2-Fluoro-N-methyl-N-{[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methyl}ethanamine

Abstract

Starting from N-methyl-1-[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methanamine (1) target compound 2 is prepared in a mild, direct alkylation approach with 2-fluoroethyl trifluoromethanesulfonate.

1. Introduction

As the norepinephrine transporter (NET) is involved in a variety of diseases, such as neurological/psychiatric disorders, [1,2], but also plays a pivotal role in cardiovascular [1,2,3], and metabolic diseases [3,4,5], the investigation of the underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest.

Today, positron emission tomography (PET), being a non-invasive molecular imaging technique, represents the most accurate method to obtain information about the transporter abundance and density in healthy and pathological living human brains. It also enables the collection of missing data and direct quantification of receptor/transporter densities in the living organism. To fully gain insight in the molecular changes of the noradrenergic system via PET, however, prior development of suitable NET-PET radioligands is required. For preclinical investigations of the respective target, non-radioactive references first need to be prepared.

Previously several 3,4-dihydro-1H-isochromene derivatives were synthesized, [6] which have been described by our research group as potential precursors and references for PET-based investigations of the NET. On the basis of these previous studies, we are reporting in this paper the synthesis of a further reference compound for the NET for future preclinical testing, namely 2-fluoro-N-methyl-N-{[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methyl}ethanamine (FE@PHOXI1) (2).

2. Results and Discussion

Derivative 1 was made accessible by reacting 1H-isochromen-4(3H)-one in a Mannich reaction with dimethylamine hydrochloride and paraformaldehyde, followed by reduction of the keto group into an alcohol group with l-Selectride [6,7]. This product was obtained as racemic mixture. The cis-isomer could be successfully separated from its trans-counterpart by proper purification using column chromatography. Subsequent reaction of the cis-isomer with 1-bromo-2-fluorobenzene then afforded 1-[(3S*,4S*)-4-(2-bromophenoxy)-3,4-dihydro-1H-isochromen-3-yl]-N,N-dimethylmethanamine, which was converted into N,N-dimethyl-1-[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methanamine. Following N-demethylation yielded compound 1 [6,7,8,9].

For the preparation of derivative 2, a mild synthesis approach was chosen, in which the secondary amine (1) was reacted at 0 °C with freshly prepared 2-fluoroethyl trifluoromethanesulfonate [10] in the presence of trimethylamine (Scheme 1). Due to the high reactivity of triflates, the alkylation was carried out in less than ten minutes while the temperature was slowly raised to 25 °C.

3. Experimental Section

3.1. General Information

The NMR spectra were recorded from a CDCl₃ solution on a Bruker Avance III 400 spectrometer (Billerica, MA, USA) (400 MHz for ¹H, 100 MHz for ¹³C, 40 MHz for ¹⁵N, 376 MHz for ¹⁹F) at 25 °C. The center of the solvent (residual) signal was used as an internal standard which was related to tetramethylsilane (TMS) with δ 7.26 ppm (¹H in CDCl₃), and δ 77.0 ppm (¹³C in CDCl₃). ¹⁹F NMR spectra were referenced by absolute referencing via Ξ ratio. Digital resolutions were 0.25 Hz/data point in the ¹H and 0.3 Hz/data point in the ¹³C-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 (EI, 70 eV, Kyoto, Japan), 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%.

3.2. 2-Fluoro-N-methyl-N-{[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methyl}ethanamine (FE@PHOXI1)

To a suspension of N-methyl-1-[(3S*,4S*)-4-(2-methylphenoxy)-3,4-dihydro-1H-isochromen-3-yl]methanamine (1) (0.07 g, 0.26 mmol) in dry acetonitrile (10 mL) was added trimethylamine (0.05 mL, 0.33 mmol) under argon atmosphere. The reaction mixture was cooled to 0 °C and 2-fluoroethyl trifluoromethansulfonate (0.04 mL, 0.31 mmol) was slowly added to the mixture. Thereafter, the solution was stirred for 10 min, during which the mixture was allowed to warm to room temperature. After evaporation of the solvent, the resulting crude product was purified by column chromatography (silica gel 60, 7% MeOH in CH₂Cl₂).

Yield: 15 mg (17%), yellow oil.

¹H-NMR (400 MHz, CDCl₃, for numbering of atoms see formula of 2): δ (ppm) 1.91 (s, 3H, benz 2-CH₃), 2.56 (s, 3H, NCH₃), 2.84–3.07 (m, 2H, NCH₂CH₂F), 3.04 (m, 1H, isochr-CH₂-N), 3.13 (m, 1H, isochr-CH₂-N), 4.22 (m, 1H, isochr H-3), 4.65 (dt, ²J_CH2,F = 47.5 Hz, ³J_CH2,CH2 = 4.8 Hz, 1H, NCH₂CH₂F), 4.90 (A-part of an AB-system, ²J = 15.2 Hz, 1H, isochr H-1), 5.04 (B-part of an AB-system, ²J = 15.2 Hz, 1H, isochr H-1ʹ), 5.19 (d, ³J = 2.1 Hz, 1H, isochr H-4), 6.91 (m, 1H, isochr H-5), 6.92 (m, 1H, benz H-4), 7.06 (m, 1H, isochr H-6), 7.07 (m, 1H, isochr H-8), 7.08 (m, 1H, benz H-3), 7.17 (m, 2H, benz H-5 and benz H-6), 7.27 (m, 1H, isochr H-7);

¹³C-NMR (100 MHz, CDCl₃): δ (ppm) 16.2 (benz 2-CH₃), 43.1 (NCH₃), 57.7 (d, ²J_C,F = 19.8 Hz, NCH₂CH₂F), 58.3 (isochr-CH₂-N), 67.7 (isochr C-1), 73.6 (isochr C-4), 74.9 (isochr C-3), 81.4 (d, ¹J_C,F = 168.0 Hz, NCH₂CH₂F), 116.7 (benz C-6), 122.0 (benz C-4), 124.2 (isochr C-8), 126.4 (isochr C-6), 126.8 (benz C-5), 128.6 (isochr C-7), 129.1 (isochr C-5), 129.8 (benz C-2), 130.9 (benz C-3), 132.0 (isochr C-4a), 134.6 (isochr C-8a), 156.2 (benz C-1);

¹⁹F-NMR (471 MHz, CDCl₃): δ (ppm) −218.6 (m, CH₂F);

MS: m/z (%) 329 (M⁺, 1), 222 (1), 188 (1), 132 (2), 115 (2), 104 (3), 90 (100), 77 (2), 44 (4);

HRMS: m/z calculated for C₂₀H₂₅FNO₂ [M + H]⁺: 330.1864. Found: 330.1831.