CN113149899A - Method for preparing 4-trifluoromethyl nicotinic acid - Google Patents
Method for preparing 4-trifluoromethyl nicotinic acid Download PDFInfo
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- CN113149899A CN113149899A CN202110446588.3A CN202110446588A CN113149899A CN 113149899 A CN113149899 A CN 113149899A CN 202110446588 A CN202110446588 A CN 202110446588A CN 113149899 A CN113149899 A CN 113149899A
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- nicotinic acid
- trifluoromethyl nicotinic
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- LMRJHNFECNKDKH-UHFFFAOYSA-N 4-(trifluoromethyl)nicotinic acid Chemical compound OC(=O)C1=CN=CC=C1C(F)(F)F LMRJHNFECNKDKH-UHFFFAOYSA-N 0.000 title claims abstract description 45
- 238000000034 method Methods 0.000 title claims abstract description 36
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- -1 2-methoxycarbonyl vinyl Chemical group 0.000 claims abstract description 19
- 238000002360 preparation method Methods 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 6
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 5
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 24
- 238000003756 stirring Methods 0.000 claims description 17
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 16
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 16
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 9
- 239000007787 solid Substances 0.000 claims description 9
- 238000000967 suction filtration Methods 0.000 claims description 8
- 238000001514 detection method Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 238000001816 cooling Methods 0.000 claims description 5
- 230000008020 evaporation Effects 0.000 claims description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 5
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 2
- 238000004321 preservation Methods 0.000 claims description 2
- 239000000575 pesticide Substances 0.000 abstract description 3
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract 1
- 239000011259 mixed solution Substances 0.000 description 7
- 238000010907 mechanical stirring Methods 0.000 description 6
- 235000019439 ethyl acetate Nutrition 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 238000011031 large-scale manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 2
- SLEJZQYOXXCDQU-UHFFFAOYSA-N 2,3,4-trifluoropyridine Chemical compound FC1=CC=NC(F)=C1F SLEJZQYOXXCDQU-UHFFFAOYSA-N 0.000 description 1
- 239000005900 Flonicamid Substances 0.000 description 1
- 229910019213 POCl3 Inorganic materials 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 238000005915 ammonolysis reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- DGJMPUGMZIKDRO-UHFFFAOYSA-N cyanoacetamide Chemical compound NC(=O)CC#N DGJMPUGMZIKDRO-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- RLQJEEJISHYWON-UHFFFAOYSA-N flonicamid Chemical compound FC(F)(F)C1=CC=NC=C1C(=O)NCC#N RLQJEEJISHYWON-UHFFFAOYSA-N 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- BMLJWZQVROONIH-UHFFFAOYSA-N methyl 3-[(4,4,4-trifluoro-3-oxobut-1-enyl)amino]prop-2-enoate Chemical compound COC(=O)C=CNC=CC(=O)C(F)(F)F BMLJWZQVROONIH-UHFFFAOYSA-N 0.000 description 1
- 229940017219 methyl propionate Drugs 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl chloride Substances ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- IBBMAWULFFBRKK-UHFFFAOYSA-N picolinamide Chemical compound NC(=O)C1=CC=CC=N1 IBBMAWULFFBRKK-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- PNQBEPDZQUOCNY-UHFFFAOYSA-N trifluoroacetyl chloride Chemical compound FC(F)(F)C(Cl)=O PNQBEPDZQUOCNY-UHFFFAOYSA-N 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
- C07D213/79—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
Abstract
The invention belongs to the technical field of synthesis of pesticide intermediates, and particularly relates to a method for preparing 4-trifluoromethyl nicotinic acid, which solves the problems that in the prior art, a preparation method of 4-trifluoromethyl nicotinic acid is large in toxicity and heavy in pollution, is not suitable for industrial production, or has complicated steps, and comprises the following steps: in a solvent, under the action of alkali, N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine is used as a raw material to prepare a target product, namely 4-trifluoromethyl nicotinic acid through a one-step method of ring closure and hydrolysis reaction. The preparation method provided by the invention is simple and convenient to operate, mild in reaction conditions, relatively environment-friendly in preparation process, high in purity and good in quality of the obtained 4-trifluoromethyl nicotinic acid product, and suitable for industrial mass production.
Description
Technical Field
The invention relates to the technical field of pesticide intermediate synthesis, in particular to a method for preparing 4-trifluoromethyl nicotinic acid.
Background
4-trifluoromethyl nicotinic acid is an important nitrogen-containing heterocyclic compound, and is widely applied in pharmaceutical chemistry due to the unique action mechanism and extremely high biological activity. The 4-trifluoromethyl nicotinic acid is a key intermediate for synthesizing the pyridine amide pesticide flonicamid, and the method for preparing the high-yield compound is significant. The literature research finds that the synthesis method reported at home and abroad at present is as follows:
the method comprises the following steps: the 4-trifluoromethyl nicotinic acid is prepared by reacting trifluoropyridine and halide thereof as raw materials with carbon dioxide under the action of strong alkali such as LDA and the like.
This preparation is reported in both US5360806A and publication eur.j.org.chem.2003, 1559-1575. The preparation method uses carbon dioxide and LDA, and industrial large-scale production cannot be realized at all.
The second method comprises the following steps: the 4-trifluoromethyl nicotinic acid is prepared by taking trifluoroacetyl acetic ether and cyanoacetamide as raw materials.
The preparation methods are reported in European patent EP1460071A1 and Chinese patent CN107286086A, CN108191749A, CN109232407A, CN108586328A and CN 109467532A. The preparation method uses POCl3And Pd/C, has high toxicity, heavy pollution and strict requirements on equipment, and is not suitable for industrial large-scale production.
The third method comprises the following steps: using trifluoroacetyl chloride or trifluoroacetic anhydride as raw materials, performing acylation and ammonolysis, reacting with 3-methoxy methyl acrylate or 3, 3-dimethoxy methyl propionate, and finally performing ring-closing hydrolysis to prepare the 4-trifluoromethyl nicotinic acid.
Such preparation processes are reported in European patent EP0744400A2 and in Japanese patent JP2007210923A and in U.S. Pat. No. 3, 005708175A.
The method four comprises the following steps: methyl acrylate is used as a raw material, and the 4-trifluoromethyl nicotinic acid is prepared through catalytic oxidation, condensation, ring closing and hydrolysis reactions.
Chinese patent CN111574440A reports the preparation method.
And the third method and the fourth method are that the N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine is firstly subjected to reflux reaction under the action of sodium methoxide, then the temperature is reduced, sodium hydroxide aqueous solution is added, the temperature is continuously increased until the reaction is finished, and hydrochloric acid is used for adjusting the pH value to be acidic to prepare the 4-trifluoromethyl nicotinic acid. The method has complicated steps and certain defects. Based on the above statement, the present invention proposes a method for preparing 4-trifluoromethyl nicotinic acid.
Disclosure of Invention
The invention aims to solve the problems that the preparation method of the 4-trifluoromethyl nicotinic acid in the prior art is high in toxicity, heavy in pollution, not suitable for industrial production or complicated in steps.
A method for preparing 4-trifluoromethyl nicotinic acid is to prepare a target product, namely 4-trifluoromethyl nicotinic acid by a one-step method of ring closing and hydrolysis reaction of N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine raw material under the action of alkali.
Preferably, the reaction equation of the preparation method is as follows:
preferably, the method for preparing 4-trifluoromethyl nicotinic acid specifically comprises the following preparation steps: controlling the temperature to be 0-5 ℃ in a solvent, carrying out heat preservation reflux reaction on N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine under the action of alkali, adding water and sodium hydroxide for stirring after the HPLC detection reaction is finished, evaporating the solvent at normal pressure, cooling to 0-5 ℃ after the evaporation is finished, dropwise adding a hydrochloric acid solution to adjust the pH to be 1-2, separating out a large amount of solids, keeping the temperature, stirring, carrying out suction filtration and drying to obtain the 4-trifluoromethyl nicotinic acid.
Preferably, the solvent is one or more of methanol, tetrahydrofuran, chloroform, ethyl acetate or ethanol.
Preferably, the alkali is one or more of sodium methoxide, sodium hydroxide, potassium carbonate, sodium hydride or sodium ethoxide.
Preferably, the N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-one-1-butenamide and the base are mixed with a solvent before reaction.
Preferably, the N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-one-1-butenamine and the base are added in a forward or reverse adding sequence; and the molar ratio of the two is 1: 2.
Preferably, the hydrochloric acid solution is concentrated hydrochloric acid or diluted hydrochloric acid prepared from concentrated hydrochloric acid and water in a weight ratio of 1: 1.
The method for preparing 4-trifluoromethyl nicotinic acid provided by the invention has the following beneficial effects:
the invention adopts N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine raw material, and prepares the target product 4-trifluoromethyl nicotinic acid by a one-step method of ring closure and hydrolysis reaction in a solvent under the action of alkali. The preparation method provided by the invention is simple and convenient to operate, mild in reaction conditions, relatively environment-friendly in preparation process, high in purity and good in quality of the obtained 4-trifluoromethyl nicotinic acid product, and suitable for industrial mass production.
Detailed Description
The present invention will be further illustrated with reference to the following specific examples.
Example 1
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
400g of methanol and 100g of N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine (448.12 mmol) are sequentially added into a reaction bottle with a mechanical stirring thermometer, the temperature is controlled at 0 ℃, a mixed solution of sodium methoxide (48.4g, 896.24mmol) and 113g of methanol is dropwise added by using a dropping funnel, after the dropwise addition is finished, the reflux reaction is kept for 6 hours, 200g of water and sodium hydroxide (8.96g, 224.06mmol) are added after the TLC tracking reaction is finished, the stirring is carried out at room temperature for 30 minutes, the TLC detection reaction is finished, then the methanol is distilled out at normal pressure, the system is cooled to 0 ℃ after the distillation is finished, concentrated hydrochloric acid is dropwise added, the PH is adjusted to be 1, a large amount of yellow solid is separated out, the stirring is kept at the temperature for 1 hour, and the suction filtration and drying are carried out, so as to obtain 50.8g of 4-trifluoromethyl nicotinic acid, and the yield is 59.3%.
Example 2
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
adding a mixed solution of sodium methoxide (48.4g, 896.24mmol) and 113g of tetrahydrofuran in turn into a reaction bottle with a mechanical stirrer and a thermometer, controlling the temperature to be 1 ℃, dropwise adding 400g of tetrahydrofuran and N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine (100g, 448.12mmol) by using a dropping funnel, starting heating after dropwise adding, keeping reflux reaction for 6 hours, adding 200g of water and sodium hydroxide (8.96g, 224.06mmol) after TLC tracking reaction is finished, stirring at room temperature for 30 minutes, detecting reaction completion by TLC, evaporating tetrahydrofuran at normal pressure, cooling the system to 1 ℃ after evaporation is finished, dropwise adding concentrated hydrochloric acid, adjusting the pH to 1.2, precipitating a large amount of yellow solid, keeping the temperature and stirring for 1 hour, performing suction filtration and drying to obtain 51.3g of 4-trifluoromethyl nicotinic acid, wherein the yield is 59.9%.
Example 3
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
400g of methanol and 100g of N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-keto-1-butenamine (448.12 mmol) are sequentially added into a reaction bottle with a mechanical stirring thermometer, the temperature is controlled to be 2 ℃, a mixed solution of sodium hydroxide (35.8g, 896.24mmol) and 113g of methanol is dropwise added by using a dropping funnel, after the dropwise addition is finished, the reflux reaction is kept for 6 hours, 200g of water and sodium hydroxide (8.96g, 224.06mmol) are added after the TLC tracking reaction is finished, the stirring is carried out at room temperature for 30 minutes, the TLC detection reaction is finished, then the methanol is distilled out at normal pressure, the system is cooled to 2 ℃ after the distillation is finished, 1:1 hydrochloric acid aqueous solution is dropwise added, the PH is adjusted to be 1.4, a large amount of yellow solid is separated out, the stirring is kept at the temperature for 1 hour, and the suction filtration and the drying are carried out, so that 48.3g of 4-trifluoromethyl nicotinic acid is obtained, and the yield is 56.4%.
Example 4
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
400g of chloroform and 100g of N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine (448.12 mmol) are sequentially added into a reaction bottle with a mechanical stirring thermometer, the temperature is controlled to be 3 ℃, a mixed solution of potassium carbonate (123.9g, 896.24mmol) and 113g of chloroform is dropwise added by using a dropping funnel, after the dropwise addition is finished, the reflux reaction is kept for 6 hours, 200g of water and sodium hydroxide (8.96g, 224.06mmol) are added after the TLC tracking reaction is finished, the stirring is carried out at room temperature for 30 minutes, the TLC detection reaction is finished, then the chloroform is distilled out at normal pressure, after the distillation is finished, the system is cooled to 3 ℃, a 1:1 hydrochloric acid aqueous solution is dropwise added, the PH is adjusted to 1.5, a large amount of yellow solid is separated out, the stirring is kept at the temperature for 1 hour, and the filtration and the drying are carried out, so that 46.3g of 4-trifluoromethylnicotinic acid is obtained, and the yield is 54.1%.
Example 5
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
adding a mixed solution of sodium hydride (21.5g, 896.24mmol) and 113g of ethyl acetate into a reaction bottle with a mechanical stirring thermometer in sequence, controlling the temperature to be 4 ℃, dropwise adding 400g of ethyl acetate and N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine (100g, 448.12mmol) by using a dropping funnel, starting heating after dropwise adding, keeping reflux reaction for 6h, adding 200g of water and sodium hydroxide (8.96g, 224.06mmol) after TLC tracking reaction is finished, stirring at room temperature for 30min, detecting that the reaction is complete by TLC, evaporating ethyl acetate at normal pressure, cooling the system to 4 ℃ after evaporation, dropwise adding concentrated hydrochloric acid, adjusting the pH to 1.6, precipitating a large amount of yellow solid, keeping the temperature and stirring for 1h, performing suction filtration and drying to obtain 48.1g of 4-trifluoromethyl nicotinic acid, wherein the yield is 56.2%.
Example 6
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
the method comprises the steps of sequentially adding a mixed solution of sodium ethoxide (61.0g, 896.24mmol) and 113g of ethanol into a reaction bottle with a mechanical stirring thermometer, controlling the temperature to be 5 ℃, dropwise adding 400g of ethanol and N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine (100g, 448.12mmol) by using a dropping funnel, starting heating after dropwise adding, keeping reflux reaction for 6 hours, adding 200g of water and sodium hydroxide (8.96g, 224.06mmol) after TLC tracking reaction is finished, stirring at room temperature for 30 minutes, detecting complete reaction by TLC, distilling off the ethanol at normal pressure, cooling the system to about 5 ℃ after distillation, starting dropwise adding concentrated hydrochloric acid, adjusting the pH to 1.8, precipitating a large amount of yellow solids, keeping the temperature and stirring for 1 hour, performing suction filtration and drying to obtain 52.1g of 4-trifluoromethyl nicotinic acid, wherein the yield is 60.9%.
Example 7
The invention provides a method for preparing 4-trifluoromethyl nicotinic acid, which comprises the following steps:
400g of chloroform and 100g of N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-one-1-butenamine (448.12 mmol) are sequentially added into a reaction bottle with a mechanical stirring thermometer, the temperature is controlled at 0 ℃, a mixed solution of sodium methoxide (48.4g, 896.24mmol) and 113g of chloroform is dropwise added by using a dropping funnel, after the dropwise addition is finished, the reflux reaction is kept for 6 hours, 200g of water and sodium hydroxide (8.96g, 224.06mmol) are added after the TLC tracking reaction is finished, the mixture is stirred at room temperature for 30 minutes, the TLC detection reaction is finished, chloroform is evaporated at normal pressure, the system is cooled to 0 ℃ after the evaporation is finished, 1:1 hydrochloric acid aqueous solution is dropwise added, the PH is adjusted to be 2, a large amount of yellow solid is separated out, the temperature is kept and the stirring is kept for 1 hour, and the mixture is subjected to suction filtration and drying to obtain 47.1g of 4-trifluoromethyl nicotinic acid, and the yield is 55.1%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (8)
1. A method for preparing 4-trifluoromethyl nicotinic acid is characterized in that N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamide raw material is subjected to ring closing and hydrolysis reaction under the action of alkali to prepare a target product 4-trifluoromethyl nicotinic acid by a one-step method.
2. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 1, wherein the reaction equation of the preparation method is as follows:
3. the method for preparing 4-trifluoromethyl nicotinic acid according to claim 1 or 2, wherein the preparation method specifically comprises the following preparation steps:
controlling the temperature to be 0-5 ℃ in a solvent, carrying out heat preservation reflux reaction on N- (2-methoxycarbonyl vinyl) -4,4, 4-trifluoro-3-ketone-1-butenamine under the action of alkali, adding water and sodium hydroxide for stirring after the HPLC detection reaction is finished, evaporating the solvent at normal pressure, cooling to 0-5 ℃ after the evaporation is finished, dropwise adding a hydrochloric acid solution to adjust the pH to be 1-2, separating out solids, keeping the temperature, stirring, carrying out suction filtration and drying to obtain the 4-trifluoromethyl nicotinic acid.
4. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the solvent is one or more of methanol, tetrahydrofuran, chloroform, ethyl acetate or ethanol.
5. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the base is one or more of sodium methoxide, sodium hydroxide, potassium carbonate, sodium hydride or sodium ethoxide.
6. The method of claim 3, wherein the N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-one-1-butenamide and the base are mixed with a solvent before the reaction.
7. The method for preparing 4-trifluoromethyl nicotinic acid according to claim 3, wherein the N- (2-methoxycarbonylvinyl) -4,4, 4-trifluoro-3-one-1-butenamide and the base are added in the order of forward addition or reverse addition; and the molar ratio of the two is 1: 2.
8. The method of claim 3, wherein the hydrochloric acid solution is concentrated hydrochloric acid or diluted hydrochloric acid prepared from concentrated hydrochloric acid and water at a weight ratio of 1: 1.
Priority Applications (1)
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| CN114349694A (en) * | 2022-01-29 | 2022-04-15 | 淮北龙溪生物科技有限公司 | Synthetic method of 4-trifluoromethyl nicotinic acid |
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| EP0744400A2 (en) * | 1995-05-26 | 1996-11-27 | Ishihara Sangyo Kaisha, Ltd. | Process for producing 4-trifluoromethylnicotinic acid |
| CN107162966A (en) * | 2017-06-06 | 2017-09-15 | 无锡市稼宝药业有限公司 | The synthetic method of flonicamid |
| CN111574440A (en) * | 2020-05-25 | 2020-08-25 | 安徽金禾实业股份有限公司 | Preparation method of 4-trifluoromethyl nicotinic acid |
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| EP0744400A2 (en) * | 1995-05-26 | 1996-11-27 | Ishihara Sangyo Kaisha, Ltd. | Process for producing 4-trifluoromethylnicotinic acid |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114349694A (en) * | 2022-01-29 | 2022-04-15 | 淮北龙溪生物科技有限公司 | Synthetic method of 4-trifluoromethyl nicotinic acid |
| CN114349694B (en) * | 2022-01-29 | 2022-11-08 | 淮北龙溪生物科技有限公司 | Synthetic method of 4-trifluoromethyl nicotinic acid |
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