Chemical process for the preparation of intermediates to obtain n-formyl hydroxylamine compounds

Abstract

Improved processes for preparing intermediates useful for preparing antibacterial N-[1-oxo2-alkyl-3-(N-hydroxyformamido)-propyl}-(carbonylamino-aryl or -heteroaryl)-azacyclo4-7alkanes or thiazacyclo4-7alkanes, which have one or more of the following features: (1) make use of a particular I3-lactam intermediate; (2) which make use of a particular resolving agents, enantiomerically pure substituted propionic acids, especially (R)-2-butyl-3-hydroxypropionic acid; (3) which avoid the use of hydrogen peroxide; and (4) which facilitate selective debenzylation reducing production of waste by-products.

1 . A process comprising contacting the compound of formula (III) 
     
       
         
         
             
             
         
       
     
     with hydrogen in the presence of a chiral ligand and a catalytic amount of a hydrogenation catalyst in a suitable solvent and under conditions suitable to form a compound of the formula (IV) 
     
       
         
         
             
             
         
       
       wherein R is alkyl; 
       each of R 2 , R 3 , and R 10  independently is hydrogen or alkyl, or (R 2  or R 3 ) collectively form a C 4 -C 7 cycloalkyl 
       and Y is a hydroxyl protecting group. 
     
   
   
       2 . The process of  claim 1  wherein the chiral ligand is (2S,5S)-Me-Duphos, or (1R,1′R,2S,2′S)-TangPhos and the hydrogenation catalyst is a metal catalyst containing rhodium (Rh I) or ruthenium (Ru II). 
   
   
       3 . The process of  claim 2  wherein the temperature is about 10° C. to about 50° C., the solvent is dioxane, methylene chloride, dichloromethane, toluene, acetone, methylethylketone, THF, isopropyl acetate, DMF, or an alcohol, the hydrogen is in the form of hydrogen gas, the pressure is about 40 psi to about 100 psi, the amount of chiral ligand is about 1 mole % to about 15 mole % relative to the substrate, the hydrogenation catalyst is bis(norbornadiene)rhodium(I) tetrafluoroborate, and the amount of catalyst is about 1 mole % to about 5 mole % relative to the substrate. 
   
   
       4 . The process of  claim 1  wherein R is methyl; R 10  is n-propyl, and each of R 2 , and R 3 , is hydrogen. 
   
   
       5 . A process comprising contacting a compound of the formula (III) 
     
       
         
         
             
             
         
       
     
     with hydrogen in the presence of (2R,5R)-Me-Duphos or (1S,1′S,2R,2′R)-TangPhos and a catalytic amount of a hydrogenation catalyst in a suitable solvent and under conditions suitable to form a compound of the formula (IV′) 
     
       
         
         
             
             
         
       
       wherein R is alkyl; 
       R 10  is hydrogen or alkyl 
       and Y is a hydroxyl protecting group. 
     
   
   
       6 - 35 . (canceled) 
   
   
       36 . The process of  claim 1  wherein the compound of the formula (III) is 2-[[(Phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester. 
   
   
       37 . The process of  claim 1  wherein the compound of the formula (IV) is 2-[[(Phenylmethoxy)amino]methyl]-(2R)-hexanoic acid methyl ester. 
   
   
       38 . The process of  claim 5  wherein R is methyl and R 10  is n-propyl. 
   
   
       39 . The process of  claim 5  wherein the compound of the formula (III) is 2-[[(Phenylmethoxy)amino]methyl]-2-hexenoic acid methyl ester. 
   
   
       40 . The process of  claim 5  wherein the compound of the formula (IV′) is 2-[[(Phenylmethoxy)amino]methyl]-(2S)-hexanoic acid methyl ester.