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Phenylacetone, also known as phenyl-2-propanone, is an organic compound with the chemical formula C6H5CH2COCH3. It is a colorless oil that is soluble in organic solvents. It is a mono-substituted benzene derivative, consisting of an acetone attached to a phenyl group. As such, its systematic IUPAC name is 1-phenyl-2-propanone.
This substance is used in the manufacture of methamphetamine and amphetamine, where it is commonly known as P2P.[2][3] Due to illicit drug labs using phenylacetone to make amphetamines, phenylacetone was declared a schedule II controlled substance in the United States in 1980.[4] In humans, phenylacetone occurs as a metabolite of amphetamine and methamphetamine via FMO3-mediated oxidative deamination.[5]
There are many routes to synthesize phenylacetone. Industry uses the gas-phase ketonic decarboxylation of phenylacetic acid using acetic acid over a ceria-aluminasolid acid catalyst.[6] A related laboratory-scale reaction has been described.[7]
An alternative route is zeolite-catalyzed isomerization of phenylpropylene oxide. Another laboratory synthesis involves conventional routes including the Friedel-Crafts alkylation reaction of chloroacetone with benzene in the presence of aluminum chloridecatalyst.[8]
To prevent illicit synthesis of amphetamine and methamphetamine, phenylacetone itself and the precursor phenylacetic acid is subject to regulation in the United States under the Chemical Diversion and Trafficking Act.
In the TV series Breaking Bad, Walter White manufactures methamphetamine using phenylacetone and methylamine through a reductive amination reaction in the presence of aluminum amalgam. Walter White produced phenylacetone in a tube furnace using phenylacetic acid and acetic anhydride with a thorium oxide or thorium nitratecatalyst.
Phenylacetone is an intermediate in the biodegradation of amphetamine. In the human liver, flavin-containing monooxygenase 3 (FMO3) deaminates amphetamines into phenylacetone, which is non-toxic to humans.[20] Phenylacetone is oxidized to benzoic acid, which is converted to hippuric acid by glycine N-acyltransferase (GLYAT) enzymes prior to excretion.
Phenylacetone can undergo para-hydroxylation to 4-hydroxyphenylacetone, which occurs as a metabolite of amphetamine in the human body.
The simplest unsubstituted phenylisopropylamine, 1-phenyl-2-aminopropane, or amphetamine, serves as a common structural template for hallucinogens and psychostimulants. Amphetamine produces central stimulant, anorectic, and sympathomimetic actions, and it is the prototype member of this class (39). ... The phase 1 metabolism of amphetamine analogs is catalyzed by two systems: cytochrome P450 and flavin monooxygenase. ... Amphetamine can also undergo aromatic hydroxylation to p-hydroxyamphetamine. ... Subsequent oxidation at the benzylic position by DA β-hydroxylase affords p-hydroxynorephedrine. Alternatively, direct oxidation of amphetamine by DA β-hydroxylase can afford norephedrine.
Dopamine-β-hydroxylase catalyzed the removal of the pro-R hydrogen atom and the production of 1-norephedrine, (2S,1R)-2-amino-1-hydroxyl-1-phenylpropane, from d-amphetamine.
Hydroxyamphetamine was administered orally to five human subjects ... Since conversion of hydroxyamphetamine to hydroxynorephedrine occurs in vitro by the action of dopamine-β-oxidase, a simple method is suggested for measuring the activity of this enzyme and the effect of its inhibitors in man. ... The lack of effect of administration of neomycin to one patient indicates that the hydroxylation occurs in body tissues. ... a major portion of the β-hydroxylation of hydroxyamphetamine occurs in non-adrenal tissue. Unfortunately, at the present time one cannot be completely certain that the hydroxylation of hydroxyamphetamine in vivo is accomplished by the same enzyme which converts dopamine to noradrenaline.
Figure 1. Glycine conjugation of benzoic acid. The glycine conjugation pathway consists of two steps. First benzoate is ligated to CoASH to form the high-energy benzoyl-CoA thioester. This reaction is catalyzed by the HXM-A and HXM-B medium-chain acid:CoA ligases and requires energy in the form of ATP. ... The benzoyl-CoA is then conjugated to glycine by GLYAT to form hippuric acid, releasing CoASH. In addition to the factors listed in the boxes, the levels of ATP, CoASH, and glycine may influence the overall rate of the glycine conjugation pathway.
The biologic significance of the different levels of serum DβH activity was studied in two ways. First, in vivo ability to β-hydroxylate the synthetic substrate hydroxyamphetamine was compared in two subjects with low serum DβH activity and two subjects with average activity. ... In one study, hydroxyamphetamine (Paredrine), a synthetic substrate for DβH, was administered to subjects with either low or average levels of serum DβH activity. The percent of the drug hydroxylated to hydroxynorephedrine was comparable in all subjects (6.5-9.62) (Table 3).
In species where aromatic hydroxylation of amphetamine is the major metabolic pathway, p-hydroxyamphetamine (POH) and p-hydroxynorephedrine (PHN) may contribute to the pharmacological profile of the parent drug. ... The location of the p-hydroxylation and β-hydroxylation reactions is important in species where aromatic hydroxylation of amphetamine is the predominant pathway of metabolism. Following systemic administration of amphetamine to rats, POH has been found in urine and in plasma.The observed lack of a significant accumulation of PHN in brain following the intraventricular administration of (+)-amphetamine and the formation of appreciable amounts of PHN from (+)-POH in brain tissue in vivo supports the view that the aromatic hydroxylation of amphetamine following its systemic administration occurs predominantly in the periphery, and that POH is then transported through the blood-brain barrier, taken up by noradrenergic neurones in brain where (+)-POH is converted in the storage vesicles by dopamine β-hydroxylase to PHN.
The metabolism of p-OHA to p-OHNor is well documented and dopamine-β hydroxylase present in noradrenergic neurons could easily convert p-OHA to p-OHNor after intraventricular administration.