N-(3-Chlorophenethyl)-2-(4-isobutylphenyl)propanamide

Abstract

N-(3-chlorophenethyl)-2-(4-isobutylphenyl)propanamide was synthesized for the first time in the reaction between 2-(3-chlorophenyl)ethan-1-amine and 2-(4-isobutylphenyl)propanoyl chloride with high yield. The newly obtained chlorine-containing ibuprofen derivative was fully analyzed and characterized using ¹H-, ¹³C-NMR, UV, and mass spectral data.

1. Introduction

The scientific literature shows that the interest in obtaining new ibuprofen derivatives continues to this day [1,2,3,4]. Ibuprofen (Figure 1) is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat pain and inflammation. Ibuprofen inhibits several enzymes that produce prostaglandins (COX1 and COX2), reducing inflammation, pain, and fever. Ibuprofen also inhibits fungal activity, inhibits smooth muscle cell mitogenesis, and acts as a central analgesic.

Installing a chlorine atom at the meta site to the ethylamine fragment makes the molecule very interesting for studying its biological activity (Figure 1) [5]. Together with nitrogen and oxygen, chlorine is one of the most common heteroatoms in medicines. There are currently over 250 approved chlorine-containing drugs on the market. A simple substitution of a hydrogen atom with chlorine has demonstrated that it can result in enormous potency improvements and profound effects on pharmacokinetic parameters such as clearance, half-life, and drug exposure in vivo [5].

A few representatives of those approved and well-known medicines used in medicinal practice containing chlorine atoms are chloramphenicol, chloroquine, chlorambucil, etc., used for their antibacterial antibiotic, anticancer, and antimalarial properties respectively (Figure 2) [6].

The synthesis of new molecules from a class of compounds, amides, containing an ibuprofen fragment attached to a 2-phenylethylamine containing a meta chlorine atom is extremely interesting in view of what properties the newly obtained molecule would inherit from both fragments.

2. Results

Herein, we report the successful synthesis of N-(3-chlorophenethyl)-2-(4-isobutylphenyl)propanamide 3, as shown in Scheme 1. For this purpose, 2-(4-isobutylphenyl)propanoyl chloride 2 (1 mmol) is added to the solution of 2-(3-chlorophenyl)ethan-1-amine 1 (1 mmol) in dichloromethane. The reaction mixture is stirred for ten minutes and then an excess of trimethylamine (1.5 mmol) is carefully added. In 30 min the examined TLC (Eluent: Petroleum: Diethyl ether = 1:1, R_f = 0.44) proved the obtaining of the final product 3. This reaction is known as the reaction of Schotten-Baumann and allows an easy and quick way for the building of amide bonds from amines and acyl chlorides.

Observing the ¹H-NMR data of the obtained new compound all 26 H atoms can clearly be seen. The signal for the NH group is a triplet at 7.97 ppm. The two equivalent methyl groups from ibuprofen residue are shown at the beginning of the spectrum as a doublet for 6 protons at 0.86 ppm. The next doublet at 1.28 ppm is for the other methyl group, connected to the asymmetric carbon atom. At 1.80 ppm a double heptet for CH, connected to the two-methyl groups is proving its existence.

¹³C-NMR spectrum allows us to confirm the structure of the newly obtained chlorine-containing hybrid molecule 3. The carbon signal for the C=O is at 173.83 ppm. The carbons for the methyl groups can be seen at 18.93 ppm (CH₃ next to the asymmetric carbon), and 22.56 ppm for the 2 equivalent CH₃ groups. The rest signals at the beginning of the spectrum are for the CH₂ and CH groups. Ten signals in the range between 126.45 and 142.57 are allowing us to identify all 12 carbon atoms.

The functional groups present in the structure were confirmed via IR-spectroscopy, and HRMS analysis verified the mass of compound 3.

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 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 Fish-er Scientific, Inc., Waltham, MA, USA). TLC was carried out on precoated 0.2 mm Fluka silica gel 60 plates (Merck KGaA, Darmstadt, Germany).

3.1. Synthesis of 2-(4-Isobutylphenyl)propanoyl Chloride 2

For ibuprofen (1 mmol, 0.206 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-(4-isobutylphenyl)propanoyl chloride was used without further purification.

3.2. Synthesis of N-(3-Chlorophenethyl)-2-(4-isobutylphenyl)propanamide 3

To a solution of amine 1 (1 mmol, 0.155 g) in dichloromethane (30 mL), an equal amount of 2-(4-isobutylphenyl)propanoyl chloride 2 (1 mmol, 0.224 g) was added. After 10 min triethylamine (1.2 mmol, 0.121 g) was added to the solution. In 30 min, the solution was washed with 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 compound was purified by filtration through short-column chromatography over neutral Al₂O₃.

N-(3-chlorophenethyl)-2-(4-isobutylphenyl)propanamide3: white solid (m.p.108–109 °C), yield 95% (0.327 g), R_f = 0.44 (petroleum/diethyl ether = 1/1), ¹H NMR (400 MHz, DMSO) δ 7.97 (t, J = 5.7 Hz, 1H), 7.25–7.22 (m, 2H), 7.21 (dd, J = 1.9, 1.1 Hz, 1H), 7.18–7.15 (m, 2H), 7.08–7.02 (m, 3H), 3.51 (q, J = 7.0 Hz, 1H), 3.34–3.18 (m, 2H), 2.68 (m, 2H), 2.40 (d, J = 7.1 Hz, 2H), 1.80 (dh, J = 13.6, 6.8 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H), 0.86 (d, J = 6.6 Hz, 6H). ¹³C NMR (101 MHz, DMSO) δ 173.83, 142.57, 139.91, 139.60, 133.28, 130.41, 129.18, 129.03, 127.97, 127.39, 126.45, 45.17, 44.74, 40.40, 40.25, 40.19, 39.99, 39.78, 39.57, 34.92, 30.10, 22.65, 18.93. λ_max, MeOH: 245 (ε = 4150) nm, 287 (ε = 360) nm. HRMS Electrospray ionization (ESI) m/z calcd for [M+H]⁺ C₂₁H₂₇ClNO⁺ = 344.1776, found 344.1780 (mass error Δ_m = 1.16 ppm). IR(KBr) ν_max, cm⁻¹: 684, 701, 786, 854 γ(C_sp²-H); 1380δ_s(CH₃); 1474, 1555 ν(C=C); 1638 ν(C=O); 2864 ν(CH₂); 2921 ν_as(CH₂); 2964, ν_as(CH₃); 3026, 3073 ν(C_sp²-H); 3242 ν(N-H).