Formation of N-protected 3,6-bis-(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 compound according to Formula I:
the method comprising mixing a cyclic amino compound according to the following formula:
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 the group consisting of 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.
2. The method of claim 1 , wherein the mixture is heated to a temperature of up to 60° C.
3. The method of claim 1 , wherein the organic solvent is THF.
4. The method of claim 1 , wherein the catalyst is an amine catalyst.
5. The method of claim 4 , wherein the amine catalyst is benzamindoxine.
6. The method of claim 5 , wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide.
7. The method of claim 6 , wherein the co-catalyst is present in an amount of about 0.2 equivalents that of the catalyst.
8. 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.
9. The method of claim 8 , wherein the organic solvent is selected from THF and ethanol.
10. The method of claim 1 , wherein the PG is selected from trifluoroacetyl, Cbz, and Boc.
11. The method of claim 1 , wherein X is C.
12. The method of claim 11 , wherein PG is trifluoroacetyl.
13. The method of claim 12 , wherein the organic solvent is selected from THF and ethanol.
14. The method of claim 13 , wherein PG is Cbz.
15. A method for the synthesis of a diketopiperazine according to Formula II,
the method comprising mixing a cyclic amino compound according to the following formula:
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 the group consisting of amide forming protecting groups and carbamate forming protecting groups, and
wherein X is selected from C, P, and S.
16. The method of claim 15 , wherein the mixture is heated to a temperature of up to 60° C.
17. The method of claim 16 , wherein the organic solvent is THF.
18. The method of claim 15 , wherein the amine catalyst is benzamindoxine.
19. The method of claim 8 , wherein the mixture comprises a co-catalyst selected form hydroxybenzotriazole and hydroxysuccinimide.
20. The method of claim 19 , wherein the PG is selected from trifluoroacetyl, Cbz, and Boc.