Salts of carnitine derivatives and methods of production

Patent metadata

Field	Value
Publication number	US-9573883-B2
Application number	US-201414570748-A
Country	US
Kind code	B2
Filing date	Dec 15, 2014
Priority date	Dec 16, 2013
Publication date	Feb 21, 2017
Grant date	Feb 21, 2017

Abstract

Disclosed are salts, such as nitrates, of acetyl-L-carnitine and propionyl-L-carnitine and methods of making the compounds.

First claim

The invention claimed is:

1. A method of producing acetyl-L-carnitine nitrate comprising:
reacting L-carnitine with acetic anhydride to produce acetyl-L-carnitine free base;
isolating the acetyl-L-carnitine free base;
reacting the acetyl-L-carnitine free base with nitric acid to produce acetyl-L-carnitine nitrate; and
isolating the acetyl-L-carnitine nitrate,
wherein reacting L-carnitine with acetic anhydride to produce acetyl-L-carnitine free base comprises dissolving the L-carnitine in acetic acid, and wherein the reaction between L-carnitine and acetic anhydride occurs at a temperature of between 30° C. and 80° C.

2. The method of claim 1 , wherein the ratio of acetic acid to L-carnitine is about 0.65 g to 3 g acetic acid for every gram of L-carnitine.

3. The method of claim 1 , wherein the reaction between L-carnitine and acetic anhydride occurs for 3 to 12 hours.

4. The method of claim 1 , wherein isolating the acetyl-L-carnitine free base comprises:
distilling the reaction of L-carnitine free base and acetyl anhydride to remove the other products of the reaction;
washing the acetyl-L-carnitine free base with acetone; and
crystallizing the acetyl-L-carnitine free base.

5. The method of claim 4 , wherein distilling the reaction of L-carnitine and acetic anhydride occurs at reduced pressure.

6. The method of claim 5 , wherein distilling the reaction of L-carnitine and acetic anhydride occurs in a vacuum.

7. The method of claim 5 , wherein washing the acetyl-L-carnitine free base with acetone comprises using an amount of acetone by grams that is two to five times the amount L-carnitine by grams.

8. The method of claim 5 , wherein crystallizing the acetyl-L-carnitine free base comprises cooling the acetyl-L-carnitine free base to below 5° C.

9. The method of claim 8 , wherein crystallizing the acetyl-L-carnitine free base further comprises maintaining the acetyl-L-carnitine free base at between 0° C. and 5° C. for at least 2 hours.

10. The method of claim 1 , wherein reacting the acetyl-L-carnitine free base with nitric acid to produce acetyl-L-carnitine nitrate comprises dissolving the acetyl-L-carnitine in acetic acid, wherein the reaction between L-carnitine and acetic anhydride occurs at a temperature of between 30° C. and 80° C.

11. The method of claim 10 , wherein the ratio of acetic acid to acetyl L-carnitine free base is about 0.8 g to 3 g acetic acid for every gram of acetyl-L-carnitine free base.

12. The method of claim 10 , wherein the reaction between the acetyl-L-carnitine free base and nitric acid occurs for about 2 to 5 hours.

13. The method of claim 1 , wherein isolating the acetyl-L-carnitine nitrate comprises:
distilling the reaction of acetyl-L-carnitine free base and nitric acid to remove the other products of the reaction;
washing the acetyl-L-carnitine nitrate with acetone; and
crystallizing the acetyl-L-carnitine nitrate.

14. The method of claim 13 , wherein washing the acetyl-L-carnitine nitrate with acetone comprises using an amount of acetone by weight that is two to five times the amount acetyl-L-carnitine free base by weight.

15. The method of claim 13 , wherein crystallizing the acetyl-L-carnitine nitrate comprises cooling the acetyl-L-carnitine nitrate to below 5° C.

16. The method of claim 15 , wherein crystallizing acetyl-L-carnitine nitrate further comprises maintaining the acetyl-L-carnitine nitrate at between 0° C. and 5° C. for at least 2 hours.

17. A method of producing propionyl-L-carnitine nitrate comprising:
reacting L-carnitine with propionic anhydride to produce propionyl-L-carnitine free base;
isolating the propionyl-L-carnitine free base;
reacting the propionyl-L-carnitine free base with nitric acid to produce propionyl-L-carnitine nitrate; and
isolating the propionyl-L-carnitine nitrate.

18. The method of claim 17 , wherein the molar ratio of propionic anhydride to L-carnitine is about 1.5:1.

19. The method of claim 17 , wherein reacting L-carnitine with propionic anhydride to produce propionyl-L-carnitine free base further comprises mixing the L-carnitine with potassium hydroxide, wherein the reaction of L-carnitine, potassium hydroxide, and propionic anhydride occurs at a temperature of about 80° C.

20. The method of claim 19 , wherein the molar ratio of L-carnitine and potassium hydroxide is 1:1.

21. The method of claim 19 , wherein a small amount of pyridine is added to the reaction of L-carnitine, potassium hydroxide, and propionic anhydride as a catalyst.

22. The method of claim 21 , wherein the reaction of L-carnitine, potassium hydroxide, and propionic anhydride occurs for between 1 to 3 hours.

23. The method of claim 17 , wherein the reaction between the propionyl-L-carnitine free base with nitric acid occurs at about 30° C.

24. The method of claim 23 , wherein the reaction between the propionyl-L-carnitine free base and nitric acid occurs for about 2 hours.

25. The method of claim 17 , wherein isolating the propionyl-L-carnitine nitrate comprises crystallizing the propionyl-L-carnitine nitrate by drying the reaction between the propionyl-L-carnitine free base and nitric acid.

26. The method of claim 25 , wherein the reaction between the propionyl-L-carnitine free base and nitric acid is dried in a vacuum.

27. The method of claim 17 , wherein isolating the propionyl-L-carnitine comprises:
filtering the reaction of L-carnitine and propionic anhydride to discard the precipitate; and
crystallizing the propionyl-L-carnitine free base.

28. The method of claim 27 , wherein crystallizing the propionyl-L-carnitine free base comprises cooling the solution product of the reaction of L-carnitine and propionic anhydride to between 0° C. and 5° C.

Assignees

• Thermolife Int Llc

Inventors

• Kramer Ronald
• Nikolaidis Alexander

Classifications

• C07C229/22 Primary

  the carbon skeleton being further substituted by oxygen atoms · CPC title

• C07C227/16 Primary

  by reactions not involving the amino or carboxyl groups · CPC title

• C07C227/42

  Crystallisation · CPC title