Method for Producing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclo-propylpropanoic Acid and the Crystalline Form Thereof for Use as a Pharmaceutical Ingredient

Abstract

The present invention relates to a novel and improved process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of the formula (I), to the compound of the formula (I) in crystalline form and to their use for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular, cardiopulmonary and cardiorenal disorders.

1 . A process for preparing (3S)-3-(4-chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3 cyclopropylpropanoic acid (I) in crystalline modification 1 (I-1), comprising stirring the compound of the formula (I) 
       
         
           
           
               
               
           
         
         in an inert solvent selected from the group consisting of heptane, 2-methoxy-2-methylpropane, ethanol, ethyl acetate and mixtures of these solvents at a temperature of from 20° C. to 120° C. and isolating the compound of the formula (I-1), optionally after cooling. 
       
     
     
         2 . (canceled) 
     
     
         3 . A process for preparing the compound of the formula (I), 
       
         
           
           
               
               
           
         
         comprising reacting the compound of the formula (V) 
       
       
         
           
           
               
               
           
         
         
           in which 
           R 1  represents (C 1 -C 4 )-alkyl, 
           in the presence of dioxane and hydrochloric acid to give the compound of the formula (I). 
         
       
     
     
         4 . A process for preparing the compound of the formula (V) 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents (C 1 -C 4 )-alkyl, 
       
       comprising reacting the compound of the formula (II) 
       
         
           
           
               
               
           
         
       
       under base-free conditions with the compound of the formula (III) 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents (C 1 -C 4 )-alkyl. 
       
     
     
         5 . A process for preparing the compound of the formula (II), 
       
         
           
           
               
               
           
         
         comprising converting the compound of the formula (XXVI) 
       
       
         
           
           
               
               
           
         
         
           in which 
           R 2  represents (C 1 -C 4 )-alkyl, 
           with sodium methoxide in methanol and subsequent addition of water into the compounds of the formulae (II-Na) and (II-A-Na) 
         
       
       
         
           
           
               
               
           
         
         
           which precipitate as solids, 
           adding a dilute mineral acid to convert the compounds of the formulae (II-Na) and (II-A-Na) into the compounds of the formulae (II) and (II-A) 
         
       
       
         
           
           
               
               
           
         
         
           reacting the compounds of the formulae (II) and (IIA) with a solution of quinine, resulting in the precipitation of the compound of the formula (II-Ch) 
         
       
       
         
           
           
               
               
           
         
         
           and adding dilute mineral acid to convert the compound of the formula (II-Ch) into the compound of the formula (II). 
         
       
     
     
         6 . The process according to  claim 5 , further comprising purifying the compound of the formula (II-Ch) in a first step by crystallization from a mixture of water and methanol in a ratio of from 1:1 to 1:5 and in a second step by crystallization from a mixture of water and ethanol in a ratio of from 1:1 to 1:10. 
     
     
         7 . A process for preparing the compound of the formula (XXVI) 
       
         
           
           
               
               
           
         
         in which 
         R 2  represents (C 1 -C 4 )-alkyl, 
       
       comprising reacting the compound of the formula (XXIV) 
       
         
           
           
               
               
           
         
         in which 
         R 2  represents (C 1 -C 4 )-alkyl, 
       
       with a lithium amide base and hydrolysing to give the compound of the formula (XXV) 
       
         
           
           
               
               
           
         
         in which 
         R 2  represents (C 1 -C 4 )-alkyl, 
       
       wherein the hydrolysis is carried out by addition of an organic acid in an inert solvent and in a further step by addition of a mineral acid, and converting the compound of the formula (XXV) in a hydrogenation reaction into the compound of the formula (XXVI). 
     
     
         8 . A process for preparing the compound of the formula (VII) 
       
         
           
           
               
               
           
         
         or a salt of this compound, 
       
       comprising converting the compound of the formula (XXXIV) 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents (C 1 -C 4 )-alkyl, 
         with a base, a protic solvent, 1,5-cyclooctadiene, [Rh(COD)Cl] 2  and a compound of the formula (XXXV-A) or (XXXV-B) 
       
       
         
           
           
               
               
           
         
         in which 
         R 4 , R 5 , R 6 , R 7 , R 8  and R 9  independently of one another represent hydrogen or (C 1 -C 4 )-alkyl, 
       
       to the compound of the formula (III-rac) 
       
         
           
           
               
               
           
         
         in which 
         R 1  represents (C 1 -C 4 )-alkyl, 
       
       conducting ester hydrolysis to give the compound of the formula (VII-rac), 
       
         
           
           
               
               
           
         
       
       reacting the compound of the formula (VII-rac) with a solution of (1S,2R)-(−)-cis-1-amino-2-indanol to give the compound of the formula (VII-I) 
       
         
           
           
               
               
           
         
       
       and adding dilute mineral acid to the compound of formula (VII-I) to form the compound of the formula (VII) or a salt thereof. 
     
     
         9 . A process for preparing the compound of the formula (III) 
       
         
           
           
               
               
           
         
         in which
 R 1  represents (C 1 -C 4 )-alkyl 
 
       
       comprising converting the compound of the formula (XXXIV) 
       
         
           
           
               
               
           
         
         in which
 R 1  represents (C 1 -C 4 )-alkyl, 
 
       
       with exclusion of oxygen, with a suitable metal precursor, a suitable diene ligand, a suitable base and a compound of the formula (XXXV-A) or (XXXV-B) 
       
         
           
           
               
               
           
         
         in which
 R 4 , R 5 , R 6 , R 7 , R 8  and R 9  independently of one another represent hydrogen or (C 1 -C 4 )-alkyl 
 
         into the compound of the formula (III). 
       
     
     
         10 . (3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid in crystalline modification 1 (I-1) 
       
         
           
           
               
               
           
         
         characterized in that the x-ray diffractogram of the compound exhibits peak maxima of the 2 theta angle at 7.0, 8.2, 11.1, 14.7, 17.2, 17.5, 18.7, 19.8. 
       
     
     
         11 . (3S)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid in crystalline modification 1 (I-1) 
       
         
           
           
               
               
           
         
         characterized in that the IR spectrum of the compound exhibits band maxima at 1709, 1660, 1534, 1491, 1263, 1167, 1131, 1093, 1016 cm −1 . 
       
     
     
         12 . The process according to  claim 3 , wherein the compound of the formula V is prepared by reacting the compound of the formula (II) 
       
         
           
           
               
               
           
         
         under base-free conditions with the compound of the formula (III) 
       
       
         
           
           
               
               
           
         
         
           in which 
         
         R 1  represents (C 1 -C 4 )-alkyl.