Formation of N-protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine

• US 10,196,366 B2
• Filed: 08/15/2016
• Issued: 02/05/2019
• Est. Priority Date: 02/10/2011
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Freeman, John J., Stamper, Adrienne, Heitmann, Melissa
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US15/237,427
• Publication Number:
  US 20160347721A1
• Time in Patent Office: 904 Days
• CPC Class Codes: B01J 2231/40 Substitution reactions at carbon centres, e.g. C-C or C-X, i.e. carbon-hetero atom, cross-coupling, C-H activation or ring-opening reactions
• CPC Class Codes: B01J 31/0225 comprising sulfonic acid groups or the corresponding salts
• CPC Class Codes: B01J 31/0258 Phosphoric acid mono-, di- or triesters ((RO)(R'O)2P=O), i.e. R= C, R'= C, H
• CPC Class Codes: B01J 31/0259 comprising phosphorous acid (-ester) groups ((RO)P(OR')2) or the isomeric phosphonic acid (-ester) groups (R(R'O)2P=O), i.e. R= C, R'= C, H
• CPC Class Codes: C07D 241/08 with oxygen atoms directly attached to ring carbon atoms

Abstract

The disclosed embodiments detail improved methods for the synthesis of diketopiperazines from amino acids. In particular improved methods for the cyclocondensation and purification of N-protected 3,6-(aminoalkyl)-2,5-diketopiperazines from N-protected amino acids. Disclosed embodiments describe methods for the synthesis of 3,6-bis-[N-protected aminoalkyl]-2,5-diketopiperazine comprising heating a mixture of an amino acid in the presence of a catalyst in an organic solvent. The catalyst is selected from the group comprising sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid and phosphorous pentoxide among others. The solvent is selected from the group comprising: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, ethyldiglyme, m-cresol, p-cresol, o-cresol, xylenes, ethylene glycol and phenol among others.

Claims

1. A method for the synthesis of a diketopiperazine according to Formula I comprising

2. The method of claim 1, wherein n is equal to 3.

3. The method of claim 1, wherein the N-protected amino acid is:

4. The method of claim 1, wherein PG is trifluoroacetyl.

5. The method of claim 1, wherein PG is Cbz.

6. The method of claim 1, wherein the solvent is N-methyl-2-pyrrolidone.

7. The method of claim 1, wherein the N-protected amino acid is ε

-trifluoroacetyl-L-lysine.

8. The method of claim 1, wherein the N-protected amino acid is ε

-Cbz-L-lysine.

9. The method of claim 1, wherein the N-protected amino acid is γ

-trifluoroacetyl-ornithine.

10. The method of claim 1, wherein the N-protected amino acid is γ

-Cbz-ornithine.

11. The method of claim 1, wherein the catalyst is phosphorous pentoxide.

12. The method of claim 11, wherein the concentration of phosphorous pentoxide is from 20% to 40% that of the N-protected amino acid.

13. The method of claim 11, wherein the concentration of phosphorous pentoxide is from 20% to 35% that of the N-protected amino acid.

14. The method of claim 1, further comprising the step of quenching the mixture with water.

15. The method of claim 1, wherein the mixture is heated to a temperature of between 110°

C. and 175°

C.

16. The method of claim 1, wherein the mixture is heated for between 0.25 and 5 hours.

17. The method of claim 1, wherein the mixture is heated to a temperature of between 150°

and 175°

C.

18. A method for the synthesis of a diketopiperazine according to Formula I comprising: