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-oxapropanein 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 manufacture of a halide salt of a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, said process comprising adding a pyridinealdoxime having the formula 
                 
 wherein R 1  is CH═NOH and 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, to a bis-halomethyl ether in liquid form at ambient temperature or at a temperature within the range of about  30 ° C. to about  100 ° C. and at a rate such that said bis-halomethyl ether remains in stoichiometric excess relative to said pyridinealdoxime during at least 75% of said addition, to yield a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, halide salt, of the formula 
                 
 
 wherein X is a halogen atom.  
 
     
     
       2. A process for the manufacture of a halide salt of an asymmetrically substituted 1,3-di-(1-pyridino)-2-oxapropane, said process comprising:
 (a) adding a pyridinealdoxime having the formula 
                 
 
 wherein R 1  is CH═NOH and R 2  a member selected from the group consisting of H, lower alkyl, —C(O)—O-(lower alkyl), —C(O)—NH 2 , and —CH═NOH, to a bis-halomethyl ether in liquid form at ambient temperature or at a temperature within the range of about  30 ° C. to about  100 ° C. and at a rate such that said bis-halomethyl ether remains in molar excess relative to said pyridinealdoxime during at least 75% of said addition, to yield a 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, halide salt, of the formula 
                 
 
 wherein X is a halogen atom, and  
 (b) reacting said 1-(hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, halide salt, with a substituted pyridine of the formula 
                 
 
 wherein 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, and R 3  and R 4  are not both identical to R 1  and R 2 , to yield a halide salt of an asymmetrical 1-(hydroxyiminomethyl-1-pyridino)-3-(1-pyridino)-2-oxapropane having the formula 
                 
 
 
     
     
       3. A process for the manufacture of a salt of an asymmetrically substituted 1,3-di-(1-pyridino)-2-oxapropane having the formula 
                 
 wherein R 1  is —CH═NOH, R 2  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, in which the anion Y of said salt is a pharmaceutically acceptable anion other than a halide ion, said process comprising converting a halide salt of said asymmetrically substituted 1,3-di-(1-pyridino)-2-oxapropane by ion exchange between said halide salt and a salt of said pharmaceutically acceptable anion.  
 
     
     
       4. The process of claims  1 ,  2  or  3  wherein said pyridinealdoxime has the formula 
                 
 
     
     
       5. The process of claims  1 ,  2  or  3  wherein said pyridinealdoxime has the formula 
                 
 
     
     
       6. The process of claims  1 ,  2  or  3  wherein said pyridinealdoxime has the formula 
                 
 
     
     
       7. The process of claims  2  or  3  wherein said substituted pyridine has the formula 
                 
 wherein R 3  is other than H.  
 
     
     
       8. The process of claims  2  or  3  wherein said substituted pyridine has the formula 
                 
 wherein R 3  is other than H.  
 
     
     
       9. The process of claims  2  or  3  wherein said substituted pyridine has the formula 
                 
 
     
     
       10. The process of claims  2  or  3  wherein said substituted pyridine has the formula 
                 
 
     
     
       11. The process of claims  2  or  3  wherein said pyridinealdoxime has the formula 
                 
 wherein R 3  is other than H, and said substituted pyridine has the formula 
                 
 
 
     
     
       12. The process of  claim 3  in which said pharmaceutically acceptable anion is a hydrocarbylsulfonate or halohydrocarbylsulfonate ion of the formula R 5 SO 3 — wherein R 5  is a member selected from the group consisting of aliphatic, haloaliphatic, cycloaliphatic, halocycloaliphatic, aromatic, and haloaromatic. 
     
     
       13. The process of  claim 12  wherein R 5  is a member selected from the group consisting of C 1 -C 4  alkyl, halo-C 1 -C 4  alkyl, cyclohexyl, and phenyl. 
     
     
       14. The process of  claim 12  wherein R 5  is C 1 -C 4  alkyl. 
     
     
       15. The process of  claim 12  wherein R 5  is methyl. 
     
     
       16. The process of  claim 1  wherein X is Br or Cl. 
     
     
       17. The process of  claim 1  wherein X is Cl. 
     
     
       18. The process of claims  2  or  3  wherein said reaction between said 1-(2-hydroxyiminomethyl-1-pyridino)-3-(halomethyl)-2-oxapropane, halide salt, and said substituted pyridine is performed in a solvent selected from the group consisting of a tetrahalomethane, dimethylformamide, dimethylsulfoxide, a trihalomethane, a dihalomethane, N,N-dimethylacetamide, 1-methyl-2-pyrrolidone, acetonitrile, dioxane, tetrahydrofuran, and 2-methyltetrahydrofuran. 
     
     
       19. The process of  claim 1  wherein said bis-halomethyl ether remains in molar excess relative to said 2 pyridinealdoxime during at least 90% of said addition. 
     
     
       20. The process of  claim 1  wherein said 2-pyridinealdoxime is added in dropwise manner to said bis-halomethyl ether during agitation of said bis-halomethyl ether. 
     
     
       21. The process of  claim 1  comprising adding said pyridinealdoxime to said bis- halomethyl ether at a temperature within the range of about  30 ° C. to about  100 ° C.   
     
     
       22. The process of  claim 1  comprising adding said pyridinealdoxime to said bis- halomethyl ether at a temperature within the range of about  35 ° C. to about  60 ° C.