Amphetamine racemic

AccessMedicine Print Chapter 9. Adrenoceptor Agonists Sympathomimetic Drugs Amphetamine, racemic mixture (generic)... 

Amphetamine (racemic /3-phenylisopropylamine see Table 10-1) acts indirectly to produce powerful stimulant actions in the CNS and a and /3 receptor stimulation in the periphery. Unlike Epi, amphetamine is effective after oral administration, and its effects last for several hours. 

The prototype, amphetamine (52), is obtained by reductive amination of phenylacetone by means of ammonia and hydrogen. Isolation of the (+) isomer by resolution gives dextroamphetamine, a somewhat more potent stimulant than the racemate. 

Fill in tine missing reagents a-d in the following synthesis of racemic meth-amphetamine from benzene. 

RESPONSE This is what, propylhexedrine We have looked at propylhexedrine, and it does retain amphetamine-like activity, but it is less potent. In rats trained to discriminate 1.5 mg/kg of racemic MDMA from saline (ED5o=0.76 mg/kg), the ED50 values for stimulus generalization to MDE and N-OH MDA are 0.73 and 0.47 mg/kg, respectively (Glermon and Misenheimer, unpublished observations). 

MPH is an amphetamine-like prescription stimulant commonly used to treat Attention Deficit Hyperactivity Disorder (ADHD) and narcolepsy in children and adults. LC/APCI-MS enantiomeric separations of racemic MPH (Ritalin ) were reported using a commercially available vancomycin CSP [111-113]. 

When using PFT with a neutral selector, it is quite difficult to avoid any entrance of the chiral selector into the ionization source, particularly at a high pH, where EOF is important. The use of BGE at low pH and/or coated capillary to minimize EOF is therefore mandatory. However, the coaxial sheath gas, which generally assists the ionization process, leads to an aspirating phenomenon of the chiral selector in the MS direction. Javerfalk et al. were the first to apply PFT with a neutral methyl-/i-CD for the separation of racemic bupivacaine and ropivacaine with a polyacrylamide-coated capillary and an acidic pH buffer (pH 3). Cherkaoui et al. employed another neutral CD (HP-/1-CD) with a PVA-coated capillary for the analysis of amphetamines and their derivatives. To prevent a detrimental aspiration effect, analyses were carried out without nebulization pressure. Numerous other studies presented excellent results such as the enantioselective separation of adrenoreceptor antagonist drugs using tandem mass spectrometry (MS/MS) the separation of clenbuterol enantiomers after solid-phase extraction (SPE) of plasma samples or the use of CD dual system for the simultaneous chiral determination of amphetamine, methamphetamine, dimethamphetamine, and p-hydroxymethamphetamine in urine. 

Amphetamines The term amphetamines is usually used in relation to racemates of amphetamine, dextroamphetamine (8.1.2.2), and methamphetamine (8.1.2.3). 

All three ADHD-approved chemical entities have at least one chiral center, a feature that has led to a number of interesting syntheses of these compounds over the years. Amphetamine (1) and methylphenidate (2) were discovered before the modern era of asymmetric and enantioselective synthesis, and are sold as racemic, single-enantiomer, and enantio-enriched formulations. Atomoxetine (3), hrst presented in a 1977 Eli Lilly patent, was developed as a single-enantiomer drug (Molloy and Schmiegel, 1977). 

Amphetamine (1) is a very simple phenethylamine, described in the chemical literature as early as 1887 (Edeleano, 1887). Smith, Kline and French (now GSK) filed a patent on the synthesis and use of amphetamine in 1930 (Nabenhauer, 1930), and the enantiomers were assigned in 1932 (Leithe, 1932 V-Braun and Friehmelt, 1933). Not surprisingly, early access to chiral material relied on classical crystallization-based resolutions (Gillingham, 1962 Nabenhaur, 1942). The early, racemic syntheses of amphetamine fall into four major classifications according to the method used to make the C-N bond ... 

At least one group attempted to synthesize enantio-enriched 1 via as5munetric reduction of 8 with modest success (Krasik and Alper, 1992). The classical resolution of racemic 1 (via the bis-tartrate salt, for example) (Nabenhaur, 1942) remains as the simplest and most economical method for preparing chiral amphetamine (1) on a large scale. 

A few years later, Hass reported an alternative synthesis of racemic amphetamine, which exemplifies the use of a nitroalkane as the source of the nitrogen atom (Scheme 17.4) (Hass et al., 1950). In this route, calcium-hydroxide-promoted Henry reaction of nitroethane and benzaldehyde (12) afforded an 86% yield of the nitro alkene 13. Simultaneous hydrogenation... 

Racemic f/zreo-methylphenidate was approved for the treatment of fatigue, nausea, and depression in 1955 under the brand name Ritalin , and was first used in children in 1958 with an approval for hyperkinetic disorder (ADHD) in 1960. Methylphenidate has an even shorter half-life than amphetamine, and its use in treating ADHD was limited by the fact that schoolchildren would need to visit a nurse during the day to take a second dose of this scheduled drug (in order to maintain efficacy throughout the entire school day). In humans, injecting methylphenidate produces effects similar to intravenous cocaine, but oral methylphenidate is adsorbed very slowly from the gut into the blood and takes an unusually long time (estimated 2.5 h) to reach a peak concentration... 

Much like amphetamine, methyiphenidate was originally approved and marketed as a racemate. Novartis and others have filed several patents on the large-scale preparation and resolution of the most potent (R,R)-isomer (Harris and Zavareh, 1997 Patrick et al., 1987 Prashad, 1998 Prashad and Bin, 2000 Zeitlin and Stirling, 1998). A 1999 Novartis process publication on the synthesis of methyiphenidate is illustrative in that, despite... 

Fenfluramine and its active isomere dexfenflu-ramine act by stimulating the release of serotonin and inhibiting its re-uptake. Dexfenluramine lacks the amphetamine-like properties of the racemic mixture which are due to L-fenfluramine. Both isomers have antiobesity activity but they were taken from the market, at least in several Western countries, because of rare but very serious cardiotoxicity. 

Methylphenidate hydrochloride, a piperidine derivative structurally similar to amphetamine, is a commonly prescribed stimulant for the treatment of ADHD in children age 6 years and older. It is a racemic mixture of d,l methyl a-phenyl-2-piperidineacetate hydrochloride. The drug is available in immediate-release, extended-release, and controlled-release formulations. It is hepatically metabolized to an inactive metabolite and excreted by the kidneys. 

It is a synthetic compound with structural similarity to ephedrine and is available in racemic and dextro isomers. It increases the systolic and diastolic blood pressure. Amphetamine is a potent CNS stimulant and causes alertness, insomnia, increased concentration, euphoria or dysphoria and increased work capacity. Amphetamine produces wakefulness and improved physical performance. It contracts the sphincter of the bladder and relaxes the bronchial smooth muscle in large doses. Amphetamines are drugs of abuse and can produce behavioural abnormalities and can precipitate psychosis. It can produce psychological but no physical dependence. 

Amphetamine is a racemic mixture of phenylisopropylamine (Figure 9-4) that is important chiefly because of its use and misuse as a central nervous system stimulant (see Chapter 32). Pharmacokinetically, it is similar to ephedrine however, amphetamine even more... 

Amphetamine and methamphetamine occur as structural isomers and stereoisomers. Structural isomers are compounds with the same empirical formula but a different atomic arrangement, e.g., methamphetamine and phentermine. Stereoisomers differ in the three-dimensional arrangement of the atoms attached to at least one asymmetric carbon and are nonsuperimposable mirror images. Therefore, amphetamine and methamphetamine occur as both d- and L-isomeric forms. The two isomers together form a racemic mixture. The D-amphetamine form has significant stimulant activity, and possesses approximately three to four times the central activity of the L-form. It is also important to note that the d- and L-enantiomers may have not only different pharmacological activity but also varying pharmacokinetic characteristics. 

Anal. (Ci2H20CINO2S) C,H. The presence of two chiral centers (the alpha-carbon of the amphetamine side chain and the sulfoxide group at the 5-position of the ring) dictates that this product was a mixture of diastereoisomeric racemic compounds. No effort was made to separate them. 

Optically active fr ws-2,3-di-/-butylcyclopropanone has been prepared by asymmetric destruction of the racemic compound with d-amphetamine.64> The (+)-cyclopropanone, [a]ls6+76° (c 0.5, CCI4) exhibits a positive Cotton effect with a peak at 370 nm. Racemization occurs upon heating. 

Fenfluramine, a racemic chemical more closely related to amphetamine than to serotonin, affects brain levels of serotonin and its metabolites at relatively low doses. It was introduced as an anorexigenic drug almost 20 years ago. Its d- isomer, J-fenfluramine (dexfenfluramine, Redux) was about twice as potent as fenfluramine. After several controlled clinical trials demonstrated that dexfenfluramine could help patients maintain weight loss for at least a year, it was quickly introduced into the market in the USA and became a best-selling drug overnight. 

Answer Only one of the two enantiomers of the drug molecule (which has a chiral center) is physiologically active, for reasons described in the answer to Problem 3 (interaction with a stereospecific receptor site). Dexedrine, as manufactured, consists of the single enantiomer (D-amphetamine) recognized by the receptor site. Benzedrine was a racemic mixture (equal amounts of D and l isomers), so a much larger dose was required to obtain the same effect. 

Usually the objective in forming diastereomers is to use a chiral reagent that is 100% of one isomer and to use an achiral chromatographic system. As an example, Clark and Barksdale33 separated the R and S enantiomers of amphetamine after reacting the racemic mixture with l[(4-nitro-... 

The reaction of racemic A-phthalimido-S-p-tolyl-S-vinylsulfoximine with a deficiency (0.5 molar equiv) of enantiomerically pure (-)-ephedrine resulted in a kinetic resolution of the vinyl sulfoximine.113 When the reaction was conducted at -30 °C the unreacted vinyl sulfoximine could be recovered with an enantiomeric purity of 46%. (-)-Amphetamine and (+)-l-phenylethylamine were not effective for kinetic resolution. The analogous (Z)-propenyl sulfoximine also underwent kinetic resolution with (-)-ephedrine, but the extent of kinetic resolution was not determined. 

Synonyms. Benzpropaminum Phosphoricum Monobasic Racemic Amphetamine Phosphate. 

Chiral separation The separation of chiral (e.g. optically active) molecnles, for instance, the R)- and (5 )-isomers of amphetamines see also Racemic mixtnre). 

SYNS ACTEDRON ADIPAN ALLODENE dl-AMPHETAMINE ANOREXIDE ( )-BENZEDRINE dl-BENZEDRINE DEOXYNOREPHEDRINE ( )-DESOXYNOREPHEDRINE racemic-DESOXYNORE-PHEDRINE ELASTONON ISOAMYCIN ISOMYN MECODRIN a-METHYLBENZENEETHANEAMINE... 

Preparative Methods racemic l,l -bi-2,2 -naphthol (BINOL) is most conveniently prepared by the oxidative coupling reaction of 2-naphthol in the presence of transition metal complexes (eq 1). The resolution of racemic BINOL with cinchonine may be performed via the cyclic phosphate (eq 2). An alternative procedure to provide directly optically active BINOL is the oxidative coupling of 2-naphthol catalyzed by Cu salt in the presence of chiral amines (eq 3). The best procedure uses (+)-amphetamine as the chiral ligand and provides BINOL in 98% yield and 96% ee. Above 25 °C the Cu /(+)-amphetamine/(5)-BINOL complex precipitates, while the more soluble Cu /(+)-amphetamine/(I )-BINOL complex is slowly transformed into the former complex. 9,9 -Biphenanthrene-10,10 -diol has also been prepared in 86% yield and with 98% ee by a similar asymmetric oxidative coupling of 9-phenanthrol in the presence of (I )- 1,2-diphenylethylamine. ... 

Goto et al. (67) synthesized the sucdnimidyl ester [14] of (—)- -methoxy-a-methyl-l-naphthaleneacetic acid for the normal-phase LC resolution of chiral amines. The reagent permitted the determination of the enantiomers of an amphetamine derivative in blood plasma after administration of racemic drug to rabbits. With detection at 280 nm, the lower limit of sensitivity was 5 ng/mL for each enantiomer (67). Several chiral acids from the "profen" group of nonsteroidal antiinflammatory drugs have been adapted as CDAs. One of these, naproxen, [15], is the S enantiomer and is commercially available as the resolved acid several of these acids have the advantage of providing fluorescent derivatives (68,69). 

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