Scheme 3. Synthesis of Roxatidine 17 and Roxatidine Acetate 18.
(b) Nemet I, Varga-Defterdarović L. Bioorg. Med. Chem. Lett.
2008;16:4551–4562;
To demonstrate the synthetic utility of our approach, we
performed the synthesis of roxatidine, a histamine H2 receptor
antagonist used in the treatment of gastric ulcers and gastro-
esophageal reflux disease.5 Following the synthetic route
reported in literature,21 we synthetized intermediate 15 and, after
formylation and dehydration, isocyanide 16 was afforded in high
yield. With this compound in our hands, we performed both the
2-hydroxymethyl benzoic acid mediated reaction and a traditional
Passerini reaction with acetic acid and formaldehyde, obtaining
both roxatidine 17 and roxatidine acetate 18 with 75 and 94% of
yield, respectively (Scheme 3).
(c) Moutevelis-Minakasis P, Neokosmidi A, Filippakou M,
Stephens D, Dennis EA, Kokotos G. J. Pept. Sci. 2007;13:634–641.
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In conclusion, we reported a novel truncated Passerini reaction
suitable for the synthesis a large array of functionalized α-
hydroxyamides. Notably, our methodology is compatible with
acid sensitive group that are not tolerated under previous reported
reaction conditions. Finally, our synthetic strategy was applied to
a novel route for the synthesis of roxatidine with high yield.
(b) Szymanski W, Zwolinska M, Klossowski S, Młynarczuk-Biały
I, Biały L, Issat T, Malejczyk J, Ostaszewski R. Bioorg. Med.
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Acknowledgments
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M.S. gratefully acknowledges Compagnia di San Paolo (Grant
No. C61J12000280007) for research fellowship.
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Supplementary Material
Experimental procedure, spectroscopic data, copies of 1H and 13
spectra (PDF).
C