4298-16-2

Usage

Uses

Used in Pharmaceutical Industry:
(d,l)-Methamphetamine hydrochloride is used as a medication for the treatment of attention deficit hyperactivity disorder (ADHD) and obesity. It provides temporary relief from the symptoms associated with these conditions due to its stimulating effects on the central nervous system.
However, it is important to note that (d,l)-Methamphetamine hydrochloride is a highly addictive substance with a high potential for abuse. It is classified as a Schedule II controlled substance by the United States Drug Enforcement Administration. Long-term use can lead to severe physical and psychological health issues, including addiction, cardiovascular problems, and neurological damage. Therefore, its use should be carefully monitored and prescribed only when necessary under the guidance of a medical professional.

Upstream product

• 7632-10-2 methamphetamin 
• 63991-26-4 ephedrine hydrochloride 
• 152614-95-4 BOC-pseudoephedrine 
• 1334921-74-2 C₁₅H₂₃NO₂ 
• 14611-52-0 (R)-(-)-deprenyl hydrochloride 
• 50-98-6 ephedrine hydrochloride 
• 345-78-8 Novafed 
• 299-42-3 ephedrine 
• 537-46-2 Methamphetamin 
• 100-44-7 benzyl chloride 

Downstream Products

• 5411-22-3 benzfetamine hydrochloride 
• 6192-97-8 (S)-1-cyclohexyl-N-methylpropan-2-amine 
• 89578-44-9 (S)-(+)-N-Propionyl-N-methylamphetamine 

Relevant academic research and scientific papers

Evaluation of characteristic deuterium distributions of ephedrines and methamphetamines by NMR spectroscopy for drug profiling

We have established a method for quantitative analysis of the deuterium contents (D/H) at the phenyl, methine, benzyl, N-methyl and methyl groups of l-ephedrine/HCl, d-pseudoephedrine/HCl and methamphetamine/HCl by 2H NMR spectroscopy. Comparison of the 5 position-specific D/H values of l-ephedrine/HCl and d-pseudoephedrine/HCl prepared by three methods (chemical synthesis, semichemical synthesis, and biosynthesis) showed that chemically synthesized ephedrines and semi-synthetic ephedrines have highly specific distributions of deuterium at the methine position and at the benzyl position, compared with the other positions. The classification of several methamphetamine samples seized in Japan in terms of the D/H values at these two positions clearly showed that the methamphetamine samples had been synthesized from ephedrines extracted from Ephedra plants or semisynthetic ephedrines but not from synthetic ephedrine. This isotope ratio analysis method should be useful to trace the origins of seized methamphetamine in Southeast Asia.

Trace decomposition of selegiline. Use of worst-case kinetics for a stable drug

A solution of selegiline hydrochloride reference standard, which contained no detectable impurities at the time of its preparation, was found by HPLC to contain a trace of a compound at the locus of methamphetamine when analyzed after 1 year. Heating selegiline solutions at pH 7 and 105 °C produced methamphetamine as the major product at a rate which closely followed the first-order rate equation. Using only these data and worst-case assumptions, rate constants were estimated at various temperatures; the activation energy was estimated to be about 25 kcal, and the stability-indicating validity of the assay used was reaffirmed. Selegiline undergoes degradation at a negligibly slow rate.

A short enantioselective synthesis of ephedrine, amphetamine and their analogues via two stereocentered Co(III)-catalyzed hydrolytic kinetic resolution of racemic syn-benzyloxy epoxide

An efficient route for the synthesis of 6 drugs belonging to phenethylamine and amphetamine classes in excellent overall yields and high optical purity has been described. The strategy involves introduction of stereogenic centers by means of two-stereocentered Co(III)-catalyzed hydrolytic kinetic resolution (HKR) of racemic syn-benzyloxy epoxide followed by Pd-catalyzed regioselective cationic hydrogenation of amino alcohols as the key reactions.

An efficient, scalable process for benzphetamine hydrochloride

Commercial manufacturing of benzphetamine hydrochloride along with its impurity profiling is disclosed. Deoxygenation of pseudoephedrine is reported with ～100% retention by shielding the amine group as its tert-butyl carbamate, which is very straightforward to eliminate at the end. Four unknown process-related impurities are isolated from the samples of final API and characterized on the basis of their NMR and mass spectral analysis. Structures of the isolated impurities are confirmed by independent syntheses and coinjecting with the isolated one.

Significant determinants of isotope composition during HI/Pred synthesis of methamphetamine

Methamphetamine HCl was synthesized using three variations of the hydriodic acid/red phosphorus (HI/Pred) synthetic route. A Plackett-Burman experimental design was used to determine how reaction parameters affected the isotopic composition of the product. Isotope ratio mass spectrometry results showed only the source of precursor 13C was significant in determining product δ13C; the manufacturer, reaction temperature, time, scale, and source of HI were not significant. The precursor was also the main determinant of product δ2H, with smaller contributions from the HI source for one method. From precursor to product, large δ2H depletion occurred for most samples. Deuterium nuclear magnetic resonance spectroscopy (2H NMR) was used to investigate the specific site of this. Significant fraction of deuterium was observed only at the benzylic position, the site of hydrogen addition during synthesis. Methamphetamine synthesized from ephedrine was shown to be depleted in this position.

Characterization of route specific impurities found in methamphetamine synthesized by the Leuckart and reductive amination methods

Impurity profiling of seized methamphetamine can provide very useful information in criminal investigations and, specifically, on drug trafficking routes, sources of supply, and relationships between seizures. Particularly important is the identification of "route specific" impurities or those which indicate the synthetic method used for manufacture in illicit laboratories. Previous researchers have suggested impurities which are characteristic of the Leuckart and reductive amination (Al/Hg) methods of preparation. However, to date and importantly, these two synthetic methods have not been compared in a single study utilizing methamphetamine hydrochloride synthesized in-house and, therefore, of known synthetic origin. Using the same starting material, 1-phenyl-2-propanone (P2P), 40 batches of methamphetamine hydrochloride were synthesized by the Leuckart and reductive amination methods (20 batches per method). Both basic and acidic impurities were extracted separately and analyzed by GC/MS. From this controlled study, two route specific impurities for the Leuckart method and one route specific impurity for the reductive amination method are reported. The intra- and inter-batch variation of these route specific impurities was assessed. Also, the variation of the "target impurities" recently recommended for methamphetamine profiling is discussed in relation to their variation within and between production batches synthesized using the Leuckart and reductive amination routes.

PROCESS FOR PREPARING BENZYLATED AMINES

This present invention relates to a process for preparing benzylated amines by the reaction of an amine selected from methamphetamine and propylhexedrine with benzyl halide. Numerous improvements are obtained by employing the amine in molar excess with respect to benzyl halide, preferably in a molar ratio of 2 to 1. The excess amine is employed to selectively neutralize by-product acid as the amine salt. The amine salt is then separated from the reaction mixture and basified to reclaim starting amine for recycle to the process.