Methods for the synthesis of 1,2,4-oxadiazole benzoic acid compounds
View Patent ↗Novel 1,2,4-oxadiazole benzoic acid compounds, methods of using and pharmaceutical compositions comprising an 1,2,4-oxadiazole benzoic acid derivative are disclosed. The methods include methods of treating or preventing a disease ameliorated by modulation of premature translation termination or nonsense-mediated mRNA decay, or ameliorating one or more symptoms associated therewith.
1. A method for preparing a compound of formula
comprising hydrolyzing a 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoate.
2. The method of claim 1 , wherein the 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoate is an alkyl benzoate.
3. The method of claim 2 , wherein the alkyl benzoate is a compound of formula
4. The method of claim 1 , wherein the 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoate is hydrolyzed using an aqueous base.
5. The method of claim 4 , wherein the base is sodium hydroxide.
6. The method of claim 1 , wherein the hydrolysis occurs in the presence of tetrahydrofuran.
7. The method of claim 1 , wherein the 3-[5-(2-fluoro-phenyl)-[1,2,4]oxadiazol-3-yl]-benzoate is refluxed at 100° C. for 2 hours.
8. The method of claim 3 , wherein the preparation of a compound of formula
comprises refluxing a compound of formula
in dichloromethane, tetrahydrofuran, toluene or dimethylformamide.
9. The method of claim 8 , wherein the refluxing occurs at reflux temperature for 4 hours.
10. The method of claim 8 , wherein the preparation of a compound of formula
comprises reacting a compound of formula
with 2-fluorobenzoyl chloride in the presence of triethyl amine or diisopropylethylamine.
11. The method of claim 10 , wherein the reaction occurs in the presence of dichloromethane, tetrahydrofuran or dimethylformamide.
12. The method of claim 11 , wherein the reaction is stirred at room temperature for 1 hour.
13. The method of claim 10 , wherein the preparation of a compound of formula
comprises reacting a compound of formula
with 50% aqueous hydroxylamine.
14. The method of claim 13 , wherein the reaction occurs in the presence of a base.
15. The method of claim 14 , wherein the base is triethyl amine, potassium carbonate or diisopropylethylamine.
16. The method of claim 10 , wherein the reaction occurs in the presence of methanol, ethanol, tert-butanol, tetrahydrofuran or dimethylformamide.
17. The method of claim 13 , wherein the preparation of a compound of formula
comprises reacting a compound of formula
with potassium carbonate followed by reacting the mixture with methyl iodide.
18. The method of claim 17 , wherein the reaction mixture is contacted with ice water after stirring to produce a precipitate.
19. The method of claim 18 , wherein the precipitate is dissolved in methanol and re-precipitated in cold water.