Formation of n-protected 3,6-bis-(4-aminoalkyl)-2,5,diketopiperazine
Inventors
Freeman, John J. • Stamper, Adrienne • Heitmann, Melissa
Assignees
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Publication Number
US-12459903-B2
Publication Date
2025-11-04
Expiration Date
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.
Core Innovation
The invention relates to a method of synthesizing an oral delivery system comprising a diketopiperazine according to Formula I. The method comprises heating an N-protected amino acid in the presence of a catalyst in an organic solvent, and then cooling the resulting mixture and quenching the mixture with additional cooling. The diketopiperazine is defined by Formula I with n being 0 to 3 and PG selected from trifluoroacetyl, CBz, and acetyl.
In one approach, the catalyst is present in a concentration of 20% to 50% that of the N-protected amino acid. Specific N-protected amino acids include γ-trifluoroacetyl-ornithine and γ-Cbz-ornithine, and specific catalysts include phosphorous pentoxide. Additional refinements specify a narrower phosphorous pentoxide concentration sub-range and a quenching medium as water.
Another approach further defines the method by heating a mixture of an N-protected amino acid of Formula II in the presence of phosphorous pentoxide in an organic solvent. The solvent is selected from dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme, and the method is carried out with defined heating, cooling, and quenching temperature ranges.
Claims Coverage
The partial content provides two independent claims, each covering a method of synthesizing an oral delivery system comprising a diketopiperazine according to Formula I. The inventive features are expressed through heating, cooling, and quenching steps, constraints on PG and n, and defined relationships between catalyst and amino acid concentration, with additional selections of N-protected amino acid, catalyst, solvent, and temperature ranges.
Oral delivery diketopiperazine synthesis by heating an N-protected amino acid with a catalyst in an organic solvent
Heating an N-protected amino acid in the presence of a catalyst in an organic solvent, followed by cooling and quenching with additional cooling, wherein n is 0 to 3 and PG is selected from trifluoroacetyl, CBz, and acetyl, and wherein the catalyst is present in a concentration of 20% to 50% that of the N-protected amino acid.
Oral delivery diketopiperazine synthesis using phosphorous pentoxide in selected organic solvents
Heating a mixture of an N-protected amino acid of Formula II in the presence of phosphorous pentoxide in an organic solvent, wherein PG is selected from trifluoroacetyl, CBz, and acetyl and n is 0 to 3, wherein phosphorous pentoxide is present in a concentration of 20% to 35% that of the amino acid, and wherein the solvent is selected from dimethylacetamide, N-methyl-2-pyrrolidone, diglyme, ethyl glyme, proglyme, and ethyldiglyme.
Across the two independent claims, the core coverage is a method for synthesizing an oral delivery system comprising a diketopiperazine of Formula I by heating N-protected amino acids in the presence of a catalyst in an organic solvent, followed by cooling and quenching. Claim coverage includes the PG and n restrictions, catalyst concentration ranges, phosphorous pentoxide as the catalyst in one claim, and the listed solvent selections in the narrower claim.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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