Process for the preparation of iopamidol

Abstract

The present invention discloses a process for the preparation of Iopamidol of formula (II) and comprising the following steps: a) reacting the Compound (I) wherein X is OR 2 or R 3 , and wherein R 2 and R 3 are a C 1 -C 6 linear or branched alkyl, C 3 -C 6 cycloalkyl, C 6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N-(S)-2-(acetyloxy)propanoyl derivative of Compound (II); c) alkaline hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b). The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.

1 . A method of X-rays contrast imaging a subject comprising administering Iopamidol to a subject and obtaining an X-rays contrast image of the subject, wherein Iopamidol is prepared according to a process comprising the following reaction: 
       
         
           
           
               
               
           
         
       
       wherein X is OR 2  or R 3 , and wherein R 2  and R 3  are a C 1 -C 6  linear or branched alkyl, C 3 -C 6  cycloalkyl, C 6  aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl;
 and comprising the following steps:
 a) reacting the Compound (I) with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the N-(S)-2-(acetyloxy)propanoyl derivative of Compound (I); 
 b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7 by adding water or a diluted alkaline solution, freeing the hydroxyls from the boron-containing protective groups, obtaining the acetyloxy derivative of Compound (II) and optional recovery of the boron derivative; 
 c) alkaline hydrolysis of the acetyloxy derivative of Compound (II) restoring the (S)-2-(hydroxy)propanoyl group to obtain Iopamidol (II). 
 
 
     
     
         2 . The method according to  claim 1 , wherein X is OR 2 . 
     
     
         3 . The method according to  claim 1 , wherein X is R 3 . 
     
     
         4 . The method according to  claim 1 , wherein said Compound of formula (I) is prepared starting from the Compound of formula (IV), according to the following reaction: 
       
         
           
           
               
               
           
         
       
       wherein X is OR 2  or R 3 , and wherein R 2  and R 3  are a C 1 -C 6  linear or branched alkyl, C 3 -C 6  cycloalkyl, C 6  aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl; and comprising:
 reacting the Compound of formula (IV) with one of a boric acid in an R 2 OH alcohol or a borate ester B(OR 2 ) 3 , wherein R 2  is as above defined, to provide the Compound of formula (I), wherein X is OR 2 ; or reacting the Compound of formula (IV) with one of a boronic acid R 3 —B(OH) 2 , or a boroxine of formula (III): 
 
       
         
           
           
               
               
           
         
         to provide the Compound of formula (I), wherein X is R 3 . 
       
     
     
         5 . The method according to  claim 4 , wherein the boronic acid is selected from the group consisting of: phenylboronic acid, tolylboronic acid and butylboronic acid or the boroxine (III) is selected from the group consisting of tri-phenylboroxine and tri-methylboroxine. 
     
     
         6 . The method according to  claim 4 , wherein said Compound of formula (IV) is prepared submitting to iodination the following Compound (V): 
       
         
           
           
               
               
           
         
       
     
     
         7 . The method according to  claim 6 , wherein said Compound (V) is prepared according to the following reaction scheme: 
       
         
           
           
               
               
           
         
         wherein:
 i) 5-nitroisophthalic acid is treated with an R 1 OH alcohol, wherein R 1  is a linear or branched C 1 -C 4 alkyl, to provide the corresponding diester; 
 ii) the 5-nitro group is reduced to the corresponding 5-amino group to provide the Compound (VII); 
 iii) the diester is reacted with 2-amino-1,3-propandiol to provide the Compound (V). 
 
       
     
     
         8 . The method according to  claim 1 , further comprising the purification and isolation of Iopamidol (II). 
     
     
         9 . The method according to  claim 8 , wherein said purification is to pharmaceutical grade.