Catalysis of diketopiperazine synthesis
View Patent ↗Provided is a method for the synthesis of N-protected bis-3,6-[4-aminobutyl]-2,5-diketopiperazine including the step of heating a solution of ε-amino protected lysine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide.
1. A method for synthesizing N-protected bis-3,6-[aminoalkyl]-2,5-diketopiperazine comprising the step of heating a solution of an amino acid having a free α-amine group and a protected amine group and a sulfuric acid, phosphoric acid, or phosphorus pentoxide catalyst; said amino acid further having a terminal carboxy group.
2. The method of claim 1 , wherein the amino acid is ornithine.
3. The method of claim 2 , wherein the protecting group is N-benzyloxycarbonyl.
4. The method of claim 2 , wherein said amino acid is (N-benzyloxycarbonyl)-ornithine (cbz-ornithine).
5. The method of claim 1 , wherein said catalyst is sulfuric acid.
6. The method of claim 1 , wherein said catalyst is phosphoric acid.
7. The method of claim 1 , wherein said catalyst is phosphorous pentoxide.
8. The method of claim 7 , wherein the concentration of phosphorus pentoxide is from about 5% to about 10%.
9. The method of claim 8 , wherein the concentration of phosphorus pentoxide is 7.5%.
10. The method of claim 1 , wherein the solution is heated to a target temperature of about 160° C. to 170° C.
11. The method of claim 10 , wherein the target temperature is achieved in about 4 to 6 hours.
12. The method of claim 1 , further comprising a solvent selected from the group consisting of m-cresol, ethylene glycol, propylene glycol, toluene, and xylene.
13. A method for the synthesis of N-protected bis-3,6-[aminoalkyl]-2,5-diketopiperazine comprising the step of heating a solution of side chain amino-protected ornithine in the presence of a catalyst selected from the group consisting of sulfuric acid, phosphoric acid, and phosphorus pentoxide, wherein synthesis is substantially complete within about 10 hours of reaching a target temperature.
14. The method of claim 13 , wherein said target temperature is about 160° C. to 170° C.
15. The method of claim 13 , wherein said synthesis is substantially complete within about 8 hours.
16. The method of claim 13 , wherein said synthesis is substantially complete within about 4 hours.
17. The method of claim 13 wherein said synthesis is substantially complete within about 3 hours.
18. The method of claim 13 , wherein said synthesis is substantially complete within about 1.5 hours.
19. The method of claim 13 , where in said catalyst is phosphorous pentoxide.
20. The method of claim 19 , wherein the concentration of phosphorus pentoxide is from about 5% to about 10%.
21. The method of claim 20 , wherein the concentration of phosphorus pentoxide is 7.5%.
22. The method of claim 13 , where in said side chain amino-protected ornithine is cbz-ornithine.