Purification of bis-quaternary pyridinium oximes
Inventors
Blumberg, Shawn T. • MENCHACA, Antonio • Dorsey, Christopher • WATERMAN, Asa
Assignees
Southwest Research Institute SwRI
Publication Number
US-12054459-B2
Publication Date
2024-08-06
Expiration Date
2042-02-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Purification of bis-quaternary pyridinium oximes (BQPO) which may serve as organophosphorus nerve agent antidotes.
Core Innovation
The invention relates to methods for improving the relative purity of bis-quaternary pyridinium oximes (BQPOs), which are compounds that may serve as antidotes to organophosphorus nerve agents. The disclosed methods provide purification protocols that significantly increase BQPO purity, thereby making them more suitable for use as active pharmaceutical ingredients (APIs) in pharmaceutical compositions.
The problem addressed by the invention involves the limitations of previous synthetic and purification methods for BQPOs, which required extremely toxic chemical compounds and resulted in the formation of large amounts of difficult-to-remove side products. Existing production routes yielded BQPOs at acceptable reagent quality but left impurities that hindered their incorporation into pharmaceutical compositions requiring high purity.
The disclosed invention presents improved procedures for extracting, purifying, and manipulating BQPOs to achieve enhanced purity. The methods involve (1) extraction of BQPOs using alkyl phosphates (such as bis-(2-ethylhexyl) phosphate), (2) ion exchange reactions to substitute undesirable counterions with chloride, and (3) purification via column chromatography using organic alcohols and metal salts. These steps enable production of BQPOs with measured increases in relative purity (as determined by HPLC), rendering them suitable for final recrystallization steps and subsequent pharmaceutical use.
Claims Coverage
There are three independent inventive features described in the patent claims related to different purification protocols for bis-quaternary pyridinium oximes.
Purification of BQPOs via alkyl phosphate extraction and acid treatment
A method of improving the relative purity of bis-quaternary pyridinium oximes comprising: 1. Supplying a bis-quaternary pyridinium oxime of a specified structure where R1, R2, R3, and R4 may be hydrogen, alkyl, —CH=NOH or —CONH2, and X− is Cl−, Br−, I−, or −OSO2CH3. 2. Treating the bis-quaternary pyridinium oxime with an alkyl phosphate of formula Z2PO4 (where Z is an alkyl group), forming a corresponding BQPO phosphate salt. 3. Treating the BQPO phosphate salt with an acid HY (where Y is Cl, Br, I, or OSO2CH3) to recover a BQPO with improved purity and Y− as counterion. The process results in recovery of a BQPO salt of improved purity compared to the supplied material.
Purification of BQPOs using ion exchange and column chromatography with organic alcohol and metal salt
A method of improving the relative purity of bis-quaternary pyridinium oximes, comprising: 1. Supplying a bis-quaternary pyridinium oxime of specified structure with R1, R2, R3, R4 variably defined and X− as Br−, I− or −OSO2CH3. 2. Subjecting the BQPO to an ion exchange reaction to convert X− to Cl−. 3. Placing the resulting BQPO chloride in an organic alcohol containing a metal salt, and eluting through a silica chromatography column. 4. Recovering the BQPO (chloride counterion) in relatively purified form following chromatography. The method achieves improved purity of BQPOs using a combination of ion exchange and chromatographic separation.
Purification of BQPOs using column chromatography in organic alcohol with metal salt
A method of improving the relative purity of bis-quaternary pyridinium oximes, comprising: 1. Supplying a bis-quaternary pyridinium oxime of defined structure (R1, R2, R3, R4 as hydrogen, alkyl, —CH=NOH, or —CONH2). 2. Placing the BQPO in an organic alcohol containing a metal salt. 3. Eluting the sample through a chromatography column containing silica as the stationary phase. 4. Recovering the bis-quaternary pyridinium oxime in a relatively purified form from the column effluent. This method provides a chromatographic purification strategy for BQPOs employing specified solvent and salt conditions.
In summary, the inventive features cover three distinct purification methodologies for bis-quaternary pyridinium oximes: alkyl phosphate extraction with acid treatment, ion exchange followed by chromatographic purification with metal salt and organic alcohol, and direct chromatographic purification under similar conditions.
Stated Advantages
The invention enables bis-quaternary pyridinium oximes to be purified to levels suitable for use as active pharmaceutical ingredients, improving their suitability for incorporation into pharmaceutical compositions.
The improved purification protocols provide higher purity yields and support further recrystallization steps, allowing HPLC purity levels to be enhanced to greater than 95% or even up to 100%.
The methods offer high overall product yield in addition to improved purity, with yields reported in the range of 80% to 100% based on the initial impure material.
Documented Applications
Use of purified bis-quaternary pyridinium oximes as active pharmaceutical ingredients (APIs) in pharmaceutical compositions for treating poisoning by organophosphorus nerve agents.
Incorporation of BQPOs at high purity into oral drugs or parenteral formulations for pharmaceutical use as effective reactivators of organophosphorus nerve agent inhibited acetylcholinesterase.
Interested in licensing this patent?