Several preparation methods of 2-chloro-4-methyl-3-nitropyridine_Industrial additives

Background and overview of several preparation methods of 2-chloro-4-methyl-3-nitropyridine

2-Chloro-4-methyl-3-nitropyridine is a pharmaceutical intermediate that can be used to prepare nevirapine. Nevirapine is an anti-AIDS drug developed by the German company Boehringer Ingelheim to prevent mother-to-child transmission of HIV. Nevirapine is an HIV-1 non-nucleoside reverse transcriptase inhibitor (Non-Nucleoside Reverse Transcriptase Inhibitor, NNRTI). Nevirapine directly connects to HIV-1 reverse transcriptase and blocks the RNA-dependent and DNA-dependent DNA polymerase activities by rupturing the catalytic end of the enzyme, thereby effectively reducing the number of viruses in the body and restoring human immune function. Nevirapine is one of the most widely used anti-AIDS drugs currently and is mainly used to prevent and treat mother-to-child viral transmission.

Several preparation methods of 2-chloro-4-methyl-3-nitropyridine

Report on several preparation methods of 2-chloro-4-methyl-3-nitropyridine 1.

Step 1, preparation of 3-nitro-4-methylpyridin-2-one (III)

To a 500 ml four-necked flask connected to a stirrer, thermometer and reflux condenser, add 100 grams of tetrahydrofuran, 13.5 grams (0.1 mol) of ethyl 2-nitroacetate, and 15.0 grams (0.1 mol) of 2-bromocroton Aldehyde, 0.5g DBU (alkali catalyst), stir and react at 40-45℃ for 5 hours, cool to 20-25℃, add 30g of 17% ammonia water, stir and react at 40-45℃ for 5 hours, cool to 20-25℃, 2 Extract with methyl chloride three times, each time with 50 grams of dichloromethane. Combine the dichloromethane phases, wash once with 10 grams of saturated sodium chloride phenylboronic acid aqueous solution, and recover the solvent by distillation to obtain 14.7 grams of 3-nitro-4-methylpyridine- 2-Ketone (Ⅲ), with a yield of 95.5% and a liquid phase purity of 99.3%, was directly used in the next step of chlorination reaction.

Step 2, preparation of 2-chloro-4-methyl-3-nitropyridine (IV)

To a 500 ml four-necked flask connected to a stirrer, thermometer and reflux condenser, add 100 grams of 1,2-dichloroethane and 15.5 grams (0.1 mol) of 3-nitro-4-methylpyridine- 2-Keto (Ⅲ), 25 grams of phosphorus oxychloride, stir and react at 70-75°C for 8 hours, cool to 20-25°C, slowly pour the reaction liquid into 300 grams of ice water, stir thoroughly, and then 40% hydroxide Neutralize the sodium aqueous solution to a pH of 7-9, extract three times with 1,2-dichloroethane, 50 grams each time, combine the organic phases, wash with 30 grams of saturated brine, and then dry with 5 grams of anhydrous sodium sulfate. The solvent was removed by rotary evaporation to obtain 15.9 g of light yellow powder 2-chloro-4-methyl-3-nitropyridine (IV), with a yield of 91.1% and a liquid phase purity of 99.3%.

Report on several preparation methods of 2-chloro-4-methyl-3-nitropyridine 2.

Step 1, preparation of 2-amino-3-nitro-4-methylpyridine

Below 0°C, drop fuming nitric acid (0.11mol) and concentrated sulfuric acid (10mL) solutions into the mixture of 2-amino-4-methylpyridine (0.10mol) and concentrated sulfuric acid (80mL). Then the temperature was naturally raised to room temperature and the reaction was continued to stir for 1-2 hr. Pour the reaction solution into ice water, adjust the pH value of the solution to neutral with ammonia water, filter, wash with water and dry to obtain 11.2g of 2-amino-3-nitro-4-methylpyridine.

Step 2, preparation of 2-hydroxy-3-nitro-4-methylpyridine

Below 0°C, add 25% sodium nitrite (0.15mol) aqueous solution dropwise into 2-amino-3-nitro-4-methylpyridine (0.07mol), water (150mL) and concentrated sulfuric acid (50mL) ) in the mixture, after the dropping is completed, the temperature is naturally raised to room temperature and the reaction is continued for 1.5-2.5 hr with stirring, then heated to reflux and reacted under reflux conditions for 3-5 hr. After cooling, pour the reaction solution into ice water, adjust its pH to weak acidity with saturated sodium carbonate aqueous solution, filter, wash with water and dry to obtain 5.7g of 2-hydroxy-3-nitro-4-methylpyridine.

Step 3, preparation of 2-chloro-4-methyl-3-nitropyridine

2-Hydroxy-3-nitro-4-methylpyridine (0.04mol) and phosphorus oxychloride (40 mL) were stirred and reacted under reflux conditions for 5-8 hours, then the phosphorus oxychloride was removed under reduced pressure, and the The reactants were slowly poured into ice water, and the pH of the solution was adjusted to weak alkalinity with saturated sodium carbonate aqueous solution, extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and the solvent was removed to obtain 2-chloro-4-methyl-3-nitrate. pyridine 5.4g.

Report 3 on several preparation methods of 2-chloro-4-methyl-3-nitropyridine.

Synthesis of (1) 2-amino-3-nitro-4-methylpyridine

In a reaction bottle, add 200ml of toluene and 1000g of 95% concentrated sulfuric acid, start stirring, and slowly add 108g of 2-amino-4-methylpyridine and 10g of barium hydroxide in batches at 25°C, and stir until completely dissolved. Then slowly add 330g of 20% dilute nitric acid dropwise. After the dropwise addition is completed, keep the mixture at 25°C for 5 hours. The reaction solution is obtained.

In another reaction bottle, add 1000ml of water, start stirring, and cool to 10°C. Slowly add the above reaction solution to the water, control the temperature at 10°C, and after the dropwise addition is completed, use ammonia water to adjust the pH to 8~8.5. The solid was collected to give a mixture of 2-amino-3-nitro-4-methylpyridine and 2-amino-4-methyl-5-nitropyridine. The molar ratio is: 2-amino-3-nitro-4-methylpyridine:2-amino-4-methyl-5-nitropyridine=100:5.

Recrystallize the above mixture with absolute ethanol to obtain 145.0g of pure 2-amino-3-nitro-4-methylpyridine. Yield: 95%, content: 99.5%.

Synthesis of (2) 2-hydroxy-3-nitro-4-methylpyridine

In a reaction bottle, add 145g of 2-amino-3-nitro-4-methylpyridine, 260g of concentrated sulfuric acid and 2000ml of water, and add sodium nitrite (83g) and water (240ml) dropwise below 10°C. After the solution was dropped, the solution was incubated for 1 hour. The solid was collected and dried to obtain 138g of 2-hydroxy-3-nitro-4-methylpyridine, yield: 95%, content (HPLC): 99.5%

(3)2-Chloro-4-methyl-3-nitropyridine compound�

In a reaction bottle, add 138g of 2-hydroxy-3-nitro-4-methylpyridine and 450g of phosphorus oxychloride, heat to reflux, and react under reflux for 4 hours. After recovering phosphorus oxychloride under normal pressure, slowly pour the reaction mixture into ice water and collect the solid. After drying, 147g of 2-chloro-4-methyl-3-nitropyridine is obtained, yield: 95%, content: 99.6%

References

[1][China invention, China invention authorization] CN2018101713 Boron trifluoride tetrahydrofuran complex 72.9 A simple preparation method of nevirapine

[2][China invention, China invention authorization] CN201410796643.12-Pyridinamine compounds and their preparation methods and applications

[3][Invented in China] Synthesis method of intermediates of CN201110249349.5 nevirapine