Process for preparing substituted quinolin-4-ol compounds

1. A process for preparing a compound of Formula (I),

wherein:

each R is independently F, Cl, Br, I, CN, (C 1 -C 6 )alkyl, OR a , or NR b R c ;

n is 0, 1, 2, 3, or 4;

each of R a , R b and R c is independently H, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, 3-6 membered heterocyclyl, —(C 1 -C 4 )alkylene-(3-6 membered heterocyclyl), (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl, or —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl), wherein each of the (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, —(C 1 -C 4 )alkylene-(C 3 -C 6 )cycloalkyl, 3-6 membered heterocyclyl, —(C 1 -C 4 )alkylene-(3-6 membered heterocyclyl), (C 6 -C 10 )aryl, —(C 1 -C 4 )alkylene-(C 6 -C 10 )aryl, 5-10 membered heteroaryl and —(C 1 -C 4 )alkylene-(5-10 membered heteroaryl) is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, CN, N 3 , OH, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, and (C 1 -C 6 )alkoxy;

and wherein the compound of Formula (I) is not one of the following compounds:

the process comprising:

contacting the compound of Formula (II):

with a dichlorobenzene of Formula (III):

to obtain a reaction mixture containing the compound of Formula (I);

wherein the dichlorobenzene of Formula (III) is

2. The process according to claim 1 , wherein each R is independently F, I, CN, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, OR a , or NR b R c .

3. The process according to claim 1 , wherein each of R a , R b and R c is independently H, (C 1 -C 4 )alkyl, (C 5 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 5 -C 6 )cycloalkyl, 5-6 membered heterocyclyl, —(C 1 -C 2 )alkylene-(5-6 membered heterocyclyl), phenyl, —(C 1 -C 2 )alkylene-phenyl, or 5-6 membered heteroaryl, wherein each of the (C 1 -C 4 )alkyl, (C 5 -C 6 )cycloalkyl, —(C 1 -C 2 )alkylene-(C 5 -C 6 )cycloalkyl, 5-6 membered heterocyclyl, —(C 1 -C 2 )alkylene-(5-6 membered heterocyclyl), phenyl, —(C 1 -C 2 )alkylene-phenyl, and 5-6 membered heteroaryl, is optionally substituted with 1, 2, 3, or 4 substitutents independently selected from F, Cl, CN, N 3 , OH, (C 1 -C 3 )alkyl, and (C 1 -C 3 )alkoxy.

4. The process according to claim 1 , wherein each of R a , R b and R c is independently H, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl.

5. The process according to claim 1 , wherein the compound of Formula (I) is compound (Ia),

6. The process according to claim 1 , wherein the compound of Formula (II) is compound (IIa),

7. The process according to claim 1 , wherein the reaction is carried out at a temperature from about 160° C. to about 220° C.

8. The process according to claim 1 , wherein the reaction is carried out at a temperature from about 170° C. to about 190° C.

9. The process according to claim 1 , wherein the molar concentration of compound of Formula (II) in the dichlorobenzene of Formula (III) is from about 0.05 M to about 0.45 M.

10. The process according to claim 1 , wherein the molar concentration of compound of Formula (II) in the dichlorobenzene of Formula (III) is from about 0.10 M to about 0.25 M.

11. The process according to claim 1 , further comprising a purification process for purifying the compound of Formula (I), wherein the purification process comprises the steps of:

(a) concentrating the reaction mixture under vacuum to provide a solid;

(b) stirring the solid of step (a) in dichloromethane (CH 2 Cl 2 ) to form a mixture;

(c) isolating the solid from the mixture of step (b) by filtration;

(d) stirring the solid of step (c) in water to form an aqueous mixture;

(e) isolating the solid from the aqueous mixture of step (d) by filtration, repeating steps (d) and (e) if needed; and

(f) drying the isolated solid of step (e) to form purified compound of Formula (I).

12. The process according to claim 11 , wherein a ratio of the weight (in gram) of the solid obtained in step (a) to the volume (in mL) of CH 2 Cl 2 used in step (b) is from about 0.4 to about 0.8.

13. The process according to claim 11 , wherein a ratio of the weight (in gram) of the solid obtained in step (a) to the volume (in mL) of CH 2 Cl 2 used in step (b) is from about 0.5 to about 0.7.

14. The process according to claim 11 , wherein the mixture in step (b) is stirred at 45° C. for 2 hours.

15. The process according to claim 11 , wherein the aqueous mixture in step (d) is stirred at 100° C. for 2 hours.

16. The process according to claim 11 , wherein the filtration in step (e) is carried out at a temperature from about 25° C. to about 60° C.