Process for making lysine-glutamic acid dipeptide derivatives

Patent metadata

Field	Value
Publication number	US-9802886-B2
Application number	US-201615348093-A
Country	US
Kind code	B2
Filing date	Nov 10, 2016
Priority date	May 15, 2012
Publication date	Oct 31, 2017
Grant date	Oct 31, 2017

Abstract

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.

First claim

The invention claimed is:

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.

Assignees

• Hoffmann La Roche

Inventors

• Puentener Kurt

Classifications

• C07C271/22 Primary

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C269/06 Primary

  by reactions not involving the formation of carbamate groups · CPC title

• C07C2603/18

  Fluorenes; Hydrogenated fluorenes · CPC title

• C07K5/06017 Primary

  and aliphatic · CPC title

• B01J19/00

  Chemical, physical or physico-chemical processes in general; Their relevant apparatus · CPC title