Process for the preparation of oxazolidinones and method of use thereof

Abstract

A process for preparing N-(substituted)-C-(substituted methyl)-oxazolidinones, C-(substituted methyl)-oxazolidinones, and N-(substituted)-C-(substituted methyl)-oxazolidinones, preferably chiral, from optically active C-(protected oxymethyl)-oxazolidinones is described. The process can be used to produce combinatorial libraries of the above substituted oxazolidinones in a two or three step reaction comprising a plurality of reagents differing in numbers of carbons or particular substituted oxazolidinones. A number of substituted oxazolidinones produced using the above process have been discovered to have antimicrobial activity.

1 . A process for producing a library of substituted oxazolidinones which comprises: 
 (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I); and    (b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group and replaces it with another group from the second reagent to produce the library of substituted oxazolidinones.    
     
     
         2 . The process of  claim 1  wherein the second reagent is a reducing agent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone to provide a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II) as the library of substituted oxazolidinones.  
     
     
         3 . The process of  claim 2  wherein the mixture of (II) is further reacted with a third reagent containing a plurality of compounds reactive with the hydroxymethyl in an anhydrous organic solvent to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones.  
     
     
         4 . The process of  claim 3  wherein the anhydrous organic solvent further includes pyridine.  
     
     
         5 . The process of  claim 3  wherein the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones.  
     
     
         6 . The process of  claim 3  wherein the third reagent produces a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.  
     
     
         7 . The process of  claim 1  wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.  
     
     
         8 . The process of  claim 1 ,  2 , or  3  wherein the substituted oxazolidinones in the library are separated chromatographically.  
     
     
         9 . The process of  claim 1 ,  2 , or  3  wherein the substituted oxazolidinones in the library are separated chromatographically and then the separated substituted oxazolidinones are each screened for biological activity.  
     
     
         10 . The process of  claim 1  wherein the protecting group is a trityl group.  
     
     
         11 . The process of  claim 1  wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.  
     
     
         12 . The process of  claim 11  wherein the alkali is an ionic hydride.  
     
     
         13 . The process of  claim 12  wherein the ionic hydride is sodium hydride.  
     
     
         14 . The process of  claim 1  wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.  
     
     
         15 . The process of  claim 14  wherein the palladium catalyst is Pd(OAc) 2 .  
     
     
         16 . The process of  claim 1  wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I) produced in step (a) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent and the substituted oxazolidinones produced in step (b) are purified by removing the solvent.  
     
     
         17 . The process of  claim 2  wherein the N-(substituted)-C-hydroxymethyl-oxazolidinones (II) are purified by removing the solvent.  
     
     
         18 . The process of  claim 3  wherein the N-(substituted)-C-(substituted methyl)-oxazolidinones (III) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.  
     
     
         19 . A process for producing a library of substituted oxazolidinones which comprises: 
 (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a plurality of compounds having different numbers of carbons which are reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce a mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I);    (b) reacting the mixture of (I) produced in step (a) in an aqueous organic solvent with a second reagent which removes the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinones to produce a mixture of N-(substituted)-C-hydroxymethyl-oxazolidinones (II); and    (c) reacting the mixture of (II) produced in step (b) in an anhydrous organic solvent with a third reagent containing a plurality of compounds reactive with the hydroxymethyl of the mixture of (II) to produce a mixture of N-(substituted)-C-(substituted methyl)-oxazolidinones (III) as the library of substituted oxazolidinones.    
     
     
         20 . The process of  claim 19  wherein the anhydrous organic solvent in step (c) further includes pyridine.  
     
     
         21 . The process of  claim 19  wherein the third reagent produces a mixture of 3-(substituted)-5-(substituted methyl)-2-oxazolidinones.  
     
     
         22 . The process of  claim 19  wherein the third reagent produces a mixture of 3-(substituted)-4-(substituted methyl)-2-oxazolidinones.  
     
     
         23 . The process of  claim 19  wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.  
     
     
         24 . The process of  claim 19 ,  21 , or  22  wherein the substituted oxazolidinones in the library are separated chromatographically.  
     
     
         25 . The process of  claim 19  wherein the protecting group is a trityl group.  
     
     
         26 . The process of  claim 19  wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.  
     
     
         27 . The process of  claim 26  wherein the alkali is an ionic hydride.  
     
     
         28 . The process of  claim 27  wherein the ionic hydride is sodium hydride.  
     
     
         29 . The process of  claim 19  wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.  
     
     
         30 . The process of  claim 29  wherein the palladium catalyst is Pd(OAc) 2 .  
     
     
         31 . The process of  claim 19  wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinones (I) produced in step (a) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.  
     
     
         32 . The process of  claim 19  wherein the N-(substituted)-C-hydroxymethyl-oxazolidinones (II) produced in step (b) are purified by removing the solvent.  
     
     
         33 . The process of  claim 19  wherein the N-(substituted)-C-(substituted methyl)-oxazolidinones (III) produced in step (c) are purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.  
     
     
         34 . A process for preparing a library of substituted oxazolidinones which comprises: 
 reacting a C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent including pyridine with a reagent containing a plurality of compounds reactive with the hydroxy group to produce a mixture of substituted oxazolidinones as the library of substituted oxazolidinones.    
     
     
         35 . The process of  claim 34  wherein the reaction produces a mixture of 5-(substituted methyl)-2-oxazolidinones.  
     
     
         36 . The process of  claim 34  wherein the reaction produces a mixture of 4-(substituted methyl)-2-oxazolidinones.  
     
     
         37 . The process of  claim 34  wherein the reaction produces a mixture of N-(substituted)-C-(hydroxymethyl)-2-oxazolidinones.  
     
     
         38 . The process of  claim 34  wherein the reaction produces a mixture of N-(substituted)-C-(substituted methyl)-2-oxazolidinones.  
     
     
         39 . The process of  claim 34  wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.  
     
     
         40 . The process of  claim 34 ,  35 ,  36 ,  37 , or  38  wherein the substituted oxazolidinones in the library are separated chromatographically.  
     
     
         41 - 53 . (canceled)  
     
     
         54 . A process for producing a substituted oxazolidinone which comprises: 
 (a) reacting a C-(protected oxymethyl)-oxazolidinone in an anhydrous organic solvent containing a first reagent including a compound which is reactive with N in the C-(protected oxymethyl)-oxazolidinone under alkylation or Buchwald conditions in an inert atmosphere to produce an N-(substituted)-C-(protected oxymethyl)-oxazolidinone;    (b) reacting the N-(substituted)-C-(protected oxymethyl)-oxazolidinone in an aqueous organic solvent with a second reagent with a second reagent which replaces the protecting group of the N-(substituted)-C-(protected oxymethyl)-oxazolidinone with a hydrogen to produce an N-(substituted)-C-hydroxymethyl-oxazolidinone; and    (c) reacting the N-(substituted)-C-hydroxymethyl-oxazolidinone in an anhydrous organic solvent with a third reagent containing a compound reactive with the hydroxy group to produce N-(substituted)-C-(substituted methyl)-oxazolidinones as the substituted oxazolidinone.    
     
     
         55 . The process of  claim 54  wherein the anhydrous organic solvent in step (c) further includes pyridine.  
     
     
         56 . The process of  claim 54  wherein substituted is selected from the group consisting of acyl, alkyl, aryl, aryl sulfonyl, heteroalkyl, heteroaryl, cycle, heterocycle, thio, and mixtures thereof.  
     
     
         57 . The process of  claim 54  wherein the protecting group is a trityl group.  
     
     
         58 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of hydrogen, acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, phenacyl, aryl sulfonyl, thio, and mixture thereof, or a hydrogen; R 2  is selected from the group consisting of acyl, alkyl, aryl, heteroalkyl, heteroaryl, heterocycle, aryl sulfonyl, phenacyl, thio, and mixture thereof, or a hydrogen, wherein hetero is an atom selected from the group consisting of O, N, P, and S; and y is a heteroatom selected from the group consisting of O, N, and S.  
     
     
         59 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R 2  is selected from the group consisting of alkyl, acyl, aryl, and thio.  
     
     
         60 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl sulfonyl, aryl sulfonyl, alkyl, acyl, aryl, and thio and R 2  is selected from the group consisting of alkyl, acyl, aryl, and thio.  
     
     
         61 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, acyl, thio, and aryl, R 2  is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO 2 , Cl, alkyl, and aryl.  
     
     
         62 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, acyl, thio, and aryl, R 2  is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO 2 , Cl, alkyl, and aryl.  
     
     
         63 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, R2 is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle, and X is selected from the group consisting of F, NO 2 , Cl, alkyl, and aryl.  
     
     
         64 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, aryl, acyl, thio, or heterocycle, R 2  is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers, and X is selected from the group consisting of F, NO 2 , Cl, alkyl, and aryl.  
     
     
         65 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of alkyl, aryl, acyl, thio, and heterocycle and R 2  is selected from the group consisting of C-3, C-4, and C-5 chiral synthons with 1, 2, or 3 chiral centers.  
     
     
         66 . The process of  claim 54  wherein the substituted oxazolidinone has the formula  
       
         
           
           
               
               
           
         
       
       wherein R 1  is selected from the group consisting of 5 alkyl, aryl, acyl, thio, and heterocycle and R 2  is selected from the group consisting of C-3, C-4, with C-5 chiral synthons with 1, 2, or 3 chiral centers.  
     
     
         67 . The process of  claim 54  wherein under the alkylation conditions in step (a) the anhydrous organic solvent further includes an alkali without substantial reducing activity.  
     
     
         68 . The process of  claim 67  wherein the alkali is an ionic hydride.  
     
     
         69 . The process of  claim 68  wherein the ionic hydride is sodium hydride.  
     
     
         70 . The process of  claim 54  wherein under the Buchwald conditions in step (a) the anhydrous organic solvent further includes a palladium catalyst.  
     
     
         71 . The process of  claim 70  wherein the palladium catalyst is Pd(OAc) 2 .  
     
     
         72 . The process of  claim 54  wherein the mixture of N-(substituted)-C-(protected oxymethyl)-oxazolidinone produced in step (a) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.  
     
     
         73 . The process of  claim 54  wherein the N-(substituted)-C-hydroxymethyl-oxazolidinone produced in step (b) is purified by removing the solvent.  
     
     
         74 . The process of  claim 54  wherein the N-(substituted)-C-(substituted methyl)-oxazolidinone produced in step (c) is purified by extracting the reaction mixture with the organic solvent, drying over a drying agent, and then removing the solvent.  
     
     
         75 - 84 . (canceled)