Process for halomethyl ethers of hydroxyiminomethyl quaternary pyridinium salts
View Patent ↗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.