Process for making lysine-glutamic acid dipeptide derivatives
The invention relates to compounds of the formula and to a process for making same and to the use of the products in the solid phase peptide synthesis. The compounds of formula I are versatile peptide intermediates for the solid phase peptide synthesis (SPPS) of peptide drugs which comprise a Glu-fatty alkyl side chain building block attached to a Lys-part of the peptide chain.
1. A process for the preparation of compounds of formula I,
and enantiomers and salts thereof, wherein:
R 1 is hydrogen or an ester protecting group;
R 2 is hydrogen;
R 3 is hydrogen or an amino protecting group and
R 4 is C 12-20 -alkyl;
the process comprising:
a) coupling the glutamic acid derivative of formula II
or a salt thereof with a lysine derivative of formula III
wherein R 2′ is an ester protecting group, or a salt thereof to form a compound of the formula Ic;
and
b) removing the ester protecting group R 2′ to provide the compound of formula I.
2. The process of claim 1 , wherein the ester protecting group is selected from C 1-4 -alkyl, optionally substituted with phenyl, C 2-4 -alkenyl, piperidinyl or dimethylaminoboranyl.
3. The process of claim 1 , wherein R 1 is hydrogen or C 1-4 -alkyl.
4. The process of claim 1 , wherein R 1 is C 1-4 -alkyl.
5. The process of claim 1 , wherein R 1 is hydrogen.
6. The process of claim 1 , wherein R 3 is 9H-fluoren-9-ylmethoxycarbonyl.
7. The process of claim 1 , wherein R 1 is t-butyl.
8. The process of claim 1 , wherein R 4 is C 14-16 -alkyl.
9. The process of claim 1 , wherein R 4 is C 15 -alkyl.
10. The process of claim 1 , wherein R 4 is pentadecyl.
11. The process of claim 1 , wherein R 3 is 9H-fluoren-9-ylmethoxycarbonyl and R 4 is C 15 -alkyl.
12. The process of claim 1 , wherein R 3 is 9H-fluoren-9-ylmethoxycarbonyl and R 4 is pentadecyl.
13. The process of claim 1 , wherein the compound of formula I is a compound of formula Ia
14. The process of claim 1 , wherein the compound of formula I is a compound of formula Ib
15. The process of claim 1 , wherein the coupling of the glutamic acid derivative of formula II with the lysine derivative of formula III is carried out by solid phase synthesis.
16. The process of claim 1 , wherein the coupling of the glutamic acid derivative of formula II with the lysine derivative of formula III is carried out by FMOC solid phase synthesis.