2.2.1. Synthesis of α-aminovalerophenone
The synthesis and characterization of the five cathinones was carried out through three steps, following the procedure formerly described (Meltzer et al., 2006). First of all, the ketone intermediate was prepared by alkylation of the nitrile compound (Step 1), followed by acidic hydrolysis. The n-BuMgCl was added in a dropwise manner to a solution of benzonitrile in toluene in anhydrous conditions. After three hours at room temperature, the reaction was complete. A solution of H2SO4 (4%) was added into the reaction mixture previously cooled. The organic layer was extracted with Et2O, dried (MgSO4), filtered and reduced in vacuo to an oil. The α-bromination reaction was carried out by adding bromine in a dropwise manner to a solution of the ketone intermediate in Et2O in presence of AlCl3 in catalytic amounts (Step 2). The excess of bromine is neutralized with a solution of Na2S2O3. The organic layer is separated, dried (MgSO4), filtrated and reduced in vacuo to an oil. The α‑bromoketone was dissolved in Et2O, and the corresponding amine (methylamine, ethylamine, diethylamine, pyrrolidine and piperidine), was added all at once (Step 3). After 24-48 h the reactions were completed. The reaction mixtures were extracted with HCl 1N and then back-extracted into Et2O by basification to pH 10 with NaOH 1 M. The organic layers were dried (MgSO4), filtered and reduced in vacuo to an oil. Each product was dissolved in EtOH and a mixture of Et2O with HCl (3M) in CPME was added in a dropwise manner in order to obtain the hydrochloride salt. Solids were collected by filtration. The identification of the five compounds was assessed by proton nuclear magnetic resonance (1H NMR) (CDCl3) yielding the following results:
α-methylaminovalerophenone hydrochloride : δ 10.55 (s, 1H), 9.16 (s, 1H), 7.96 (dd, J = 8.4, 1.2 Hz, 2H), 7.70 – 7.64 (m, 1H), 7.53 (t, J = 7.8 Hz, 2H), 4.94 (s, 1H), 2.81 (s, 3H), 2.30 – 2.16 (m, 1H), 2.16 – 2.02 (m, 1H), 1.61 – 1.46 (m, 1H), 1.45 – 1.29 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H); α -ethylaminovalerophenone hydrochloride : d 7.99 – 7.98 (d, J = 7.4 Hz, 2H), 7.72 – 7.68 (t, J = 7.4 Hz, 1H), 7.58 – 7.54 (t,J = 7.6 Hz, 2H), 6.99 (s, 0H), 4.97 (s, 1H), 3.24 (s, 1H), 3.04 (s, 1H), 2.33 – 2.29 (d, J = 12.4 Hz, 1H), 2.21 – 2.14 (m, 1H), 1.56 – 1.53 (t, J = 7.2 Hz, 3H), 1.48 – 1.32 (m, 2H), 0.90 – 0.86 (t, J = 7.2 Hz, 3H); α -diethylaminovalerophenone hydrochloride : 8.18 - 8.10 (m, 2H), 7.75 (ddt, J = 7.9, 7.0, 1.2 Hz, 1H), 7.66 - 7.57 (m, 2H), 5.34 (dd, J = 6.3, 4.9 Hz, 1H), 3.48 (dq, J = 14.6, 7.3 Hz, 1H), 3.36 - 3.25 (m, 3H), 3.11 (dq,J = 14.3, 7.3 Hz, 1H), 2.06 - 1.92 (m, 2H), 1.41 (t, J = 7.3 Hz, 3H), 1.33 (t, J = 7.3 Hz, 3H), 1.30 - 1.12 (m, 3H), 0.86 (t, J = 7.3 Hz, 3H); α ‑ pyrrolidinopentiophenone hydrochloride: d : 12.42 (s, 1H), 8.02-7.96 (m, 2H), 7.72-7.67 (m, 1H), 7.58-7.54 (m, 2H), 5.25 (dt, J = 8.0, 5.1 Hz, 1H), 3.82 (m, 2H), 3.62 (m, 1H), 2.95 (dq, J = 10.5, 7.7 Hz, 1H), 2.03 (m, 2H), 2.19 (m, 3H), 1.35 (m, 1H), 1.47 (m, 1H), 0.89 (t, J = 7.3 Hz, 3H); α ‑ N‑piperidylvalerophenone hydrochloride : d : 12.40 (s, 1H), 8.02 – 7.97 (m, 2H), 7.73 – 7.67 (ddt, J = 7.4 Hz, 2H), 7.58 – 7.52 (m, 1H), 5.03 (dt, J = 10.3, 3.8 Hz, 1H), 3.67 (d, J = 12.0 Hz, 1H), 3.51 – 3.45 (m, 1H), 3.42 – 3.37 (d, J = 21.1 Hz, 1H), 2.75 – 2.64 (m, 1H), 2.53 – 2.45 (m, 1H), 2.41 – 2.33 (m, 1H), 2.30 – 2.17 (m, 1H), 2.03 – 1.97 (m, 2H), 1.96 – 1.87 (m, 2H), 1.75 – 1.63 (d, J = 12.5 Hz, 1H), 1.47 – 1.30 (m, 2H), 0.91 (t, 3H).
Chemical purity of the obtained compound was also assessed by thin layer chromatography 1H NMR, 13C NMR and mass spectrometry. All analytical data were consistent with the assigned structure with over 98% purity for the cathinone derivative.