Catalysis of diketopiperazine synthesis

• US 20060041133A1
• Filed: 08/19/2005
• Published: 02/23/2006
• Est. Priority Date: 08/20/2004
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Moye-Sherman, Destardi, Stevenson, John J.
• Granted Patent: US 7,709,639 B2
• Time in Patent Office: Days
• US Class Current: 544/358
• CPC Class Codes: B01J 27/16 containing oxygen , i.e. acids, anhydrides and their derivates with N, S, B or halogens without carriers or on carriers based on C, Si, Al or Zr; also salts of Si, Al and Zr
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms

Abstract

Provided is a method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine including the step of heating a solution of c-amino protected lysine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide.

Claims

1. A method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine comprising the step of heating a solution of ε

-amino protected lysine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide.

2. The method of claim 1 wherein said c-amino protected lysine is (N-benzyloxycarbonyl)-lysine (Cbz-L-lysine).

3. The method of claim 1 wherein said catalyst is sulfuric acid.

4. The method of claim 1 wherein said catalyst is phosphoric acid.

5. The method of claim 1 wherein said catalyst is phosphorous pentoxide.

6. The method of claim 5 wherein the concentration of phosphorus pentoxide is from about 5% to about 10%.

7. The method of claim 6 wherein the concentration of phosphorus pentoxide is 7.5%.

8. The method of claim 1 wherein the solution is heated to a target temperature of about 160°

C. to 170°

C.

9. The method of claim 8 wherein the target temperature is achieved in about 4 to 6 hours.

10. A method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine comprising the step of heating a solution of ε

-amino protected lysine in the presence of a catalyst wherein synthesis is substantially complete within about 10 hours of reaching a target temperature.

11. The method of claim 10 wherein said target temperature is about 160°

C. to 170°

C.

12. The method of claim 10 wherein said synthesis is substantially complete within about 8 hours.

13. The method of claim 10 wherein said synthesis is substantially complete within about 4 hours.

14. The method of claim 10 wherein said synthesis is substantially complete within about 3 hours.

15. The method of claim 10 wherein said synthesis is substantially complete within about 1.5 hours.

16. The method of claim 10 where in said catalyst is phosphorous pentoxide.

17. The method of claim 16 wherein the concentration of phosphorus pentoxide is from about 5% to about 10%.

18. The method of claim 17 wherein the concentration of phosphorus pentoxide is 7.5%.

19. The method of claim 10 where in said ε

-amino protected lysine is Cbz-L-lysine.

20. A method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine comprising the step of heating a solution of ε

-amino protected lysine in the presence of a catalyst wherein said synthesis has a yield of greater than 50%.

21. The method of claim 20 wherein said catalyst is phosphorous pentoxide.

22. The method of claim 21 wherein the concentration of phosphorus pentoxide is from about 5% to about 10%.

23. The method of claim 22 wherein the concentration of phosphorus pentoxide is 7.5%.

24. The method of claim 20 wherein the ε

-amino protected lysine is Cbz-L-lysine.