Catalysis of diketopiperazine synthesis

• US 9,346,766 B2
• Filed: 04/30/2014
• Issued: 05/24/2016
• Est. Priority Date: 08/20/2004
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Stevenson, John J., Moye-Sherman, Destardi
• Primary Examiner(s): Wilson, James O
• Assistant Examiner(s): Sackey, Ebenezer O
• Application Number:
  US14/266,632
• Publication Number:
  US 20140243530A1
• Time in Patent Office: 755 Days
• Field of Search: 544/385
• US Class Current: 1/1
• 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 ε-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 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising heating a solution comprising N-benzyloxycarbonyl-lysine and phosphorus pentoxide.

2. The method of claim 1, wherein the solution is heated to a temperature range of between 160°

C. and 170°

C.

3. The method of claim 1, wherein said phosphorous pentoxide is provided in a concentration from about 5% to about 10%.

4. The method of claim 3, wherein the concentration of phosphorus pentoxide is about 7.5%.

5. The method of claim 1, wherein the solution further comprises m-cresol, ethylene glycol, propylene glycol, toluene, or xylene.

6. The method of claim 1, wherein the N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine is 3,6-bis[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine.

7. The method of claim 2, wherein the solution is heated for up to 6 hours.

8. The method of claim 2, wherein the solution is heated for up to 4 hours.

9. The method of claim 2, wherein the solution is heated for up to 3 hours.

10. The method of claim 2, wherein the solution is heated for up to 1.5 hours.

11. A method for the synthesis of 3,6-di(4-fumarylaminobutyl)2,5-diketopiperazine comprising heating a solution comprising N-benzyloxycarbonyl-lysine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide, to synthesize N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine.

12. The method of claim 11, wherein the N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine is 3,6-bis[(N-benzyloxycarbonyl)-4-aminobutyl]-2,5-diketopiperazine.

13. The method of claim 11, wherein the solution is heated to a target temperature range of between 160°

C. and 170°

C.

14. The method of claim 11, wherein said catalyst is provided in a concentration from about 5% to about 10%.

15. The method of claim 14, wherein the concentration of said catalyst is about 7.5%.

16. The method of claim 11, wherein the solution further comprises m-cresol, ethylene glycol, propylene glycol, toluene, or xylene.

17. The method of claim 13, wherein synthesis is substantially complete within about 6 hours after reaching the target temperature.

18. The method of claim 13, wherein synthesis is substantially complete within about 4 hours after reaching the target temperature.

19. The method of claim 13, wherein synthesis is substantially complete within about 3 hours after reaching the target temperature.

20. The method of claim 13, wherein synthesis is substantially complete within about 1.5 hours after reaching the target temperature.

21. The method of claim 11 wherein the catalyst is sulfuric acid.

22. The method of claim 11 wherein the catalyst is phosphoric acid.

23. The method of claim 11 wherein the catalyst is phosphorus pentoxide.

24. The method of claim 23, wherein the N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine is 3,6-bis[(N-benzyloxycarbonyl)-4- aminobutyl]-2,5-diketopiperazine.