CN110818629A - Method for synthesizing fluoroisonicotinic acid derivative - Google Patents
Method for synthesizing fluoroisonicotinic acid derivative Download PDFInfo
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- CN110818629A CN110818629A CN201911231694.9A CN201911231694A CN110818629A CN 110818629 A CN110818629 A CN 110818629A CN 201911231694 A CN201911231694 A CN 201911231694A CN 110818629 A CN110818629 A CN 110818629A
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- acid derivatives
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- fluoroisonicotinic
- fluoroisonicotinic acid
- fluoride
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
Abstract
The invention discloses a method for synthesizing fluoroisonicotinic acid derivatives, which takes 2, 6-dichloroisonicotinic acid derivatives, 2, 6-dibromoisonicotinic acid derivatives, 2, 6-dinitroisonicotinic acid derivatives or 2, 6-ditrifluoromethanesulfonyl isonicotinic acid derivatives as substrates, takes potassium fluoride, cesium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride as a fluoro reagent, and directly synthesizes the fluoroisonicotinic acid isopropyl derivatives by fluoro in a solvent. The method disclosed by the invention is safe and environment-friendly, and is high in yield and simple and convenient to operate.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing fluoroisonicotinic acid derivatives.
Background
Nicotinic acid and isonicotinic acid derivatives have been studied more and more since the 20 th century and are useful as pharmaceutical and medical intermediates, polymerization stabilizers, antioxidants for photosensitive materials, etc., and among them, most remarkable are halogenated nicotinic acid and halogenated isonicotinic acid series compounds. The halogenated isonicotinic acid series compounds comprise chloro, bromo and fluoro, wherein fluoro has a plurality of properties superior to those of the chloro and bromo, and has great application potential.
The current commercial process for the production of fluoroisonicotinic acid derivatives is generally by pyrolysis of fluoroborates, which are relatively dangerous and explosive. The method has certain limitation and is not beneficial to industrial production.
Disclosure of Invention
The invention aims to provide a method for synthesizing fluoroisonicotinic acid derivatives, which aims to overcome the defects of the prior art.
The invention adopts the following technical scheme:
a method for synthesizing fluoroisonicotinic acid derivatives comprises the step of directly fluorinating a substrate and a fluorinating reagent in a solvent to obtain the fluoroisonicotinic acid derivatives, wherein the substrate comprises 2, 6-dichloroisonicotinic acid derivatives, 2, 6-dibromoisonicotinic acid derivatives, 2, 6-dinitroisonicotinic acid derivatives or 2, 6-bistrifluoromethanesulfonyl isonicotinic acid derivatives, the fluorinating reagent comprises potassium fluoride, cesium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride, and the fluoroisonicotinic acid derivatives comprise 2, 6-difluoroisonicotinic acid derivatives, 2, 6-difluoroisonicotinic acid methyl ester derivatives, 2, 6-difluoroisonicotinic acid ethyl ester derivatives or 2, 6-difluoroisonicotinic acid isopropyl ester derivatives.
Further, the solvent includes N, N-dimethylformamide, dimethylsulfoxide or N-methylpyrrolidone.
Further, the substrate is dissolved in a solvent, a fluoro reagent is added, the mixture is heated and stirred for reaction, and then the fluoro isonicotinic acid derivative is obtained after post-treatment.
Further, the mass-to-volume ratio of the substrate to the solvent is 1 g: 3-15 ml.
Further, the amount of the fluoro reagent added is 2 to 6 equivalents based on the substrate.
Further, reacting at 80-170 ℃ for 4-120 hours.
Further, the stirring speed was 150-.
Further, the post-treatment comprises filtration, washing, reduced pressure distillation, crystallization and drying.
The invention has the beneficial effects that:
1. the invention takes 2, 6-dichloroisonicotinic acid derivatives, 2, 6-dibromoisonicotinic acid derivatives, 2, 6-dinitroisonicotinic acid derivatives or 2, 6-bistrifluoromethanesulfonyl isonicotinic acid derivatives as substrates, takes potassium fluoride, cesium fluoride, tetramethyl ammonium fluoride or tetrabutyl ammonium fluoride as a fluoro reagent, and directly fluoro synthesizes the fluoro isonicotinic acid isopropyl derivatives in a solvent. The method disclosed by the invention is safe and environment-friendly, and is high in yield and simple and convenient to operate.
2. The synthetic method of the invention has the advantages that the raw materials are easy to prepare (the mono-substituted and the di-substituted substrates can be very smoothly prepared by conventional reactions such as chlorination, bromination, nitration and the like), and metal fluoride or ammonium fluoride with high stability is used instead of fluorine reagents such as highly dangerous gas fluorine and highly corrosive and toxic hydrofluoric acid in the fluorination process, so the synthetic method has the advantages of safety, environmental protection, simple operation process and the like, and is suitable for industrial mass production.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
A method for synthesizing fluoroisonicotinic acid derivatives comprises the steps of directly fluorinating a substrate and a fluorinating reagent in a solvent to obtain the fluoroisonicotinic acid derivatives, wherein the substrate comprises 2, 6-dichloroisonicotinic acid derivatives, 2, 6-dibromo-isonicotinic acid derivatives, 2, 6-dinitroisonicotinic acid derivatives or 2, 6-bis-trifluoromethanesulfonyl-isonicotinic acid derivatives, the fluorinating reagent comprises potassium fluoride (KF), cesium fluoride (CsF), tetramethyl ammonium fluoride (TMAF) or tetrabutyl ammonium fluoride (TBAF), the solvent comprises N, N-Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) or N-methylpyrrolidone (NMP), the fluoroisonicotinic acid derivatives comprise 2, 6-difluoroisonicotinic acid derivatives, 2, 6-difluoroisonicotinic acid methyl ester derivatives, 2, 6-difluoroisonicotinic acid ethyl ester derivatives or 2, a derivative of isopropyl 6-difluoroisonicotinate.
The method comprises the following specific steps: dissolving a substrate in a solvent, wherein the mass-volume ratio of the substrate to the solvent is 1 g: 3-15 ml; adding a fluoro reagent, wherein the adding amount of the fluoro reagent is 2-6 equivalents based on the substrate; stirring at the temperature of 80-170 ℃ and 600rpm for reaction for 4-120 hours, and then carrying out post-treatment such as filtration, water washing, reduced pressure distillation, crystallization, drying and the like to obtain the fluoroisonicotinic acid derivative.
The reaction equation is as follows:
example 1
Adding 50g of 2, 6-dichloroisonicotinic acid into a 1000ml reaction bottle, adding 500ml of N, N-dimethylformamide, adding 61g of potassium fluoride, heating to 100 ℃, stirring at 500rpm for reaction for 96 hours, cooling to room temperature, adding 200ml of ethyl acetate (the addition of the ethyl acetate can reduce the solubility of the by-product and can be used as an extractant of the later step), filtering the by-product potassium chloride and the excessive potassium fluoride, adding 200ml of water into the filtrate for washing, layering, adding anhydrous sodium sulfate into the organic phase for drying and filtering, decompressing the filtrate to evaporate the ethyl acetate, adding 100ml of water for stirring and crystallizing, filtering, and drying overnight in vacuum to obtain 25.1g of white solid 2, 6-difluoroisonicotinic acid with the purity of 94.1 percent determined by HPLC and the molar yield of 60.6 percent.
Example 2
Adding 50g of 2, 6-dinitroisonicotinic acid into a 1000ml reaction bottle, adding 500ml of dimethyl sulfoxide, adding 73.2g of tetramethylammonium fluoride, heating to 80 ℃, stirring at 500rpm for reaction for 8 hours, cooling to room temperature, adding 200ml of ethyl acetate, filtering, adding 200ml of water into filtrate for washing, layering, adding anhydrous sodium sulfate into organic phase for drying and filtering, evaporating ethyl acetate from filtrate under reduced pressure, adding 100ml of water for stirring and crystallizing, filtering, and drying in vacuum overnight to obtain 26.5g of white solid 2, 6-difluoroisonicotinic acid, wherein the purity is 96.8 percent by HPLC (high performance liquid chromatography) and the molar yield is 71 percent.
Example 3
Adding 50g of 2, 6-dibromo isonicotinic acid into a 1000ml reaction bottle, adding 500ml of N-methyl pyrrolidone, adding 41g of potassium fluoride, heating to 140 ℃, stirring at 500rpm for reaction for 96 hours, cooling to room temperature, adding 200ml of ethyl acetate, filtering, adding 200ml of water into filtrate for washing, layering, adding anhydrous sodium sulfate into organic phase for drying and filtering, evaporating ethyl acetate from filtrate under reduced pressure, adding 100ml of water for stirring and crystallizing, filtering, and drying in vacuum overnight to obtain 21.2g of white solid 2, 6-difluoro isonicotinic acid, wherein the purity is 96.5 percent by HPLC (high performance liquid chromatography) and the molar yield is 75 percent.
Example 4
50g of 2, 6-bistrifluoromethanesulfonylisonicotinic acid is added into a 1000ml reaction bottle, 500ml of N-methylpyrrolidone is added, 43.1g of tetramethylammonium fluoride is added, the mixture is heated to 80 ℃, stirred and reacted for 6 hours at 500rpm, cooled to room temperature, 200ml of ethyl acetate is added, the mixture is filtered, 200ml of water is added into filtrate for washing, layers are separated, anhydrous sodium sulfate is added into organic phase for drying and filtering, the filtrate is decompressed and distilled out of ethyl acetate, 100ml of water is added for stirring and crystallization, the filtration is carried out, vacuum drying is carried out overnight, 12.2g of white solid 2, 6-difluoroisonicotinic acid is obtained, the purity is 95.8 percent by HPLC.
Example 5
50g of methyl 2, 6-dichloroisonicotinate is added into a 1000ml reaction bottle, 500ml of N, N-dimethylformamide is added, 145g of cesium fluoride is added, the mixture is heated to 100 ℃, stirred and reacted for 72 hours at 500rpm, cooled to room temperature, 200ml of ethyl acetate is added, filtration is carried out, 200ml of water is added into filtrate for washing, layers are separated, anhydrous sodium sulfate is added into organic phase for drying and filtration, ethyl acetate is evaporated under reduced pressure from filtrate, 100ml of water is added for stirring and crystallization, filtration is carried out, vacuum drying is carried out overnight, 22g of white solid methyl 2, 6-difluoroisonicotinate is obtained, the purity is 94.6 percent by HPLC, and the molar yield is 53.
Claims (8)
1. A method for synthesizing fluoroisonicotinic acid derivatives is characterized in that a substrate and a fluoro reagent are directly fluorinated in a solvent to obtain the fluoroisonicotinic acid derivatives, wherein the substrate comprises 2, 6-dichloroisonicotinic acid derivatives, 2, 6-dibromoisonicotinic acid derivatives, 2, 6-dinitroisonicotinic acid derivatives or 2, 6-bistrifluoromethanesulfonyl isonicotinic acid derivatives, the fluoro reagent comprises potassium fluoride, cesium fluoride, tetramethylammonium fluoride or tetrabutylammonium fluoride, and the fluoroisonicotinic acid derivatives comprise 2, 6-difluoroisonicotinic acid derivatives, 2, 6-difluoroisonicotinic acid methyl ester derivatives, 2, 6-difluoroisonicotinic acid ethyl ester derivatives or 2, 6-difluoroisonicotinic acid isopropyl ester derivatives.
2. The method of synthesizing fluoroisonicotinic acid derivatives according to claim 1, characterized in that the solvent comprises N, N-dimethylformamide, dimethyl sulfoxide or N-methylpyrrolidone.
3. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 1 or 2, characterized by dissolving the substrate in a solvent, adding a fluorinating agent, heating and stirring for reaction, and then post-treating to obtain fluoroisonicotinic acid derivatives.
4. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 3, characterized in that the mass/volume ratio of substrate to solvent is 1 g: 3-15 ml.
5. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 3, characterized in that the amount of the fluoro reagent added is 2 to 6 equivalents based on the substrate.
6. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 3, characterized by reacting at 80-170 ℃ for 4-120 hours.
7. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 3, characterized in that the stirring speed is 150-600 rpm.
8. The method for synthesizing fluoroisonicotinic acid derivatives according to claim 3, wherein the post-treatment comprises filtration, washing with water, distillation under reduced pressure, crystallization and drying.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750705A (en) * | 1995-08-21 | 1998-05-12 | Basf Aktiengesellschaft | Substituted trifluoromethylpyridines |
| CN101228129A (en) * | 2005-04-20 | 2008-07-23 | 詹森药业有限公司 | Fluorinated pyridine N-oxide thrombin modulators and process for N-oxidation of nitrogen containing heteroaryls |
| CN101519373A (en) * | 2008-12-30 | 2009-09-02 | 凯莱英医药化学（天津）有限公司 | Method for synthesizing 2,6-difluoropyridine |
| CN108026042A (en) * | 2015-08-04 | 2018-05-11 | 美国陶氏益农公司 | Method for being fluorinated compound |
-
2019
- 2019-12-05 CN CN201911231694.9A patent/CN110818629A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5750705A (en) * | 1995-08-21 | 1998-05-12 | Basf Aktiengesellschaft | Substituted trifluoromethylpyridines |
| CN101228129A (en) * | 2005-04-20 | 2008-07-23 | 詹森药业有限公司 | Fluorinated pyridine N-oxide thrombin modulators and process for N-oxidation of nitrogen containing heteroaryls |
| CN101519373A (en) * | 2008-12-30 | 2009-09-02 | 凯莱英医药化学（天津）有限公司 | Method for synthesizing 2,6-difluoropyridine |
| CN108026042A (en) * | 2015-08-04 | 2018-05-11 | 美国陶氏益农公司 | Method for being fluorinated compound |
Non-Patent Citations (1)
| Title |
|---|
| SYDONIE D. SCHIMLER，等: "Anhydrous Tetramethylammonium Fluoride for Room-Temperature SNAr Fluorination", 《THE JOURNAL OF ORGANIC CHEMISTRY》 * |
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Application publication date: 20200221 |