Formation of N-protected bis-3,6-(4-aminobutyl)-2, 5-diketopiperazine through a cyclic alpha-N-protected amino ester
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.
1. A method for the synthesis of a diketopiperazine, the method comprising mixing a cyclic amino compound according to the following formula:
with a catalyst in an organic solvent and heating the mixture, wherein R is a C1 to C8 N-protected alkyl amine, wherein the protecting group is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups and wherein X is selected from C, P, and S.
2. The method of claim 1 , wherein the organic solvent is selected from THF, acetonitrile, dioxane, and ethanol.
3. The method of claim 1 , wherein the catalyst is present in an amount of 0.25 to 2.5 equivalents based on the amount of the cyclic amino compound.
4. The method of claim 1 , wherein the catalyst is selected from aziridine, benzamidoxime, 4-nitrobenzamidoxime, hydroxysuccinimide, p-nitrophenol, and hydroxybenzotriazole.
5. The method of claim 1 , wherein the catalyst is an amine catalyst.
6. The method of claim 1 , wherein R is —(CH 2 ) n -NHPG, wherein n is 3-5.
7. The method of claim 6 , wherein PG is selected from acetyl, trichloroacetyl, trifluoroacetyl, benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (Boc).
8. The method of claim 7 , wherein PG is selected from trifluoroacetyl, Cbz, and Boc.
9. The method of claim 8 , wherein PG is trifluoroacetyl.
10. The method of claim 1 , wherein X is C.
11. The method of claim 1 , wherein X is P.
12. The method of claim 1 , wherein X is S.
13. A method for the synthesis of a diketopiperazine, the method comprising mixing a cyclic amino compound according to the following formula:
with a catalyst in an organic solvent and heating the mixture, wherein PG is selected from the group consisting of amide forming protecting groups and carbamate forming protecting groups and wherein X is selected from C, P, and S.
14. The method of claim 13 , wherein the organic solvent is selected from THF, acetonitrile, dioxane, and ethanol.
15. The method of claim 13 , wherein the organic solvent is selected from THF and ethanol.
16. The method of claim 13 , wherein the catalyst is selected from aziridine, benzamidoxime, 4-nitrobenzamidoxime, hydroxysuccinimide, p-nitrophenol, and hydroxybenzotriazole.
17. The method of claim 13 , wherein the catalyst is present in an amount of 0.25 to 2.5 equivalents based on the amount of cyclic amino compound.
18. The method of claim 13 , wherein PG is selected from acetyl, trichloroacetyl, trifluoroacetyl, benzyloxycarbonyl (Cbz) and t-butoxycarbonyl (Boc).
19. The method of claim 13 , wherein PG is trifluoroacetyl.
20. The method of claim 13 , wherein X is C.