Patent Watch

May 7, 2012

Make a nerve agent antidote without using a toxic reagent. Dipyridinium aldoxime salts commonly called HI-6 are antidotes for poisoning by organophosphate nerve agents. The synthesis of the dichloride salt asoxime chloride uses highly toxic, carcinogenic (ClCH2)2O. Other salts of HI-6 (e.g., the bismethanesulfonate [bismesylate] salt 1) are also effective, but some routes for preparing them also use (ClCH2)2O.

J. Eddolls, P. McCormack, and A. Hodgson disclose a route to the bismesylate salt of 1, outlined in Figure 1, that does not require (ClCH2)2O. The process starts with the reaction of O-protected aldoxime 2 with the ether 3 to give mesylate salt 4. This product is not isolated, but it is treated with amide 5 in the presence of excess 3 to form bismesylate salt 6. This salt is deprotected with EtOH to give 95% pure (HPLC) HI-6 salt 1, recovered in 53% yield based on 2. Recrystallization from aq EtOH gives the desired product in 78% yield and >99% HPLC purity. An important aspect of the process is choosing an ether such as 3 that will provide the anion for pyridinium salts 4 and 6.

The inventors discuss alternative means for protecting the oxygen atom in pyridine aldoxime 2 before quaternization. When more readily removable groups such as benzoyl are used, the quaternization reaction destroys the oxime function via β-elimination. When the oxygen is protected as an acetate, β-elimination does not occur to any appreciable extent.

An additional advantage of using the acetyl protective group is that impurities can be easily removed. Byproduct 7 can be formed when the starting material is free aldoxime 8 (Figure 2) if an excess of amide 5 is present. Impurity 7 is difficult to remove because its solubility is similar to that of 1. When protected aldoxime 2 is used, the solubility difference between 7 and 6 makes 7 easy to remove.

The reactions in Figure 1 take place in one pot without isolating any intermediates. A 1992 patent, US 5,130,438, describes a route in which the first step in Figure 1 is the reaction of 3 with unprotected oxime 8. This gives low yields and high levels of impurity 7. The inventors of the current patent state that at one point in the workup of the earlier method, a tarlike paste is produced that would be difficult to handle on a manufacturing scale. Hence, it is advantageous to use the protected oxime in this reaction.

Aldoxime 2 is prepared from 8 by treating it with Ac2O in the presence of Et3N and 4-dimethylaminopyridine (DMAP) (Figure 2). The product is isolated in 91% yield as a pale yellow oil that solidifies over time.

The inventors prepared other protected aldoximes, including the ethyl and triethoxysilyl ethers. Basic 1H and 13C NMR data are given for 1 and all of the protected aldoximes. (Phoenix Chemicals [Bromborough, UK]. US Patent 8,143,406, March 27, 2012; Keith Turner)

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