IP Library › Patent Application 19359883
Patent Application
App. No. 19/359,883

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

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Patent No.
US None
App. No.
19/359,883
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 (28)

1 . An oral delivery system comprising a diketopiperazine according to Formula I, the diketopiperazine synthesized by the method comprising

heating a N-protected amino acid to a temperature of 110° C. to 175° C. in the presence of a catalyst in an organic solvent;

wherein n is 0 to 3; wherein PG is selected from trifluoroacetyl, CBz, and acetyl;

wherein the catalyst is present in a concentration of 20% to 50% that of the N-protected amino acid.

2 . The oral delivery system of claim 1 , wherein n is equal to 3.

3 . The oral delivery system of claim 1 , wherein PG is trifluoroacetyl.

4 . The oral delivery system of claim 1 , wherein PG is Cbz.

5 . The oral delivery system of claim 1 , wherein the solvent is N-methyl-2-pyrrolidone.

6 . The oral delivery system of claim 1 , wherein the N-protected amino acid is-trifluoroacetyl-L-lysine.

7 . The oral delivery system of claim 1 , wherein the catalyst is selected from sulfuric acid, phosphoric acid, p-toluenesulfonic acid, 1-propylphosphonic acid cyclic anhydride, tributyl phosphate, phenyl phosphonic acid and phosphorous pentoxide.

8 . The oral delivery system of claim 1 , wherein the mixture is heated for between 0.25 and 6 hours.

9 . The oral delivery system of claim 1 , wherein the N-protected amino acid is ε-trifluoroacetyl-L-lysine.

10 . The oral delivery system of claim 1 , wherein the N-protected amino acid is ε-Cbz-L-lysine.

11 . The oral delivery system of claim 1 , wherein the N-protected amino acid is γ-trifluoroacetyl-ornithine.

12 . The oral delivery system of claim 1 , wherein the N-protected amino acid is γ-Cbz-ornithine.

13 . The oral delivery system of claim 1 , wherein the catalyst is phosphorous pentoxide.

14 . The oral delivery system of claim 13 , wherein the concentration of phosphorous pentoxide is from 20% to 40% that of the N-protected amino acid.

15 . The oral delivery system of claim 13 , wherein the concentration of phosphorous pentoxide is from 20% to 35% that of the N-protected amino acid.

16 . The oral delivery system of claim 1 , further comprising the step of quenching the mixture with water.

17 . The oral delivery system of claim 1 , wherein the mixture is heated to a temperature of between 130° C. and 175° C.

18 . The oral delivery system of claim 1 , wherein the mixture is heated to a temperature of between 150° and 175° C.

19 . The oral delivery system of claim 1 , wherein the mixture is heated for between 0.25 and 5 hours.

20 . An oral delivery system comprising a diketopiperazine according to Formula I, the diketopiperazine synthesized according to the method comprising:

heating a mixture of an N-protected amino acid of Formula II 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 phosphorous pentoxide, and is present in a concentration of 20% to 35% 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 6 hours.