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  • Convergent synthesis of the potent P2Y receptor antagonist MG 50-3-1 based on a regioselective Ullmann coupling reaction.

Convergent synthesis of the potent P2Y receptor antagonist MG 50-3-1 based on a regioselective Ullmann coupling reaction.

Molecules (Basel, Switzerland) (2012-03-07)
Younis Baqi, Christa E Müller
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
Triethylamine, for amino acid analysis, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, for protein sequence analysis, ampule, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, ≥99.5%
Sigma-Aldrich
Triethylamine, BioUltra, ≥99.5% (GC)
Sigma-Aldrich
Triethylamine, puriss. p.a., ≥99.5% (GC)
Sigma-Aldrich
Bromaminic acid sodium salt
Sigma-Aldrich
Triethylamine, ≥99%
Sigma-Aldrich
Triethylamine hydrochloride, ≥99.0% (AT)