In 1999, Hélène Perrier and Marc Labelle [J. Org. Chem. 1999, 64 2110-2113 ] proposed using a 3-quinolinecarboxylate protecting group on a growing intermediate substrate to assist in isolating them at each step in a process by precipitating these substances as insoluble quinolinium salts.
The proposal seemed promising but at scale the cost of that protecting group inhibited adoption.
The KiloMentor blog has always aimed to promote and enhance methods that streamline isolation, purification, and workup procedures in synthetic organic chemistry.
In this particular instance, KiloMentor wishes to propose an inexpensive synthesis of a related 6-methyl-3-pyridinecarboxylic acid that might serve in the same way but that could be much cheaper to prepare.
The chemical literature already teaches the high-yield, simple, scalable synthesis of 2-methyl-5-aldehydo-4-pyridone in 75% isolated yield. [ F. Arya, J. Bouquant J. Chuche, Synthesis Communications 1983, 946-948 ] by continuous hot tube pyrolysis from the inexpensive inputs isopropyl amine, ethylformate and dimethylmalonate.
The conversion of this 2-methyl-5-aldehydo-4-pyridone to 6-methyl-pyridine-3-carboxylic acid has not, as far as I know, been reported; however, it would seem that it might be made simply by the addition of the compound gradually to strong aqueous alkali to oxidize the aldehyde, reduce the ketone (Cannizzaro like) and then dehydrate the ring to aromatize the moiety. The resultant amino acid should be easily separated because of its acid-base properties.
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