organic phase to obtain 118.97g of ammonium chloride with the purity of 95.27% and the yield of 98.87%.
Example 6
450g of dichloromethane and 95.57g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ under stirring, 65.41g of thionyl chloride is slowly dropped, the temperature is kept for 1 hour, 67.18g of 4-dimethylaminopyridine is added, the temperature is kept for 1 hour, 50.92g of aminoacetonitrile hydrochloride is added, the temperature is raised to the room temperature and kept for 2 hours, after the reaction in sampling is finished, a proper amount of ammonium chloride aqueous solution is added for washing once, and the organic phase is desolventized and recrystallized to obtain 116.56g, the purity is 96.73 percent, and the yield is 98.37 percent.
Comparative example
450g of dichloromethane and 95.51g of 4-trifluoromethyl nicotinic acid are added into a reaction bottle with a thermometer and a stirring paddle, the temperature is reduced to 0 ℃ by stirring, 65.44g of thionyl chloride is slowly dropped, the temperature is kept for 1 hour, 50.92g of aminoacetonitrile hydrochloride is added, the temperature is raised to room temperature, the temperature is kept for 2 hours, after sampling and controlling the reaction, a proper amount of ammonium chloride aqueous solution is added for washing once, and the organic phase is desolventized to obtain 111.85g, the purity is 91.54 percent and the yield is 89.42 percent.
Finally, it should be noted that: the above examples are only intended to illustrate the technical solution of the present invention, and not to limit it; although the present invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions of the embodiments of the present invention.
Claims (10)
1. A synthetic method of flonicamid is characterized in that 4-trifluoromethyl nicotinic acid or metal salt thereof is used as a starting material to generate an intermediate with a structure shown in a formula (I) or a formula (II), and the intermediate and aminoacetonitrile salt are subjected to substitution reaction to obtain the flonicamid;
2. the method for synthesizing flonicamid as claimed in claim 1, wherein the method comprises the following steps: 4-trifluoromethyl nicotinic acid or metal salt thereof and vilsmeier reagent are used as raw materials to generate the compound shown in the formula (I) through addition reaction.
3. The method for synthesizing flonicamid as claimed in claim 2, wherein the vilsmeier reagent is prepared by chlorination reaction of N, N-disubstituted amide and acyl chloride;
and/or the N, N-disubstituted amide is N, N-dimethylformamide; the acyl chloride is POCl 3 Thionyl chloride, oxalyl chloride or phthaloyl chloride, preferably thionyl chloride.
4. The method for synthesizing flonicamid as claimed in claim 2 or 3, wherein the molar ratio of the 4-trifluoromethyl nicotinic acid or the metal salt thereof, the aminoacetonitrile salt and the vilsmeier reagent is 1: (1-2): (1 to 3), preferably 1:1.1:1.1;
and/or the temperature of the addition reaction is-80-50 ℃, preferably-20-0 ℃;
and/or the temperature of the substitution reaction is-20 to 150 ℃, preferably 0 to 25 ℃.
5. The method for synthesizing flonicamid as claimed in claim 1, wherein the method comprises the following steps: 4-trifluoromethyl nicotinic acid or metal salt thereof and acyl chloride reagent are taken as raw materials, and the generated acyl chloride product and 4-dimethylamino pyridine undergo electrophilic substitution reaction to generate the compound shown in the formula (II).
6. The method for synthesizing flonicamid as claimed in claim 5, wherein the acyl chloride reagent is thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosgene, preferably thionyl chloride.
7. The method for synthesizing flonicamid as claimed in claim 5 or 6, wherein the molar ratio of 4-trifluoromethyl nicotinic acid or metal salt thereof, the acyl chloride reagent, and the 4-dimethylamino pyridine to the aminoacetonitrile salt is 1: (1-2): (1-2): (1-2), preferably 1:1.1:1.1:1.1;
and/or the process is carried out at a temperature of-10 to 150 ℃, preferably 0 to 25 ℃.
8. A method of synthesis of flonicamid as claimed in any one of claims 1 to 7 wherein the method is carried out in a solvent which is one or more of dichloromethane, dichloroethane, dioxane, methyl tert-butyl ether, tetrahydrofuran toluene, ethyl acetate, acetonitrile, preferably dichloromethane;
and/or the weight of the solvent is 3 to 8 times, preferably 3 to 5 times that of the 4-trifluoromethyl nicotinic acid or the metal salt thereof.
9. A method of synthesis of flonicamid as claimed in any one of claims 1 to 8 wherein the method is carried out in the presence or absence of a base; the alkali is selected from one or more of pyridine, piperidine, triethylamine, 4-dimethylamino pyridine, sodium carbonate and potassium carbonate, and pyridine is preferred or no alkali is added.
10. A method of synthesis of flonicamid as claimed in any one of claims 1 to 9 wherein the aminoacetonitrile salt is aminoacetonitrile hydrochloride or aminoacetonitrile sulphate, preferably aminoacetonitrile hydrochloride.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104761493A (en) * | 2015-03-09 | 2015-07-08 | 无锡市稼宝药业有限公司 | A synthetic method of N-cyanomethyl-4-(trifluoromethyl)nicotinamide |
| CN107162966A (en) * | 2017-06-06 | 2017-09-15 | 无锡市稼宝药业有限公司 | The synthetic method of flonicamid |
| CN107417606A (en) * | 2017-06-12 | 2017-12-01 | 河北科技大学 | N cyanogen methyl is double（Trifluoromethyl）Niacinamide is converted into method and the application of flonicamid |
| CN109851552A (en) * | 2018-12-28 | 2019-06-07 | 京博农化科技有限公司 | A kind of N- cyanogen methyl -4-(trifluoromethyl) niacinamide synthetic method |
| WO2020050297A1 (en) * | 2018-09-06 | 2020-03-12 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | Plant disease control agent |
| CN111925322A (en) * | 2020-08-20 | 2020-11-13 | 厦门优孚利生物医药科技有限公司 | Method for preparing flonicamid |
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2021
- 2021-04-21 CN CN202110431024.2A patent/CN115215795B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104761493A (en) * | 2015-03-09 | 2015-07-08 | 无锡市稼宝药业有限公司 | A synthetic method of N-cyanomethyl-4-(trifluoromethyl)nicotinamide |
| CN107162966A (en) * | 2017-06-06 | 2017-09-15 | 无锡市稼宝药业有限公司 | The synthetic method of flonicamid |
| CN107417606A (en) * | 2017-06-12 | 2017-12-01 | 河北科技大学 | N cyanogen methyl is double（Trifluoromethyl）Niacinamide is converted into method and the application of flonicamid |
| WO2020050297A1 (en) * | 2018-09-06 | 2020-03-12 | Ｍｅｉｊｉ Ｓｅｉｋａファルマ株式会社 | Plant disease control agent |
| CN109851552A (en) * | 2018-12-28 | 2019-06-07 | 京博农化科技有限公司 | A kind of N- cyanogen methyl -4-(trifluoromethyl) niacinamide synthetic method |
| CN111925322A (en) * | 2020-08-20 | 2020-11-13 | 厦门优孚利生物医药科技有限公司 | Method for preparing flonicamid |
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