Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts

Abstract

A halide salt of a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane is prepared by adding a pyridinealdoxime to a bis-halomethylether in such a manner that the bis-halomethylether is maintained in excess throughout the addition. This procedure produces the halide salt of a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane in high yield and purity, which facilitates its use as an intermediate in the manufacture of an asymmetrically substituted 1,3-di(1-pyridino)-2-oxapropane, a class of compounds that are generally useful antidotes to various toxic agents. A prominent member of the class is the dimethylsulfonate salt of 1-(2-hydroxyiminomethyl-1-pyridino)-3-(4-carbamoyl-1-pyridino)-2-oxapropane. The use of mercaptoalkyl-functionalized polymers is disclosed as a preferred metal ion scavenger for a final purification step in the manufacture of these compounds.

1 . A process for the purification of a dimethanesulfonate salt of a 1,3-di-(1-pyridino)-2-oxapropane from a product mixture that is the result of an ion exchange reaction of a halide salt of said 1,3-di-(1-pyridino)-2-oxapropane with a metallic methanesulfonate, said process comprising contacting a liquid solution of said product mixture with a water-insoluble mercaptoalkyl-functionalized polymer. 
     
     
         2 . The process of  claim 1  wherein said metallic methanesulfonate is silver methanesulfonate. 
     
     
         3 . The process of  claim 1  wherein said mercaptoalkyl-functionalized polymer is a mercapto-(C 1 -C 5  alkyl)-functionalized silica gel or a mercapto-(C 1 -C 5  alkyl)-functionalized polyalkyl fiber. 
     
     
         4 . The process of  claim 1  wherein said mercaptoalkyl-functionalized polymer is a mercapto-(C 2 -C 4  alkyl)-functionalized silica gel or a mercapto-(C 1 -C 5  alkyl)-functionalized polyalkyl fiber. 
     
     
         5 . The process of  claim 1  wherein said mercaptoalkyl-functionalized polymer is a mercaptopropyl-functionalized silica gel. 
     
     
         6 . The process of  claim 1  wherein said 1,3-di-(1-pyridino)-2-oxapropane is a substituted 1,3-di-(1-pyridino)-2-oxapropane. 
     
     
         7 . The process of  claim 1  wherein said 1,3-di-(1-pyridino)-2-oxapropane is an asymmetrically substituted 1,3-di-(1-pyridino)-2-oxapropane. 
     
     
         8 . The process of  claim 1  wherein said 1,3-di-(1-pyridino)-2-oxapropane is substituted with at least one substituent on a pyridino group, and at least one of said substituents is 1-hydroxyiminomethyl. 
     
     
         9 . The process of  claim 1  wherein said 1,3-di-(1-pyridino)-2-oxapropane is of the formula 
       
         
           
           
               
               
           
         
       
       wherein R 1  is —CH═NOH, R 2  is a member selected from the group consisting of H, lower alkyl, —C(O)—O-(lower alkyl), —C(O)—NH 2 , and —CH═NOH, and R 3  and R 4  are members independently selected from the group consisting of H, lower alkyl, —C(O)—O-(lower alkyl), —C(O)—NH 2 , and —CH═NOH. 
     
     
         10 . The process of  claim 9  wherein said metallic methanesulfonate is silver methanesulfonate and R 1  is —CH═NOH, R 2  is H, R 3  is —C(O)—NH 2 , and R 4  is H. 
     
     
         11 . The process of  claim 9  wherein said metallic methanesulfonate is silver methanesulfonate and R 1  is 2-CH═NOH, R 2  is H, R 3  is 4-C(O)—NH 2 , and R 4  is H.