title: Convergent synthesis of the potent P2Y receptor antagonist MG 50-3-1 based on a regioselective Ullmann coupling reaction.
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-dihydro-anthracene 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.
authors.affiliation: PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn, An der Immenburg 4, D-53121 Bonn, Germany.
authors.forename: Younis
authors.initials: Y
authors.lastname: Baqi
authors.forename: Christa E
authors.initials: CE
authors.lastname: Müller
mesh_terms: D000814:Aniline Compounds / Q000737:chemistry; D000873:Anthracenes / Q000138:chemical synthesis*; D000880:Anthraquinones / Q000737:chemistry; D002384:Catalysis; D060326:Chemistry Techniques, Synthetic; D003300:Copper / Q000737:chemistry; D005021:Ethylamines / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008872:Microwaves; D058921:Purinergic P2Y Receptor Antagonists / Q000138:chemical synthesis*; D012997:Solvents / Q000737:chemistry; D013451:Sulfonic Acids / Q000737:chemistry; D014227:Triazines / Q000138:chemical synthesis*
chemical_list: D000814:Aniline Compounds; D000873:Anthracenes; D000880:Anthraquinones; D005021:Ethylamines; C509172:MG 50-3-1; D058921:Purinergic P2Y Receptor Antagonists; D012997:Solvents; D013451:Sulfonic Acids; D014227:Triazines; D003300:Copper; C087418:bromamine acid; C023650:aniline; C016162:triethylamine