Crystal forms of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one

Abstract

The instant invention describes a method for crystallizing (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one from a solvent and anti-solvent 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, such as between about a temperature of 40° C. and 50° C.

What is claimed is:  
     
         1 . 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 crystallization.  
     
     
         2 . 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 water to reach the desired solvent composition of about 30% to about 50% and milling the slurry as needed during the addition;  
 (7) slowly cooling the slurry to about 5° C. to about 20° 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;  
 (11) washing the wetcake once with about Ito 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 wetcake at about 40° C. to about 90° C. under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less than 0.5 weight percent.  
 
     
     
         3 . The process as recited in  claim 2  wherein the solvent is defined as (C 1 -C 6 )-alcohol.  
     
     
         4 . The process as recited in  claim 3  wherein the anti-solvent is defined as water.  
     
     
         5 . The process as recited in  claim 2  wherein the temperature during the anti-solvent addition (Step 3) is about 20° C. to about 25° C.  
     
     
         6 . The process as recited in  claim 2  wherein the temperature used during the drying of the washed wetcake (Step 12) is about 40° C. to about 60° C.  
     
     
         7 . The process as recited in  claim 4  wherein the solvent volume to anti-solvent volume ratio used is about 30% to about 50%.  
     
     
         8 . The process as recited in  claim 7  wherein the (C 1 -C 6 )-alcohol is selected from methanol, ethanol and 2-propanol.  
     
     
         9 . The process as recited in  claim 8  wherein the (C 1 -C 6 )-alcohol is 2-propanol.  
     
     
         10 . The process as recited in  claim 9  wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about a 30% to about a 40% ethanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         11 . The process as recited in  claim 7  wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 40% to about 50% methanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         12 . The process as recited in  claim 7  wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35% 2-propanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         13 . The process as recited in  claim 11  wherein the total solvent system volume per gram of compound is about 15 ml/gm of about 30% 2-propanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         14 . 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° 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° 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 wetcake 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 wetcake at about 40° C. to about 90° C. under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less then 0.5 weight percent.  
 
     
     
         15 . The process as recited in  claim 14  wherein solvent is defined as acetonitrile, dimethyl acetamide, dimethyl formamide or alcohol.  
     
     
         16 . The process as recited in  claim 15  wherein the anti-solvent is defined as water.  
     
     
         17 . The process as recited in  claim 16  wherein the alcohol solvent is defined as (C 1 -C 6 )-alcohol.  
     
     
         18 . The process as recited in  claim 14  wherein the temperature of the solution during the compound-solvent solution/anti-solvent addition (Step 2) is about 5° C. to about 20° C.  
     
     
         19 . The process as recited in  claim 14  wherein the temperature used during the drying of the washed wetcake (Step 7) is about 40° C. to about 60° C.  
     
     
         20 . The process as recited in  claim 17  wherein the alcohol to anti-solvent volume to volume ratio used is about 30% to about 50%.  
     
     
         21 . The process as recited in  claim 20  wherein the alcohol solvent is selected from methanol, ethanol and 2-propanol.  
     
     
         22 . The process as recited in  claim 21  wherein the 7 solvent is 2-propanol.  
     
     
         23 . 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 of about a 30% to about a 40% ethanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         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 of about 40% to about 50% methanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         25 . The process as recited in  claim 22  wherein the total solvent system volume per gram of compound is about 12 ml/gm to about 20 ml/gm of about 25% to about 35% 2-propanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         26 . The process as recited in  claim 24  wherein the total solvent system volume per gram of compound is about 15 ml/gm of about 30% 2-propanol to water solvent to anti-solvent volume to volume ratio.  
     
     
         27 . Form I of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterized by an X-ray powder diffraction pattern as exhibited in FIG. 3.  
     
     
         28 . Form II of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterized by an X-ray powder diffraction pattern as exhibited in FIG. 4.  
     
     
         29 . Form III of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one which is characterized by an X-ray powder diffraction pattern as exhibited in FIG. 5.  
     
     
         30 . Form III of (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one as recited in  claim 29 , which is further characterized by a DSC curve as exhibited in FIG. 6.  
     
     
         31 . 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 characterized by a TG analysis as exhibited in FIG. 7.