1-( 3-Amino-1-phenylpropyl )-3-( 2-fluorophenyl )-1 , 3-dihydro-2 H-benzimidazol-2one

Starting from 1-(2-fluorophenyl)-1,3-dihydro-2H-benzimidazol-2-one (1) and (1-bromo-3-chloropropyl)benzene (2), the target compound 3, which represents a precursor for future radiolabeling, is prepared in a three-step synthesis.


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Thus, the investigation of the underlying dysregulation-mechanism of the noradrenergic system is of major interest.
As a non-invasive molecular imaging technique, positron emission tomography (PET) is the most suitable technique today to gain information about the transporter abundance and density in healthy and pathological living human brains [6]. It represents an accurate approach towards the collection of missing data in the living organism and also enables direct quantification of receptor and transporter densities in vivo. To fully gain insight into the molecular changes of the noradrenergic system via PET, however, prior development of suitable NET-PET radioligands is required. Currently, only PET tracers derived from reboxetine have been used in clinical studies [7] displaying certain limitations in their applicability, e.g. due to metabolic considerations [8].

Results and Discussion
As previously published, derivative 1 was made accessible by reacting 1-fluoro-2-nitrobenzene with 2-fluoroaniline, followed by reduction of the nitro group. Subsequent cyclization with 1,1′-carbonyldiimidazole then afforded 1 [10]. For the preparation of side chain 2, the keto moiety of commercially available 3-chloro-1-phenylpropan-1-one was reduced with sodium borohydride and bromination of the resulting intermediate with aqueous hydrogen bromide led to the formation of 2 [10].
In the next reaction step, core compound 1 and side chain 2 were subjected to a condensation reaction under alkaline conditions (Scheme 1, (i)). Then, the chloro group of the resulting product was converted into an iodo group in a Finkelstein reaction (Scheme 1, (ii)). After purification, this intermediate was heated for 12 h in a solution of NaN3 and DMF to obtain the respective azide compound, which after treatment with triphenylphosphine eventually afforded target compound 3 (Scheme 1, (iii)).

General Information
The NMR spectrum was recorded from a CDCl3 solution on a Bruker Avance III 400 spectrometer (Karlsruhe, Germany, 400 MHz for 1 H, 100 MHz for 13 C, 40 MHz for 15 N, 376 MHz for 19 F) at 25 °C. The center of the solvent (residual) signal was used as an internal standard which was related to trimethylsilane (TMS) with δ 7.26 ppm ( 1 H in CDCl3), and δ 77.0 ppm ( 13 C in CDCl3). 19 F-NMR spectra were referenced by absolute referencing via Ξ ratio. Digital resolutions were 0.25 Hz/data point in the 1 H and 0.3 Hz/data point in the 13 C-NMR spectra. Coupling constants (J) are quoted in Hz. The following abbreviations were used to show the multiplicities: s: singlet, d: doublet, t: triplet, q: quadruplet, dd: doublet of doublet, m: multiplet. Mass spectra were obtained on a Shimadzu QP 1000 instrument (Kyoto, Japan, EI, 70 eV), high-resolution mass spectrometry (HRMS) was carried out on a maXis HD ESI-Qq-TOF mass spectrometer (Bruker Daltonics, Bremen, Germany) in the positive-ion mode by direct infusion. Compound purity: all compounds synthesized featured a purity of at least 95%.
(ii) The resulting orange resin (0.84 g, 2.20 mmol) was dissolved in acetone (7 mL) and NaI (0.66 g, 4.40 mmol) was added. The mixture was refluxed for 24 h, after which the formed precipitate was filtered and concentrated prior to purification via column chromatography (silica gel 60) with petroleum ether/ethyl acetate 9:1, to give the intermediate product as yellow crystals.
(iii) The obtained product (0.15 g, 0.32 mmol) was dissolved in DMF (3 mL) and heated to 75 °C upon addition of NaN3 (0.05 g, 0.65 mmol). After 12 h the reaction was quenched with H2O (10 mL) and the resulting mixture was extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with brine (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified via column chromatography (silica gel 60, petroleum ether/ethyl acetate 8.5:1.5) and was introduced in the subsequent reaction step.
Triphenylphosphine (0.07 g, 0.27 mmol) was added to a solution of the prior synthesized azide (0.07 g, 0.18 mmol) in THF (3 mL) and the mixture was stirred for 10 h at 25 °C. Thereafter, H2O was added and the reaction was stirred for another 16 h. The resulting reaction product was concentrated in vacuo and purified by column chromatography (silica gel 60, CH2Cl2/MeOH 9:1).