Highly pure cilostazol and an improved process for obtaining same
View Patent ↗A novel process for preparing highly pure cilostazol, effected by reacting 6-hydroxy-3,4-dihydroquinolinone and 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in the presence of a hydrated inorganic base, is disclosed. Further disclosed is highly pure cilostazol, and particularly highly pure cilostazol that is substantially free of 6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butoxy]-1-[4-(1-cyclohexyl-1H-tetrazol-5-yl)-butyl ]-3,4-dihydro-1H-quinolin-2-one.
1. A process of preparing 6-(4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone (Cilostazol), the process comprising:
reacting 6-hydroxy-3,4-dihydroquinolin-2(1H)-one with 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole in the presence of a hydrated inorganic base, to thereby obtain a reaction mixture containing Cilostazol;
isolating the Cilostazol from the reaction mixture;
slurrying the Cilostazol in an organic solvent; and
crystallizing the Cilostazol in the presence of a base, to produce Cilostazol, which is substantially free of N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone, and has a purity of at least 99.9%.
2. The process of claim 1 , wherein the cilostazol contains less than 0.06 weight percent N-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butyl]-6-[4-(1-cyclohexyl-1H-tetrazol-5-yl)butoxy]-3,4-dihydro-2(1H)-quinolinone.
3. The process of claim 1 , wherein said hydrated inorganic base contains at least 5 weight percentages of water.
4. The process of claim 1 , wherein said hydrated inorganic base contains at least 10 weight percentages of water.
5. The process of claim 1 , wherein said hydrated inorganic base contains at least 15 weight percentages of water.
6. The process of claim 1 , wherein said reacting is performed in a solvent.
7. The process of claim 6 , wherein said solvent comprises methanol, ethanol, 1-propanol, 2propanol, 1-butanol, 2-butanol or a combination thereof.
8. The process of claim 7 , wherein said solvent further comprises water.
9. The process of claim 8 , wherein said solvent comprises a mixture of 1-propanol and water.
10. The process of claim 9 , wherein the ratio between said 1-propanol and said water ranges from 20:1 to 1:1.
11. The process of claim 10 , wherein said ratio is 18:1.
12. The process of claim 1 , wherein said inorganic base is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate.
13. The process of claim 1 , wherein said inorganic base is potassium hydroxide.
14. The process of claim 1 , wherein the molar ratio between said 6-hydroxy-3,4-dihydroquinolin-2(1H)-one and said 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole ranges from about 1:1 to about 2:1.
15. The process of claim 14 , wherein said molar ratio is about 1.3:1.
16. The process of claim 1 , wherein the molar ratio between said hydrated inorganic base and said 5-(4-chlorobutyl)-1-cyclohexyl-1H-tetrazole ranges from about 1:1 to about 2:1.
17. The process of claim 16 , wherein said molar ratio is about 1.2:1.
18. The process of claim 6 , wherein said reacting is performed at the reflux temperature of said solvent.
19. The process of claim 1 , wherein said isolating is effected by precipitating the cilostazol from said reaction mixture at a temperature lower than 15° C.
20. The process of claim 1 , wherein said slurrying precedes said crystallizing.
21. The process of claim 1 , wherein said crystallizing precedes said slurrying.
22. The process of claim 1 , wherein said slurrying is performed in ethyl acetate.
23. The process of claim 1 , wherein said crystallizing is performed in 1-propanol.
24. The process of claim 1 , wherein said crystallizing is performed in the presence of sodium hydroxide.