Thoughts

The structure of the parent ring system settled by H. Antaki and V. Petrow, 1951 characterised by ultraviolet spectroscopy, 1958–1962 — now the core of marketed medicines The Question and the Era This article reconstructs, from original documents, an obscure but consequential sequence in the history of a valuable scaffold. Its purpose is not to claim priority beyond what the evidence supports, but to preserve a precise account: what was corrected, how the correction was proved, how the work expanded into a general chemistry of condensed pyrimidines, and where that chemistry stands today. The events belong to a period of structural chemistry now difficult to reconstruct fairly. Questions that can often be approached today by combining nuclear magnetic resonance, mass spectrometry, crystallography, and computation had to be answered by chemical behaviour, degradation, analogy, electronic reasoning, and independent synthesis. It would therefore be misleading to judge the difficulty of the problem retrospectively, using instruments and concepts that were not available to those who faced it. The importance of an early structural determination does not lie merely in whether its conclusion appears simple after the fact. The achievement was to find the reasoning by which the structure could be understood within the knowledge and tools of the time. The question is not how quickly the structure might be assigned in a modern laboratory, but how Antaki identified the decisive uncertainty and devised a way to resolve it under the conditions of 1950. The Road (1950) The compound at the centre of the question had been prepared early in the century, and by 1950 its structure had been approached and re-approached for nearly four decades. In his doctoral thesis, Contributions to the Chemistry of Heterocyclic Compounds (University of London, 1950), H. Antaki set out that long history in full — and then identified the question within it that remained unanswered. He gave each earlier worker their due. The ring skeleton had been established; Seide, he noted, had fixed it by oxidative degradation, and Antaki marshalled the further evidence that confirmed it. What no method had yet settled was a different and finer question: the position of the carbonyl group within that skeleton. The standard tool of the day — oxidative degradation — could establish the skeleton but was, by its nature, blind to this. That was the open question, and Antaki saw it precisely. What the thesis added was an explanation of why the ring formed as it did. The closure to one skeleton rather than its isomer, Antaki argued, “receives a ready explanation on the basis of current electronic theory. The electronegativity of the nitrogen atom is known to be greater than that of carbon.” An electron-releasing group at the appropriate position, he continued, “leads to an increase in the electron density on the nuclear nitrogen. Prototropic rearrangement follows,” directing the closure to the observed product. This was not assignment by analogy or by elimination. It was an argument from electronic structure for why the molecule had to be what it was — the reasoning of a chemist who understood the system from its principles, not merely its products. The Correction (1951) The following year, the work was published — with V. Petrow — in the Journal of the Chemical Society. The paper addressed a question the available methods had been unable to settle: not the ring skeleton, which was by then established, but the position of the carbonyl group within it. Earlier workers had assigned the product as the 2-oxo compound. Antaki and Petrow showed it was the 4-oxo. The difficulty, and the reason the question had stood open, was stated by them directly: “oxidation, per se, cannot distinguish between” the two structures. The standard tool for deciding such a question gave the same degradation product from either candidate, and so could not choose between them. A different kind of evidence was required. They supplied it by independent synthesis. Reacting 2-bromopyridine with ethyl β-aminocrotonate, they built the 4-oxo compound by a route that could yield only that structure, and found it identical to the long-disputed product. The assignment was no longer an inference from degradation but a result fixed by construction: the compound was the 4-oxo isomer because it had been made, unambiguously, as the 4-oxo isomer. The same paper introduced the reagent that made the route general. Ethyl β-aminocrotonate, the authors found, was “markedly superior” to the older reagent for this class of condensation, and its use “enabled a series of related compounds to become available for the first time.” The correction of a single structure was, in the same stroke, the opening of a general method. A General Chemistry (1951–1962) The correction of a single structure would have been a closed achievement. What followed made it the foundation of a field. In the same 1951 paper, Antaki and Petrow used the new reagent to carry the reaction beyond 2-aminopyridine to a range of cyclic amidines, building a series of fused ring systems — among them several the authors reported for the first time. The corrected structure was not an endpoint but a template: once the parent was understood, the same chemistry could be extended outward, and each new system was built on the assignment the parent had established. Antaki then turned to the question of what united these compounds. Across two further papers — in the Journal of the American Chemical Society (1958) and the Journal of Organic Chemistry (1962) — he determined their ultraviolet absorption spectra and used them to read the electronic identity of the class. He identified a band common to the whole family, attributable to the same conjugated system of the pyrimidine ring, and showed that it persisted across the related ring systems while a second band shifted with the amidine portion. The family was not a loose collection of compounds that happened to share a reaction. It was a single class with a common electronic signature, and ultraviolet spectroscopy was the instrument that revealed it. By 1962 the work formed a connected whole: a corrected parent structure, a general method for building on it, and a spectroscopic account of what the resulting family had in common. The chemistry that began as the resolution of one disputed structure had become a chemistry of condensed pyrimidines. The Confirmations The structural correction did not rest on the authors’ word. Within a year, and repeatedly over the following two decades, it was confirmed independently. Adams and Pachter (J. Am. Chem. Soc. 1952, 74, 5491) synthesised the parent 2-one and 4-one, recorded their ultraviolet spectra as reference standards, and concluded on that basis that the Antaki and Petrow product was the 4-one. The assignment was relied upon by later workers and confirmed again by independent modern methods. Yale and colleagues at the Squibb Institute for Medical Research repeated the reactions and found their products “identical in m.p., ir, uv, and pmr spectra… as described by Antaki and Petrow,” verifying the 4-one structures by X-ray crystallography and NMR. The result was reached again by other groups working separately — among them Shur and Israelstam (1968) and Kato and colleagues at Tohoku University (1972), the latter reproducing Antaki’s synthesis and upholding the 4-one assignment against a contrary proposal. A Later Question: the Cyanoacetate Series (1958) In his 1958 paper, Antaki extended the chemistry to ethyl ethoxymethylenecyanoacetate. With 4-methyl-2-aminopyridine this reaction is complicated by a molecular rearrangement, and Antaki addressed it directly: he prepared both the 4-substituted compounds and the isomeric 2-keto compounds, distinguished the two by their ultraviolet spectra, and assigned each correctly. The 2-keto isomers were identified by their anomalous absorption — the same spectroscopic method he had established for the class. Later review literature sometimes compresses this into a claim that Antaki assigned a structure in error and was subsequently corrected. The primary sources do not support that reading. Michael C. Seidel, in his own 1972 paper (J. Org. Chem. 37, 600), states plainly that “Antaki’s compound most probably was the isomeric 4-keto compound,” and supports this by the similarity of its ultraviolet spectrum to his 4-keto reference. Seidel confirms Antaki’s assignment; he does not overturn it. Nishigaki and colleagues, in their 1971 paper (J. Heterocyclic Chem. 8, 759), open by noting that this condensation “has been reported earlier by Antaki,” confirm that the cyclized products are the 4H-pyrido[1,2-a]pyrimidin-4-one-3-carboxylic acids, and refine only the cis/trans geometry of the open-chain intermediates — a stereochemical detail they resolved using nuclear magnetic resonance, an instrument unavailable to Antaki in 1958. This is a refinement of geometry by later methods, not a correction of structure. Read in their own words, the two papers most often cited as having corrected Antaki in this series instead confirm his ring assignments and extend only the stereochemical description. His structural work stands. Marketed Medicines on the Ring The pyrido[1,2-a]pyrimidin-4-one is not a laboratory curiosity. It is described in the medicinal-chemistry literature as a privileged scaffold — a molecular framework that, decorated in different ways, yields compounds active against many unrelated biological targets. Confirmed marketed medicines built on this ring span strikingly different therapeutic areas. Medicine Use Form of the ring Risperidone Antipsychotic Reduced (tetrahydro) Paliperidone (Invega) Antipsychotic; the 9-hydroxy metabolite of risperidone Reduced (tetrahydro) Pemirolast Antiallergic; used ophthalmically for allergic conjunctivitis Aromatic Risdiplam (Evrysdi) First approved oral therapy for spinal muscular atrophy Aromatic Rimazolium (Probon) Non-narcotic analgesic; marketed in Hungary from 1975 Reduced (tetrahydro) That a single core serves an antipsychotic, an antiallergic, an analgesic, and a treatment for a severe genetic neuromuscular disease — in both its aromatic and reduced forms — is what the literature means in calling it a privileged scaffold. Marketed medicines on this ring span half a century, from rimazolium (1975) to risdiplam (2020). Rimazolium itself was developed at the Hungarian company CHINOIN by a research group that included István Hermecz and Zoltán Mészáros — the same chemists whose 1983 review of the ring system records its structure as first described by Antaki. The ring system was structurally established by Antaki and Petrow in 1951. The reduction, the substitution, the drug design, and the pharmacology of each medicine are the work of the companies that developed them. What the medicines share is the core ring. “Rimazolium was developed at CHINOIN by a group that included István Hermecz and Zoltán Mészáros, who later co-authored a major review of pyrido[1,2-a]pyrimidine chemistry in which Antaki’s work was repeatedly cited.” A Second Field: Agrochemicals The same ring system later reappeared in crop protection. DuPont developed mesoionic derivatives of the pyrido[1,2-a]pyrimidinone framework into the commercial insecticides triflumezopyrim and dicloromezotiaz. In describing the class, the DuPont team noted that mesoionic pyrido[1,2-a]pyrimidinones had been “known for several decades” before systematic biological investigation began. The ring whose structure Antaki and Petrow settled in 1951 thus underlies marketed products in two separate industries — pharmaceuticals and agrochemicals. Recognition Antaki’s work on this ring is cited throughout the standard reference literature. The canonical review of the ring system is that of Hermecz and Mészáros (Advances in Heterocyclic Chemistry, Vol. 33, 1983), which names him in its running text as structural figure, priority worker, and spectroscopic analyst. The ring’s chemistry is treated again in Comprehensive Heterocyclic Chemistry II (1996), drawing on his 1951, 1958 and 1962 papers across its treatment of structure, spectroscopy and synthesis. His 1958 paper is cited as the primary reference for the reagent ethyl ethoxymethyleneacetoacetate in Wiley’s Encyclopedia of Reagents for Organic Synthesis (e-EROS). Primary Sources Antaki, H.; Petrow, V. J. Chem. Soc. 1951, 551–556. Antaki, H. J. Am. Chem. Soc. 1958, 80, 3066–3069. Antaki, H. J. Org. Chem. 1962, 27, 1371–1374. Antaki, H. Contributions to the Chemistry of Heterocyclic Compounds, Ph.D. thesis, University of London, 1950. Adams, R.; Pachter, I. J. Am. Chem. Soc. 1952, 74, 5491. Seidel, M. C. J. Org. Chem. 1972, 37, 600. Nishigaki, S.; Ichiba, M.; Shinomura, K.; Yoneda, F. J. Heterocyclic Chem. 1971, 8, 759.

Thoughts

Thursday, 18 June 2026

The history of thePyrido[1,2-a]pyrimidin-4-one

Friday, 13 May 2011

Just some photos South America 2011

Thursday, 23 December 2010

Getting into USA!