Background and overview of the preparation method of 2-amino-5-fluoropyridine
2-Amino-5-fluoropyridine is an important organic intermediate, mainly used in the synthesis of various enzymes, hormone inhibitors, antagonists and other pharmaceutical intermediates. It is also a new type of enzyme, polypeptide and hormone receptor. The raw materials of inhibitors, antagonists and modulators are also the main raw materials of new fluoroquinolone antibiotics, so they play an important role in the field of pharmaceutical intermediates.
Preparation method of 2-amino-5-fluoropyridine
A preparation method of 2-amino-5-fluoropyridine, including the following steps:
Preparation method of 2-amino-5-fluoropyridine (1) Preparation of catalyst
Mix ferric nitrate solution and zirconium acetate solution, add potassium hydroxide solution dropwise, then slowly raise the temperature to 40-50°C, stir for 30 minutes, then add graphene oxide dispersion dropwise, stir and mix, and transfer to a hydrothermal kettle , react for 3 hours at 150°C. After the reaction is completed, filter the reaction solution. After the solid is dried, it is placed in a muffle furnace and treated at 700-730°C for 2 hours under a hydrogen atmosphere. After the treatment is completed, the furnace is cooled to obtain The solid is placed in the ethanol solution of the silane coupling agent, slowly heated to 50-60°C, stirred and refluxed to react 1 trioctyl borate for 1 h. After the reaction, the reaction solution was filtered and dried to obtain a catalyst; among them, iron nitrate The mass ratio of graphene oxide is 3:0.1; the mass ratio of solid and silane coupling agent is 1:0.05;
Preparation method of 2-amino-5-fluoropyridine (2) Preparation of 2-amino-5-nitropyridine
in the three-necked flask, and then slowly add 2-aminopyridine dropwise into the three-necked flask, stirring while dropping. During the stirring process, control the temperature of the reaction system in the three-necked flask below 50°C, and then continue to add dropwise into the three-necked flask. After the fuming nitric acid is added dropwise, keep stirring at 45-50°C for 1 hour. After the reaction is completed, add the ice-water mixture to the three-necked flask and stir for 2 hours. Finally, filter the reaction solution and dry the solid obtained with water. Recrystallize, decolorize, filter, and dry the obtained solid to obtain 2-amino-5-nitropyridine with a yield of 91.5%; among which, the molar ratio of sulfuric acid, 2-aminopyridine, and fuming nitric acid is 1.5 :0.1:0.2;
Preparation method of 2-amino-5-fluoropyridine (3) Preparation of 2-acetamido-5-nitropyridine
Add the 2-amino-5-nitropyridine and acetic anhydride prepared above into a three-necked flask at the same time, slowly raise the temperature to 120-130°C and react for 1 hour, cool and filter, and dry the solid obtained to prepare 2 -acetamido-5-nitropyridine, yield 80.9%;
Preparation method of 2-amino-5-fluoropyridine (4) Preparation of 2-acetamido-5-aminopyridine
Add the catalyst, glacial acetic acid and deionized water prepared above into a three-necked flask, slowly raise the temperature to 100-110°C, stir and reflux for 10 minutes, and then add 2-acetamido-5-nitropyridine to the three-necked flask. , and then continue to stir and reflux for 30 minutes. After the reaction is completed, cool to room temperature, filter, and remove the solvent in the filtrate to obtain 2-acetylamino-5-aminopyridine with a yield of 92.9%; among them, the catalyst, glacial acetic acid, 2- The mass ratio of acetamido-5-nitropyridine is 3:0.1:10;
Preparation method of 2-amino-5-fluoropyridine (5) Preparation of target product 2-amino-5-fluoropyridine
Add fluoroboric acid aqueous solution to ethanol, stir and mix evenly, add 2-acetylamino-5-aminopyridine, stir until the solid is dissolved, then add the catalyst prepared above, and add isopentyl nitrite dropwise in an ice-water bath After the dropwise addition of ester is completed, continue to stir the reaction for 1 hour. After the reaction is completed, add tetrahydrofuran to the reaction system and filter with suction. The obtained solid is vacuum dried and added to a three-necked flask. First, treat it at 130°C for 10 minutes, and then add it to the three-necked flask. Add sodium hydroxide solution, wash the solid on the condenser tube into the reaction bottle, heat to reflux, solids will continue to precipitate on the condenser tube, collect the solid, repeat the above operation, and obtain the target product 2-amino-5-polycarbonate. Fluoropyridine, the yield is 89.5%; among them, the mass ratio of fluoroboric acid, 2-acetylamino-5-aminopyridine, catalyst, and isoamyl nitrite is 18:22:0.1:6.
References
[1][Chinese invention] CN201711023088.9 A preparation method of 2-amino-5-fluoropyridine
