Method for preparation of benzimidazole derivatives
The present invention provides a method for preparing a compound with a benzimidazole structure with an excellent yield using a low-cost starting material, not requiring an additional separation process, or not using a dangerous reagent during the manufacturing process. Furthermore, the present invention also provides an intermediate and a final product produced by the preparing method.
1. A method for preparing benzimidazole derivatives, comprising:
1) preparing a compound represented by the Chemical Formula 10 by reacting a compound represented by the Chemical Formula 8 with a compound represented by the Chemical Formula 9; and
2) preparing a compound represented by the Chemical Formula 1 by reacting the compound represented by the Chemical Formula 10 with a compound represented by the Chemical Formula 11:
wherein,
R 1 and R 2 are independently C 1-4 alkyl, and
R 3 is C 1-4 alkyl, C 1-4 haloalkyl or phenyl.
2. A method of preparing a compound represented by the Chemical Formula 1-1 by reacting a compound represented by the Chemical Formula 1 of claim 1 in the presence of a base selected from potassium carbonate or sodium bicarbonate:
wherein,
R 1 and R 2 are independently C 1-4 alkyl.
3. A method of preparing a compound represented by the Chemical Formula 1-2 by reacting a compound represented by the Chemical Formula 1 of claim 1 in the presence of a base selected from sodium hydroxide or potassium hydroxide:
wherein,
R 1 is C 1-4 alkyl.
4. A method of preparing a compound represented by the Chemical Formula 1-3 by reacting a compound represented by the Chemical Formula 1-2 of claim 3 with dimethylamine in the presence of thionyl chloride:
wherein,
R 1 is C 1-4 alkyl.
5. The method of claim 1 , wherein R 1 are independently methyl, ethyl, propyl or tert-butyl.
6. The method of claim 1 , wherein R 3 is methyl, trifluoromethyl or phenyl.
7. The method of claim 1 , wherein step 1) is performed in the presence of a base selected from the group consisting of potassium tert-butoxide, sodium ethoxide and sodium methoxide.
8. The method of claim 1 , wherein step 1) is performed using a solvent selected from the group consisting of methanol, ethanol, acetonitrile and methylene chloride.
9. The method of claim 1 , wherein step 2) is performed using acetonitrile as a solvent.
10. The method of claim 1 , wherein the compound represented by the Chemical Formula 8 is prepared by a method comprising:
a) preparing a compound represented by the Chemical Formula 4 by reacting a compound represented by the Chemical Formula 2 with a compound represented by the Chemical Formula 3;
b) preparing a compound represented by the Chemical Formula 6 by reacting the compound represented by the Chemical Formula 4 with a compound represented by the Chemical Formula 5 below; and
c) preparing the compound represented by the Chemical Formula 8 by reacting the compound represented by the Chemical Formula 6 with a compound represented by the Chemical Formula 7;
wherein,
R 1 is C 1-4 alkyl, and
R 4 is C 1-4 alkyl.
11. The method of claim 10 , wherein R 1 is methyl, ethyl, propyl or tert-butyl.
12. The method of claim 10 , wherein R 4 is methyl or ethyl.
13. The method of claim 10 , wherein hydrochloric acid, bromic acid or acetic acid is added in step a).
14. The method of claim 10 , wherein acetyl chloride is added in step a).
15. The method of claim 10 , wherein step c) is performed in the presence of a base selected from the group consisting of potassium carbonate, triethylamine, sodium hydroxide and diisopropylethylamine.
16. The method of claim 3 , wherein the reaction is performed using a solvent selected from the group consisting of methanol, ethanol, water and a mixed solution thereof.
17. A compound represented by the Chemical Formula 1, Chemical Formula 1-1, Chemical Formula 1-2 or Chemical Formula 1-3:
wherein,
R 1 and R 2 are independently C 1-4 alkyl, and
R 3 is C 1-4 alkyl, C 1-4 haloalkyl or phenyl.
18. The compound of claim 17 , wherein R 1 and R 2 are independently methyl, ethyl; propyl or tert-butyl.
19. The compound of claim 17 , wherein R 3 is methyl, trifluoromethyl or phenyl.
20. The compound of claim 17 , wherein the compound represented by the Chemical Formula 1, the Chemical Formula 1-1, the Chemical Formula 1-2 or the Chemical Formula 1-3 is selected from the group consisting of,
1) ethyl 4-acetoxy-1-benzyl-2-methyl-1H-benzo[d]imidazole-6-carboxylate,
2) ethyl 4-acetoxy-1-benzyl-2-ethyl-1H-benzo[d]imidazole-6-carboxylate,
3) ethyl 4-acetoxy-1-benzyl-2-tert-butyl-1H-benzo[d]imidazole-6-carboxylate,
4) ethyl 4-trifloromethoxy-1-benzyl-2-methyl-1H-benzo[d]imidazole-6-carboxylate,
5) ethyl 4-benzoyloxy-1-benzyl-2-methyl-1H-benzo[d]imidazole-6-carboxylate,
6) ethyl 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylate,
7) ethyl 1-benzyl-4-hydroxy-2-ethyl-1H-benzo[d]imidazole-6-carboxylate,
8) ethyl 1-benzyl-4-hydroxy-2-tert-butyl-1H-benzo[d]imidazole-6-carboxylate,
9) 1-benzyl-4-hydroxy-2-methyl-1H-benzo[d]imidazole-6-carboxylic acid, and
10) 1-benzyl-4-hydroxy-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxyamide.