Effect of Reaction Time and Temperature on the Impurity Profile of Amphetamine in the Leuckart Method

Illicit amphetamine synthesis is frequently conducted using the well-known Leuckart method, generating complex impurity profiles that provide forensic insights. This study reports the effect of reaction temperature and time during the first step of the Leuckart synthesis on subsequent conversion efficiency and impurity profile. Controlled syntheses were conducted at 120°C, 140°C, and 160°C, with samples collected at defined intervals. Reaction progress was monitored by gas chromatography-flame ionization detection (GC-FID), and impurity profiling followed the European harmonized method for profiling amphetamine (EHMPA) using GC-mass spectrometry (GC-MS). In addition, preparative liquid chromatography (prep-LC) followed by LC-high-resolution MS (LC-HRMS) was employed to isolate and characterize previously unidentified impurities. Results indicate that higher temperatures and longer reaction times accelerate benzyl methyl ketone (BMK) conversion, increasing the formation of N-formylamphetamine (after step 1) and amphetamine (after step 2). Lower temperatures and shorter reaction times result in incomplete conversion and the persistent presence of BMK, along with several impurities, including unsaturated ketones (3,5-diphenyl-4-methyl-3-penten-2-one and 1,5-diphenyl-4-methyl-3-penten-2-one), 1,3-dimethyl-2-phenylnaphthalene (Naphthalene 1), and 1-benzyl-3-methylnaphthalene (Naphthalene 2). Elevated temperatures favor the formation of 4-methyl-5-phenylpyrimidine (4M5PP), 4-benzylpyrimidine (4BP), N,N-bis-(‒1-phenylpropan-2-yl)formamide (DPIF), and Unknowns A2, B1, and B2, which were tentatively identified as N-[3,5-diphenyl-4-methyl-3-penten-2-yl]amine, and the cis/trans isomers of N-[1,5-diphenyl-4-methyl-3-penten-2-yl]amine, respectively. These amines form via hydrolysis of N-formylamino derivatives generated from unsaturated ketone intermediates. These findings demonstrate that reaction temperature and time strongly govern both amphetamine formation and impurity composition. The identified impurities serve as distinct chemical indicators, enabling reconstruction of illicit synthesis conditions and supporting intelligence on amphetamine production.