Ainley-King-Sargent synthesis

What is Ainley-King-Sargent synthesis?

The Ainley-King-Sargent synthesis, also known as the Ainley-King synthesis, was initially reported by Ruzicka et al. in 1924 and was subsequently extended by Ainley and King in 1935.

This multistep synthesis involves the production of α-piperidyl-4-quinolinemethanols (or quinolyl-4-α-piperidylcarbinols) by undergoing several reactions.

Ainley-King-Sargent synthesis - general reaction scheme - Ainley-King synthesis
Ainley-King-Sargent synthesis (cont.)
Ainley-King-Sargent synthesis - general reaction scheme - Ainley-King synthesis
Ainley-King-Sargent synthesis

These reactions include the amidation of p-anisidine by an acetoacetic ester, electrophilic cyclization to form 2-hydroxy-lepidine, replacement of the 2-hydroxyl group by a chlorine atom, Pd/C catalyzed hydrogenation in AcOH to remove the chlorine, condensation with benzaldehyde followed by oxidation to produce 4-quininic acid in 50 % pyridine, esterification of the 4-quininic acid, Claisen-Geuther ester condensation of ethyl quininate with ethyl ε-benzamidocaproate, hydrolysis of the ester and β-decarboxylation, α-bromination and cyclization, and reduction of the carbonyl group to a secondary hydroxyl group via hydrogenation.

This synthesis played a crucial role in producing large quantities of quinine for antimalarial treatment during World War II and is commonly known as the Ainley and King synthesis. The reaction has been modified by various researchers, particularly by Sargent in 1946, and is now often referred to as the Ainley-King-Sargent synthesis. The Claisen-Geuther ester condensation was optimized to 64 % by substituting sodium ethoxide with sodium or sodium amide. Additionally, the cyclization process to form the piperidinyl ring is now conducted in a two-phase solvent system (H2O and ether) using sodium carbonate as the base.

Several modifications were made to this reaction in subsequent studies. For example, lepidine can be easily isolated by carrying out the preparation of lepidine at the stage of dehalogenation in warm alcoholic KOH in the presence of Raney nickel, or by using zinc and acetic acid. Moreover, it was found that the formation of quininic acid via oxidation in acetone was superior to that in 50 % pyridine due to the easier isolation of the product.

In the 1940s, this reaction served as a fundamental plan for the manufacturing of quinine, which was extensively utilized for the cure of malaria.