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 bis N-protected 3,6-aminoalkyl-2,5-diketopiperazine of Formula I,
wherein PG is selected from CBz, Boc, trifluoroacetyl, and acetyl and wherein n is from 1 to 8;
the method comprising: adding a cyclic α-N protected active amino ester according Formula II
wherein PG is selected from CBz, Boc, trifluoroacetyl, and acetyl, wherein X is selected from C, S, and P, and wherein n is from 1 to 8; to a mixture of an amine catalyst in an organic solvent, the amine catalyst selected from the group comprising: aziridine and benzamidoxime.
2. The method of claim 1 , wherein PG is trifluoroacetyl.
3. The method of claim 1 , wherein PG is acetyl.
4. The method of claim 1 , wherein PG is Boc.
5. The method of claim 1 , wherein n is 3.
6. The method of claim 1 , wherein X is C and the amine catalyst is aziridine.
7. The method of claim 1 , wherein X is C and the amine catalyst is an amidoxime.
8. The method of claim 1 , wherein X is C and PG is trifluoroacetyl.
9. The method of claim 1 , wherein the organic solvent is ethanol and the amine catalyst is aziridine.
10. The method of claim 1 , wherein the organic solvent is THF and the amine catalyst is aziridine.
11. The method of claim 10 , wherein the addition is at room temperature.
12. The method of claim 1 , wherein the PG is removed prior to isolation of the diketopiperazine.
13. The method of claim 1 , wherein PG is CBz.
14. The method of claim 13 , wherein X is C, THF is the organic solvent and the cyclic α-N-protected active amino ester is added over 4 hours with heat.