Convergent approach to the total synthesis of telmisartan via a suzuki cross-coupling reaction
Methods of synthesizing the angiotensin II receptor antagonist telmisartan in high yield and purity are provided. The methods involve the coupling of two structurally distinct benzimidazole units via a Suzuki cross-coupling reaction. Methods of regioselectively synthesizing one of the benzimidazole units are also provided.
1. A method of synthesizing telmisartan, comprising the step of coupling
i) potassium(1-((2′-carboxy-[1,1′-biphenyl]-4-yl)methyl)-4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate and
ii) 2-bromo-1-methylbenzimidazole,
wherein said step of coupling is carried out under Suzuki cross-coupling reaction conditions, to form said telmisartan.
2. The method of claim 1 , wherein said step of coupling is carried out using microwave assisted heating.
3. The method of claim 1 , further comprising the step of forming said potassium(1-((2′-carboxy-[1,1′-biphenyl]-4-yl)methyl)-4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate by
i) pre-treating potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate with potassium tert-butoxide; and
ii) alkylating pretreated potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate with methyl 4′-bromomethyl-biphenyl-2-carboxylate, to form said potassium(1-((2′-carboxy-[1,1′-biphenyl]-4-yl)methyl)-4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate.
4. The method of claim 1 , further comprising the step of forming said 2-bromo-1-methylbenzimidazole by
regioselectively brominating a 2-position of 1-methylbenzimidazole to form 2-bromo-1-methylbenzimidazole.
5. The method of claim 3 further comprising the step of forming said potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate by
i) performing reductive cyclization of 4-bromo-2-methyl-6-nitroaniline in the presence of n-butyraldehyde and sodium dithionite to form 6-bromo-4-methyl-2-propylbenzimidazole; and
ii) converting said 6-bromo-4-methyl-2-propylbenzimidazole to a trifluoroborate salt, to form said potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate.
6. The method of claim 5 , wherein said step of converting is performed by
reacting said 6-bromo-4-methyl-2-propylbenzimidazole with diboron pinacol ester in the presence of a catalyst to form a boronic acid pinacol ester; and
converting said boronic acid pinacol ester to said potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate.
7. The method of claim 6 , wherein the catalyst is a Pd catalyst.
8. The method of claim 7 , wherein the Pd catalyst is PdCl 2 dppf.
9. The method of claim 5 , wherein said step of converting is performed by
reacting said 6-bromo-4-methyl-2-propylbenzimidazole with diboronic acid in the presence of a catalyst to form 6-boronic acid-4-methyl-2-propylbenzimidazole; and
contacting said 6-boronic acid-4-methyl-2-propylbenzimidazole with KHF 2 to form said potassium(4-methyl-2-propyl-benzimidazole-6-yl) trifluoroborate.
10. The method of claim 9 , wherein the catalyst is a Pd catalyst.
11. The method of claim 10 , wherein the Pd catalyst is PdCl 2 (PPh 3 ) 2 .
12. The method of claim 1 , wherein said step of coupling is catalyzed by a Pd catalyst.
13. The method of claim 12 , wherein said Pd catalyst is a homogenous Pd catalyst.
14. The method of claim 13 , wherein said homogenous Pd catalyst is PdCl 2 dppf.
15. The method of claim 12 , wherein said Pd catalyst is a heterogenous Pd catalyst.
16. The method of claim 15 , wherein said heterogenous Pd catalyst is graphene supported Pd nanoparticles.
17. The method of claim 4 , wherein said step of regioselectively brominating is performed by brominating a 2-position of 1-methylbenzimidazole by, in a solution with tetrahydrofuran (THF) as solvent, contacting an imidazole ring of said 1-methylbenzimidazole with a brominating agent, to form said 2-bromo-1-methylbenzimidazole.
18. The method of claim 17 wherein said brominating agent is N-bromosuccinimide.