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.