| 摘要 |
FIELD: chemistry.SUBSTANCE: present invention relates to a simple and cost effective method for synthesis of a diarylpyrimidine non-nucleoside reverse transcriptase inhibitor, such as etravirine. The method of producing etravirine includes steps of a) condensing 2,4,6-trichloropyrimidine with 3,5-dimethyl-4-hydroxybenzonitrile in the presence of a base in an inert solvent to obtain 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethylbenzonitrile (compound of formula (V)); b) converting the compound of formula (V) into 4-[[6-chloro-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (compound of formula (VI)), via condensation with 4-aminobenzonitrile using an alkoxide as a base; c) optionally purifying the compound of formula (VI); d) ammonolysis of the compound of formula (VI) to form 4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethylbenzonitrile (compound of formula (IV)) and e) bromating the compound of formula (IV) in an inert solvent to form etravirine. Preferably, step (a) is carried out in the presence of 1,4-dioxane as an inert solvent, and N,N-diisopropylethylamine as a base; step (b) is carried out in the presence of tertiary potassium butoxide as a base, using an inert solvent selected from ethanol, 1-methyl-2-pyrrolidone, N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, dimethylsulphoxide, tetraline, sulpholane and acetonitrile. The inert solvent at step (b) is preferably 1-methyl-2-pyrrolidone. Step (c) is normally carried out using ethyl acetate for washing. Step (d) is carried out using an aqueous solution of ammonia in 1,4-dioxane at 120-130°C; step (e) is carried out using a free halogen (bromine). The method enables to obtain end and intermediate products with a higher output. The increase in the overall output of the end product is achieved over a shorter time. Etravirine is typically synthesized using 2,4,6-trichloropyrimidine and 3,5-dimethyl-4-hydroxybenzonitrile.EFFECT: simple methods of condensing 4-aminobenzonitrile with a compound of formula (V), ie, 4-[(2,6-dichloro)-4-pyrimidinyloxy]-3,5-dimethylbenzonitrile.8 cl, 4 ex |
