Synthesis of 2-Fluoro-11-hydroxy-N-propylnoraporphine:  A Potential Dopamine D₂ Agonist

Abstract

[structure: see text]. 2-Fluoro-11-hydroxy-N-propylnoraporphine 4 (2-F-11-OH-NPa) was synthesized from thebaine in 13 steps with an overall yield of 1.35%. The key steps included the Pd-catalyzed 3-dehydroxylation of 14-hydroxymorphine, S(N)2 substitution of Ts(-) by F(-), and CH(3)SO(2)OH-promoted rearrangement of the substituted morphinandiene. The dopamine binding affinity of this compound was also investigated on rat brain membranes, and as expected, this compound displayed high affinity and selectivity at the D(2) receptor.

Transition metals in organic synthesis: Highlights for the year 2005

“…Palladium complexes, together with a hydride source, such as tributyltin hydride, triethylsilane, and triethylamine-formic acid catalyzed the reduction organic bromides, iodides, and triflates. Synthetic applications include, 1,8-naphthyrine C-nucleosides [592], cylindramine [324], azadirachtin [593], dihydroxerulic and xerulinic acid [38], bergapten [594], 3-methoxyelipticine and elipticine [595], (−)-scabronine G [44], (−)-galanthamine and (−)-morphine [447], toward (+)-sorangicin [268], 2-fluoro-11-hydroxy-N-propylnoraporphine [596], hetsine alkaloids [597], pancracine [430] and the DEF-rings of FR182877 [598].…”

Thiol-Reactive Analogues of Galanthamine, Codeine, and Morphine as Potential Probes to Interrogate Allosteric Binding within Nicotinic Acetylcholine Receptors

“…It was observed that when aged samples of DMP were used for the oxidation, a small portion of codeinone (5) was further oxidized to afford 14-hydroxycodeinone, identified by NMR comparison with the literature. [20] This over-oxidation is believed to result from traces of 2-iodoxybenzoic acid formed when DMP is hydrolyzed by adventitious moisture.…”

“…The pseudo-first order kinetics of the reaction between codeinone (5) or morphinone (6) and a 20-fold excess of N-acetyl-L-cysteine methyl ester (20) were studied under conditions as close as possible to those employed in covalent trapping experiments. Reactions were conducted in triplicate, and the enone concentration was determined by liquid chromatography-mass spectrometry (LCMS).…”

“…The kinetics of the reaction between narwedine (4) and a 20-fold excess of N-acetyl-L-cysteine methyl ester (20) were monitored under slightly different conditions. Because the reaction was much slower under the buffered aqueous conditions and concentrations (25 mM) typically used during LCMS analysis of codeinone or morphinone, the reaction was monitored using 1 H NMR spectroscopy, which allows for much higher concentrations (mM).…”

Pd-catalyzed ortho-arylation of 3,4-dihydroisoquinolones via C–H bond activation: synthesis of 8-aryl-1,2,3,4-tetrahydroisoquinolines

“…10 These various pharmacological activities have prompted intensive structure-activity relationship studies over the past three decades. 11 Despite many methods for the synthesis of isoquinolines 12 and tetrahydroisoquinolines, 13 only one attempt was made by Ellefson using aryloxazolines 14 as key intermediates to access the 8-aryl-1,2,3,4-tetrahydroisoquinolines, which possess the basic structural features of the aporphine skeleton without the C-7 methylene unit. 15 This limited synthetic route prompted us to investigate more efficient and convergent approaches to 8-aryl-1,2,3,4-tetrahydroisoquinolines.…”