preparation | (1) 300g 2-amino -6-methylpyridine is added to 1.5L concentrated sulfuric acid in batches, the temperature of the solution is kept lower than 20 ℃ during the adding process, after adding, stir for half an hour, and add mixed acid (mixed with 150ml concentrated sulfuric acid and 150ml concentrated nitric acid) dropwise, when dropping, keep the temperature at 0 ℃. After dropping, the temperature rises to 20 ℃ and stir for 13 hours. Then pour the reaction solution into ice water, adjust the pH to neutral, filter, dissolve the filter cake with ethyl acetate, decolorize with activated carbon, dry with sodium sulfate, filter, and evaporate under pressure to remove ethyl acetate, at this time, a mixture of the product 2-amino-5-nitro-6-methylpyridine and the by-product 2-amino-3-nitro-6-methylpyridine is obtained. The above mixture is dispersed into 1.5L toluene, heated to boiling reflux for 3 hours, filtered while hot, and the filter cake is dried under normal pressure to obtain 196g 2-amino-5-nitro-6-methylpyridine product with 46% yield. (2) Take the product 2-amino -5-nitro -6-methylpyridine (196g) obtained in step (1), add 400mL of water, add 800mL of concentrated sulfuric acid dropwise under an ice bath, control the temperature to be lower than 20 ℃, finish the addition, cool to 0 ℃, add sodium nitrite aqueous solution dropwise (dissolve 93g of sodium nitrite in 300mL of water), after dropping, the temperature of the solution rises to 20 ℃ and stir for 2 hours, filtration and atmospheric drying to obtain 170g of product 2-hydroxy-5-nitro-6-methylpyridine with 86% yield. (3) The products 2-hydroxy -5-nitro -6-methylpyridine (170g) and 230g of phosphorus pentachloride obtained in step (2) are added to 169g of phosphorus oxychloride, heated to 110 ℃, stirred for 3 hours, cooled, added with ice water, filtered and dried to obtain 175g of product 2-chloro -5-nitro -6-methylpyridine with a yield of 92%. (4) The product 2-chloro -5-nitro -6-methylpyridine (175g) obtained in step (3) is taken, dissolved in 2L dimethylformamide, 242gN,N-dimethylformamide dimethylacetal is added, heated to 90 ℃ and stirred for 12 hours, and the reaction solution is concentrated to obtain 200g of crude product of enamine intermediate. (5) 200g of the crude product of the enamine intermediate obtained in step (4) is taken, dissolved in 2.5L ethanol, 30g of Raney nickel is added, hydrogen is introduced, reacted at normal temperature and pressure for 16 hours, the Raney nickel is filtered to remove, the reaction solution is concentrated to remove ethanol to obtain 150g of the crude product, the crude product is recrystallized in toluene/ethyl acetate (volume ratio 5:1) to obtain 105g of the final product 5-chloro -4-azaindole,(4)(5) The total yield of the two steps is 68%. The mass concentration of concentrated sulfuric acid used in steps (1) and (2) is 98%, and the mass concentration of concentrated nitric acid is 65%. |