Formation of N-protected 3,6-bis-(4-aminobutyl) -2, 5-diketopiperazine through a cyclic α-
View Patent ↗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 N-protected-bis-3,6-aminoalkyl-2,5-diketopiperazine, the method comprising: adding a cyclic α-N protected active amino ester according to Formula II
wherein PG is selected from the group consisting of amide forming protecting groups and carbamate protecting groups; and
wherein n is from 1 to 8;
to a mixture of an amine catalyst in an organic solvent, wherein the amine catalyst is present in amount of 0.25 to 2.5 eq based on the amount of cyclic α-N protected active amino ester; and
heating the mixture after adding the cyclic α-N protected active amino ester.
2. The method of claim 1 , wherein PG is trifluoroacetyl.
3. The method of claim 1 , wherein n is 3.
4. The method of claim 1 , wherein the amine catalyst is aziridine.
5. The method of claim 1 , wherein the amine catalyst is an amidoxime.
6. The method of claim 1 , wherein the amine catalyst is benzamidoxime.
7. The method of claim 1 , wherein the amine catalyst is present in an amount of 1 to 2 eq based on the amount of cyclic α-N protected active amino ester.
8. The method of claim 1 , wherein the amine catalyst is present in an amount of 1.5 eq based on the amount of cyclic α-N protected active amino ester.
9. The method of claim 1 , wherein the mixture further comprises a second catalyst.
10. The method of claim 1 , wherein the organic solvent is ethanol and the amine catalyst is aziridine.
11. The method of claim 1 , wherein the organic solvent is THF and the amine catalyst is aziridine.
12. The method of claim 1 , wherein PG is acetyl.
13. The method of claim 1 , wherein PG is Boc.
14. The method of claim 1 , wherein PG is CBz.
15. A method for the synthesis of a N-protected-bis-3,6-aminoalkyl-2,5-diketopiperazine, the method comprising: adding a cyclic α-N protected active amino ester according to Formula II
wherein PG is trifluoroacetyl; and
wherein n is from 1 to 8;
to a mixture of an amine catalyst in an organic solvent, wherein the amine catalyst is present in amount of 1 to 2 eq based on the amount of cyclic α-N protected active amino ester and heating the mixture after adding the cyclic α-N protected active amino ester.
16. The method of claim 15 , wherein the organic solvent is selected from ethanol and THF and the amine catalyst is aziridine.
17. The method of claim 15 , wherein the organic solvent is selected from ethanol and THF and the amine catalyst is benzamidoxime.
18. The method of claim 15 , wherein n is 3.
19. The method of claim 15 , wherein the amine catalyst is present in amount of 1.5 eq based on the amount of cyclic α-N protected active amino ester.
20. A method for the synthesis of a N-protected-bis-3,6-aminoalkyl-2,5-diketopiperazine, the method comprising: adding a cyclic α-N protected active amino ester according to Formula II
wherein PG is selected from the group consisting of amide forming protecting groups and carbamate protecting groups; and
wherein n is from 1 to 8;
to a mixture of an amine catalyst and a second catalyst in an organic solvent,
wherein the amine catalyst is present in amount of 0.25 to 2.5 eq based on the amount of cyclic α-N protected active amino ester.