Method of preparing alkylated salicylamides via a dicarboxylate intermediate

1. A method of preparing a protected dicarboxylated salicylamide from a protected and activated salicylamide that is protected to prevent reaction of the hydroxy moiety and activated at the Nitrogen atom of the amide group, the method comprising the step of (a) alkylating the protected and activated salicylamide at the Nitrogen atom of the amide group with a dicarboxylate alkylating agent to form the protected dicarboxylated salicylamide.

2. A method of preparing an alkylated salicylamide from a protected and activated salicylamide that is protected to prevent reaction of the hydroxy moiety and activated at the Nitrogen atom of the amide group, the method comprising the steps of (a) alkylating the protected and activated salicylamide at the Nitrogen atom of the amide group with a dicarboxylate alkylating agent to form a protected and activated dicarboxylated salicylamide, and (b)(i) deprotecting, (ii) deactivating, and (iii) decarboxylating the protected and activated dicarboxylated salicylamide to form the alkylated salicylamide.

3. The method of claim 2 , wherein the protected and activated salicylamide has the formula

wherein

R 1 , R 2 , R 3 , and R 4 are independently hydrogen; halogen; C 1 -C 4 alkoxy, optionally substituted with —OH or F; —OH; C 1 -C 4 alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH 3 ; —SO 3 H; nitrile; or —NR 9 R 10 ;

R 9 and R 10 are independently hydrogen, C 1 -C 4 alkyl, or oxygen;

R 5 is a protecting group;

R 6 is an activating group; or

R 5 and R 6 are combined to form a substituted or unsubstituted cyclic group.

4. The method of claim 3 , wherein the protected and activated salicylamide has the formula

5. The method of claim 2 , wherein the dicarboxylate alkylating agent has the formula

wherein

R 7 is a linear or branched, C 1 -C 20 alkylene, alkenylene, or alkynylene;

R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl;

R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;

R 8 and R 11 are independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

X is a suitable leaving group.

6. The method of claim 2 , wherein the molar ratio of protected and activated salicylamide to dicarboxylate alkylating agent is from about 1:1 to about 1:0.5.

7. The method of claim 2 , wherein the alkylating step is performed in the presence of a base.

8. The method of claim 7 , wherein the molar ratio of base to protected and activated salicylamide is greater than 1.

9. The method of claim 8 , wherein the base is pyridine, picoline, tetramethylguanidine, triethylamine, diisopropylethylamine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or any combination of any of the foregoing.

10. The method of claim 9 , wherein the base is sodium carbonate.

11. The method of claim 2 , wherein the alkylating step is performed at a temperature of from about 40 to about 80° C.

12. The method of claim 11 , wherein the alkylating step is performed at a temperature of from about 60 to about 80° C.

13. The method of claim 2 , wherein the protected and activated dicarboxylate salicylamide has the formula

where

R 1 , R 2 , R 3 , and R 4 are independently hydrogen; halogen; C 1 -C 4 alkoxy, optionally substituted with —OH; or F; —OH; C 1 -C 4 alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH 3 ; —SO 3 H; nitrile; or —NR 9 R 10 ;

R 9 and R 10 are independently hydrogen, C 1 -C 4 alkyl, or oxygen;

R 5 is a protecting group;

R 6 is an activating group; or

R 5 and R 6 are combined to form a substituted or unsubstituted cyclic group;

R 7 is a linear or branched, C 1 -C 20 alkylene, alkenylene, or alkynylene;

R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl;

R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen or sulfur;

R 8 and R 11 are independently C 1 -C 4 alkyl or C 1 -C 4 haloalkyl; and

R 9 and R 10 are independently hydrogen, C 1 -C 4 alkyl, or oxygen.

14. The method of claim 2 , wherein deprotecting and deactivating the protected and activated dicarboxylated salicylamide comprises performing basic hydrolysis and acidic hydrolysis on the protected and activated dicarboxylated salicylamide.

15. The method of claim 2 , wherein the deprotecting, deactivating, and decarboxylating step comprises performing basic hydrolysis and acidic hydrolysis on the protected and activated dicarboxylated salicylamide.

16. The method of claim 2 , wherein the deprotecting step comprises hydrolysis.

17. The method of claim 16 , wherein the deprotecting step comprises basic hydrolysis.

18. The method of claim 17 , wherein the deactivating step comprises neutralization.

19. The method of claim 2 , further comprising hydrolyzing one or more carboxyl moieties of the alkylated salicylamide after steps (b)(i) an (b)(ii) to form the free acid of the dicarboxylated salicylamide.

20. The method of claim 19 , wherein the decarboxylating step is performed after the deprotecting, deactivating, and hydrolyzing steps.

21. The method of claim 2 , wherein decarboxylating comprises heating the dicarboxylated salicylamide in an organic solvent to a temperature ranging from about 140 to about 200° C.

22. The method of claim 21 , wherein the organic solvent has a boiling point of at least about 110° C.

23. The method of claim 21 , wherein the organic solvent is selected from xylenes, toluene, heptane, dimethyl acetamide, dimethyl formamide, methyl sulfoxide, isoparaffins, and any combination of any of the foregoing.

24. The method of claim 2 , wherein the alkylated salicylamide has the formula

wherein

R 1 , R 2 , R 3 , and R 4 are independently hydrogen; halogen; C 1 -C 4 alkoxy, optionally substituted with —OH or F; —OH; C 1 -C 4 alkyl, optionally substituted with —OH or F; —COOH; —OC(O)CH 3 ; —SO 3 H; nitrile; or —NR 9 R 10 ;

R 7 is a linear or branched, C 1 -C 20 alkylene, alkenylene, or alkynylene;

R 7 is optionally substituted with C 1 -C 4 alkyl, C 1 -C 4 alkenyl, oxygen, nitrogen, sulfur, halogen, —OH, C 1 -C 4 alkoxy, aryl, heteraryl, or vinyl;

R 7 is optionally interrupted with aryl, heteroaryl, vinyl, oxygen, nitrogen, or sulfur;

R 9 and R 10 are independently hydrogen, C 1 -C 4 alkyl, or oxygen; and

R 18 and R 19 are independently hydrogen, carboxyl or a salt thereof, carboxylate, nitrile, halogen, ester, amine or salt thereof, alcohol, or thiol and at least one of R 18 and R 19 is not hydrogen, and R 18 and R 19 are not both selected from carboxyl or a salt thereof, or carboxylate.

25. The method of claim 24 , wherein R 19 is hydrogen.

26. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-7-amino)heptanoic acid or a salt thereof.

27. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-8-amino)octanoic acid or a salt thereof.

28. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxybenzoyl)-10-amino)decanoic acid or a salt thereof.

29. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxy-5-chlorobenzoyl)-4-amino)butyric acid or a salt thereof.

30. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxy-5-chlorobenzoyl)-8-amino)octanoic acid or a salt thereof.

31. The method of claim 2 , wherein the alkylated salicylamide is N-(2-hydroxy-4-methoxybenzoyl)-8-amino)octanoic acid or a salt thereof.

32. A method of preparing an alkylated salicylamide from a protected and activated dicarboxylated salicylamide that is protected to prevent reaction of the hydroxy moiety and activated at the Nitrogen atom of the amide group comprising the step of deprotecting, deactivating, decarboxylating, and hydrolyzing the protected and activated dicarboxylated salicylamide to form the alkylated salicylamide.