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