35146-32-8

White powder

1-(Triphenylmethyl)-L-histidine is a reactant in the synthesis of falcitidin acyl tetrapeptides as antimalarial agent.

H-His(Trt)-OH, also known as 1-(Triphenylmethyl)-L-histidine, is a histidine derivative. It can be obtained by removing fmoc group protection from Fmoc-His(Trt)-OH. L-histidine (HIS) is an essential amino acid with unique roles in proton buffering, metal ion chelation, scavenging of reactive oxygen and nitrogen species, erythropoiesis, and the histaminergic system.

The amino acid N(im)-trityl-D-histidine was dissolved in dichloromethane, followed by the addition of triethylamine and trimethylsilyl chloride (3.5 equivalents). After 2 hours of gentle reflux, the mixture was ready to be used for in situ coupling to the anhydride of the carboxylic acid. Thus, isovaleric acid was separately dissolved in THF and maintained at -20 ℃ using an ice-salt bath. N-methyl morpholine (1.2 equivalents) was added, followed by the addition of ethyl chloroformate (1.0 equivalent). After 15-20 minutes at -20 ℃, the bis-TMS amino acid reaction mixture was added directly to the anhydride solution and left stirring at room temperature overnight. After 8 hours, the reaction mixture was concentrated in vacuo. Finally, H-His(Trt)-OH was obtained after purification.

General procedure for the synthesis of N'-(triphenylmethyl)-L-histidine from N-Fmoc-N'-trityl-L-histidine: Fmoc-His(Trt)-OH (100 g, 0.161 mol, 1 eq.) was dissolved in THF (2000 mL) and piperidine (140 g, 1.614 mol, 10 eq.) was added under stirring conditions. The reaction mixture was stirred for 2 hours using a mechanical stirrer. The progress of the reaction was monitored by thin layer chromatography (TLC) to confirm the complete removal of the Fmoc protecting group. Subsequently, water (~4 L) was added to the reaction system and stirring was continued for 30 min. The precipitate was collected by filtration. The filtrate was concentrated to remove THF completely. pH of the solution was adjusted to 2.5 with dilute hydrochloric acid and the mixture was stirred overnight. Filtration yielded 53 g of colorless crystals (83% yield) and the product was dried in air overnight.

[1] Patent: WO2012/136604, 2012, A1. Location in patent: Page/Page column 42-43
[2] Tetrahedron Letters, 2014, vol. 55, # 11, p. 1949 - 1951