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

Younis Baqi, Christa E. Müller*

*المؤلف المقابل لهذا العمل

نتاج البحث: المساهمة في مجلةArticleمراجعة النظراء

18 اقتباسات (Scopus)


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 (IC 50 4.6 nM) for "P2Y 1-like" nucleotideactivated membrane receptors in guinea-pig taenia coli responsible for smooth muscle relaxation. Full characterization of the compound, however, e.g., at the human P2Y 1 receptor, which is a novel potential target for antithrombotic drugs, as well as other P 2 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, CuCl 2, and CuSO 4) were investigated at different pH values of sodium phosphate buffer, and in water in the absence or presence of base. Results showed that CuSO 4 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.

اللغة الأصليةEnglish
الصفحات (من إلى)2599-2615
عدد الصفحات17
مستوى الصوت17
رقم الإصدار3
المعرِّفات الرقمية للأشياء
حالة النشرPublished - مارس 2012

ASJC Scopus subject areas

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