Processes for the preparation of 1,2,4-oxadiazole benzoic acids
View Patent ↗Provided herein are processes for the preparation of compounds useful for the treatment, prevention or management of diseases associated with a nonsense mutation. More specifically, provided herein are processes for the synthesis of 1,2,4-oxadiazoles. In particular, provided herein are processes useful for the preparation of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]-benzoic acid.
1. A process for preparing a 1,2,4-oxadiazole benzoic acid or a pharmaceutically acceptable salt thereof comprising the steps of:
(1) reacting a cyanobenzoic acid methyl ester with hydroxylamine;
(2) acylation with a halobenzoyl chloride;
(3) condensation; and
(4) hydrolysis of the methyl ester,
wherein each reaction step is carried out in the same organic solvent.
2. The process of claim 1 , wherein the organic solvent is tetrahydrofuran, dioxane, isobutyl acetate, isopropyl acetate, ethyl acetate, methanol, ethanol, isopropanol, isobutanol, propanol, butanol or tert-amyl alcohol.
3. The process of claim 1 , wherein the organic solvent is tert-butanol.
4. The process of claim 1 , wherein steps (1)-(3) are carried out without isolation of an intermediate.
5. A process for preparing a compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 CH 2 O) n R 6 or any biohydrolyzable group;
R 6 is H or unsubstituted alkyl;
X is at each occurrence independently F, Cl, Br or I;
n is an integer from 1 to 7; and
m is an integer from 1 to 5,
comprising performing the following steps in the same solvent:
(1) reacting the cyanobenzoic acid ester:
with hydroxylamine, to give:
followed by (2) acylation with a halobenzoyl chloride, to give:
followed by (3) condensation.
6. The process of claim 5 , wherein X is F.
7. process of claim 5 , wherein m is 1.
8. The process of claim 5 , wherein X is F and m is 1.
9. The process of claim 5 , wherein R 1 is methyl.
10. The process of claim 5 , wherein steps ( l )-(3) are carried out without isolation of an intermediate.
11. The process of claim 10 , wherein the solvent is tert-butanol.
12. The process of claim 5 , wherein the halobenzoyl chloride is 2-fluorobenzoyl chloride.
13. The process of claim 5 , further comprising:
(4) hydrolysis of the ester of a compound of the formula:
to give:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —(CH 2 CH 2 O) n R 6 or any biohydrolyzable group;
R 6 is H or unsubstituted alkyl;
X is at each occurrence independently F, Cl, Br or I;
n is an integer from 1 to 7; and
m is an integer from 1 to 5.
14. The process of claim 13 , wherein the hydrolysis is carried out in tert-butanol.
15. The process of claim 14 , wherein R 1 is methyl.