The Synthesis of (S)-5-Fluoro-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole, a Norepinephrine/Serotonin Reuptake Inhibitor for the Treatment of Fibromyalgia

Abstract

Compound 1, a norepinephrine/serotonin reuptake inhibitor (NSRI) for the treatment of fibromyalgia, has been synthesized in optically pure form in six linear steps and 48% overall yield with no chromatography. This route features a novel and efficient intramolecular cyclization to generate the indazolone core Wia a diazotization reaction and the preparation of a stable polymorph of the tartaric acid salt as the desired final form. The original synthetic route has been modified to avoid the use of toxic and expensive reagents, thus enabling the preparation of multigram quantities of API for toxicology studies.Figure 1. Structures of fibromyalgia drugs.

Substituted Indazoles as Nav1.7 Blockers for the Treatment of Pain

“…While similar analogs have been reported in the literature, 27 the analogs described here lack the basic amine side chain pharmacophore of the previously reported structures. Although 4 showed reasonable in vitro activity at Na v 1.7 in both the FRET (IC 50 = 0.76 µM)…”

“…We next made a series of related amides (24)(25)(26)(27)(28)(29)31) which all demonstrated good selectivity for Na v 1.7 versus Na v 1.5. In the series of amides described, the (S)-3-fluoropyrrolidine 27 exhibited good activity at Na v 1.7 (FRET IC 50 = 0.37 µM, EP IC 50 = 0.48 µM; manual EP IC 50 = 0.57 µM), good selectivity versus Na v 1.5 (>33 µM) and good pharmacokinetic properties (F = 83%; t 1/2 = 1.7 h).…”

“…oxoethyl}imidazolidin-2-one, (27). This mixture was allowed to stir at ambient temperature for 16 h then was quenched with water (5 mL) and diluted with ethyl acetate (10 mL).…”

Solvent-free microwave-promoted Michael addition of aza-nucleophiles to benzo[b]thiophen-2-yl-2-propenone

“…As an extension of this work, the scope of this approach was explored for a variety of azanucleophiles 1-7 of pharmacological interest, [20][21][22] reacting with 1-(4,7-dimethoxybenzo[b]thiophen-2-yl)-2-propen-1-one 4, as Michael acceptor under microwave conditions ( Table 1). …”

Synthesis of indazole motifs and their medicinal importance: An overview

“…Thus, in the course of the preparation of 1H-indazolone compound acting as the construction of the 1H-indazolone core structure of precursor has been accomplished via the decomposition of a diazonium salt and capture of the resulting aryl cation by an ortho-disposed hydrazide (Scheme-32) [46].…”