Formation of N-protected 3,6-bis-(4-aminobutyl)-2,5-diketopiperazine through a cyclic alpha-N-protected amino ester
Inventors
Freeman, John J. • Phanstiel, Otto • Bay, William Elliot • Kraft, Kelly Sullivan
Assignees
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Publication Number
US-12049453-B2
Publication Date
2024-07-30
Expiration Date
Abstract
A method for the synthesis of N-protected 3,6-aminoalkyl-2,5-diketopiperazines is provided. The method includes obtaining a cyclic α-N protected active amino ester and adding it to a mixture of an amine catalyst in an organic solvent.
Core Innovation
The patent discloses an improved method for the synthesis of a compound according to Formula I through cyclization involving a cyclic amino compound mixture. The method includes mixing a cyclic amino compound in a first organic solvent and adding the mixture to a catalyst in an organic solvent selected from THF, dioxane, and acetonitrile, followed by mixing for at least 2 hours. The cyclic amino compound mixture is added dropwise over a period of greater than one hour.
The cyclic amino compound is defined with structural and protecting-group constraints, including R as a C3 to C5 N-protected alkyl amine, PG as protecting groups selected from amide forming protecting groups and carbamate forming protecting groups, n from 2-4, and X selected from C, P, and S. The described approach is intended to be compatible with diverse N-protecting groups, including amide-forming and carbamate-forming protecting groups such as acetyl, trifluoroacetyl, Cbz, and Boc.
The patent further discloses synthesis of a diketopiperazine according to Formula II using a cyclic amino compound, where the mixture is combined dropwise with a catalyst in an organic solvent selected from THF, dioxane, and acetonitrile and mixed for at least 2 hours. After formation of the diketopiperazine, the PG is removed. In the disclosed embodiments, amine catalysts such as benzamidoxime and aziridine are used, and the method reports yields and purities for the resulting compounds.
Claims Coverage
The partial content identifies two independent claims (clm-00001 and clm-00015). Each claim centers on cyclization/synthesis using a cyclic amino compound, an organic-solvent framework, dropwise addition, extended mixing, and defined substituent/protecting-group constraints, with clm-00015 additionally requiring removal of the PG after formation of the diketopiperazine.
Formula I synthesis using cyclic amino compound with catalyst in selected solvents
Mixing a cyclic amino compound in a first organic solvent, adding the mixture to a catalyst in an organic solvent selected from THF, dioxane, and acetonitrile, and mixing for a period of at least 2 hours, wherein the cyclic amino compound mixture is added dropwise over a period of greater than one hour; wherein R is a C3 to C5 N-protected alkyl amine; wherein the protecting group (PG) is selected from amide forming protecting groups and carbamate forming protecting groups; wherein n is from 2-4; and wherein X is selected from C, P, and S.
Formula II diketopiperazine synthesis with catalyst addition and PG removal
Mixing a cyclic amino compound with a first organic solvent and dropwise combining the mixture with catalyst in an organic solvent selected from THF, dioxane, and acetonitrile, mixing for a period of at least 2 hours, and removing the PG after formation of diketopiperazine; wherein R is a C4 N-protected alkyl amine; wherein the protecting group (PG) is selected from amide forming protecting groups and carbamate forming protecting groups; and wherein X is selected from C, P, and S.
Overall, the claims define cyclization/synthesis methods that use a cyclic amino compound, an organic solvent selected from THF, dioxane, and acetonitrile, dropwise addition, and at least 2 hours of mixing. They further constrain the substituent/protecting-group structure (R, PG, n, and X), and the diketopiperazine method additionally requires removing the PG after formation.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Not explicitly described in patent.
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