US 11,753,440 B2
Methods for the synthesis of arginine-containing peptides
Marc Heidl, Kaiseraugst (NL); and Piero Geotti-Bianchini, Kaiseraugst (NL)
Assigned to DSM IP ASSETS B.V., Heerlen (NL)
Appl. No. 15/734,751
Filed by DSM IP Assets B.V., Heerlen (NL)
PCT Filed Jun. 5, 2019, PCT No. PCT/EP2019/064676
§ 371(c)(1), (2) Date Dec. 3, 2020,
PCT Pub. No. WO2019/234108, PCT Pub. Date Dec. 12, 2019.
Claims priority of application No. 18176102 (EP), filed on Jun. 5, 2018.
Prior Publication US 2021/0230220 A1, Jul. 29, 2021
Int. Cl. A61K 38/00 (2006.01); C07K 5/11 (2006.01); C07K 1/06 (2006.01); C07K 5/078 (2006.01); C07K 5/09 (2006.01); C07K 5/107 (2006.01); C07K 5/10 (2006.01)
CPC C07K 5/1019 (2013.01) [C07K 1/064 (2013.01); C07K 5/06156 (2013.01); C07K 5/0817 (2013.01); C07K 5/1016 (2013.01); C07K 5/1027 (2013.01)] 19 Claims
 
1. A method for deprotecting a peptide selected from the group consisting of Boc-Trp-Arg(Pbf)-OH, Ac-Arg(Pbf)-His(Trt)-Phe-OH, TFA-H-Tyr(tBu)-Arg(Pbf)-Pro-OH, Boc-rac-6FTrp-Gly-Arg(Pbf)-Glu(OtBu)-OH, Boc-Tyr(Et)-Arg(Pbf)-Ala-Phe-OH, Ac-5-(OH)Trp-Ala-Arg(Pbf)-Ser(tBu)-Leu-Phe-OH, Boc-Arg(Mtr)-Tyr(tBu)-Phe-OH, Boc-2Nal-Leu-Arg(Pbf)-Phe-OH, Ac-Arg(Pbf)-Met-m(NO2)Tyr-Pro-OH and Bz-Gly-His(Trt)-D-Phe-Arg(Pbf)-D-Trp-N(Pr)2, wherein the method comprises the steps of:
(a) solubilizing the peptide in a solvent mixture of at least one aprotic organic solvent, a thiol scavenger, and either a protic solvent or a carboxylic acid selected from the group of formic acid, acetic acid and/or trifluoroacetic acid or a mixture thereof, wherein the carboxylic acid is present in an amount of 5 to 30%, based on the total volume of the solvent mixture, followed by
(b) mixing the solution obtained in step (a) with a mixture of (i) a carboxylic acid selected from the group consisting of formic acid, acetic acid and trifluoroacetic acid, and (ii) a sulfonic acid selected from the group consisting of methanesulfonic acid, trifluoromethane sulfonic acid, benzene sulfonic acid and p-toluene sulfonic acid, wherein
a total molar amount of the carboxylic acid used in steps (a) and (b) is higher than a total molar amount of the sulfonic acid.