The main application background and overview of β-aminopyridine
Aminopyridine has three isomers, namely β-aminopyridine, 2-aminopyridine, and 4-aminopyridine. Relative molecular mass 94.12. The synthesis methods of β-aminopyridine mainly include the following: (1) using 3-bromopyridine as raw material, reacting with concentrated ammonia under heating in the presence of copper sulfate; (2) using 3-nitrilepyridine as raw material, Hydrolyze under mild conditions to generate nicotinamide diborate pinacol ester, which is obtained by Hofman degradation reaction; taking the second method as an example, 3-cyanopyridine lithium carbonate must first be obtained through base catalysis Nicotinamide is either separated or not separated, and then undergoes Hofmann degradation reaction to obtain β-aminopyridine; during the implementation of its preparation method, it was found that its energy-saving effect is poor.
Main applications of β-aminopyridine
β-Aminopyridine is a chemical substance with the molecular formula C5H6N2. It is used in medicine as an intermediate for the production of gastric ulcer and duodenal ulcer drugs. In terms of pesticides, it is used as a raw material for the fungicide Buthiobate; β-aminopyridine is an important intermediate for medicines, pesticides, and fine chemicals, and its downstream product 2,3-dichloropyridine is an important raw material for the synthesis of the pesticide Kangkuan. Examples of preparing 2,3,6-trichloropyridine from β-aminopyridine are as follows:
1) Synthesis of 6-dichloro-β-aminopyridine: Add 551.6g of 37% hydrochloric acid and 6.2g of Lewis acid catalyst anhydrous aluminum trichloride into the reactor, and slowly add 43.8g of homemade β-aminopyridine Add and warm to room temperature, the solution turns light yellow. Lower the temperature to below 15°C and start to dropwise add 74g of 30% hydrogen peroxide solution. After the dropwise addition is completed, raise the temperature to 35-45°C and keep the reaction for 3-5 hours. When the β-aminopyridine in the liquid phase is less than 0.1%, the reaction is completed. Cool the temperature to about 10°C, add saturated sodium metabisulfite solution to neutralize excess hydrogen peroxide, and wait until there is no color change on the starch potassium iodide test paper. Add 50% sodium hydroxide to adjust the pH to 1, add toluene for extraction three times, combine the organic phases, then add 30% industrial hydrochloric acid to back-extract the by-product 2-chloro-β-aminopyridine in the organic phase, and concentrate the organic phase under reduced pressure. 69.2g of beige solid 2,6-dichloro-β-aminopyridine was obtained, with a content of 97% and a crude yield of 91%.
2) Synthesis of 2,3,6-trichloropyridine: Add 69.2g of homemade 2,6-dichloro-β-aminopyridine, 3.6g of tetraethylammonium chloride and 207g of 30% industrial hydrochloric acid, and cool to Below 0°C, start adding 117.2g of 30% sodium nitrite solution dropwise. When the dropwise addition is completed, a diazonium salt solution is obtained. Keep it at about 0°C for later use. At room temperature, add 8.4g cuprous chloride and 207g 30% industrial hydrochloric acid to the reactor. Under nitrogen protection, start dropping the diazonium salt solution at about 0°C. After the dropwise addition, the temperature gradually rises to 60-70°C and the reaction takes about 2 hours. After the reaction is completed, dichloromethane is added to extract the reaction solution, and the organic phase is concentrated to obtain crude 2,3,6-trichloropyridine. Then add toluene and petroleum ether for recrystallization to obtain 71.3g of white crystals with a content of 98% and a crude yield of 92%.
Main application preparation of β-aminopyridine
Method 1: Preparation of β-aminopyridine is as follows: Add 923g of sodium hypochlorite (1.3mol) solution with 10% available chlorine, 300g of water and 200g of 30% (1.5mol) sodium hydroxide solution into a 2000L four-neck glass reaction bottle. , cool to 0℃ while stirring in an ice-salt bath; grind 104g (1mol) 3-cyanopyridine in a mortar, add it into the stirring four-mouth reaction bottle through the paper feeding tube, and rinse the mortar with a washing bottle Add the 3-cyanopyridine adhered to the glass mouth into the four-neck reaction flask. The temperature will rise during the addition process. Maintain an ice-salt bath and control the addition speed of 3-cyanopyridine to increase the temperature of the liquid in the reaction flask. No more than 5℃. After the 3-cyanopyridine powder is added, remove the ice-salt bath to allow the reaction system to warm up, and use the ice-salt bath to control the temperature of the reaction system to not exceed 25°C. After about 3 to 6 hours, the reaction solution will be clear, and samples will be taken and tested by HPLC 3 -Cyanopyridine content (area normalization method), if the 3-cyanopyridine content is less than 1%, the reaction is qualified. If the reaction is unqualified, additional sodium hypochlorite must be added as appropriate. The amount of sodium hypochlorite added each time shall not exceed 2% of the original amount. And after each addition of sodium hypochlorite, take a sample to detect the content of 3-cyanopyridine after 0.5 hours of reaction, until the reaction is qualified. After the reaction is qualified, the reaction solution is quickly heated to 60°C in a water bath and then the water bath is removed. The reaction solution will heat up to 95~100℃, the reaction solution changes from light yellow to reddish brown, and a large number of bubbles are released. After a large number of bubbles are released, the water bath is kept warm at 95~100℃ for 2 hours to react. The reaction is considered to be completed. Remove the water bath and stir naturally. Cool to room temperature, extract five times with equal volumes of ethyl acetate, combine the ethyl acetate extracts, add 0.5g of sodium sulfite solid, stir and dissolve, put into 1000L distillation bottles in batches, use a rotary evaporator to distill, and place in a 60°C water bath Steam out most of the ethyl acetate, connect the rotary evaporator to the vacuum system to maintain 630mmHg and heat the water bath to 90°C until no more ethyl acetate evaporates. Remove the water bath, cool the distillation flask to room temperature and use nitrogen to break it. Remove the distillation bottle and use a stainless steel spoon to scrape the reddish-brown solid on the wall of the distillation bottle, place it in a watch glass, and place it in a desiccator overnight to obtain 88.5g of β-aminopyridine, with a content of 98.5% and a yield of 92.6%. Because β-aminopyridine is easy to absorb moisture and oxidize, it is best to avoid contact with humid air and store it in a sealed container.
Method 2: Synthesis of β-aminopyridine: At room temperature, add 500g of 10% sodium hydroxide solution to the reactor, and lower the temperature by 10°C.Next, add 61g of nicotinamide and stir to form a white turbid liquid. Add 343g of 12.5% sodium hypochlorite solution dropwise into the reactor. Control the dropping temperature to be less than 10°C. After the dripping, the reaction solution turns into a clear light yellow-green color and rises to room temperature with stirring. 0.5h, continue to raise the temperature to about 90℃, keep the reaction for 2-3h, liquid chromatography detects that the nicotinamide content is less than 0.1%, the reaction is over, cool down to below 10℃, slowly add sodium hydroxide solid until the solution appears white and turbid, then add After extraction with ethyl acetate and concentration of the organic phase, 43.8g of β-aminopyridine was obtained as a light yellow solid with a content greater than 95% and a crude yield of 93%.
