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.
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