Catalysis of diketopiperazine synthesis

• US 9,796,688 B2
• Filed: 04/12/2016
• Issued: 10/24/2017
• 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): Rao, Deepak
• Assistant Examiner(s): DANIEL, LAURA M
• Application Number:
  US15/097,124
• Publication Number:
  US 20160221967A1
• Time in Patent Office: 560 Days
• 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 an N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising heating a solution comprising:

a. an amino acid having a free α

-amine group and a protected amine group, and

b. means for catalyzing dehydrative cyclocondensation of said amino acid;

c. wherein said solution is heated to a target temperature between 160°

C. and 170°

C., and the target temperature is achieved in 4-6 hours and said target temperature is maintained for up to 8 hours.

2. The method of claim 1, wherein said target temperature is maintained for up to 6 hours.

3. The method of claim 1, wherein said synthesis is-complete within 8 hours of reaching said target temperature.

4. The method of claim 1, wherein said means for catalyzing dehydrative cyclocondensation of said amino acid comprises addition of a catalyst to the solution, wherein said catalyst comprises at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide.

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

6. A method for the synthesis of N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising:

a. a step for catalyzing a dehydrative cyclocondensation reaction of an amino acid having a free α

-amine group and a protected amine group, and

b. collecting the N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine on a filter;

c. wherein said dehydrative cyclocondensation reaction comprises heating to a target temperature between 160°

C. and 170°

C. and the target temperature is achieved in 4-6 hours and said target temperature is maintained for up to 8 hours.

7. The method of claim 6, wherein said-target temperature is maintained for up to 6 hours.

8. The method of claim 6, wherein said synthesis is complete within 8 hours of reaching said target temperature.

9. The method of claim 6, wherein said step for catalyzing dehydrative cyclocondensation of said amino acid comprises using at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide as the catalyst.

10. A method for the synthesis of N-protected 3,6-bis[4-aminoalkyl]-2,5-diketopiperazine comprising:

a. adding an amino acid having a free α

-amine group and a protected amine group to a solvent, and b. a step for catalyzing dehydrative cyclocondensation of the amino acid having a free α

-amine group and a protected amine group, wherein said step for catalyzing comprises heating said solvent containing said amino acid to a target temperature between 160°

C. and 170°

C. and the target temperature is achieved in 4-6 hours and said target temperature is maintained for up to 8 hours.

11. The method of claim 10, wherein said target temperature is maintained for up to 6 hours.

12. The method of claim 10, wherein said synthesis is-complete within about 8 hours of reaching said target temperature.

13. The method of claim 10, wherein said step for catalyzing dehydrative cyclocondensation of said amino acid comprises addition of a catalyst to the solution, wherein said catalyst comprises at least one of sulfuric acid, phosphoric acid, or phosphorus pentoxide.