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10. (WO2013138200) GREEN CHEMISTRY SYNTHESIS OF THE MALARIA DRUG AMODIAQUINE AND ANALOGS THEREOF
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

What we claim is:

1. A one-pot process without requiring isolation of an intermediate for preparing a compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the formula:


wherein X is a substituent at the 5, 6, 7, or 8-position of the quinoline ring and represents halide, alkyl, alkyloxy, halo-alkyl, or halo-alkyloxy, and R1 and R2 are independently alkyl, aryl or hetero-aryl, wherein said method comprises heating a mixture formed in situ comprised of aminophenol, and an at least di-substituted quinoline having a suitable leaving group in the 4-position of the quinoline ring in a polar acidic solvent; and combining the reaction mixture with an aldehyde and a secondary amine, without isolating intermediates or precursors before conducting the combining step, to obtain the compound or its pharmaceutically acceptable salt.

2. A one-pot process for preparing a compound or its pharmaceutical salts according to claim 1, wherein said compound is represented by the formula:

wherein X is a halogen, and

R1 and R2 are independently alkyl, aryl or hetero-aryl, wherein said method comprises:

(a) heating a mixture comprising aminophenol, a 4,7 di-halo substituted- quinoline in a polar acidic solvent; and

(b) combining the reaction mixture with an aldehyde and a secondary amine, without isolating intermediates or precursors, to obtain the compound.

3. The process of claim 2, wherein R1 and R2 are alkyl.

4. The process of claim 2, wherein R1 and R2 are C1 -C6 alkyl and the secondary amine is di-(C1 -C6) alkylamine.

5. The process of claim 1, wherein R1 and R2 are isopropyl and the secondary amine is di-isopropylamine.

6. The process of claim 2, wherein R1 and R2 are ethyl and the secondary amine is diethylamine.

7. The process of claim 2, wherein R1 and R2 are aryl and the secondary amine is an arylamine.

8. The process of claim 2, wherein R1 and R2 are heteroaryl and the secondary amine is a heteroarylamine.

9. The process of claim 1, wherein the pharmaceutically acceptable salts comprises a salt of hydrochloric acid, hydrobromic acid, acetic acid, trifluoroacetic acid, citric acid, oxalic acid, benzoic acid, benzenesulfonic acid, toluenesulfonic acid, sulfuric acid, tartaric acid, fumaric acid, maleic acid, malic acid, lactic acid, and methanesulfonic acid.

10. The process of claim 1, wherein X is a substituent at the 5, 6, 7, or 8-position of the quinoline ring and represents halogen.

11. The process of claim 2, wherein in step (a) the halogen of 4,7 di-halo substituted quinoline is selected from fluorine, chlorine bromine, and iodine and X is the halogen selected for the 4,7 di-halogen substituted quinoline.

12. The process of claim 9, wherein in step (a) the halogen of 4,7 di-halo substituted quinoline is selected from chlorine and bromine.

13. The process of claim 2, wherein in step (a) the halogen of 4,7 di-halo substituted quinoline is chlorine and X is chlorine.

14. The process of claim 2, wherein in the compound produced is an amodiaquine-analog

R1 and R2 are alkyl groups, and the hydroxyl group is in the ortho-substituted position relative to the substituent bearing R1 and R2.

15. The process of claim 2, wherein in the compound produced is an amodiaquine-analog having the hydroxyl group in the ortho-substituted position relative to the substituent bearing R1 and R2.

16. The process of claim 1, wherein the aminophenol is 4-aminophenol.

17. The process of claim 1, wherein the aminophenol is 3-aminophenol.

18. The process of claim 12, wherein in step (a) the molar ratio of aminophenol to 4,7-dichloroquinoline is about 0.80 to about 1.20.

19. The process of claim 12, wherein in step (a) the molar ratio of aminophenol to 4,7-dichloroquinoline is about 0.85 to about 1.10.

20. The process of claim 12, wherein in step (a) the molar ratio of aminophenol to 4,7-dichloroquinoline is about 0.95 to about 1.10.

21. The process of claim 12, wherein in step (a) the molar ratio of aminophenol to 4,7-dichloroquinoline is about 1.00 to about 1.10.

22. The process of claim 12, wherein in step (a) the molar ratio of aminophenol to 4,7-dichloroquinoline is about 1.03 to about 1.10.

23. The process of claim 1, wherein the polar acidic solvent comprises acetic acid.

24. The process of claim 1, wherein the polar acidic solvent includes an alcohol.

25. The process of claim 24, wherein the alcohol comprises at least one of methanol, ethanol, propanol, and isopropanol.

26. The process of claim 23, wherein in step (a) the acetic acid is in a concentration of about 0.5 Molar to about 6 Molar.

27. The process of claim 12, wherein in step (a) the mixture is heated to reflux.

28. The process of claim 1, wherein in step (a) the mixture is heated to a temperature of about 60°C to about 140°C.

29. The process of claim 1, wherein step (a) the mixture is heated to a temperature up to about 110°C.

30. The process of claim 2, wherein the compound produced is amodiaquine having not more than about 10% impurities.

31. The process of claim 2, wherein the compound produced is amodiaquine produced having less than about 10% impurities in total, and the impurities may be represented by:

32. The process of claim 2, wherein the compound produced is amodiaquine at a yield of amodiaquine of at least about 85%.

33. The process of claim 2, wherein the compound produced is amodiaquine at a yield of at least about 92%.

34. The process of claim 2, wherein in step (b) is performed in an acidic solution.

35. The process of claim 34, wherein in step (b) the aqueous acidic solution is an acetic acid solution.

36. The process of claim 34, wherein in step (b) the aqueous acidic solution is a solution of aqueous hydrochloric acid and acetic acid.

37. The process of claim 36, wherein in step (b) the hydrochloric acid solution has a hydrochloric acid concentration of about 0% to about 30% by volume.

38. The process of claim 2, wherein step (b) is performed in an organic acid solution.

39. The process of claim 38, wherein in step (b) the organic acid solution is a trifluoroacetic acid solution.

40. The process of claim 39, wherein in step (b) the trifluoroacetic acid solution has a concentration of about 5% to about 35%.

41. The process of claim 2, wherein in step (b) the aldehyde is formaldehyde.

42. The process of claim 1, wherein there is about 3-5 kilograms of waste generated per kilogram of product produced.

43. The process of claim 2, wherein step (a) is conducted for about one hour to about five hours.

44. The process of claim 43, wherein step (a) is conducted for about one hour.

45. The process of claim 2, wherein step (a) is conducted for about three hours.

46. The process of claim 43, wherein step (b) is conducted for about three hours to about twenty hours.

47. The process of claim 46, wherein step (b) is conducted for about four hours.

48. The process of claim 46, wherein step (b) is conducted for about fourteen hours.