Intermediate compounds and processes for the preparation of quinoline derivatives such as Laquinimod sodium

1. A process for the preparation of a compound formula (I),

or a salt thereof, wherein

R 1 is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and allyl;

R 2 is selected from methyl, ethyl, n-propyl, iso-propyl, methoxy, ethoxy, halogen, trifluoromethyl and trifluoromethoxy;

R 3 is hydrogen; or

R 2 and R 3 together are selected from methylenedioxy, ethylenedioxy and isopropylidenedioxy;

the process comprising the steps of:

a) reacting an anthranilate derivative of formula (7A)

wherein R is an alkyl, aryl or alkylaryl, with a 3-oxopropanoic acid derivative of formula (8A)

wherein X is OH or a leaving group, so as to obtain a compound of formula (9A):

b) optionally, saponifying the ester group CO 2 R in compound (9A) to the corresponding carboxylic acid CO 2 H so as to obtain a compound formula (10A), and converting acid (10A) to an activated derivative thereof of formula (11A):

wherein Y is a leaving group; and

c) converting compound (9A) obtained in step (a), or compound (11A) obtained in step (b) to a compound of formula (I) or a salt thereof in the presence of a base.

2. The process according to claim 1 , comprising the steps of:

a) reacting an anthranilate derivative of formula (7A) with a 3-oxopropanoic acid derivative of formula (8A) so as to obtain a compound of formula (9A); and

b) converting compound (9A) obtained in step (a) to a compound of formula (I) or a salt thereof in the presence of a base.

3. The process according to claim 1 , comprising the steps of:

a) reacting an anthranilate derivative of formula (7A) with a 3-oxopropanoic acid derivative of formula (8A) so as to obtain a compound of formula (9A);

b) saponifying the ester group CO 2 R in compound (9A) to the corresponding carboxylic acid CO 2 H so as to obtain a compound formula (10A), and converting acid (10A) to an activated derivative thereof of formula (11A); and

c) converting compound (11A) obtained in step (b) to a compound of formula (I) or a salt thereof in the presence of a base.

4. The process according to claim 1 , wherein R 1 is ethyl, R 2 is chloro and R 3 is H, and the compound of formula (I) is Laquinimod, which is represented by the structure of formula (1):

or a salt of said compound of formula (1).

5. The process according to claim 4 , wherein the salt is the sodium salt.

6. The process according to claim 4 , comprising the steps of:

a) reacting N-methyl 6-chloroanthranilate of formula (7)

with a 3-(ethyl(phenyl)amino)-3-oxopropanoic acid derivative of formula (8)

so as to obtain 2-chloro-6-(3-(ethyl(phenyl)amino)-N-methyl-3-oxopropanamido)benzoate of formula (9)

b) optionally, saponifying the ester group CO 2 R in compound (9) to the corresponding carboxylic acid CO 2 H so as to obtain a compound formula (10), and converting acid (10) to an activated derivative thereof of formula (11):

and

c) converting compound (9) obtained in step (a) or compound (11) obtained in step (b) to Laquinimod (1) or a salt thereof in the presence of a base.

7. The process according to claim 6 , comprising the steps of:

a) reacting N-methyl 6-chloroanthranilate of formula (7) with a 3-(ethyl(phenyl)amino)-3-oxopropanoic acid derivative of formula (8) so as to obtain 2-chloro-6-(3-(ethyl(phenyl)amino)-N-methyl-3-oxopropanamido)benzoate of formula (9); and

b) converting the compound (9) obtained in step (a) to Laquinimod (1) or a salt thereof in the presence of a base.

8. The process according to claim 6 , comprising the steps of:

a) reacting N-methyl 6-chloroanthranilate of formula (7) with a 3-(ethyl(phenyl)amino)-3-oxopropanoic acid derivative of formula (8) so as to obtain 2-chloro-6-(3-(ethyl(phenyl)amino)-N-methyl-3-oxopropanamido)benzoate of formula (9);

b) saponifying the ester group CO 2 R in compound (9) to the corresponding carboxylic acid CO 2 H so as to obtain a compound formula (10), and converting acid (10) to an activated derivative thereof of formula (11); and

c) converting the compound of formula (11) obtained in step (b) to Laquinimod (1) or a salt thereof in the presence of a base.

9. The process according to claim 1 ,

wherein R is methyl, ethyl or benzyl; or

wherein X and Y are each a halogen; or

wherein X is OH.

10. The process according to claim 1 , wherein step (a) is conducted in the presence of an activating agent selected from the group consisting of a chloroformic acid ester; diphosgene, triphosgene and an acyl chloride.

11. The process according to claim 1 , wherein in step (a) compound (8A) is prepared in a separate step and then introduced into the reaction with compound (7A).

12. The process according to claim 1 , wherein in step (a) compound (8A) is prepared in situ and is reacted with compound (7A) in one step.

13. The process according to claim 1 , wherein step (a) is conducted in the presence of a base; or

wherein the step of converting compound (9A) to compound (I) is conducted in the presence of an alkali metal alkoxide; or

wherein the step of converting compound (11A) to compound (I) is conducted in the presence of an alkali metal alkoxide and, optionally, in the presence of a Lewis acid.

14. The process according to claim 1 , which produces a salt of the compound of formula (I).

15. The process according to claim 1 , which produces a sodium salt of the compound of formula (1) (Laquinimod sodium).

16. The process according to claim 14 , wherein said salt is formed by converting a compound of formula (I) to a salt thereof.

17. The process according to claim 15 , wherein the Laquinimod sodium is formed by reacting Laquinimod (1) with a sodium containing base.

18. The process according to claim 6 , wherein

the step of converting compound (9) to Laquinimod (1) is conducted in the presence of an alkali metal alkoxide; or

wherein the step of converting compound (11) to Laquinimod (1) is conducted in the presence of an alkali metal alkoxide and, optionally, in the presence of a Lewis acid.