Methods for the preparation of 6-aminoisoquinoline

1. A method of preparing 6-aminoisoquinoline,

the method comprising:

reacting 6-nitroisoquinoline-1,3(2H,4H)-dione,

with R 1 —P(O)Cl 2 , wherein R 1 is aryl, alkyl, or chloro;

to form 1,3-dichloro-6-nitroisoquinoline,

converting 1,3-dichloro-6-nitroisoquinoline to crude 6-aminoisoquinoline;

decolorizing the 6-aminoisoquinoline;

dissolving the 6-aminoisoquinoline in an acidic solution and washing with solvent;

extracting with base; and

recrystallizing to obtain about 99.9% pure 6-aminoisoquinoline;

wherein reacting 6-nitroisoquinoline-1,3(2H,4H)-dione with R 1 —P(O)Cl 2 comprises heating at a temperature of at least 120° C.

2. The method of claim 1 , wherein R 1 is aryl.

3. The method of claim 1 , further comprising:

reacting 2-(carboxymethyl)-4-nitrobenzoic acid,

with urea in the presence of an acid;

to form 6-nitroisoquinoline-1,3(2H,4H)-dione.

4. The method of claim 3 , wherein reacting 2-(carboxymethyl)-4-nitrobenzoic acid with urea comprises heating at a temperature of at least 90° C.

5. The method of claim 3 , wherein the acid is acetic acid.

6. The method of claim 3 , further comprising:

reacting a compound of formula (III),

wherein R is alkyl;

with a base, to form 2-(carboxymethyl)-4-nitrobenzoic acid.

7. The method of claim 6 , wherein the base is an alkali metal hydroxide or an alkaline earth metal hydroxide.

8. The method of claim 6 , wherein the base is an alkali metal hydroxide.

9. The method of claim 6 , wherein the base is potassium hydroxide.

10. The method of claim 6 , further comprising:

reacting a compound of formula (I),

wherein X is halogen or OSO 2 R a ; and R a is aryl, alkyl or haloalkyl;

with a compound of formula (II),

wherein R is alkyl;

to form the compound of formula (III).

11. The method of claim 10 , wherein reacting the compound of formula (I) with the compound of formula (II) comprises adding a base, a catalyst, and a solvent.

12. The method of claim 11 , wherein the base is a metal alkoxide.

13. The method of claim 11 , wherein the catalyst comprises copper.

14. The method of claim 11 , wherein the solvent is ethanol.

15. The method of claim 10 , further comprising heating at a temperature of at least 60° C.

16. The method of claim 6 , wherein R is C 1 -C 6 alkyl.

17. The method of claim 6 , wherein R is ethyl.

18. The method of claim 10 , wherein X is halogen.

19. The method of claim 10 , wherein X is Cl.

20. The method of claim 1 , wherein the 6-aminoisoquinoline is decolorized with activated charcoal.

21. The method of claim 1 , wherein the crude 6-aminoisoquinioline is filtered using methanol.

22. The method of claim 1 , wherein the acid is citric acid.

23. The method of claim 1 , wherein the base is concentrated ammonium hydroxide, 10% aqueous potassium hydroxide, and 10% aqueous potassium carbonate.

24. The method of claim 1 , wherein the 6-aminoisoquinioline is recrystallized using ethanol.

25. The method of claim 1 , wherein the 6-aminoisoquinoline is at least about 99.9% pure.

26. The method of claim 25 , wherein the 6-aminoisoquinoline is substantially free of higher molecular weight impurities, nitroso and nitro containing impurities, and chlorinated impurities.

27. A method of preparing 6-aminoisoquinoline,

the method comprising:

(a) reacting 2-chloro-4-nitrobenzoic acid,

with diethyl malonate, to form 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid,

(b) reacting 2-(1,3-diethoxy-1,3-dioxopropan-2-yl)-4-nitrobenzoic acid with a base to form 2-(carboxymethyl)-4-nitrobenzoic acid,

(c) reacting 2-(carboxymethyl)-4-nitrobenzoic acid with urea to form 6-nitroisoquinoline-1,3(2H,4H)-dione,

(d) reacting 6-nitroisoquinoline-1,3(2H,4H)-dione with R 1 —P(O)Cl 2 to form 1,3-dichloro-6-nitroisoquinoline,

wherein R 1 is aryl;

(e) converting 1,3-dichloro-6-nitroisoquinoline to 6-aminoisoquinoline;

(f) decolorizing the 6-aminoisoquinoline;

(g) dissolving the 6-aminoisoquinoline in an acidic solution and washing with solvent;

(h) extracting with base; and

(i) recrystallizing to obtain 99.9% pure 6-aminoisoquinoline.