Substituted thiazoles
This invention is directed to processes for making substituted thiazoles. The substituted thiazole, ethyl 2-(4-hydroxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate, also known as TEI-6720, is useful for treatment of gout and hyperuricemia. This compound belongs to a class of substituted thiazoles that inhibit xanthine oxidase and thus block uric acid production.
1. A process for the preparation of a compound of formula (IV)
wherein
R 1 is selected from the group consisting of heteroaryl, phenyl, or phenyl substituted with one, two, three, or four substituents independently selected from the group consisting of C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, —OH, —F, —Cl, —Br, —I, —NH 2 and —NO 2 ;
R 2 is selected from a group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl; and
R 3 is selected from a group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl;
the process comprising reacting a compound having formula (I)
R 1 —(C═S)—NH 2 (I),
with a compound having formula (V)
wherein
X is selected from the group consisting of —Cl, —Br, —I, and —F.
2. The process of claim 1 , wherein the process is conducted at a temperature of about 0° C. to about 150° C.
3. The process of claim 1 , wherein the process is conducted in a solvent.
4. The process of claim 3 , wherein the solvent is ethanol.
5. The process of claim 1 , wherein R 1 is phenyl substituted with one —OH substituent.
6. The process of claim 1 , wherein R 2 is ethyl.
7. The process of claim 1 , wherein R 3 is methyl.
8. The process of claim 1 , wherein X is —Cl.
9. The process for the preparation of ethyl 2-(4 hydroxyphenyl)-4-methyl-1,3-thiazole-S-carboxylate, the process comprising reacting 4-hydroxybenzene carbothiomide with ethyl-2-chloroacetoacetate at a temperature of about 0° C. to about 150° C. in an organic solvent.
10. The process of claim 9 , wherein the temperature is 80° C. and the organic solvent is ethanol.
11. A process for the preparation of a compound of formula (IV)
R 1 is selected from the group consisting of heteroaryl, phenyl, or phenyl substituted with one, two, three, or four substituents independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, C 2 -C 6 -alkynyl, —OH, —F, —Cl, —Br, —I, —NH 2 ;
R 2 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl; and
R 3 is selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, C 2 -C 6 -alkenyl, and C 2 -C 6 -alkynyl;
the process comprising the steps of:
(a) reacting a compound having formula (II)
R 1 —C≡N (II),
with a base and H 2 S to provide a compound of formula (I)
R 1 —(C═S)—NH 2 (I);
and
(b) reacting the product of step (a) with a compound having formula (V)
wherein
X is selected from the group comprising —Cl, —Br, —I, and —F.
12. The process of claim 11 , wherein the base in step (a) is a compound of formula (III)
(M) + (YH) − (III),
wherein
M is sodium, potassium, lithium, or —NH 4 ; and
Y is oxygen or sulfur.
13. The process of claim 11 , wherein step (a) is conducted under a pressure of at least 10 psi.
14. The process of claim 11 , wherein steps (a) and (b) are conducted in solvents.
15. The process of claim 11 , wherein steps (a) and (b) are conducted at a temperature of about 0° C. to about 150° C.
16. The process of claim 11 , which is conducted as a continuous process.
17. A process for the preparation of ethyl 2-(4 hydroxyphenyl)-4-methyl-1,3-thiazole-S-carboxylate,
the process comprising the steps of:
(a) reacting 4-hydroxybenzonitrile, sodium hydroxide, and hydrogen sulfide under a pressure of at least 10 psi at a temperature of about 0° C. to about 150° C. in a solvent; and
(b) reacting the product of step (a) and ethyl-2-chloroacetoacetate at a temperature of about 0° C. to about 150° C. in a solvent.
18. The process of claim 17 , wherein in (a) the pressure is 60 psi, the temperature is 70° C., and the solvent is water, and in (b) the temperature is 80° C. and the solvent is ethanol.
19. The process of claim 18 , wherein the solvent used in (a) is the same solvent used in (b).
20. The process of claim 18 , wherein in (a) the pressure is 60 psi, the temperature is 70° C., and the solvent is ethanol, and in (b) the temperature is 80° C. and the solvent is ethanol.