Process for obtaining quinapryl hydrochloride and solvates useful for isolating and purifying quinapryl hydrochloride

Abstract

The process for obtaining quinapril hydrochloride (I) comprises the stages of: a) hydrogenolysis of the benzyl ester of quinapril (II) by treatment in an alcoholic solvent, with concentrated hydrochloric acid or a solution of hydrogen chloride in isopropanol, and hydrogenation; b) removal of the solvent; c) addition of toluene to precipitate the quinapril hydrochloride as a toluene solvate; d) treatment of said solvate with a Class 3 solvent which forms a solvate of quinapril hydrochloride from which it can be removed by drying without degrading; and e) drying of the solvate from step d) to yield quinapril hydrochloride (I), an antihypertensive agent.

1. A process for obtaining quinapril hydrochloride of formula (I) 
                 
 
       which comprises the stages of:
 a) treatment of the benzyl ester of quinapril (II) 
                 
 
 
       where Bz is the benzyl radical, with alcohol and hydrochloric acid or hydrogen chloride and hydrogenation of same through the addition of an appropriate hydrogenation catalyst;
 b) removal of the solvent used in step a);  
 c) addition of toluene to precipitate the quinapril hydrochloride as a toluene solvate;  
 d) treatment of the toluene solvate of quinapril hydrochloride with a solvent belonging to class 3, capable of forming a solvate of quinapril hydrochloride from which it is possible to eliminate said solvent by drying in an oven without degrading the quinapril hydrochloride; and  
 e) drying of the solvate obtained in step d) at a temperature between 40° C. and 50° C. to yield quinapril hydrochloride (I).  
 
     
     
       2. A process according to  claim 1  wherein the hydrogenolysis reaction of the benzyl ester of quinapril (II) is carried out in a alcoholic solvent, with treatment with concentrated hydrochloric acid or with a solution of hydrogen chloride in isopropanol, and hydrogenation with hydrogen gas in the presence of a hydrogenation catalyst. 
     
     
       3. A process according to  claim 2 , wherein said alcoholic solvent is chosen from between  either ethanol or isopropanol. 
     
     
       4. A process according to  claim 2 , wherein the hydrogenation is carried out at a pressure comprised  in the range of 10 4  Pa and 2×10 5  Pa. 
     
     
       5. A process according to  claim 2 , wherein the hydrogenation is carried out at a temperature comprised  in the range of 10 and 40° C. 
     
     
       6. A process according to  claim 2 , wherein the hydrogenation catalyst is Pd/C. 
     
     
       7. A process according to  claim 2 , wherein the hydrogenolysis reaction of the benzyl ester of quinapril (II) is carried out using ethanol as a solvent, concentrated hydrochloric acid, at a pressure of 1×10 5  Pa (1 bar) and at room temperature. 
     
     
       8. The process according to  claim 2 , wherein the hydrogenolysis reaction of the benzyl ester of quinapril (II) is carried out using isopropanol as a solvent, a solution of hydrogen chloride in isopropanol, a pressure of 2×10 5  Pa (1 bar) and a temperature of approximately 30° C. 
     
     
       9. A process according to  claim 2  wherein the molar ratio between the benzyl ester of quinapril (II) and the hydrochloric acid can be equal or greater in a proportion of 1.1 (benzyl ester of quinapril (II)) to 1 (hydrochloric acid) with respect to stoichiometric one. 
     
     
       10. A process according to  claim 1 , wherein the removal of the solvent used in stage a) is carried out by vacuum-distillation. 
     
     
       11. A process according to  claim 1 , wherein the Class 3 solvent used to treat the toluene solvate of quinapril hydrochloride is chosen from among ethyl formate and methyl acetate. 
     
     
       12. A process according to  claim 1 , wherein the treatment of the toluene solvate of quinapril hydrochloride with the class 3 solvent is carried out at a temperature comprised  between 40° C. and 45° C., for a period of time comprised  between 1 and 2 hours, and is subsequently cooled down to a temperature comprised  between 20° C. and 25° C. for a period of time comprised  between 1 and 2 hours. 
     
     
       13. A process according to  claim 1 , wherein the Class 3 solvent solvate of quinapril hydrochloride is chosen from among ethyl formate solvate of quinapril hydrochloride and the methyl acetate solvate of quinapril hydrochloride. 
     
     
       14. A process according to  claim 1 , wherein the Class 3 solvent solvate of quinapril hydrochloride is dried in a vacuum oven, at a temperature comprised  between 40 and 50° C. for a period of time comprised  between 12 and 24 hours. 
     
     
       15. A process according to  claim 1 , wherein the hydrogenation of the product resulting after the addition of hydrochloric acid or hydrogen chloride to the benzyl ester of quinapril ( II )  in stage a ) , is carried out without prior isolation of the intermediate formed.    
     
     
       16. A process according to  claim 1 , wherein the benzyl ester of quinapril ( II )  is obtained by condensation of the N - carboxyanhydride of N -[   1   -( S )- ethoxycarbonyl -   3   - phenylpropyl ]- L - alanine and of the benzyl ester of  ( S )   1 , 2 , 3 , 4   - tetrahydro -   3   - isoquinolinecarboxylic acid, followed by hydrogenation in an acid medium.    
     
     
       17. A process according to  claim 16 , wherein the benzyl ester of quinapril ( II )  obtained is used without prior isolation.    
     
     
       18. A toluene solvate of quinapril hydrochloride characterized in that its infrared spectrum presents the following peaks:
   IR  ( KBr ) ( ν, cm   −1 )    3520 ,  3026 ,  3003 ,  2928 ,  2802 ,  1755 ,  1742 ,  1711 ,  1646 ,  1558 ,  1538 ,  1495 ,  1455 ,  1203 ,  758 ,  737 .      
     
     
       19. An ethyl formate solvate of quinapril hydrochloride characterized in that its x- ray diffraction pattern presents the following characteristics:                        X-Ray Diffraction (powder)         Ethyl formate solvate of quinapril hydrochloride                           Angle (2θ°)       Relative Intensity (%)                                     8.82       32.7             10.88       23.3             11.47       20.9             12.05       16.5             13.63       34.4             15.89       12.5             16.08       17.2             16.48       27.4             16.85       32.7             18.05       10.4             18.42       17.8             18.68       24.6             19.52       50.7             19.75       33.2             20.11       45.3             21.20       36.6             21.86       100.0             23.07       15.3             23.59       30.1             24.50       42.5             26.66       14.5             27.16       22.7             27.45       10.6             28.34       13.1             28.71       15.6             29.66       29.5             30.56       14.5             34.87       13.5.                                                                        
       
        
       
     
     
       20. An ethyl formate solvate of quinapril hydrochloride according to  claim 19 , characterized in that its infrared spectrum presents the following peaks:
   IR  ( KBr ) ( ν, cm   −1 ) :  3520 ,  3028 ,  3001 ,  2979 ,  2935 ,  2857 ,  1744 ,  1718 ,  1648 ,  1546 ,  1495 ,  1462 ,  1454 ,  1432 ,  1388 ,  1260 ,  1199 ,  756 .      
     
     
       21. A methyl acetate solvate of quinapril hydrochloride characterized in that its x- ray diffraction pattern presents the following characteristics:                        X-Ray Diffraction (powder)         Methyl acetate solvate of quinapril hydrochloride                           Angle (2θ°)       Relative intensity (%)                                     8.86       26.0             10.95       26.0             11.79       19.2             13.73       45.9             16.18       18.2             16.57       37.7             16.87       60.4             18.76       18.6             18.93       18.6             19.59       33.2             20.16       81.9             20.91       19.2             21.56       30.7             21.93       100.0             22.18       28.7             23.22       14.6             23.65       35.4             24.62       52.6             27.17       34.0             28.51       16.6             28.93       22.9             30.69       21.6             30.85       14.0.                                                                   
       
        
       
     
     
       22. A methyl acetate solvate of quinapril hydrochloride according to  claim 21 , characterized in that its infrared spectrum presents the following peaks:
   IR  ( KBr ) ( ν, cm   −1 )    3500 ,  3084 ,  3003 ,  2860 ,  1746 ,  1735 ,  1706 ,  1648 ,  1545 ,  1495 ,  1455 ,  1259 ,  1196 ,  755 .      
     
     
       23. A solvate of quinapril hydrochloride, wherein said solvate is formed using a Class  3  solvent.  
     
     
       24. The solvate of quinapril hydrochloride according to  claim 23 , wherein said Class  3  solvent is selected from the group consisting of ethyl formate and methyl acetate.  
     
     
       25. A solvate of quinapril hydrochloride, said solvate obtained by
   a )  treating a benzyl ester of quinapril having the following structure:                          where Bz is the benzyl group, with a solvent of alcohol and hydrochloride acid or hydrogen chloride and hydrogenating through the addition of an appropriate hydrogenation catalyst;        b )  removing the solvent used in step a ) ;        c )  adding toluene to precipitate the quinapril hydrochloride as a toluene solvate; and        d )  treating the toluene solvate of quinapril hydrochloride with a solvent belonging to Class  3 , capable of forming a solvate of quinapril hydrochloride from which it is possible to eliminate said solvent by drying in an oven without degrading the quinapril hydrochloride.      
     
     
       26. A toluene solvate of quinapril hydrochloride.  
     
     
       27. A toluene solvate according to  claim 26 , wherein said toluene solvate is obtained by
   a )  treating a benzyl ester of quinapril having the following structure:                          where Bz is the benzyl group, with a solvent of alcohol and hydrochloric acid or hydrogen chloride and hydrogenating through the addition of an appropriate hydrogenation catalyst;        b )  removing the solvent used in step a ) ;        c )  adding toluene to precipitate the quinapril hydrochloride as a toluene solvate.      
     
     
       28. A process of producing quinapril hydrochloride, said process comprising forming a solvate of quinapril hydrochloride using a Class  3  solvent.  
     
     
       29. The process according to  claim 28 , wherein the Class  3  solvent is selected from the group consisting of ethyl formate and methyl acetate.