CN112321496A - Method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine - Google Patents
Method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine Download PDFInfo
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- CN112321496A CN112321496A CN202011315193.1A CN202011315193A CN112321496A CN 112321496 A CN112321496 A CN 112321496A CN 202011315193 A CN202011315193 A CN 202011315193A CN 112321496 A CN112321496 A CN 112321496A
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- 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
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- C07D213/73—Unsubstituted amino or imino radicals
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Abstract
A method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine, belonging to the technical field of organic synthesis. In particular, the method starts from 2-aminopyridine and relates to three-step chemical reactions of bromination, chlorination and coupling, wherein two organic solvents are used in the whole process; after the three-step reaction, carrying out recrystallization treatment to obtain the high-purity 2-amino-3-chloro-5-trifluoromethylpyridine. The method has mild reaction conditions, is easy to control, and the obtained product has high purity; the reaction raw materials and the organic solvent are easy to obtain and low in price, and a new way is provided for large-scale production.
Description
Technical Field
The invention relates to a method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine, belonging to the technical field of organic synthesis.
Background
The fluazinam production process technology is a novel process technology for replacing aniline broad-spectrum bactericides in fine chemical production of pesticide intermediates, fluazinam has the excellent characteristics of long lasting period and the like, and meanwhile fluazinam has a special effect on various gray mold diseases caused by botrytis cinerea. Has no cross resistance with benzimidazoles, dicarboximide and the existing bactericides on the market at present. It also has good activity on diseases caused by pathogenic bacteria of Alternaria, Phytophthora, Plasmopara, Sclerotinia and Venturia.
2-amino-3-chloro-5-trifluoromethylpyridine, CAS: 79456-26-1, light yellow powder, melting point 84-94 deg.C. As a key intermediate for preparing fluazinam, 2, 3-dichloro-5-trifluoromethylpyridine is generally used as a raw material for synthesis, and is subjected to high-temperature or high-pressure reaction with sodium amide or ammonia water, and the high-temperature or high-pressure reaction has certain danger and should be avoided as much as possible industrially.
2-amino-3-chloro-5-trifluoromethylpyridine has good market prospects, so that it is still necessary to find a suitable alternative route to meet the increasing market demand.
Disclosure of Invention
The invention provides a method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine with high purity and high yield. Starting from 2-aminopyridine, three chemical reactions of bromination, chlorination and coupling are involved, and two organic solvents are used in the whole process; after the three-step reaction, carrying out recrystallization treatment to obtain the high-purity 2-amino-3-chloro-5-trifluoromethylpyridine. The method has mild reaction conditions, is easy to control, and the obtained product has high purity; the reaction raw materials and the organic solvent are easy to obtain and low in price, and a new way is provided for large-scale production.
The method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine adopts an equation as follows:
in particular, starting from 2-aminopyridine, it is obtained by bromination, chlorination and coupling, comprising the following steps:
firstly, mixing 2-aminopyridine and an organic solvent, cooling to-5-0 ℃, and adding NBS (N-bromosuccinimide) for reaction to obtain a 2-amino-5-bromopyridine reaction solution;
secondly, adding NCS into the 2-amino-5-bromopyridine reaction solution, heating to 80-100 ℃ and reacting to obtain 2-amino-3-chloro-5-bromopyridine;
and thirdly, adding a palladium catalyst and potassium trifluoromethyl trifluoroborate into the 2-amino-3-chloro-5-bromopyridine, and heating in an organic solvent for coupling reaction to obtain the 2-amino-3-chloro-5-trifluoromethylpyridine.
Further, in the above technical solution, in the first step, the organic solvent is selected from MIBK, THF, acetone or dichloroethane.
Further, in the above technical solution, in the third step, the organic solvent is selected from dioxane, ethanol, tetrahydrofuran, or dimethyl sulfoxide.
Further, in the above technical solution, in the first step, the molar ratio of the 2-aminopyridine to NBS is 1: 1.1-1.3.
Further, in the above technical scheme, in the second step, the molar ratio of the 2-amino-5-bromopyridine to the NCS is 1: 1-1.1.
Further, in the above technical solution, in the third step, the molar ratio of the 2-amino-3-chloro-5-bromopyridine, PdCl2dppf and CF3BF3K is 1: 0.01-0.03: 1-1.2.
Furthermore, in the technical scheme, the purity of the 2-amino-3-chloro-5-trifluoromethylpyridine can reach 99.5 percent, and the yield can reach 90 to 97 percent.
According to the invention, 2-aminopyridine which is a cheap and easily available raw material is subjected to selective 5-bit bromination by NBS, then subjected to temperature rise reaction with NCS to perform selective 3-bit chlorination, and finally subjected to high-selectivity coupling with CF3BF3K to obtain a high-purity 2-amino-3-chloro-5-trifluoromethylpyridine product.
The method has mild reaction conditions, enables continuous selective control reaction to occur by optimizing the reaction conditions, and provides a new way for large-scale production.
Detailed Description
Example 1:
adding 2-aminopyridine (9.4g,1.0mol) into MIBK (48mL), stirring until the mixture is clear, and cooling to-5-0 ℃ by using an ice machine. NBS (18.2g,0.102mol) was dissolved in MIBK (100mL) solvent. And (3) dropwise adding the NBS solution into the 2-aminopyridine solution at the reaction temperature of-5 ℃, controlling the dropwise adding time to be 1.5-2 hours, and after the dropwise adding is finished, controlling the kettle temperature to be-5 ℃ and carrying out heat preservation reaction for 4 hours. The content of 2-aminopyridine in liquid phase analysis was 0.01%.
NCS (15.4g,0.115mol) is dissolved in MIBK (160mL), the clear solution of NCS is put into the reaction kettle, the kettle temperature is controlled to be 90-100 ℃, the reaction is carried out for 15 hours under the condition of heat preservation, and the content of 2-amino-5-bromopyridine is 0.03% by liquid phase analysis. And (3) carrying out reduced pressure distillation, removing more than 90% of MIBK solvent, adding a mixed solvent of ethanol (150mL) and water (15mL), heating to 60-70 ℃, dissolving, recrystallizing, carrying out suction filtration, and leaching to obtain the 2-amino-3-chloro-5-bromopyridine.
Adding the 2-amino-3-chloro-5-bromopyridine solid into dioxane (162mL), heating to 55-60 ℃ for dissolving, sequentially adding PdCl2dppf catalyst (0.73g,0.001mol), potassium acetate (14.7g,0.15mol) and CH3BF3K (19.4g,0.11mol), controlling the kettle temperature at 80-100 ℃ for reaction for 12 hours, and analyzing the content of the 2-amino-3-chloro-5-bromopyridine to be 0.05% by liquid phase.
Cooling the reaction solution to room temperature, carrying out suction filtration, dioxane washing, solvent distillation, activated carbon decolorization, ethanol and heptane (1/5 volume ratio) pulping, and drying to obtain 2-amino-3-chloro-5-trifluoromethylpyridine (13.9 g).
The content of the example in the group is 99.75%, and the yield is 71%.
Example 2:
adding 2-aminopyridine (9.4g,0.1mol) into dichloroethane (35mL), stirring until the mixture is clear, and cooling to-5-0 ℃ by using an ice machine. NBS (17.8g,1.0mol) was dissolved in dichloroethane (68mL) and the temperature was reduced to-5 to 0 ℃. And (3) dropwise adding the NBS solution into the 2-aminopyridine solution at the reaction temperature of-5 ℃, controlling the dropwise adding time to be 1.5-2 hours after dropwise adding reaction, and controlling the kettle temperature to be-5 ℃ for heat preservation reaction for 6 hours. The content of 2-aminopyridine in liquid phase analysis was 0.03%.
Dissolving NCS (14.4g,0.108mol) in dichloroethane (66mL) to form a uniform solution, putting the clear solution of NCS into a reaction kettle, controlling the kettle temperature to be 80-90 ℃ for reflux reaction, keeping the temperature for reaction for 12 hours, and analyzing the content of 2-amino-5-bromopyridine by a liquid phase to be 0.02%. And (3) carrying out reduced pressure distillation, removing more than 90% of dichloroethane, adding ethanol (144mL) and water (14mL), heating to 60-70 ℃, dissolving, recrystallizing, carrying out suction filtration and leaching to obtain the 2-amino-3-chloro-5-bromopyridine.
Adding 2-amino-3-chloro-5-bromopyridine solid into DMSO (226mL), heating to 55-60 ℃ for dissolving, sequentially adding PdCl2dppf catalyst (0.73g,0.001mol), potassium acetate (14.7g,0.15mol) and CH3BF3K (19.4g,0.11mol), controlling the kettle temperature at 90-100 ℃ for reaction for 12 hours, and analyzing the content of 2-amino-3-chloro-5-bromopyridine to be 0.03% by liquid phase.
The reaction solution was cooled to room temperature, filtered, washed with DMSO, the solvent distilled, decolorized with activated carbon, slurried with ethanol and heptane (1/5 vol.), and dried to give 2-amino-3-chloro-5-trifluoromethylpyridine (14.5 g).
The content of the example in the group is 99.83%, and the yield is 74%.
Example 3:
2-aminopyridine (9.4g,0.1mol) was dissolved in tetrahydrofuran (18mL) and cooled to-5-0 ℃ using an ice machine. NBS (18.7g,0.105mol) was dissolved in tetrahydrofuran (32mL) to form a homogeneous solution, which was cooled to-5-0 ℃. And (3) dropwise adding the clear NBS solution into the 2-aminopyridine solution at the reaction temperature of-5 ℃, controlling the overall dropwise adding time to be 2-2.5 hours after dropwise adding reaction, and controlling the kettle temperature to be-5 ℃ for heat preservation reaction for 4.5 hours. The content of 2-aminopyridine in liquid phase analysis was 0.02%.
NCS (16.0g,0.12mol) is dissolved in tetrahydrofuran (62mL) to form a uniform solution, the NCS solution is put into the reaction kettle, the kettle temperature is controlled to be 80-90 ℃, the temperature is kept for reaction for 15 hours, and the content of 2-amino-5-bromopyridine is 0.01% by liquid phase analysis. Vacuum reduced pressure distillation is carried out to remove more than 90 percent of tetrahydrofuran solvent. Adding ethanol (160mL) and water (16mL), heating to 60-70 ℃, dissolving, recrystallizing, performing suction filtration and leaching to obtain the 2-amino-3-chloro-5-bromopyridine.
Adding 2-amino-3-chloro-5-bromopyridine solid into dioxane (185mL) for dissolving, heating to 55-60 ℃ for dissolving, sequentially adding PdCl2dppf catalyst (0.73g,0.001mol), potassium acetate (14.7g,0.15mol) and CH3BF3K (19.4g,0.11mol), controlling the kettle temperature at 100 ℃ and 105 ℃ for reacting for 6 hours, and analyzing the content of 2-amino-3-chloro-5-bromopyridine to be 0.01% by liquid phase.
Cooling the reaction solution to room temperature, carrying out suction filtration, dioxane washing, solvent distillation, activated carbon decolorization, ethanol and heptane (1/5 volume ratio) pulping, and drying to obtain 2-amino-3-chloro-5-trifluoromethylpyridine (14.9 g).
The content of the group of examples is 99.85%, and the yield in the three steps is 76%.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (8)
1. A method for synthesizing 2-amino-3-chloro-5-trifluoromethylpyridine, which is characterized by using the following equation:
2. the process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 1, characterized by comprising the following steps:
firstly, mixing 2-aminopyridine and an organic solvent, cooling to-5-0 ℃, and adding NBS (N-bromosuccinimide) for reaction to obtain a 2-amino-5-bromopyridine reaction solution;
secondly, adding NCS into the 2-amino-5-bromopyridine reaction solution, heating to 80-100 ℃ and reacting to obtain 2-amino-3-chloro-5-bromopyridine;
and thirdly, adding a palladium catalyst and potassium trifluoromethyl trifluoroborate into the 2-amino-3-chloro-5-bromopyridine, and heating in an organic solvent for coupling reaction to obtain the 2-amino-3-chloro-5-trifluoromethylpyridine.
3. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 2, characterized in that: in the first step, the organic solvent is selected from MIBK, THF, acetone or dichloroethane.
4. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 2, characterized in that: in the third step, the organic solvent is selected from dioxane, ethanol, tetrahydrofuran or dimethyl sulfoxide.
5. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 1 or 2, characterized in that: in the first step, the molar ratio of 2-aminopyridine to NBS is 1: 1.1-1.3.
6. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 1 or 2, characterized in that: in the second step, the molar ratio of the 2-amino-5-bromopyridine to the NCS is 1: 1-1.1.
7. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 1 or 2, characterized in that: in the third step, the molar ratio of the 2-amino-3-chloro-5-bromopyridine to PdCl2dppf to CF3BF3K is 1: 0.01-0.03: 1-1.2.
8. The process for the synthesis of 2-amino-3-chloro-5-trifluoromethylpyridine according to claim 1 or 2, characterized in that: the purity of the 2-amino-3-chloro-5-trifluoromethyl pyridine can reach 99.5 percent, and the yield can reach 90 to 97 percent.
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Cited By (3)
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| CN113527194A (en) * | 2021-03-15 | 2021-10-22 | 武威广达科技有限公司 | Preparation method of 2-amino-3-chloro-5-trifluoromethylpyridine |
| CN114478365A (en) * | 2022-02-11 | 2022-05-13 | 大连九信作物科学有限公司 | Purification method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate |
| CN114790168A (en) * | 2021-05-18 | 2022-07-26 | 上海素馨化工科技有限公司 | Preparation method of 2-amino-4-trifluoromethylpyridine and 2-amino-4-trifluoromethylpyridine |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113527194A (en) * | 2021-03-15 | 2021-10-22 | 武威广达科技有限公司 | Preparation method of 2-amino-3-chloro-5-trifluoromethylpyridine |
| CN113527194B (en) * | 2021-03-15 | 2023-10-03 | 武威广达科技有限公司 | Preparation method of 2-amino-3-chloro-5-trifluoromethyl pyridine |
| CN114790168A (en) * | 2021-05-18 | 2022-07-26 | 上海素馨化工科技有限公司 | Preparation method of 2-amino-4-trifluoromethylpyridine and 2-amino-4-trifluoromethylpyridine |
| CN114790168B (en) * | 2021-05-18 | 2024-02-09 | 上海素馨化工科技有限公司 | Preparation method of 2-amino-4-trifluoromethyl pyridine and 2-amino-4-trifluoromethyl pyridine |
| CN114478365A (en) * | 2022-02-11 | 2022-05-13 | 大连九信作物科学有限公司 | Purification method of 2-aminomethyl-3-chloro-5-trifluoromethylpyridine acetate |
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