Background and overview[1]
(4-Bromo-1-methyl-3-pyrazolyl)methanol has a simple structure and many active groups. It is a good intermediate. Its derivatives are known to be involved in medicine, aerospace, and functional materials. , petroleum processing and other fields. However, in the synthesis process disclosed in the prior art, there are often problems such as difficulty in purification, many side reactions, low reaction yield, low product purity, and are not suitable for large-scale industrial production.
Preparation[1]
(4-Bromo-1-methyl-3-pyrazolyl)methanol is prepared as follows:
1) Oxidize 1,3-dimethylpyrazole to 1-methyl-3-carboxy-pyrazole
Dissolve 160g potassium permanganate in 1L water and place it in a 5L four-necked flask. Connect one end to mechanical stirring, one end to the dropping funnel, and the other end to three consecutive buffer balls to prevent the material from being flushed. Heat it up to 40. Slowly drop in 100g of 1,3-dimethylpyrazole (dissolved in 500mL of water). When the temperature of the reaction solution rises to 60 degrees, unplug the heating mantle. As the substrate is dropped into the reaction solution, the temperature of the reaction solution will rise. to 70-80 degrees, control the dripping speed to ensure that the reaction temperature is within 80 degrees to avoid flushing (stop dripping when it reaches 80 degrees), and finish dripping in 3 hours (central control 1). After the dripping, add the remaining 240g potassium permanganate in batches and complete the addition in 3 hours. After the addition of materials, the reaction was at 65 degrees (when the reaction temperature is 60 degrees, the difference is not big) for 2 hours, and the raw materials on the TLC plate have basically completed the reaction (center control 2).
After the reaction is completed, add 300mL (350mL, mL, 450mL, 500mL) methanol to the reaction flask to quench excess potassium permanganate, filter out the manganese dioxide in the reaction flask, and evaporate the filtrate to When the volume is about 800mL (or 1/2, 1/3, 1/4 of the total volume), adjust the pH to 3-4 with dilute hydrochloric acid, then evaporate the water (80-90 degrees), and add 800mL ( 850mL, 900mL, 950mL, 1000mL) can also be used, beat for half an hour, filter out the white solid that is insoluble in methanol (the solid is an inorganic salt), collect the filtrate, and spin dry to obtain 85.2g of light yellow solid, HPLC purity 89.8% ( Central control 3).
2) Esterify 1-methyl-3-carboxy-pyrazole into 1-methyl-3-ester-pyrazole
Place 180g of crushed 1-methylpyrazole-3-carboxylic acid into a 500mL four-necked flask, add 360g of toluene, add 5 drops of N,N’-dimethylformamide (DMF), and stir , the reaction is a white turbid liquid. When the temperature rises to 75°C, start adding the thionyl chloride dropwise. The dripping process is endothermic, but the gas is released violently. Control the dropping speed to avoid flushing. After the dropwise addition of the thionyl chloride is completed, the solution is heated to 75°C. Keep stirring for 30 minutes until the reaction solution becomes clear. Then add anhydrous methanol dropwise at this temperature and release the gas vigorously. Control the dropping speed. After the methanol addition is completed, reflux for 30 minutes. Take a sample for testing (Central Control 1) and then cool the reaction solution to 40°C. , the solvent was removed from the reaction solution under reduced pressure (60-70 degrees) to obtain 172.4g of 1-methylpyrazole-3-carboxylic acid methyl ester, which was directly used in the next step of the reaction without purification.
3) Halogenate 1-methyl-3-ester-pyrazole to 4-bromo-1-methyl-3-ester-pyrazole
Add 140g of 1-methylpyrazole-3-carboxylic acid methyl ester and 320ml of dichloromethane into the reaction flask, protect it with nitrogen, stir and clarify, cool it in an ice bath outside the reaction flask, when the internal temperature is 10°C, add it in batches 157.3g of hydantoin dibromide is exothermic during the addition, and the solution turns yellow and turbid. Control the speed of adding hydantoin dibromide so that the reaction temperature is no higher than 15°C. After the addition, plate TLC (center control 1).
Without the raw materials, post-processing, slowly add the reaction solution to 300g (350mL, mL, 450mL, 500mL can also be used) water, stir for 30min, separate layers, use sodium sulfite with 10% concentration of calcium zinc heat stabilizer for the organic layer Wash once with 200g of the solution (150g, 250g, 300g can also be used). The potassium iodide starch test paper will not change to blue, separate into layers, and then wash the organic layer three times with saturated sodium bicarbonate solution, 200g each time (150g, 250g, 300g can also be used) , the solvent was removed from the organic layer under reduced pressure (30-40 degrees) to obtain 214.1g of 4-bromo-1-methyl-3-pyrazole carboxyl methyl ester (Central Control 2). The product can be used directly in the next reaction without purification.
Thickener
4) Reduction of 4-bromo-1-methyl-3-ester-pyrazole to (4-bromo-1-methyl-3-pyrazolyl)methanol
The reaction system is protected with nitrogen, 171g of 4-bromo-1-methyl-3-pyrazole carboxyl ester methyl ester is put into the flask, and 600g of toluene (chlorobenzene, benzene, p-toluene, etc. can also be used) is added. Stir to clarify and cool the flask in an ethanol-dry ice bath. When the internal temperature is -10°C, start adding 455g of red aluminum (70% toluene solution) dropwise. The dripping process will generate heat. At the beginning, there is a trace amount of moisture in the reaction system, which will cause the dropwise addition of red aluminum to outgas. Control the dropwise addition of red aluminum. speed so that the temperature does not exceed 0°C.
After the dropwise addition of red aluminum is completed, stir for 30 minutes at -10-0°C. Take a sample and detect that there is no raw material (Central Control 1). Start adding 350g of saturated sodium carbonate solution dropwise. At the beginning of the dropwise addition, heat and gas release are violent, control The dropping speed is such that the temperature of the reaction solution does not exceed 20°C. After the saturated sodium bicarbonate solution is added, stir for 30 minutes, then let it stand for 30 minutes, separate the organic layer, and use 100g toluene (150g, 250g can also be used for the other layer of turbid liquid). , 300g of chlorobenzene, benzene, p-toluene, etc.), extract the layers, and then extract once with 100g (150g, 250g, 300g of chlorobenzene, benzene, p-toluene, etc.) toluene, combine the organic layers, and use 200g ( You can also use 150g, 250g, 300g) to wash once with water, and then remove the solvent from the organic layer under reduced pressure (60-70 degrees) to obtain 141.3g of (4-bromo-1-methyl-3-pyrazolyl)methanol.
Main reference materials
[1] CN201410605615.7 A preparation method of 4-bromo-3-chloromethyl-1-methyl-1H-pyrazole
