Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction
Abstract
:1. Introduction
2. Results and Discussion
2.1. Optimization of the Ullmann Coupling Reaction of Bromaminic Acid with Aniline
Entry | Solvent mixture (mL) b | pH value | Cu | CuCl | CuCl2 | CuSO4 | |||||
---|---|---|---|---|---|---|---|---|---|---|---|
NaH2PO4 (0.12 M) | Na2HPO4 (0.20 M) | Time (min) | Conversion (%) c | Time (min) | Conversion (%) c | Time (min) | Conversion (%) c | Time (min) | Conversion (%) c | ||
1 | Water (5) | 7.0 | 20 | ca. 50 | 150 | 0 | 150 | 0 | 150 | 0 | |
2 | 5 | 0 | 4.8 | 25 | ca. 50 | 150 | 0 | 150 | 0 | 150 | 0 |
3 | 4 | 1 | 7.0 | 5 | 100 | 5 | 100 | 125 | ca. 50 | 125 | ca. 50 |
4 | 3 | 2 | 7.4 | 5 | 100 | 5 | 100 | 65 | 100 | 35 | 100 |
5 | 2 | 3 | 7.8 | 5 | 100 | 5 | 100 | 65 | 100 | 35 | 100 |
6 | 1 | 4 | 8.2 | 5 | 100 | 5 | 100 | 35 | 100 | 35 | 100 |
7 | 0 | 5 | 9.4 | 5 | 100 | 5 | 100 | 35 | 100 | 25 | 100 |
2.2. Regioselective Ullmann Coupling Reaction of Bromaminic Acid with 2,5-Diaminobenzene Sulfonate
Entry | Solvent mixture (mL) | pH value | Time (min) | Catalyst | Conversion (%) b | ortho:meta ratio b | Yield (%) c | |
---|---|---|---|---|---|---|---|---|
NaH2PO4 (0.12 M) | Na2HPO4 (0.20 M) | |||||||
1 | 5 | 0 | 4.8 | 10 | Cu | ca. 50 | 1:1 | ca. 25 |
2 | 4 | 1 | 7.0 | 5 | Cu | ca. 50 | 1:1 | ca. 25 |
3 | 3 | 2 | 7.4 | 5 | Cu | 100 | 1:3 | > 50 |
4 | 2 | 3 | 7.8 | 5 | Cu | 100 | 1:3 | > 50 |
5 | 1 | 4 | 8.2 | 5 | Cu | 100 | 1:4 | > 75 |
6 | 0 | 5 | 9.4 | 5 | Cu | 100 | 1:4 | > 75 |
8 | 4 | 1 | 7.0 | 5 | CuCl | 100 | 1:6 | > 75 |
9 | 4 | 1 | 7.0 | 5 | CuSO4 | 100 | 1:6 | > 75 |
Entry | Solvent | Time (min) | Catalyst | Conversion (%)b | ortho:meta ratio | Yield (%)c |
---|---|---|---|---|---|---|
1 | water | 15 | Cu | ca. 60 | 3:1 | ca. 50 |
2 | water | 15 | CuCl | ca. 40 | 2:1 | ca. 25 |
3 | water | 20 | CuSO4 | ca. 30 | 1.5:1 | ca. 20 |
4 | water/Et3N | 5 | Cu | ca. 70 | 1:1 | ca. 40 |
5 | water/Et3N | 5 | CuCl | ca. 90 | 1:3 | > 50 |
6 | water/Et3N | 5 | CuSO4 | 100 | 1:3 | > 75 |
2.3. Regioselective Ullmann Coupling Reaction of Bromaminic Acid with 2,4-Diaminobenzene Sulfonate
Entry | Solvent mixture (mL) | pH value | Time (min) | Conversion (%) b | ortho:para ratio b | Yield (%) c | |
---|---|---|---|---|---|---|---|
NaH2PO4 (0.12 M) | Na2HPO4 (0.20 M) | ||||||
1 | 5 | 0 | 4.8 | 10 | ca. 25 | 1.5:1 | ca. 25 |
2 | 4 | 1 | 7.0 | 5 | ca. 25 | 1:1 | ca. 25 |
3 | 3 | 2 | 7.4 | 5 | ca. 25 | 1:1.5 | ca. 25 |
4 | 2 | 3 | 7.8 | 5 | ca. 50 | 1:2 | >50 |
5 | 1 | 4 | 8.2 | 5 | 100 | 1:3 | >50 |
6 | 0 | 5 | 9.4 | 5 | 100 | 1:3 | >50 |
Entry | Solvent | Time (min) | Catalyst | Conversion (%) b | ortho:para ratio | Yield (%) c |
---|---|---|---|---|---|---|
1 | water | 15 | Cu | ca. 50 | >99:1 | ca. 20 |
2 | water | 15 | CuCl | ca. 50 | >99:1 | ca. 20 |
3 | water | 20 | CuSO4 | ca. 50 | >99:1 | ca. 20 |
4 | water/Et3N | 5 | Cu | ca. 80 | 1.5:1 | ca. 50 |
5 | water/Et3N | 5 | CuCl | 100 | 5:1 | >75 |
6 | water/Et3N | 5 | CuSO4 | 100 | 2:1 | >50 |
2.4. Synthesis of MG 50-3-1 (3)
3. Experimental
3.1. General
3.2. General Procedure A: Coupling Reaction of Bromaminic Acid with Aniline
3.3. General Procedure B: Coupling Reaction of Bromaminic Acid with 2,5-Diaminobenzensulfonic Acid (5) or with 2,4-Diaminobenzensulfonic Acid (6)
3.4. Synthesis of Disodium 1-Amino-4-(4-amino-2-sulfophenylamino)-9,10-dioxo-9,10-dihydroanthracene 2-Sulfonate (8)
3.5. Synthesis of Sodium 2-(4,6-dichloro-1,3,5-triazin-2-ylamino)benzenesulfonate (13)
3.6. Synthesis of 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 (3, MG 50-3-1)
4. Conclusions
Conflict of Interest
Acknowledgments
- Sample Availability: Samples of the compounds are available from the authors.
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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. https://doi.org/10.3390/molecules17032599
Baqi Y, Müller CE. Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction. Molecules. 2012; 17(3):2599-2615. https://doi.org/10.3390/molecules17032599
Chicago/Turabian StyleBaqi, Younis, and Christa E. Müller. 2012. "Convergent Synthesis of the Potent P2Y Receptor Antagonist MG 50-3-1 Based on a Regioselective Ullmann Coupling Reaction" Molecules 17, no. 3: 2599-2615. https://doi.org/10.3390/molecules17032599