Process for preparing polymorphic forms of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one
Disclosed herein is a novel process for preparing polymorphic Forms of (S)-6-chloro-(cyclopropylethynyl)-1,4-di-hydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one referred as M 1 , I, II, β, and ω.
1. A process for preparing (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one polymorphic Form β, comprising:
dissolving efavirenz in a solvent;
cooling the reaction mass;
seeding the cooled reaction mass containing polymorphic Form β of efavirenz;
adding an anti-solvent; and
isolating the pure polymorphic Form β of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
2. The process according to claim 1 , wherein the step of dissolving efavirenz in the solvent is carried out at room temperature.
3. The process according to claim 1 , wherein the solvent is selected from the group consisting of lower aliphatic alcohols, lower aliphatic carboxylic acids, hetero aromatics, polar aprotic solvents, esters, aliphatic hydrocarbons, and mixtures thereof with water.
4. The process according to claim 3 , wherein the solvent is selected from methanol, ethanol, isopropyl alcohol, formic acid, acetic acid, ethyl acetate, isopropyl acetate, dimethylformamide, 1-methyl-2-pyrrolidinone and mixtures thereof.
5. The process according to claim 1 , wherein the reaction mass is cooled to 0-10° C.
6. The process according to claim 1 , wherein the anti-solvent is selected from water, n-heptane or mixtures thereof.
7. A process for preparing (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one polymorphic Form β, comprising:
providing a mixture of water and water miscible organic solvent;
dissolving efavirenz into the mixture; and
removing the solvent and isolating the polymorphic Form β of (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one.
8. The process according to claim 7 , wherein the miscible organic solvent is selected from methanol, ethanol, isopropyl alcohol, acetone, and mixtures thereof.
9. The process according to claim 8 , wherein the solvent is removed by employing freeze drying or distillation method.
10. The process according to claim 1 , wherein the reaction mass is cooled to 0-5° C.
11. The process according to claim 1 , wherein the anti-solvent comprises water.