Formation of N-Protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine
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 of synthesizing an oral delivery system comprising a diketopiperazine according to Formula I
the method comprising:
mixing a N-protected amino acid in an organic solvent selected from the group consisting of: dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme;
adding a catalyst to the mixture wherein the molar ratio of catalyst to N-protected amino acid is from 0.15:1 to about 0.5:1;
heating the mixture to a temperature of 110° C. to 175° C.;
wherein n is 0 to 3; wherein PG is selected from trifluoroacetyl, CBz, and acetyl;
cooling the mixture,
quenching the mixture,
holding the quenched mixture at a temperature of below 100° C. for at least 1 hour after quenching; and
isolating the diketopiperazine.
2 . The method of claim 1 , wherein n is equal to 3.
3 . The method of claim 1 , wherein PG is trifluoroacetyl.
4 . The method of claim 1 , wherein PG is Cbz.
5 . The method of claim 1 , wherein the solvent is N-methyl-2-pyrrolidone.
6 . The method of claim 1 , wherein the N-protected amino acid is ϵ-trifluoroacetyl-L-lysine.
7 . The method 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 method of claim 1 , wherein the mixture is heated for between 0.25 and 6 hours.
9 . The method of claim 1 , wherein the N-protected amino acid ϵ-Cbz-L-lysine.
10 . The method of claim 1 , wherein the N-protected amino acid is γ-trifluoroacetyl-ornithine.
11 . The method of claim 1 , wherein the N-protected amino acid is γ-Cbz-ornithine.
12 . The method of claim 1 , wherein the catalyst is phosphorous pentoxide.
13 . The method of claim 12 , wherein the molar ratio of catalyst to N-protected amino acid is from about 0.15:1 to about 0.4:1.
14 . The method of claim 13 , wherein the molar ratio of catalyst to N-protected amino acid is from about 0.15:1 to about 0.3:1.
15 . The method of claim 1 , wherein the mixture is quenched with water.
16 . The method of claim 1 , wherein the mixture is heated to a temperature of between 130° C. and 175° C.
17 . The method of claim 1 , wherein the mixture is heated to a temperature of between 150° and 175° C.
18 . The method of claim 1 , wherein the mixture is heated for between 0.25 and 5 hours.
19 . A method of synthesizing an oral delivery system comprising a diketopiperazine according to Formula I
the method comprising:
heating a mixture of an N-protected amino acid of Formula II 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 mixture does not include a catalyst; 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.
20 . The method of claim 19 , wherein the N-protected amino acid is ϵ-trifluoroacetyl-L-lysine.