1,2,4-oxadiazole derivatives as immunomodulators
The present invention relates to synthetic methods for 1,2,4-oxadiazole compounds. The general synthetic scheme is: R 1 represents −CH 2 O t Bu or −CH(CH 3 )O t Bu, R 3 represents −CH 2 C(O)NHCPh 3 , −CH 2 CH 2 C(O)NHCPh 3 , −CH 2 C(O)O t Bu, or −CH 2 CH 2 C(O)O t Bu, and Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is esterified, and wherein the hydroxy moiety of the side chain of Thr or Ser is substituted with tbutyl; the base is triethylamine; and the solvent is tetrahydrofuran.
1. A method of making a compound according to the following scheme:
wherein:
R 1 represents —CH 2 O t Bu or —CH(CH 3 )O t Bu;
Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is esterified, and wherein the hydroxy moiety of the side chain of Thr or Ser is substituted with t-butyl;
R 3 represents —CH 2 C(O)NHCPh 3 , —CH 2 CH 2 C(O)NHCPh 3 , —CH 2 C(O)O t Bu, or —CH 2 CH 2 C(O)O t Bu;
the base is triethylamine; and
the solvent is tetrahydrofuran.
2. The method of claim 1 , wherein:
Aaa is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is esterified, and wherein the hydroxy moiety of the side chain of Thr or Ser is substituted with t-butyl;
R 1 represents —CH 2 O t Bu or —CH(CH 3 )O t Bu; and
R 3 represents (a) —CH 2 C(O)NHCPh 3 or —CH 2 CH 2 C(O)NHCPh 3 or (b) —CH 2 C(O)O t Bu, or —CH 2 CH 2 C(O)O t Bu—;
said method further comprising the step of contacting the compound of formula
with trifluoroacetic acid, to form a compound of formula
wherein:
Aaa′ is an amino acid residue selected from Thr and Ser; wherein the C-terminus thereof is a free terminus;
R 1a represents CH 2 OH or —CH(CH 3 )OH; and
R 3a represents (a) —CH 2 C(O)NH 2 or —CH 2 CH 2 C(O)NH 2 or (b) —CH 2 C(O)OH or —CH 2 CH 2 C(O)OH.