Synthesis and structure of 4-hydroxy-N-isopropyltryptamine (4-HO-NiPT) and its precursors

Abstract

The title compound, 4-hydroxy-N-isopropyltryptamine (4) or 4-HO-NiPT (systematic name: 3-{2-[(propan-2-yl)amino]ethyl}-1H-indol-4-ol), C13H18N2O, was synthesized in three steps from 4-benzyloxyindole (1) (systematic name: 4-phenoxy-1H-indole), C15H13NO. (1) was treated with oxalyl chloride and isopropylamine to produce N-isopropyl-4-benzyloxy-3-indoleglyoxylamide (2) {systematic name: 2-[4-(benzyloxy)-1H-indol-3-yl]-2-oxo-N-(propan-2-yl)acetamide}, C20H20N2O3. (2) was reduced to generate 4-benzyloxy-N-isopropyltryptamine (3) or 4-HO-NiPT, which was characterized as its chloride salt 4-benzyloxy-N-isopropyltryptammonium chloride (3a) (systematic name: {2-[4-(benzyloxy)-1H-indol-3-yl]ethyl}(propan-2-yl)azanium chloride), C20H25N2O·Cl. Finally the benzyl group of (3) was removed via hydrogenation to generate 4-HO-NiPT. The crystal structures of the title compound and all three synthetic precursors are presented.

N-Cyclohexyltryptamine: freebase, bromide and fumarate

“…This includes the zwitterionic natural product baeocystin (Naeem, Sherwood et al, 2022), its metabolite norpsilocin as both its freebase and fumarate (Chadeayne et al, 2020b), and its synthetic prodrug 4-acetoxy-N-methyltryptamine as a chloride salt (Glatfelter et al, 2022b). The remaining three are N-methylserotonin hydrogen oxalate (Naeem, Anas et al, 2023), 4-benzyloxy-N-isopropyltryptammonium chloride and 4-hydroxy-N-isopropyltryptamine (Laban et al, 2023) There are only four structures of freebase tryptamines known without indole substitution: the natural products tryptamine (Nowell et al, 2002) and N,N-dimethyltryptamine (Falkenberg, 1972), as well as N-methyl-N-propyltryptamine (Chadeayne et al, 2019b), and 3-[2-(piperidin-1-yl)ethyl]-1Hindole (Sahoo et al, 2020), while many other tryptamine freebases have been reported including serotonin .…”