(±)-N-(3-Chlorophenethyl)-2-(6-methoxynaphthalen-2-yl)propanamide

Abstract

Herein we report the synthesis of (±)-N-(3-chlorophenethyl)-2-(6-methoxynaphthalen-2-yl)propanamide in the reaction between 2-(3-chlorophenyl)ethan-1-amine and (±)-naproxen. The newly obtained bio-functional hybrid molecule was fully characterized via ¹H, ¹³C NMR, UV, IR, and mass spectral data.

1. Introduction

Inflammation is a localized physical state characterized by swelling, redness, and heat, as well as discomfort, and is mediated by the release of proinflammatory mediators such as bradykinin and cytosine, which enhance the rate of prostaglandin production [1,2].

A common anti-inflammatory and analgesic drug is naproxen 1 (Figure 1), a propionic acid derivative. Its action is thought to be connected to the COX enzyme’s inhibition, which lowers the levels of prostaglandin in various fluids and tissue types. Due to their free carboxylic groups, aryl propionic acids such as naproxen 1 (Figure 1) are thought to cause digestive issues. Thus, masking this acidic group might result in a reduction or elimination of gastrointestinal toxicity.

The presence of chlorine atoms played a pivotal role in a number of natural products such as the antibiotics clindamycin 2 [3], chloramphenicol 3 [4], and griseofulvin 4 (Figure 2). Over time, it has been empirically discovered that inserting a chlorine atom into one or more specific positions of a biologically active molecule can significantly boost its inherent biological activity [5].

A chlorine substituent increases the lipophilicity of the whole molecule, resulting in greater partitioning of a chlorinated substance into the lipophilic phase of a cell membrane or the lipophilic domains of a protein. Chlorine as a substituent on an aromatic, heteroaromatic, or olefinic molecule has the most significant influence on the biological activity of many compounds.

Chlorine-containing molecules are not necessarily dangerous or toxic. As one of many possible substituents used in synthetic organic chemistry, the chlorine atom will continue to be an important tool for probing structure-activity relationships in life science research and as a molecular component in commercialized compounds, in order to provide safer, more selective, and environmentally compatible products with higher activity for medicine and agriculture [6].

The application of chlorine in medicinal chemistry is one of the fastest-growing hot areas in chemistry due to the fascinating and instructive role of halogen distribution in the field of drug development. Surprisingly, among the four halogens, chlorine is the one that is more frequently found in drugs than others, even fluorine [6,7].

Phenethylamine (given in blue in Figure 3) is a natural alkaloid that acts as a central nervous system stimulant. It is produced by a diverse spectrum of species throughout the plant and animal worlds, including humans [8,9]. Many substituted phenethylamine derivatives are psychoactive drugs, belonging to different drug classes, including central nervous system stimulants such as amphetamine 5, vasopressors such as ephedrine 6, antidepressants such as bupropion 7, etc. (Figure 3).

Obtaining a new hybrid molecule constructed from a naproxen fragment attached to a phenethylamine-containing chlorine atom on a meta position is particularly fascinating in order to examine its bio functionality.

2. Results

Herein we report the successful synthesis of (±)-N-(3-chlorophenethyl)-2-(6-methoxynaphthalen-2-yl)propanamide 10, as shown in Scheme 1. For this purpose, (±)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride 9 (1 mmol) was added to the solution of 2-(3-chlorophenyl)ethan-1-amine 8 (1 mmol) in dichloromethane. The reaction mixture was stirred for 10 min and then an excess of trimethylamine (1.5 mmol) was carefully added. After 30 min the examined TLC proved the obtaining of the final product 10. This reaction is known as the Schotten-Baumann reaction, and it allows for the facile formation of amide functions from amines and acyl chlorides. As we used racemic naproxen, a mixture of two enantiomers was obtained as a product.

Observing the new hybrid’s ¹H NMR spectral data the signals for all 22 protons can be seen very clearly. A doublet for 3 three for the CH₃ group is at 1.38 ppm. A triplet at 2.69 ppm indicates the CH₂ group and at 3.27 ppm is observed quartet of triplets for the second methylene group, next to the NH. The signal for the hydrogen on the chiral carbon is a quartet at 3.69 ppm. The methoxy group signal is the next singlet at 3.87 ppm. The signal for the NH is a triplet at 8.04 ppm. In the area between 7.02–7.55 ppm are observed 10 aromatic protons (see Supplementary Materials).

¹³C NMR spectrum allows us to confirm the structure of the newly obtained hybrid molecule 10. The signal for the C=O is at 179.79 ppm. The signal for the CH₃ group is at 18.88 ppm, the two methylene carbon signals are at 34.92 ppm and 40.31 ppm. At 55.60 ppm the signal for the methoxy group carbon is observed. At 157.43 ppm is the aromatic carbon connected to the methoxy group.

The IR spectra also confirmed the existence of all functional groups, and the HRMS analysis unambiguously confirmed the structure of the new hybrid molecule 10.

3. Materials and Methods

All reagents and chemicals were purchased from commercial sources (Sigma-Aldrich S.A. and Riedel-de Haën, Sofia, Bulgaria) and used as received. The NMR spectral data were recorded on a Bruker Avance Neo 400 spectrometer (BAS-IOCCP—Sofia, Bruker, Billerica, MA, USA). ¹H NMR and ¹³C NMR spectra for all compounds were taken in DMSO-d₆ at 400 MHz and 101 MHz, respectively. Chemical shifts are given in relative ppm and were referenced to tetramethylsilane (TMS) (δ = 0.00 ppm) as an internal standard; the coupling constants are indicated in Hz. The NMR spectra were recorded at room temperature (ac. 295 K). The melting point was determined on a Boetius hot stage apparatus and is uncorrected. Absorbance was measured with a spectrophotometer Camspec M508, Leeds, UK. The MS analysis was performed on a Q Exactive Plus high-resolution mass spectrometer (HRMS) with a heated electrospray ionization source (HESI-II) (Thermo Fisher Scientific, Inc., Bremen, Germany) equipped with a Dionex Ultimate 3000RSLC ultrahigh-performance liquid chromatography (UHPLC) system (Thermo Fisher Scientific, Inc., Waltham, MA, USA). TLC was carried out on precoated 0.2 mm Fluka silica gel 60 plates (Merck KGaA, Darmstadt, Germany). IR spectra was measured on a Bruker Alpha II FT IR spectrometer.

3.1. (±)-2-(6-Methoxynaphthalen-2-yl)propanoyl Chloride 9

For (±)-naproxen 1 (1.0 mmol, 0.230 g) dissolved in toluene (30 mL), an excess of thionyl chloride (1.2 mmol, 0.087 mL) was added. The reaction mixture was stirred under reflux for two hours. The excess of thionyl chloride and the toluene were removed under reduced pressure. The obtained (±)-2-(6-Methoxynaphthalen-2-yl)propanoyl chloride 9 was used without further purification.

3.2. Synthesis of (±)-N-(3-Chlorophenethyl)-2-(6-methoxynaphthalen-2-yl)propanamide 10

To a solution of amine 8 (1.0 mmol, 0.155 g) in dichloromethane (30 mL), an equal amount of (±)-2-(6-methoxynaphthalen-2-yl)propanoyl chloride 9 (1 mmol, 0.248 g) was added. After 10 min triethylamine (1.2 mmol, 1.67 mL) was added to the solution. After 30 min, the solution was washed with a diluted hydrochloric acid, saturated solution of Na₂CO₃, and brine. The combined organic layers were dried over anhydrous Na₂SO₄, and the solvent was removed under reduced pressure. The new hybrid molecule was purified by filtration through short-column chromatography over neutral Al₂O₃.

(±)-N-(3-chlorophenethyl)-2-(6-methoxynaphthalen-2-yl)propanamide 10: white solid (m.p. 101–102 °C), yield 92% (0.339 g), R_f = 0.81 (petroleum/diethyl ether = 1/1), ¹H NMR (400 MHz, DMSO) δ 8.04 (t, J = 5.7 Hz, 1H), 7.75 (dd, J = 12.1, 8.8 Hz, 2H), 7.68 (d, J = 1.8 Hz, 1H), 7.40 (dd, J = 8.5, 1.8 Hz, 1H), 7.28 (d, J = 2.6 Hz, 1H), 7.22–7.11 (m, 4H), 7.02 (dt, J = 7.3, 1.5 Hz, 1H), 3.87 (s, 3H), 3.69 (q, J = 7.0 Hz, 1H), 3.27 (qt, J = 13.1, 6.6 Hz, 2H), 2.69 (t, J = 6.5 Hz, 2H), 1.38 (d, J = 7.0 Hz, 3H). ¹³C NMR (101 MHz, DMSO) δ 173.79, 157.43, 142.55, 137.80, 133.61, 133.27, 130.37, 129.56, 129.01, 128.85, 127.95, 127.04, 126.89, 126.43, 125.72, 118.98, 106.14, 55.60, 45.50, 40.31, 34.92, 18.88. UV λ_max, MeOH: 254 (ε = 32900) nm, 285 (ε = 4700) nm, 252 (ε = 1770) nm. HRMS Electrospray ionization (ESI) m/z calcd for [M+H]⁺ C₂₂H₂₃ClNO₂ = 368.1412, found 368.1416 (mass error Δ_m = 1.06 ppm). IR(KBr) ν_max, cm⁻¹: 685, 699, 785, 857 γ(Csp²-H); 1391 δ_s(CH₃); 1460, 1537 ν(C=C); 1643 ν(C=O); 2889 ν(CH₂); 2940 ν_as(CH₂); 2980, ν_as(CH₃); 3002, 3057 ν(Csp²-H); 3314 ν(N-H).