The synthesis of the reverse transcriptase inhibitor (RTI), (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H3,1-benzoxazin-2-one, also known as DMP-266 has been described in U.S. Pat. No. 5,519,021 issued on May 21, 1996 and the corresponding PCT International Patent Application WO 95/20389, which published on Aug. 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 937-940, as well as the PCT publication, WO 96/37457, which published on Nov. 28, 1996.
The compound was previously crystallized from a heptanetetrahydrofuran (THF) solvent system. The crystallization procedure required the use of high temperatures (about 90xc2x0 C.) to dissolve the final product. Crystals formed by nucleation during the cooling process. The crystals which were produced were Form II and are converted to the desired Form I while drying under vacuum at 90xc2x0 C. This crystallization provided minimal purification and produced material with inconsistent physical properties. The final product slurry was extremely difficult to mix and handle due to its high viscosity and heterogeneous nature.
The instant invention describes a method for crystallizing (xe2x88x92)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl 1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, as low at 40xc2x0 C.
A process for the crystallization of a compound of the structural formula 
comprising the use of a solvent to effect the dissolution of the compound followed by the addition of an anti-solvent to initiate the crystallization.
USPTO Backgrounds
USPTO Backgrounds