Process for the Manufacture of the Calcium Salt of Rosuvastatin (E)-7-'4-(4-Fluorophenyl)-6-Isopropyl-2-'Methyl (Methylsulfonyl) Amino ! Pyrmidin -5-Yl! (3R, 5S)-3,5-Dihydroxyhept-6-Enoic Acid and Crystalline Intermediates Thereof

Abstract

A process for the manufacture of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)3,5-dihydroxyhept-6-enoic acid, useful as an HMGCoA reductase inhibitor, from a compound of the formula (7) wherein A is an acetal or ketal protecting group and R is alkyl, via isolated crystalline compounds of the formula (8) or of formula (10) is described. Crystalline intermediates of formulae 7, 8 and 10 are also described.

1 . A process for the manufacture of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising: 
 a) acid hydrolysis of an acetal protecting group in a compound of the formula (7)                          wherein A is an acetal or ketal protecting group and R is (1-6C)alkyl, and isolation of a resulting crystalline compound of the formula (8);                          b) optional recrystallisation of the compound of the formula (8);    c) hydrolysis of the ester group in the compound (8) to give a dihydroxy carboxylate derivative (9) (wherein M is hydrogen or a metal counterion other than calcium) or a compound of the formula (1); and                          d) where necessary, conversion of a compound of the formula (9) into a compound of the formula (1).    
   
   
       2 . A process as claimed in  claim 1  wherein the compound of the formula (7) is a compound of the formula (7a).  
     
       
         
         
             
             
         
       
     
   
   
       3 . A process for the manufacture of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, from a crystalline compound of formula (8) as claimed in steps c) and d) of  claim 1 .  
   
   
       4 . A process as claimed in  claim 1  or  claim 2  or  claim 3  wherein R is methyl, ethyl, iso-propyl, tert-butyl or hexyl.  
   
   
       5 . A process as claimed in any one of  claims 1  to  4  wherein R is ethyl, iso-propyl or tert-butyl.  
   
   
       6 . A crystalline compound of the formula 7 as defined in  claim 1 , which crystalline compound is methyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate having an X-ray powder diffraction pattern with peaks at 2-theta=9.5, 13.6 and 17.5.  
   
   
       7 . A crystalline compound of the formula 7 as defined in  claim 1 , which crystalline compound is ethyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate having an X-ray powder diffraction pattern with peaks at 2-theta=15.9, 18.4 and 19.5.  
   
   
       8 . A crystalline compound of the formula 7 as defined in  claim 1 , which crystalline compound is iso-propyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate having an X-ray powder diffraction pattern with peaks at 2-theta=7.8, 11.6 and 15.5.  
   
   
       9 . A crystalline compound of the formula 7 as defined in  claim 1 , which crystalline compound is n-hexyl(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2-dimethyl[1,3]dioxan-4-yl)acetate having an X-ray powder diffraction pattern with peaks at 2-theta=5.3, 7.1 and 18.9.  
   
   
       10 . A crystalline compound of the formula 8 as defined in  claim 1 , which crystalline compound is ethyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern with peaks at 2-theta=8.1, 11.3 and 19.9.  
   
   
       11 . A crystalline compound of the formula 8 as defined in  claim 1 , which crystalline compound is iso-propyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern with peaks at 2-theta=9.8, 17.3 and 21.1.  
   
   
       12 . A crystalline compound of the formula 8 as defined in  claim 1 , which crystalline compound is tert-butyl-(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoate having an X-ray powder diffraction pattern with peaks at 2-theta=18.2, 19.9 and 20.8.  
   
   
       13 . A process for the manufacture of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, comprising: 
 a) acid hydrolysis of an acetal protecting group in a compound of the formula (7)                          wherein A is an acetal or ketal protecting group and R is (1-6C)alkyl, and isolation of the resulting crystalline compound of the formula (10);                          b) optional recrystallisation of the compound of the formula (10);    c) hydrolysis of the compound of formula (10) to give a dihydroxy carboxylate derivative (9) (wherein M is a metal counterion other than calcium) or a compound of the formula (1); and                          d) where necessary, conversion of a compound of the formula (9) into a compound of the formula (1).    
   
   
       14 . A process as claimed in  claim 13  wherein the compound of the formula (7) is a compound of the formula (7a).  
     
       
         
         
             
             
         
       
     
   
   
       15 . A process for the manufacture of the calcium salt of (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid, from a crystalline compound of formula (10) as claimed in steps b) and c) of  claim 13 .  
   
   
       16 . Crystalline(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid-(3,6)-lactone having an X-ray powder diffraction pattern with peaks at 2-theta=7.9, 11.9, 15.9, 20.3, 21.7 and 22.5.  
   
   
       17 . A process for formation of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt comprising isolation of a crystalline compound as claimed in  claim 16  from a solution and subsequent conversion to the amorphous form of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt.  
   
   
       18 . The use of a compound as claimed in  claim 16  as a processing aid for isolation of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt.  
   
   
       19 . The use of a compound as claimed in  claim 16  as a processing aid for recovery of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt from waste solutions.  
   
   
       20 . The use of a compound as claimed in  claim 16  as an intermediate in the manufacture of amorphous bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid]calcium salt.