Generation and Fate of Regioisomeric Side-Chain Impurities in the Preparation of Fosinopril Sodium
Citations Over Time
Abstract
A regioisomeric impurity is routinely formed during preparation of the first intermediate of the fosinopril sodium side chain. This first step, the radical-initiated condensation of 4-phenyl-1-butene (1) and aqueous hypophosphorous acid, provides low levels of the phosphinic acid (8) resulting from carbon−phosphorus bond formation to the internal olefin carbon. This impurity was isolated by preparative chromatography, and its structure was proven by independent synthesis. Subsequent reactions of 8 in the two following steps produce the corresponding regioisomeric impurities. Pure samples of these impurities were prepared for HPLC analysis to determine potential impact on the quality of intermediates downstream. The initial regioisomer averages 2 area % in manufacturing batches, and the levels of regioisomeric impurities diminish sharply with sequential conversion to further side-chain intermediates. After two steps, the levels of the regioisomeric impurities have been less than 0.08 area % in production batches; therefore, no significant amount of side-chain regioisomeric impurities (i.e., <0.1%) is expected to be found in production batches of fosinopril sodium side chain.
Related Papers
- → The simultaneous determination of vitamins A, E and β-carotene in bovine milk by high performance liquid chromatography–ion trap mass spectrometry (HPLC–MSn)(2012)63 cited
- Determination of linezolid in human serum by reversed-phase high-performance liquid chromatography with ultraviolet and diode array detection.(2013)
- Rapid determination of nitazoxanide in tablets using reversed-phase ultra-performance liquid chromatography (UPLC) and high-performance liquid chromatography.(2008)
- Determination of zinc pyrithione in shampoos by HPLC and HPLC-MS/MS.(2015)
- → ChemInform Abstract: Direct Formation of a Substituted (5.5.5.5)Fenestrane by Intramolecular Arene‐Olefin Photocycloaddition.(1989)