Preparation of benzoxazinones by adding acetonitrile and p-toluenesulfonic acid with heat

摘要

A process for the preparation of asymmetric synthesis of (S)-6-chloro-4-cycpropylethynynl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one of Formula (II-i) comprising: (1) heating an acetonitrile solution of substituted aniline of Formula (XII) and p-toluenesulfonic acid to a temperature of 65oC to 85oC while stirring; (2) adding acetonitrile solution of a benzyl alcohol of Formula (XIII) over a period of 2 to 10 hours to heated acetonitrile solution of the substituted aniline and p-toluenesulfonic acid; (3) heating and stirring the reaction mixture for about 30 minutes to about 4 hours to give a crude solution of the compound of formula (Il-i); (4) cooling the crude solution of the compound of formula (Il-i); (5) adding seed crystals at a temperature of 20oC to 30oC; (6) slowly adding water while stirring at a temperature of 30oC to 35oC to form a slurry of the crystalline compound of formula (Il-i); (7) stirring the slurry for a reaction time of 2 hours to 12 hours at room temperature; (8) filtering the slurry of crystalline compound of formula (II-i) to isolate the crystalline compound of formula (II-i); (9) washing the crystalline material with a mixture of acetonitrile and water in a volume to volume ratio of about 60:40 to about 40:60; and (10) drying the material under an inert atmosphere at a temperature of 50oC. The compounds are useful as human immunodeficiency virus (HIV) reverse transcriptase inhibitor.