An ANTIMALARIAL ALKALOID FROM HYDRANGEA. IX. SYNTHESIS OF 3-[Β-Keto-Γ-(4-Hydroxy-2-Piperidyl)propyl]-4-Quinazolone, AN ISOMER

Abstract

One of the structures considered highly possible for the Hydrangea alkaloid was 3-[0-keto-7-(4-hydroxy-2-piperidyl) propyl]-4-quinazolone (XXVI) (1). At-tempts to synthesize this compound via the diketone approach were described in the preceding paper (2). The second type of approach used for these compounds involved 2-piperidineacetic acid as the key intermediate (3). This approach has been found feasible through 4-methoxy-2-piperidineacetic acid.Of the methods in the literature for preparation of 4-piperidols, the Dieckmann cyclization approach (4,5) appeared attractive. The requisite amino triester (IV) was obtained by the reductive amination of ethyl acetonedicarboxylate (I) with 0-alanine ester (II) in 40-45% yield or by addition of 0-alanine ester (II) to methyl glutaconate (III). Benzoylation to V followed by Dieckmann cyclization gave only 38-40% yields of the keto esters, VI and VII. Decarbalkoxylation was accompanied by debenzoylation under acid conditions (4), the benzoyl acid, VIII, being isolated in 8-12% yield after rebenzoylation. Hydrogenation of the carbonyl group at 120°in alkaline solution in the presence of a nickel catalyst gave a mixture of oily 4-piperidol isomers, IX. Acetylation and conversion to the acid chloride, X, allowed isolation of one of the isomers in crystalline form.Treatment of the crystalline isomer or the mixed isomers with diazomethane, then with hydrogen bromide gave a negligible yield of bromo ketone, XI. Sufficient material could not be obtained for studying this last reaction due to the consecutive low yields and the fact that larger scale preparation of IV from I gave greatly diminished yields. In some larger runs no triester, IV, could be isolated. The poor conversion of X to XI was subsequently found to be due to the benzoyl blocking group and probably could have been overcome by choice of a different N-blocking group. This point will be discussed later.The piperidine-2-acetic acids (XX) were then synthesized by a modification of the well known -aminoketone cyclization (6-8) followed by hydrogenation. The 5-carbobenzoxyaminovaleric acids (XII) (2) were converted to the ketomalonates, XIV, via the acid chlorides, XIII.The conversion of the ketomalonates (XIV) to the piperidine-2-acetic acids (XX) involved two variables, first, the new modification of the amino ketone ring closure by hydrogenolysis of the carbobenzoxy group, ring closure, and reduction to XVII and, secondly, the influence of the methoxy group (R = CH30) on this method. In order to eliminate the second variable and study only the reductive cyclization reaction, the series R = H was investigated since the intermediate XVIIa should be convertable to 1 -benzoyl-2-piperidineacetic acid (XXIIIa), a compound characterized in an earlier publication (3).

An ANTIMALARIAL ALKALOID FROM HYDRANGEA. VIII. ATTEMPTED SYNTHESIS OF 3-[Β-Keto-Γ-(4-Hydroxy-2-Piperidyl)propyl]-4-Quinazolone BY THE DIKETONE APPROACH

“…The anilide was obtained in 53% yield, m.p. 101-103°, via the unstable acid chloride (8). Recrystallization from benzene gave white crystals, m.p.…”

“…When XXVI was converted to the ketal then treated with one mole of hydrazine, no phthalhydrazide could be isolated, but a hydrazone was obtained. Treatment with a second mole of hydrazine then removed the 0 il 0 0 Work on this diketone approach was postponed when a subsequent method was found satisfactory (8).…”

An Antimalarial Alkaloid From Hydrangea. Iii. Degradation

“…The stability of the compound to acid and the lack of formation of formaldehyde on periodate oxidation indicated the alkaloid was most probably 3-[/3keto--(3or 4-hydroxy-2-piperidyl)propyl]-4-quinazolone or 3-[/3-keto-y-(3-or 4-hydroxymethyl)-2-pyrrolidyl)propyl]-4-quinazolone. The correctness of this postulate was demonstrated when Baker and associates synthesized these compounds (4,5,6) and proved the hydrangea alkaloid to be 3…”

A Novel Synthesis of the Efficient Anti-Coccidial Drug Halofuginone Hydrobromide

“…The preparation of piperidine analogues was the most expensive part, and deemed to be the real difficulty to produce halofuginone as well. So far, a lot of methods have been reported: The method illustrated in Scheme 3 was originally developed by Baker’s team [ 18 , 22 , 23 , 24 , 25 , 26 ]. Afterwards, the method was optimized a bit by Barringer et al, via changing reagents and catalyst, which successfully improved the yield by reducing the number of steps but without lowering the cost.…”