Method for producing 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide

Abstract

The invention relates to a method for producing 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide starting from 5-chlorothiophene-2-carbonyl chloride, (2S)-3-amino-propane-1,2-diol and 4-(4-aminophenyl)-3-morpholinone.

1 . A process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of the formula (I)  
       
         
           
           
               
               
           
         
         comprising  
         preparing 5-chlorothiophene-2-carbonyl chloride (IV) in a first step by chlorinating 5-chlorothiophene-2-carboxylic acid;  
         reacting said 5-chlorothiophene-2-carbonyl chloride (IV) in a second step with (2S)-3-aminopropane-1,2-diol hydrochloride (VII) to give N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII);  
         converting said N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) in a third step to N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX);  
         converting said N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) in a fourth step by reacting with 4-(4-aminophenyl)-3-morpholinone (III) to N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X);  
         reacting said N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) in a fifth step with phosgene or a phosgene equivalent.  
       
     
     
         2 . A process for preparing N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII), comprising reacting 5-chlorothiophene-2-carbonyl chloride (IV) with (2S)-3-aminopropane-1,2-diol hydrochloride (VII).  
     
     
         3 . A process for preparing N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX), comprising reacting N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) with hydrobromic acid in acetic acid.  
     
     
         4 . A process for preparing N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X), comprising reacting N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) with 4-(4-aminophenyl)-3-morpholinone (III).  
     
     
         5 . A process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of the formula (I), comprising reacting N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) with phosgene or a phosgene equivalent.  
     
     
         6 . The process as claimed in  claim 5 , characterized in that the phosgene equivalent is N,N-carbonyldiimidazole.  
     
     
         7 . The process as claimed in  claim 6 , characterized in that from 1.1 to 1.3 equivalents of N,N-carbonyldiimidazole are used.  
     
     
         8 . The process of  claim 5 , wherein the reaction takes place in a solvent mixture of 1-methyl-2-pyrrolidone and toluene.  
     
     
         9 . The process of  claim 5 , further comprising preparing said N—{(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide (X) by reacting N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) with 4-(4-aminophenyl)-3-morpholinone (III).  
     
     
         10 . The process of  claim 9 , further comprising preparing the N—((S)-3-bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide (IX) by reacting N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII)  with hydrobromic acid in acetic acid.  
     
     
         11 . The process of  claim 10 , further comprising preparing said N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) by reacting 5-chlorothiophene-2-carbonyl chloride (IV) with (2S)-3-aminopropane-1,2-diol hydrochloride (VII).  
     
     
         12 . N—{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide of the formula (X)  
       
         
           
           
               
               
           
         
       
     
     
         13 . N—((S)-3-Bromo-2-hydroxypropyl)-5-chlorothiophene-2-carboxamide of the formula (IX)  
       
         
           
           
               
               
           
         
       
     
     
         14 . The process of  claim 3  or  10 , wherein N—((S)-2,3-dihydroxypropyl)-5-chlorothiophene-2-carboxamide (VIII) is reacted with hydrobromic acid in acetic acid in the presence of acetic anhydride.  
     
     
         15 . N—{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide of the formula (X)  
       
         
           
           
               
               
           
         
         produced in accordance with the process of  claim 4 .  
       
     
     
         16 . A composition consisting essentially of N—{(R)-2-Hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]propyl}-5-chlorothiophene-2-carboxamide of the formula (X)