2021-01-13
Synthesis of HIV-1 inhibitor etravirin
The synthesis of 1.2.1,4-bis (2,6-dichloropyridine-4-oxo) - 3,5-dimethylbenzonitrile (IV) was studied. 12.46 g (67.95 mmo1) 2,4,6-trimethylpyrimidine (II), 10.00 (67.95 mmo1) 3,5-dimethyl-4-hydroxybenzonitrile (III), 10.54 g (81.54 mmo1) n, n-diisopropylacetylamine and 4 ml 1,4-dioxane were put into the reaction flask The reaction was carried out at 65 ℃ for 1.5 h and 70 ℃ for 1 h. After the reaction solution was cooled to about 10 ℃, the filter cake was washed with 10 ml cold 1,4-dioxane, then the filter cake was added into 40 ml water at 25 ℃, stirred for 30 min and filtered. After drying, 16.44 g of intermediate Ⅳ was obtained in the yield of 82.3 m.p.2o7.8-209.6 ℃ (literature value) [16] Synthesis of 16.00g (54.40mmo1) intermediate IV and 6.43g (54.40mmo1) p-aminobenzonitrile (V) in 70ml N-methylpyrrolidone (N-methylpyrrolidone); H NMR (dmso-d, 400 MHz): 82.12 (s, 6h), 7.61 (s, 1H), 7.74 (s, 2h), 1.2.24-6-chloro-2-bis (4-cyanophenyl) amino) pyridine-4-oxo-3,5-dimethylbenzonitrile (V) Add 12.21g (108.80mmo1) potassium TERT butanol in batches at 0-5 ℃, add it for 30min, continue to stir for 2h, then slowly add 300ml water, filter, suspend the filter cake in 180ml water, adjust it to pH 6-7 with concentrated hydrochloric acid. After filtration, the filter cake still contains more impurities (isomer of V) after drying. Add the filter cake Then, the filter cake was washed with 2 ml cold ethyl acetate and dried in vacuum at 55-60 ℃ to obtain 12.61 g intermediate V with a yield of 61.7.mp.278.1-279.6 ℃ (reference value [16]: 278.5-280.5 ℃); MS (ESI)+ )Synthesis of 1.2.3 4 - (6-amino-2-one ((4-cyanophenyl) amino) pyridine-4-oxy) - 3,5-dimethylbenzonitrile (VI). 10.00g (26.60mmo1) intermediate V, 5 () ml of 25 mass fraction ammonia and 80ml 1,4-dioxane were added to the autoclave and stirred at 120 ℃ for 12h. The reaction solution was cooled to 5O ℃ After that, add 2 ml water, cool to 5 ℃, stir for 1 h, filter, wash the filter cake twice w