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

Younis Baqi, Christa E. Müller

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 (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.

Original languageEnglish
Pages (from-to)2599-2615
Number of pages17
JournalMolecules
Volume17
Issue number3
DOIs
Publication statusPublished - Mar 2012

Fingerprint

sulfonates
Signal transduction
Muscle Relaxation
Microwave irradiation
Water
synthesis
Microwaves
sodium
Smooth Muscle
Muscle
guinea pigs
smooth muscle
Copper
Signal Transduction
Buffers
Guinea Pigs
Colon
Sodium
Membranes
water

Keywords

  • Anthraquinone
  • Convergent synthesis
  • P2Y receptor antagonist
  • Regioselective coupling
  • Ullmann reaction

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Convergent synthesis of the potent P2Y receptor antagonist MG 50-3-1 based on a regioselective Ullmann coupling reaction. / Baqi, Younis; Müller, Christa E.

In: Molecules, Vol. 17, No. 3, 03.2012, p. 2599-2615.

Research output: Contribution to journalArticle

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AB - 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.

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