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:
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;
cooling the resulting mixture by 10° C. to 75° C.;
quenching the mixture with additional cooling;
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 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 7 , wherein the mixture is heated for between 0.25 and 6 hours.
9 . The method of claim 1 , wherein the N-protected amino acid is 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 concentration of phosphorous pentoxide is from 20% to 40% that of the N-protected amino acid.
14 . The method of claim 12 , wherein the concentration of phosphorous pentoxide is from 20% to 35% that of the N-protected amino acid.
15 . The method of claim 1 , wherein the mixture is quenched with water.
16 . The method of claim 8 , 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 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, cooling the mixture by between 50° and 75° C.; and quenching the mixture with additional cooling.