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Molecules 2012, 17(3), 2599-2615; doi:10.3390/molecules17032599

Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction

PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany
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Received: 25 January 2012 / Revised: 25 February 2012 / Accepted: 27 February 2012 / Published: 5 March 2012
(This article belongs to the Section Medicinal Chemistry)
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Abstract

MG 50-3-1 (3, trisodium 1-amino-4-{4-[4-chloro-6-(2-sulfophenylamino)-1,3,5-triazin-2-ylamino]-2-sulfophenylamino}-9,10-dioxo-9,10-dihydroanthracene 2-sulfonate) is the most potent and selective antagonist (IC50 4.6 nM) for “P2Y1-like” nucleotide-activated membrane receptors in guinea-pig taenia coli responsible for smooth muscle relaxation. Full characterization of the compound, however, e.g., at the human P2Y1 receptor, which is a novel potential target for antithrombotic drugs, as well as other P2 receptor subtypes, has been hampered due to difficulties in synthesizing the compound in sufficient quantity. MG 50-3-1 would be highly useful as a biological tool for detailed investigation of signal transduction in the gut. We have now developed a convenient, fast, mild, and efficient convergent synthesis of 3 based on retrosynthetic analysis. A new, regioselective Ullmann coupling reaction under microwave irradiation was successfully developed to obtain 1-amino-4-(4-amino-2-sulfophenylamino)-9,10-dioxo-9,10-dihydro­anthracene 2-sulfonate (8). Four different copper catalysts (Cu, CuCl, CuCl2, and CuSO4) were investigated at different pH values of sodium phosphate buffer, and in water in the absence or presence of base. Results showed that CuSO4 in water in the presence of triethylamine provided the best conditions for the regioselective Ullmann coupling reaction yielding the key intermediate compound 8. A new synthon (sodium 2-(4,6-dichloro-1,3,5-triazin-2-ylamino)benzenesulfonate, 13) which can easily be obtained on a gram scale was prepared, and 13 was successfully coupled with 8 yielding the target compound 3.
Keywords: anthraquinone; convergent synthesis; P2Y receptor antagonist; regioselective coupling; Ullmann reaction anthraquinone; convergent synthesis; P2Y receptor antagonist; regioselective coupling; Ullmann reaction
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MDPI and ACS Style

Baqi, Y.; Müller, C.E. Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction. Molecules 2012, 17, 2599-2615.

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