Large‐scale synthesis of hematoregulatory nonapeptide SK&F 107647 by fragment coupling

Abstract

Linear and convergent routes for the large-scale preparation of the hematoregulatory nonapeptide (Glp-Glu-Asp)2-DAS-(Lys)2 (2, SK&F 107647) were investigated. A convergent approach ('3 + 2'-route employing Boc-and benzyl ester protecting groups) was selected for the preparation of multihundred-gram quantities of 2. Key steps were the preparation and the coupling of tripeptide hydrochloride (HCl.H)2-DAS-(Lys(Z)-OBn)2 (6, DAS-2,7-L,L-diaminosuberic acid) and tripeptide Glp-Glu(OBn)-Asp(OBn)-OH (26). Several coupling reagents were investigated in order to reduce the amount of epimerization of this fragment coupling. TDBTU [O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl-1,1,3,3-tetrameth yluronium tetrafluoroborate] was identified as the condensation reagent of choice. Using this synthetic route > 97% pure final product in an overall yield of 35% calculated on di-Boc protected 2,7-L,L-diaminosuberic acid was prepared.

Synthesis of Novel 4‐Substituted Coumarins, Docking Studies, and DHODH Inhibitory Activity

“…Initial attempts to couple the coumarin‐4‐acetic acids with methyl esters of α‐amino acids by using acid amine coupling agents like DCC, HATU, and HBTU under different conditions and solvent combinations have failed, resulting in the formation of decarboxylated product, 4‐methyl coumarins instead of corresponding acetamides. When propylphosphonic anhydride (T 3 P) was employed as the coupling agent in dichloromethane, the desired coumarin‐4‐acetyl amino acid methyl esters 4 ( a – o ) were obtained in high yields . All the compounds were purified by column chromatography using 230–400 silica gel and characterized by nuclear magnetic resonance (NMR) and liquid chromatography–mass spectrometry (LCMS) analysis.…”

Peptide synthesis: chemical or enzymatic

“…Reverse micelles have, however, several drawbacks: they are mechanically week, there are no rational methods for its optimization and the surfactant impairs the recovery and purification of products (Bordusa, 2002). t-Boc-ArgGly-OEt and Ac-Gly-Asp-diOMe have been successfully synthesized under kinetic control in organic medium using proteases immobilized in reverse micelles (Chen et al 1998;Chen et al 1999). …”

“…This technique is highly flexible with respect to the chemistry of coupling and the combination of the peptidic blocks. New strategies for synthesis in solution have been developed, going from the design of functional groups for the side chains and condensation of fragments for the synthesis of large molecules (Nishiuchi et al 1998) to the use of new coupling reagents (Hiebl et al 1999). …”

N-Acylation in combinatorial chemistry

“…68 The uronium salt TDBTU (33) reduces racemization efficiently and often gives better yields than other reagents (HBTU and HATU etc.) as reported for liquid- 69 and solid-phase studies of the racemization of chiral PNAs. 3d DEPBT (34) as a phosphate of HO-Dhbt was described as slightly better reagent than TDBTU (33) for increasing the enantiomeric purity.…”