Preparation and application background and overview of 2-cyano-4-methylpyridine
2-Cyano-4-methylpyridine is an organic intermediate that can be obtained by first oxidizing 4-methylpyridine to prepare 4-methyl-pyridine-N-oxide, and then substituting it with a cyano group. 4-Methyl-pyridine-N-oxide can be used to prepare 4-methyl-2,6-dicarboxypyridine, a very useful pyridine derivative that is also A very important intermediate compound widely used in the pharmaceutical field.
Preparation and application of 2-cyano-4-methylpyridine
Preparation and application report of 2-cyano-4-methylpyridine 1.
A synthesis method of 2-cyano-4-methylpyridine, specifically including the following steps:
4-Methyl-pyridine-N-oxide (0.109g, 1mmol), trimethylsilyl cyanide (0.119g, 1.2mmol), H-diethyl phosphite (0. Sodium percarbonate 276g, 2mmol) ), carbon tetrachloride (0.308g, 2mmol), triethylamine (0.202g, 2mmol), and 10mL acetonitrile in a 50mL three-necked flask, react at room temperature for 6 hours. After the reaction is completed, remove the solvent under reduced pressure and pass through the column. After chromatographic separation (petroleum ether/ethyl acetate, V/V=4:1), the target compound was obtained as a colorless liquid with a yield of 80%. Nuclear magnetic spectrum data: 1H NMR (CDCl3, MHz,) δ: 2.28 (s, 3H), 8.01-7.98 (m, 1H), 8.10 (s, 1H),8.79-8.76(d,1H); 13 Rubidium CarbonateC NMR (100MHz, CDCl3)δ:21.1,116.4,128.5,130.6,133.4,147.9 ,150.1.
Preparation and application report 2 of 2-cyano-4-methylpyridine,
Dissolve 250g of compound 1 in 1.5L acetic acid, heat to 80°C, slowly add 300mL of hydrogen peroxide dropwise, and heat to 100°C to react for 24 hours. TLC spot plate monitoring, after the raw material reaction is complete, cool to room temperature. Concentrate to dryness under reduced pressure, then add 500 mL of toluene and concentrate with water to quantitatively obtain 297 g of light yellow solid compound 2, with a yield of 100%.
Dissolve 280g of compound 2 and 380g of TMSCN in 2L of methylene chloride, and stir at room temperature for 20 minutes. Cool to 10°C, slowly add 260g of dimethylaminoformamide dropwise to the above reaction solution, and stir at room temperature for 12 hours after the addition is completed. After TLC monitors that the reaction is complete, pour the reaction solution into 3L of 10% potassium carbonate aqueous solution. After stirring for 1 hour, separate the layers. The aqueous phase is extracted with dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. , the crude product was slurried with isopropyl alcohol/petroleum ether to obtain 275g of off-white solid compound 3, with a yield of 91%.
Preparation and application of 2-cyano-4-methylpyridine
Dissolve 260g of compound 3 (2-cyano-4-methylpyridine) in 2L acetic acid, heat to 80°C, slowly add 280mL of hydrogen peroxide dropwise, and heat to 100°C for 12 hours. TLC spot plate monitoring, after the raw material reaction is complete, cool to room temperature. Concentrate to dryness under reduced pressure, then add 500 mL of toluene and concentrate with water to quantitatively obtain 300 g of yellow solid compound 4, with a yield of 100%.
Dissolve 200g of compound 2 and 300g of TMSCN in 1.5L of methylene chloride, and stir at room temperature for 20 minutes. Cool to 10°C, slowly add 210g of dimethylaminoformamide dropwise to the above reaction solution, and stir at room temperature for 12 hours after the addition is completed. After TLC monitors that the reaction is complete, pour the reaction solution into 3L of 10% potassium carbonate aqueous solution. After stirring for 1 hour, separate the layers. The aqueous phase is extracted with dichloromethane. The organic phases are combined, dried over anhydrous sodium sulfate, filtered, and spin-dried. , the crude product was pulped with isopropyl alcohol/petroleum ether to obtain 175g of white solid compound 5, with a yield of 82%.
Dissolve 160g of compound 5 in a mixed solvent of 1L methanol and 2L 10% sodium hydroxide solution, heat to 60°C for 6 hours, cool to room temperature, concentrate under reduced pressure to a volume of about 1L, and cool to 0°C. Concentrated hydrochloric acid was added dropwise until the system pH=2. After a large amount of white solid precipitated, it was filtered and dried under vacuum to obtain 171g of white solid compound 6 (4-methyl-2,6-dicarboxypyridine), with a yield of 85%.
References
[1] [Chinese invention] CN201910638495.3 A synthesis method of 2-cyanoquinoline derivatives
[2] [Chinese invention] CN201410753032.9 Preparation method of 4-methyl-2,6-dicarboxypyridine
