Key intermediates for the synthesis of rosuvastatin or pharmaceutically acceptable salts thereof

Abstract

The present invention relates in general to the field of organic chemistry and in particular to the preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5-methylpyrimidin-2-yl)-N-methylmethanesulfonamide (I), N-(4-(4-fluorophenyl)-5-(bromomethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (II) and N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (III), key intermediates in preparation of Rosuvastatin.

1 . A process for preparing the compound of formula II 
       
         
           
           
               
               
           
         
         comprising the steps of: 
         providing a compound of formula I: 
       
       
         
           
           
               
               
           
         
         and converting the compound of formula I by bromination into the compound of formula II. 
       
     
     
         2 . The process according to  claim 1 , wherein said bromination is performed with an N-bromoamide as a brominating agent, wherein said N-bromoamide is selected from the group consisting of N-bromoacetamide, N,N-dibromobenzene sulfonamides, N-bromosuccinimide, N-bromophthalimide, N-bromoglutarimide, 3-bromo-hydantoin and 1,3-dibromo-5,5-dimethylhydantoin. 
     
     
         3 . The process according to  claim 2 , wherein the initial amount of brominating agent is from about 1 to about 3 times the molar stoichiometric amount based on compound I. 
     
     
         4 . The process according to  claim 1 , wherein the bromination reaction is performed in an organic solvent selected from the group consisting of acetone, ethyl acetate, hydrocarbons, aromatic hydrocarbons, acetonitrile and a mixture thereof. 
     
     
         5 . The process according to  claim 1  avoiding use of HBr and PBr 3 . 
     
     
         6 . The process according to  claim 1 , which is performed under treatment of ultraviolet radiation, wherein said ultraviolet radiation has a wavelength of about 200 to 400 nm. 
     
     
         7 . The process according to  claim 1 , wherein the bromination is carried out at a temperature between 0 to 90° C. 
     
     
         8 . The process according to  claim 1 , further comprising a step of purifying of the compound of formula II. 
     
     
         9 . A process for preparing a compound of formula I 
       
         
           
           
               
               
           
         
         comprising a step of reacting a compound of formula IX or IX′ 
       
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  respectively denote same or different hydroxy protecting groups and R is selected from alkyl or aryl; 
         with a compound of formula X or X′ 
       
       
         
           
           
               
               
           
         
         wherein Z is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         and wherein Rx, Ry, and Rz, are the same or different and are selected from optionally substituted C 1 -C 8  alkyl or C 3 -C 6  cycloalkyl or C 1 -C 8  alkenyl or C 5 -C 6  cycloalkenyl or aryl, and X θ  is an anion; 
         wherein in said reaction the compound of formula X or X′ is used in molar excess over the compound of formula IX or IX′, and/or wherein the reaction takes place in the presence of water or other protic molecules, 
         to obtain the compound of formula I. 
       
     
     
         10 . The process according to  claim 9 , wherein the compound of formula I is obtained as a product besides a compound selected from formulas XI or XI′ 
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  respectively denote same or different hydroxy protecting groups; 
         wherein the obtained compound selected from formulas XI and XI′ is used to be subsequently converted to Rosuvastatin or its salt. 
       
     
     
         11 . A process for preparing rosuvastatin, comprising:
 (a) reacting a compound of formula IX or IX′   
       
         
           
           
               
               
           
         
         
           wherein P 1  and P 2  respectively denote same or different hydroxy protecting groups and R is selected from alkyl or aryl; 
           with a compound of formula X or X′ 
         
       
       
         
           
           
               
               
           
         
         
           wherein Z is selected from the group consisting of: 
         
       
       
         
           
           
               
               
           
         
         
           and wherein Rx, Ry, and Rz, are the same or different and are selected from optionally substituted C 1 -C 8  alkyl or C 3 -C 6  cycloalkyl or C 1 -C 8  alkenyl or C 5 -C 6  cycloalkenyl or aryl and X θ  is an anion; 
         
         (b) obtaining reaction products of
 a compound of formula I 
 
       
       
         
           
           
               
               
           
         
         and
 a compound selected from formulas XI or XI′ 
 
       
       
         
           
           
               
               
           
         
         wherein P 1  and P 2  are as defined above; 
         (c) using the obtained compound selected from formulas XI and XI′ for conversion into Rosuvastatin or its salt; and 
         (d) using the obtained compound of formula I for providing said compound in a process according to  claim 1  in a recycling process for producing rosuvastatin. 
       
     
     
         12 . The process according to  claim 11 , wherein in step (b) the obtained reaction products are respectively separated into the compound of formula I and the compound selected from formulas XI or XI′, prior to the respective use in step (d). 
     
     
         13 . A process for preparing a compound of formula III 
       
         
           
           
               
               
           
         
         comprising the step of converting the compound of formula II 
       
       
         
           
           
               
               
           
         
         by hydrolysis into the compound of formula III. 
       
     
     
         14 . The process according to  claim 13 , wherein hydrolysis is performed in the presence of an inorganic base. 
     
     
         15 . A one-pot process for preparing the compound of formula III 
       
         
           
           
               
               
           
         
         comprising converting a compound of formula I 
       
       
         
           
           
               
               
           
         
         by reaction via non-isolated compound of formula II 
       
       
         
           
           
               
               
           
         
         into the compound of formula III. 
       
     
     
         16 . The process according to  claim 13 , further comprising the step of purifying compound of formula III. 
     
     
         17 . A process for the preparation of Rosuvastatin or pharmaceutically acceptable salt of Rosuvastatin, comprising the steps of:
 a) carrying out a process for preparing the compound of formula I according to  claim 9 , carrying out a process for preparing the compound of formula II by converting the compound of formula I by bromination into the compound of formula II
 or carrying out a process for preparing the compound of formula III by converting the compound of formula II by hydrolysis into the compound of formula III, and 
   b) subjecting the compound of formula I, II or III respectively to further synthesis steps to yield Rosuvastatin or pharmaceutically acceptable salts thereof.   
     
     
         18 . A process for the preparation of a pharmaceutical composition comprising Rosuvastatin as active ingredient, comprising the steps of:
 a) preparing Rosuvastatin or pharmaceutically acceptable salts thereof according to the process according to  claim 17 , and   b) admixing the thus prepared Rosuvastatin or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient.   
     
     
         19 . A process for the preparation of a pharmaceutical composition comprising Rosuvastatin as active ingredient, comprising the steps of:
 a) preparing Rosuvastatin or pharmaceutically acceptable salts thereof according to the process according  claim 10 ,   b) admixing the thus prepared Rosuvastatin or pharmaceutically acceptable salt thereof with at least one pharmaceutically acceptable excipient.   
     
     
         20 . (canceled)