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

Patent metadata

Field	Value
Publication number	US-9416113-B2
Application number	US-201414543464-A
Country	US
Kind code	B2
Filing date	Nov 17, 2014
Priority date	Feb 10, 2011
Publication date	Aug 16, 2016
Grant date	Aug 16, 2016

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.

First claim

What is claimed is:

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

heating a mixture of an amino acid of general formula I in the presence of a catalyst in an organic solvent;
wherein PG is selected from the group consisting of trifluoroacetyl, CBz, and acetyl, and n is 0 to 3;
wherein the catalyst is selected from the group consisting of: sulfuric acid, and phosphorous pentoxide, and is present in a concentration of 20 to 50% that of the amino acid; and
wherein the solvent is selected from the group consisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme.

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

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

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 amino acid is ε-trifluoroacetyl-L-lysine.

8. The method of claim 1 , wherein the amino acid is ε-Cbz-L-lysine.

9. The method of claim 1 , wherein the amino acid is γ-trifluoroacetyl-ornithine.

10. The method of claim 1 , wherein the 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 amino acid.

13. The method of claim 11 , wherein the concentration of phosphorous pentoxide is from 20% to 35% that of the 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 3,6-bis-[N-protected aminoalkyl]-2,5-diketopiperazine comprising:

heating a mixture of an amino acid of general formula I in the presence of a catalyst in an organic solvent;
wherein PG is selected from the group consisting of trifluoroacetyl, CBz, and acetyl, and n is 3;
wherein the catalyst is phosphorous pentoxide, and is present in a concentration of 20 to 50% that of the amino acid; and
wherein the solvent is selected from the group consisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme; and
wherein the mixture is heated to a temperature of between 150° and 175° C. for between 0.25 and 5 hours.

Assignees

• Mannkind Corp
• Mannkind Corp

Inventors

• Freeman John J
• Stamper Adrienne
• Heitmann Melissa

Classifications

• B01J31/0225

  comprising sulfonic acid groups or the corresponding salts · CPC title

• B01J2231/40

  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 title

• B01J27/16

  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 title

• B01J31/0259

  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 title

• C07D241/08 Primary

  with oxygen atoms directly attached to ring carbon atoms · CPC title