Synthesis of Dextroamphetamine Sulfate and Methamphetamine Hydrochloride from D-Phenylalanine

An enantiospecific method was developed for the synthesis of 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-7-substituted-1,2,3,4-tetrahydroisoquinolines (THIQs) from phenylalanine. Biochemical evaluation of the enantiomers of these compounds at both PNMT and the alpha(2)-adrenoceptor indicates that both sites display similar stereoselectivity. Overall the R-enantiomer was usually the more potent enantiomer at both PNMT and the alpha(2)-adrenoceptor for these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs. The one exception is 3-hydroxymethyl-7-nitro-THIQ (9), which was found to display the opposite stereoselectivity at the alpha(2)-adrenoceptor. A comparison of the PNMT inhibitory potency of the enantiomers of these 3-fluoromethyl-, 3-hydroxymethyl-, and 3-chloromethyl-THIQs indicates that all of the 3-substituted-THIQs displayed similar inhibitory potency for PNMT. However, the nature of the 3-substituent was found to have a major effect on the alpha(2)-adrenoceptor affinity of these compounds with the 3-hydroxymethyl- and 3-fluoromethyl-THIQs having the highest affinity and THIQs containing the 3-chloromethyl moiety the least. Compounds R-3-fluoromethyl-7-cyano-THIQ (R-12) and R-3-fluoromethyl-7-N-(4-chlorophenyl)aminosulfonyl-THIQ (R-13) and both enantiomers of 3-chloromethyl-7-nitro-THIQ (R- and S-30) are the most selective inhibitors in this study and display selectivities (alpha(2)-adrenoceptor K(i)/PNMT K(i)) greater than 200. These compounds give important insight into the steric and stereochemical preferences of both PNMT and the alpha(2)-adrenoceptor, which should assist in the development of new PNMT inhibitors.

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“…Bulb-to-bulb distillation (120°C, 0.1 mmHg) gave R-18 as a white solid (6.67 g, 82%): mp 91-93°C (lit. 23 …”

Section: R-(+)-2-amino-3-phenylpropanol (R-18)mentioning

confidence: 97%

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α₂-Adrenoceptor

Grunewald

Caldwell

et al. 1999

J. Med. Chem.

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“…Dexamphetamine can be synthesized by various methods, for example, starting from chiral precursors such as D ‐phenylalanine 5 or from chiral β‐hydroxyphenylethylamines such as 1 R ,2 S ‐(−)‐norephedrine or 1 S ,2 S ‐(+)‐norpseudoephedrine 6, 7. Alternatively, the compound can be obtained from racemic amphetamine synthesized from phenylacetone (1‐phenyl‐2‐propanone, benzyl methyl ketone) by Leuckart reaction or by reduction of the oxime 8, 9 followed by fractional crystallization with L ‐(+)‐tartaric acid 10.…”

Section: Introductionmentioning

confidence: 99%

CE assay for simultaneous determination of charged and neutral impurities in dexamphetamine sulfate using a dual CD system

Sungthong¹,

Scriba²

2010

Electrophoresis

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A CE assay for the simultaneous determination of charged and uncharged potential impurities (1S,2S-(1)-norpseudoephedrine, 1R,2S-(À)-norephedrine, phenylacetone and phenylacetone oxime) of dexamphetamine sulfate including the stereoisomer levoamphetamine was developed and validated. The optimized background electrolyte consisted of a 50 mM sodium phosphate buffer, pH 3.0, containing 80 mg/mL sulfobutylether-b-CD and 25 mg/mL sulfated b-CD. Separations were performed in 40.2/35 cm, 50 mm id fused-silica capillaries at a temperature of 201C and an applied voltage of -10 kV. 1R,2S-(À)-ephedrine was used as internal standard. The assay was validated in the range of 0.05-1.0% for the related substances and in the range of 0.05-5.0% for levoamphetamine. The LOD was 0.01-0.02% depending on the analyte. The assay also allowed the separation of the E,Z-stereoisomers of phenylacetone oxime. The effect of the degree of substitution of sulfobutylether-b-CD was investigated. In commercial samples of dexamphetamine sulfate between 3.2 and 3.7% of levoamphetamine were found. Furthermore, phenylacetone and phenylacetone oxime could be observed at the LOD, indicating the synthetic origin of the investigated samples. The effect in attention deficit hyperactivity disorder is believed to be mediated via several mechanisms including the binding of the drug to the pre-synaptic dopamine transporter inducing a reversed transport process as well as stimulation of pre-synaptic inhibitory autoreceptors, resulting in reduced activity in dopaminergic and noradrenergic pathways [4]. Dexamphetamine can be synthesized by various methods, for example, starting from chiral precursors such as D-phenylalanine [5] or from chiral b-hydroxyphenylethylamines such as 1R,2S-(À)-norephedrine or 1S,2S-(1)-norpseudoephedrine [6,7]. Alternatively, the compound can be obtained from racemic amphetamine synthesized from phenylacetone (1-phenyl-2-propanone, benzyl methyl ketone) by Leuckart reaction or by reduction of the oxime [8,9] followed by fractional crystallization with L-(1)-tartaric acid [10]. Thus, charged as well as neutral starting materials or synthetic by-products as well as the enantiomer levoamphetamine (2R-(À)-amphetamine) may be present as related substances in the drug.Dexamphetamine sulfate is described in monographs by the United States Pharmacopeia 32 (USP 32) [11]

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“…L-MAMP-d 6 (L-1-phenyl-2-methyl-d 3 -aminopropane-3,3,3-d 3 ) was obtained from L-phenylalanine by following a modified version of the procedure reported by Repke et al [11], and L-AMP-d 3 (L-1-phenyl-2-aminopropane-3,3,3-d 3 ) was obtained as a by-product. The products were isolated on an alumina column and were crystallized as L-MAMP-d 6 hydrochloride and L-AMP-d 3 sulfate.…”

Section: Methodsmentioning

confidence: 99%

Two simple methods for enantiomeric analyses of urinary amphetamines by GC/MS using deuterium-labeled l-amphetamines as internal standards

et al. 2006

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Two simple methods for enantiomeric analyses of amphetamines in urine by gas chromatography-mass spectrometry (GC-MS) using L-amphetamine-d 3 and L-methamphetamine-d 6 as internal standards are presented. One method (method A) employs extractive derivatization on a diatomaceous column with (S)-(−)-N-(trifluoroacetyl)prolyl chloride (TPC) followed by separation with a conventional capillary column. The second method (method B) uses headspace solid-phase microextraction (HD-SPME) after derivatization with heptafluoro-n-butyryl chloride (HFB), followed by separation with an enantiomeric capillary GC column. By the two methods, all enantiomers were well separated in each chromatogram, and good linearity was obtained in practical concentration ranges (0.1-1.6 µg/ml for method A and 0.05-1 µg/ml for method B) for every compound by selected-ion monitoring. The precision studies indicated satisfactory coefficients of variation (<5%) for every enantiomer at 0.1 µg/ml by both methods. Both methods were also evaluated by applying them to an actual poisoning case. Both methods are recommended for use in forensic analysis, because of their simplicity, high precision, and sufficient sensitivity.

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Synthesis of Dextroamphetamine Sulfate and Methamphetamine Hydrochloride from D-Phenylalanine

Cited by 15 publications

References 19 publications

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α₂-Adrenoceptor

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α₂-Adrenoceptor

CE assay for simultaneous determination of charged and neutral impurities in dexamphetamine sulfate using a dual CD system

Two simple methods for enantiomeric analyses of urinary amphetamines by GC/MS using deuterium-labeled l-amphetamines as internal standards

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Synthesis of Dextroamphetamine Sulfate and Methamphetamine Hydrochloride from D-Phenylalanine

Cited by 15 publications

References 19 publications

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α2-Adrenoceptor

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α2-Adrenoceptor

CE assay for simultaneous determination of charged and neutral impurities in dexamphetamine sulfate using a dual CD system

Two simple methods for enantiomeric analyses of urinary amphetamines by GC/MS using deuterium-labeled l-amphetamines as internal standards

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Resources

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Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α₂-Adrenoceptor

Enantiospecific Synthesis of 3-Fluoromethyl-, 3-Hydroxymethyl-, and 3-Chloromethyl-1,2,3,4-tetrahydroisoquinolines as Selective Inhibitors of PhenylethanolamineN-Methyltransferase versus the α₂-Adrenoceptor