Patent EA-001805-B1 (EA)
Title: Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent
Inventor: CLARKE WILLIAM
IPC: C07D265/18
Filed: 1998-02-02
Abstract: 1. A process for the crystallization of a compound of the structural formula   comprising the steps of: (1) dissolving the compound in a solvent in a ratio of about 3.0 ml to about 10.0 ml of solvent to 1 gram of the compound; (2) filtering the solution of the compound to remove any particulate matter; (3) adding the anti-solvent to the stirring solution at room temperature over a period of about 30 minutes to about an hour to reach the saturation point of the solution containing the compound; (4) adding to the solution a solid seed charge of the compound in the amount of about 2 to about 10 percent by weight to form a slurry; (5) milling the slurry to reduce the thickness of the slurry; (6) adding the remaining anti-solvent to reach the desired solvent-containing composition of about 30% to about 50% and milling the slurry as needed during the addition; (7) slowly cooling the slurry to about 5 degree C to about 20 degree C; (8) aging for about 2 to about 16 hours until the supernatant concentration reaches equilibrium; (9) milling the slurry, as needed, to reduce the thickness of the slurry; (10) filtering the milled slurry to isolate a wet cake of the crystalline compound on the filter; (11) washing the wet cake once with about 1 to about 2 bed volumes of the final crystallization solvent composition and then twice with water using about 5-10 ml water per gram of compound; and (12) drying the washed wet cake at about 40 degree C to about 90 degree C under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less than 0.5 weight percent. 2. The process as recited in Claim 1 wherein the solvent is defined as (C1-C6)-alcohol. 3. The process as recited in Claim 2 wherein the anti-solvent is defined as water. 4. The process as recited in Claim 1 wherein the temperature during the anti-solvent addition (Step 3) is about 20 degree C to about 25 degree C. 5. The process as recited in Claim 1 wherein the temperature used during the drying of the washed wet cake (Step 12) is about 40 degree C to about 60 degree C. 6. The process as recited in Claim 3 wherein the solvent volume to anti-solvent volume ratio used is about 30% to about 50%. 7. The process as recited in Claim 6 wherein the (C1-C-6)-alcohol is selected from methanol, ethanol and 2-propanol. 8. The process as recited in Claim 7 wherein the (C1-C6)-alcohol is 2-propanol. 9. The process as recited in Claim 8 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and by ratio of about a 30% to about a 40% ethanol to anti-solvent volume which is water. 10. The process as recited in Claim 6 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and by ratio of about 40% to about 50% methanol to anti-solvent volume which is water. 11. The process as recited in Claim 6 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and by ratio of about 25% to about 35% 2-propanol to anti-solvent volume which is water. 12. The process as recited in Claim 10 wherein the total solvent system volume per gram of compound is about 15 ml/gm, and the ratio of 2-propanol to anti-solvent volume, which is water, is 30%. 13. A process for the crystallization of a compound of the structural formula   comprising the steps of: (1) mixing about 10% to about 20% by weight of the final amount of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in the desired v/v ratio of solvent to anti-solvent at about 20 degree C to form the heel; (2) adding the solution of solvent and (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, and anti-solvent to the heel simultaneuosly at constant rates over about 6 hours maintaining the v/v ratio of solvent to anti-solvent; (3) milling the slurry during the addition to reduce the thickness of the slurry; (4) cooling the slurry to about 10 degree C over about 3 hours and aging slurry until the supernatant concentration reaches equilibrium; (5) filtering the milled slurry to isolate a wet cake of the crystalline compound; (6) washing the wet cake once with about 1 to about 2 bed volumes of the final crystallization solvent composition and then twice with water using about 5 ml to about 10 ml water per gram of compound; and (7) drying the washed wet cake at about 40 degree C to about 90 degree C under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less then 0.5 weight percent. 14. The process as recited in Claim 13 wherein solvent is defined as acetonitrile, dimethylacetamide, dimethylformamide or alcohol. 15. The process as recited in Claim 14 wherein the anti-solvent is defined as water. 16. The process as recited in Claim 15 wherein the alcohol solvent is defined as (C1-C6)-alcohol. 17. The process as recited in Claim 13 wherein the temperature of the solution during the compound solvent solution/anti-solvent addition (Step 2) is about 5 degree C to about 20 degree C. 18. The process as recited in Claim 13 wherein the temperature used during the drying of the washed wet cake (Step 7) is about 40 degree C to about 60 degree C. 19. The process as recited in Claim 16 wherein the alcohol to anti-solvent volume to volume ratio used is about 30% to about 50%. 20. The process as recited in Claim 19 wherein the alcohol solvent is selected from methanol, ethanol and 2-propanol. 21. The process as recited in Claim 20 wherein the solvent is 2-propanol. 22. The process as recited in Claim 20 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and the ratio of ethanol to anti-solvent, which is water, volume to volume ratio is from 30% to about 40%. 23. The process as recited in Claim 20 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and the ratio of methanol to anti-solvent volume, which is water, is about 40% to about 50%. 24. The process as recited in Claim 21 wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm, and the ratio of 2-propanol to anti-solvent volume, which is water, is about 25% to about 35%. 25. The process as recited in Claim 23 wherein the total solvent system volume per gram of compound is about 15 ml/gm, and ratio of 2-propanol to anti-solvent volume, which is water, is about 30%. 26. Form I of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern as exhibited in Figure 3 or crystallographic D-intervals, which are 14,5, 8,5, 8,0, 7,2, 6,7, 6,2, 5,2, 4,6, 4,4, 4,2, and 3,6 Angstroem unit. 27. Form II as claimed in Claim 26, which does not have detectable peaks of Form II or Form III in it's X-ray powder diffraction pattern. 28. Form II of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern as exhibited in Figure 4 or crystallographic D-intervals, which are 24,3, 13,9, 8,0, 6,9, 6,6, 5,5, 4,6, 4,5, 4,3, 4,2, 3,9, 3,6, 3,4, 3,3, and 3,2 Angstroem unit. 29. Form II as claimed in Claim 28, which does not have detectable peaks of Form I or Form III in it's X-ray powder diffraction pattern. 30. Form III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern as exhibited in Figure 5 or crystallographic D-intervals, which are 12,2, 8,1, 6,4, 6,1, 4,7, 4,3, 4,1, 4,0, 3,9, 3,8, 3,7, 3,6, 3,3, 3,2, and 3,0 Angstroem unit. 31. Form III as claimed in Claim 30, which does not have detectable peaks of Form I or Form II in it's X-ray powder diffraction pattern. 32. Form III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as recited in Claim 30, which is further characterised by a DSC curve as exhibited in Figure 6. 33. Form III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as recited in Claim 32, which is further characterised by a TG analysis as exhibited in Figure 7.