Amphetamine

[HEISENBERG]

General information

Amphetamine (also known as alpha-methylphenethylamine, amfetamine, and speed) is a classical stimulant substance of the phenethylamine class. It is the parent compound of the substituted amphetamines, a diverse group that includes methamphetamine, MDMA, cathinone, and bupropion. The mechanism of action involves promoting release of the neurotransmitters dopamine and norepinephrine.

Amphetamine, a substance discovered over 100 years ago, is one of the most restricted controlled drugs. It was previously used for a large variety of conditions and this changed until this point where its use is highly restricted. Amphetamine, with the chemical formula alpha-methylphenethylamine, was discovered in 1910 and first synthesized by 1927. After being proven to reduce drug-induced anesthesia and produce arousal and insomnia, amphetamine racemic mix was registered by Smith, Kline and French in 1935. Amphetamine structure presents one chiral center and it exists in the form of dextro- and levo-isomers. The first product of Smith, Kline and French was approved by the FDA on 1976.

In the 1930s, it was sold over-the-counter under the name "Benzedrine" as a decongestant. It became widely used to treat a range of ailments such as alcohol hangover, narcolepsy, depression, and obesity. During World War II, amphetamine was used to promote wakefulness in the soldiers. This use derived into a large overproduction of amphetamine and all the surplus after the war finalized ended up in the black market, producing the initiation of the abuse. Due to issues with addiction and abuse, it was eventually listed as a controlled substance under the United Nations 1971 "Convention on Psychotropic Substances".

Amphetamine is now primarily a prescription drug used to treat attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Additionally, it sees widespread illicit use as a performance enhancing agent and recreational substance.

Physical properties

• Formula C9H13N
• Molar mass 135.210 g/mol
• Density 0.936 g/cm3 at 25 °C
• Melting point 11.3 °C (52.3 °F)
• Boiling point 200-203 °C (397 °F) at 760 mmHg

Chemical properties

The free base of amphetamine is a colorless volatile oily liquid with a characteristic "fishy" odor and acrid, burning taste, poorly soluble in water, readily soluble in organic solvents, boiling point 200-203 °C.

Amphetamine is a methyl homolog of the mammalian neurotransmitter phenethylamine with the chemical formula C9H13N. The carbon atom adjacent to the primary amine is a stereogenic center, and amphetamine is composed of a racemic 1:1 mixture of two enantiomers. This racemic mixture can be separated into its optical isomers: levoamphetamine and dextroamphetamine (l- and d- isomers). Frequently prepared solid salts of amphetamine include amphetamine hydrochloride, phosphate, sulfate. Dextroamphetamine sulfate is the most common enantiopure salt. Amphetamine is also the parent compound of its own structural class, which includes a number of psychoactive derivatives.

Synthesis ways

There are list of most popular amphetamine synthesis ways. All of them have own advantages and disadvantages. Most popular non-selective synthesis is P2NP reduction, which can be carried out with aluminium(Al) amalgam. Also, it is possible to reduce by NaBH4, LAH or hydrogen gas with catalyst (PtO2 or Pd/C) and excess pressure. P2NP can be synthesized by simple condensation of nitroethane with benzaldehyde.

One of the most common methods of clandestine amphetamine production is the Leuckart reaction, which consists of the condensation of phenylacetone (phenyl-2-propanone, P2P) with formamide or ammonium formate in the presence of formic acid and subsequent acid hydrolysis of the resulting N-formylamphetamine.

A mphetamine can also be prepared by reductive amination of phenylacetone (P2P) in the presence of a metal catalyst. The reaction proceeds with the formation of an intermediate imine. Examples of a reaction are: Heterogeneous catalytic reduction of phenylacetone with ammonia. The catalyst may be palladium on carbon, platinum oxide or Raney nickel. Restoration with aluminum, zinc or magnesium amalgams.

If necessary, the amphetamine stereoisomers dextroamphetamine and levoamphetamine can be separated using tartaric acid. In addition, a method has been published for the stereoselective synthesis of dextroamphetamine, which consists in the reductive amination of phenylacetone with S-α-methylbenzylamine. The imine, which was obtained, is reduced with Pd/C or Raney nickel and recrystallized as the hydrochloride. The N-benzyl group is then hydrogenolyzed in the presence of palladium on charcoal to form high optical purity dextroamphetamine.

Analysis and purification

Toxic and dangerous substances are used in any synthesis way of amphetamine. There are two amphetamine purification methods "Product Washing" and more advanced method "Acid-base Extraction".

Drug washing is an essential and final part of almost any synthesis. Sometimes repeated several times. The method is available to anyone, does not require skills, can significantly improve the quality of product and presentation. The method is Ideal for small quantities. Washing is indicated for residues of P2NP, alkalis, acids and so on. Washing will not remove contaminants (acetaminophen, caffeine, etc.) and mercury salts.

The most accessible, and therefore easier, is to wash amphetamine with isopropyl alcohol (IPA). More difficult to use is anhydrous acetone. IPA does not contain water, and therefore it does not dissolve amph salt. The key to the process success is the lack of water. It is needing for avoiding amph from dissolution with pollutants because they will be thrown out.

Acid-base extraction (ABE), as a purification method, allows you to get a high-quality drug. Method is good by reason of using available reagents, tools and instruments.

Amphetamine is cut unacceptably often by caffeine, starch, nootropics such as Cinnarizine and Piracetam, a-PVP, methamphetamine and other stimulants and pharmacy substances. There are several methods to check your amphetamine. The most popular and easiest way is Drugs testing reagents. You can read about other methods in Amphetamine assessment protocol.

There are pictures of different amphetamine samples after tests by reagents

Effects and dosage

Subjective effects include stimulation, focus enhancement, motivation enhancement, increased libido, appetite suppression, and euphoria. It is usually taken orally, but can also be insufflated, injected, or administered rectally. Lower doses tend to increase focus and productivity while higher doses tend to increase sociability, sexual desire, and euphoria.

Amphetamine has high abuse potential. Chronic use (i.e. high dose, repeat administration) is associated with compulsive redosing, escalating tolerance, and psychological dependence. Additionally, abuse has been linked to a number of health conditions, especially cardiovascular issues such as high blood pressure and increased risk of stroke. It is highly advised to use harm reduction practices if using this substance.

[SPOILER=Physical effects]

Stimulation - Amphetamine is reported to be very energetic and stimulating. It can encourage physical activities such as dancing, socializing, running, or cleaning. The particular style of stimulation that amphetamine produces can be described as forced. This means that at higher dosages, it becomes difficult or impossible to keep still. Jaw clenching, involuntary bodily shakes, and vibrations become present, resulting in extreme shaking of the entire body, unsteadiness of the hands, and a general loss of fine motor control. This is replaced with mild fatigue and general exhaustion during the offset of the experience.

• Spontaneous bodily sensations - The "body high" of amphetamine can be described as a moderate euphoric tingling sensation that encompasses the entire body. This sensation maintains a consistent presence that steadily rises with the onset and hits its limit once the peak has been reached.

• Physical euphoria

• Abnormal heartbeat

• Increased heart rate

• Increased blood pressure- By about 30mmHg systolic and 20mmHg diastolic, from naive users taking 40mg d-AMP.

• Appetite suppression

• Bronchodilation

• Dehydration

• Dry mouth

• Frequent urination

• Difficulty urinating

• Increased bodily temperature

• Increased perspiration

• Mania - Amphetamine can produce mania in genetically predisposed individuals, such as those on the spectrum of bipolar disorder or schizophrenia. Higher doses and sleep deprivation appears to increase the risk.

• Nausea - This can be mitigated by eating before dosing and throughout the experience.

• Pupil dilation - This effect is experienced only at common to high dosages and is more prominent on the comedown.

• Reflex syncope

• Stamina enhancement

• Teeth grinding - Teeth grinding may be present at higher doses. However, it is less intense than that of MDMA.

• Temporary erectile dysfunction

• Vasoconstriction - Amphetamine use causes blood vessels to constrict resulting in not enough blood reaching some parts of the body. This can cause feelings of tingling or pain, a cold feeling, numbness, paleness, or skin color changes especially in the fingers and toes.

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[SPOILER=Visual effect]

• The visual effects of amphetamine are inconsistent and occur only mildly noticeable at higher doses. They are somewhat comparable to deliriant visuals and occur more readily in darker areas.

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[SPOILER=Distortions]

• Drifting - This effect is usually subtle and barely noticeable and only occurs at higher dosages or when combined with cannabis. Commonly this consists of level 1-2 drifting.

• Brightness alteration - Amphetamine can make spaces seem brighter as a result of its pupil dilating effects.
• Tracers - This effect is imperceptible with low dosages. It's most pronounced with bigger dosages and especially when someone becomes sleep deprived, what on the other hand can be easily provoked by other effects of this substantion. Transformations - This effect occurs very rarely, and typically only when the user has taken high doses, is coming down, or has been awake for unusually long periods. They are usually very mild when they do occur.

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[SPOILER=Hallucinatory states]

• Transformations - This effect occurs very rarely, and typically only when the user has taken high doses, is coming down, or has been awake for unusually long periods. They are usually very mild when they do occur.

• Geometry - This effect is reported by some users of amphetamine and related substances, typically at heavier doses when one is attempting to sleep. It can be described in its variations as simplistic, algorithmic, synthetic, dimly lit, multicolored, glossy, sharp edges, zoomed out, smooth, angular, immersive, and progressive. It typically occurs at level 3 however may progress to 4 and 5 when combined with substances like cannabis or DXM.

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[SPOILER=Cognitive effects]

• Analysis enhancement
• Cognitive euphoria
• Compulsive redosing
• Ego inflation
• Emotion suppression - This effect is typically most intense at light and common doses, and is more commonly reported from medical usage rather than recreational.
• Focus enhancement - This effect is most effective at low to moderate doses as anything higher will usually impair concentration.
• Increased libido - While amphetamine use can cause feelings of sexual enhancement, the constricting of blood vessels may make it difficult to get or maintain an erection.
• Increased music appreciation
• Irritability - This is more likely to occur at higher doses.
• Memory enhancement
• Motivation enhancement
• Psychosis - This effect only occurs in either predisposed individuals, or after chronic, high frequency use, or due to sleep deprivation.
• Suggestibility suppression
• Thought acceleration
• Thought organization
• Time distortion - This can be described as the experience of time speeding up and passing much quicker than it usually would when sober.
• Wakefulness

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[SPOILER=After effects]

The effects which occur during the offset of a stimulant experience generally feel negative and uncomfortable in comparison to the effects which occurred during its peak. This is often referred to as a "comedown" and occurs because of neurotransmitter depletion. Its effects commonly include:

• Anxiety - Anxiety can reach severe levels during the comedown in some users.
• Appetite suppression
• Cognitive fatigue
• Depression
• Increased heart rate - While blood concentration of amphetamine and most subjective effects are highest about 3 hours after administration, heart rate peaks much later at 10 hours after administration.
• Irritability
• Motivation suppression
• Restless legs
• Sleep paralysis - Some users note sleep paralysis after consuming amphetamine.
• Dream suppression
• Thought deceleration
• Wakefulness - The insomnia following a repeated series of amphetamine doses can last for longer than a day in some users.
• Motivation suppression - Experiences can range from mild demotivation to extreme states of disinterest. This effect is more prominent at common and heavy doses.

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Pharmacology

Amphetamine exerts its behavioural effects by increasing the signaling activity of neurotransmitters norepinephrine and dopamine in the reward and executive function pathways of the brain. The reinforcing and motivational effects of amphetamine are mostly due to enhanced dopaminergic activity in the mesolimbic pathway.

The euphoric and locomotor-stimulating effects of amphetamine are dependent upon the magnitude and speed by which it increases synaptic dopamine and norepinephrine concentrations in the striatum.

It is a potent full agonist of the trace amine-associated receptor 1 (TAAR1) and interacts with vesicular monoamine transporter 2 (VMAT2). Combined action on TAAR1 and VMAT2 results in increased concentrations of dopamine and norepinephrine in the synapses, which stimulates neuronal activity.

Dextroamphetamine is a more potent agonist of TAAR1 than levoamphetamine. Consequently, dextroamphetamine produces greater CNS stimulation than levoamphetamine, roughly three to four times more, but levoamphetamine has slightly stronger cardiovascular and peripheral effects.

The exact bioavailability of amphetamine is not known, but it is believed to be over 75% by mouth, and higher by injection or intranasal administration. Its absorption and excretion may be pH dependent. As it is a weak base hence the more basic the environment the more of the drug is found in a lipid-soluble form and the absorption through lipid-rich cell membranes is highly favored. The peak response of amphetamine occurs 1-3 hours after oral administration and approximately 15 minutes after injection. Complete amphetamine absorption is usually done after 4-6 hours. The basic form is more readily absorbed in the intestine and less readily removed by the kidneys, potentially increasing its half life. It is removed by the kidneys via excretion and a small amount is removed by hepatic enzymes.

Ilegal market data

Global supply of amphetamine-type stimulants (ATS)

A record quantity of over 525 tons of ATS was seized in 2020, which represents a 15 per cent increase year on year 1 and continued the upward trend observed over the period 2010–2020. The quantities of methamphetamine seized grew five fold over that 10-year period, the quantities of amphetamine seized almost quadrupled andthequantities of “ecstasy” seized more than tripled.

Use of amphetamines continued to rise but signs of decrease in demand for treatment in 2020. Primarily on the basis of self-reported responses to general population surveys, a total of 34 million people aged 15–64, or 0.7 per cent of the global population, are estimated to have used amphetamines in the past year, and 20 million (0.4 per cent) are estimated to have used “ecstasy”-type substances. Some of those users had used both types of substances. The two most commonly used amphetamines are amphetamine and methamphetamine.

The global estimate of amphetamines use was similar in 2010, with 33 million past year users or 0.7% of the population aged 15-64. However, these estimates have to be interpreted with caution owing to the lack of data from major consumer countries in Asia where other market indicators, such as seizures and prices, suggest an expansion over the last decade. Qualitative information based on perceptions of trends reported by national experts to UNODC shows a continued increase both in terms of the use of amphetamines and the number of people in treatment for amphetamines over the past decade. However, data for 2020 show that this increasing trend has paused and that the number of people in treatment for amphetamines may have decreased, consistent with an overall decrease in treatment as a result of the COVID-19 pandemic. e Trends derived from such qualitative information are consistent with the available supply indicators, such as prices and seizures, which indicate continued global expansion of the market for amphetamines. Qualitative information of this type suffers from methodological limitations, but it has an advantage in that it takes into consideration small-scale studies and expert observations regarding countries where drug use surveys are not regularly implemented. Qualitative information on trends in the use of “ecstasy” was reported under different categories by countries before the implementation by UNODC of its new data collection tool (the updated annual report questionnaire, which came into use in 2020), thus qualitative reports of trends in “ecstasy” use are limited to the period 2019–2020. These reports suggest a moderate increase globally. At the same time, studies from countries where “ecstasy” is used in recreational settings suggest that the use of “ecstasy” declined more than any other drug during the pandemic in those countries. Wastewater analysis, while limited in geographical coverage to Europe, North America and some parts of Asia and Oceania, also suggests that the use of “ecstasy” declined between 2019 and 2020 more than the use of amphetamines. In the majority of analyzed locations, increased levels of consumption of MDMA were identified, while in a slight majority of those locations, increased amphetamine use and decreased methamphetamine use were detected. Early wastewater analysis data from 2021 suggest an overall increase in amphetamine consumption in the majority of locations monitored by the Sewage Analysis CORe group, most of which are in Europe, between 2020 and 2021; an increase and a decrease in methamphetamine consumption in about the same number of locations; and a continuous decrease in MDMA consumption in a large majority of locations.

 

[Doktor Faust]

Amphetamine

DRAFT

Comments, Additions and Suggested Corrections on the Amphetamine Synthetic Procedures and Related Matters​

This document is a draft, and presents an overview of the general synthetic procedures for the preparation of amphetamine and its analogues, mainly on large-scales.

The document is prepared as a supplement and correction to the current article on amphetamine, mainly to the section on synthetic procedures. Various comments, additions and suggested corrections are included.

​

Various representations of the amphetamine enantiomers

Fig. 1 Basic representation of two enantiomers, (+) S and (-) R


View attachment FOknWcvPsy.jpg

Fig. 2. Image of (+) S amphetamine, geometry only (png, transparent background, 600 dpi)

Fig. 3. Image of (+) S amphetamine, geometry only (png, transparent background, ~500 dpi, different rendering)

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Fig. 4. Image of (+) S amphetamine, geometry and the approximate volume, semitransparent​

Introduction

While there are numerous methods to synthesize amphetamine and its analogues on a small, laboratory scale, (generally <1 g), only a few procedures are suitable for multi-gram and kilogram quantities. To that end, many factors must be considered, including cost-effectiveness, availability of the equipment and chemicals, potential hazards, (e.g. explosion risks, fire hazards, noxious by- products, necessary personal protection measures), number and complexity of the reaction steps, size of the batches, overall time needed to produce the required amounts and others.

The equipment considered herein includes various reactor flasks, up to the volume of 20 L, low pressure, steel hydrogenation vessels of the similar capacity, large-volume mechanical and magnetic stirrers, the appropriate heating systems, standard laboratory glassware and plastic-ware, etc. Industrial-scale production equipment (particularly metal reactor vessels) has not been considered.

The chemical precursors needed for the syntheses are limited to phenylacetone (BMK) or its substituted analogues, as well as benzaldehyde and its derivatives. In depth, multi-steps syntheses of the required precursors could be described in a separate document.

Careful examination of the published scientific literature (papers, patents, reports etc.), as well as the extensive first-hand experience, essentially reduce the available methodology to four general procedure, as shown in Scheme 1. (Apart from the direct reductive alkylation of BMK, the procedures correspond to the reactions briefly mentioned in the current article on amphetamine).

The document consists of five short chapters. Four correspond to the reaction procedures denoted as A, B, C and D in Scheme 1, while chapter E represents a procedure to separate two enantiomers of amphetamine: (+)S and (-)R.

After the each chapter, relevant references are provided, mainly to the specific examples. Each reference can be downloaded, free of charge and anonymously, from the provided direct download links.​

Scheme 1. General practical methods, A-D, for the synthesis of amphetamine and some of its analogues​

References for Introduction

(General references in organic chemistry, synthesis and pharmacology)​

1. March’s Advanced Organic Chemistry Reactions, Mechanisms, And Structure 6th Ed. Michael B. Smith, ; Jerry March. Wiley-Interscience, A John Wiley & Sons, Inc., Publication, Copyright 2007. ISBN 13: 978-0-471-72091-1; ISBN 10: 0-471-72091-7

Download from Library Genesis, https://libgen.is/ (and other domains if any) and the mirror links therein (some may not work). Search the site using ISBN 978-0-471-72091-1

2. Vogel's Textbook Of Practical Organic Chemistry, 5th Ed. Longman Scientific & Technical. Longman Group UK Limited. ©Longman Group UK Limited I989. ISBN 0-582-46236-3.

Download from: https://archive.org/details/TextbookOfPracticalOrganicChemistry5thEd (version: pdf with text) or:

https://libgen.is/ (and other Library Genesis domains if any), and the mirror links therein (some may not work). Search using ISBN 0-582-46236-3

3. Comprehensive Organic Synthesis Reference Work • Second Edition • 2014. Editor-in-Chief: Paul Knochel ISBN 978-0-08-097743-0 Copyright © 2014 Elsevier Ltd.

Download from https://libgen.is/ (and other Library Genesis domains if any) and the mirror links therein (some may not work). Search the site using ISBN 978-0-08-097743-0

4. Comprehensive Organic Synthesis Reference Work • 1991 Editors-in-Chief: Barry M. Trost and Ian Fleming. ISBN 978-0-08-052349-1 Copyright © 1991 Elsevier Science Ltd.

Download from : https://libgen.is/ (and other domains if any) and the mirror links therein (some may not work). Search the site using text "Comprehensive Organic Synthesis Trost", pdf version, each volume is a separate file.

5. Goodman&Gilman's The Pharmacological Basis of Therapeutcs, 14th Ed. Editors: Laurence L. Brunton, PhD, Björn C. Knollmann, MD, PhD. Copyright © 2023 by McGraw Hill LLC. ISBN: 978-1-26-425808-6

Download from: https://libgen.is/ (and other domains if any) and the mirror links therein (some may not work). Search the site using ISBN 978-1-26-425808-6

Chapter A.



A General, Two-Step Procedure For The Preparation of

Various Amphetamines via the Reduction of Aryl-Nitroalkenes

​

Aryl-nitroalkenes are readily prepared by condensing aromatic aldehydes with aliphatic nitroalkanes (nitromethane, nitroethane etc). The condensation is a two-step process, which involves nitroaldol reaction (Henry reaction)1, followed by the spontaneous dehydration. Subsequently, the total reduction of aryl-nitroalkenes (both of the nitro group and double bond), provides the corresponding primary amine, such as amphetamine, as shown in Scheme 2.​

Scheme 2. Overall procedure for the synthesis of amphetamines, via aryl-nitroalkenes

The first step, aldol condensation/dehydration, is performed in the presence of a catalyst, mainly mild bases, such as butyl amine in toluene, ammonium acetate in acetic acid or a neat, solid ammonium acetate. (The use of aniline, C6H5NH2, as a catalyst, shown in the original Scheme, has not been identified in the literature, it might be possible, though it forms stable imines with aromatic aldehydes, known as Shiff bases.) The procedure is exemplified by three references.2​

Reduction of the obtained nitroalkenes, using various reagents, is elaborated below.

It is noteworthy that a partial reduction of nitroalkenes, using metallic iron and hydrochloric acid, produces the corresponding ketones (such as phenylacetone and its analogues), rather then the amphetamines, example in Scheme 3. 3,4

Scheme 3 Partial reduction of aryl-nitroalkenes to aryl-acetones and related ketones

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The second, reduction step produces a saturated amine (e.g. amphetamine). An overwhelming majority of these reductions were performed using lithium aluminum hydride (LiAlH4, LAH), in ether or tetrahydrofuran (THF), as shown in the selected references.5a-5d

Only a few examples involved catalytic hydrogenation (e.g. H2, Pd/C, 1 atm, HCl, ethanol).5e

Very recently, a novel method has been published, using NaBH4/CuCl2 as a reducing agent. The method appears to be simple, inexpensive and practical, however the paper has not been peer-reviewed, and so far, the results do not seem to have been independently verified.5f

In conclusion, the formation and reduction of aryl-nitroalkene represents an efficient and reliable, two step method, to prepare various amphetamines, including amphetamine itself. It requires the use of LiAlH4 (LAH) as a reducing agent and various ethers as solvent (mainly diethyl ether or tetrahydrofuran, THF). The main drawbacks of the procedure, particularly on large scales, is the need of strictly anhydrous solvents, moisture exclusion during the reduction, as well as the explosion risks. The explosion may occur if LAH comes in contact with water, alcohols or acids, either during the work-up, or accidentally. Also, ethers are highly flammable, and vapors can easily ignite explosively. (Electrostatic sparks are commonly encounter in labs, production facilities and households, and are unrelated to the sparks produced by electric appliances ). In addition, if not properly stabilized, and in contact with air, ethers readily form peroxides which are highly and spontaneously explosive, without any heat source. The explosions can be devastating (and potentially lethal), as witnessed first-hand.​

In conclusion, the original Scheme, shown below, as well as the main text, may be modified according to the Scheme 2 and the above discussion.

References for chapter A



1. Reviews of Henry reaction (nitroaldol reaction):



1a) Goffredo Rosini, 1.10 - The Henry (Nitroaldol) Reaction, in Comprehensive Organic Synthesis,

Pergamon, 1991, Pages 321-340, Editor(s): Barry M. Trost, Ian Fleming, ISBN 9780080523491,

https://doi.org/10.1016/B978-0-08-052349-1.00032-9.

Download from the site https://sci-hub.se/ using provided DOI number (10.1016/B978-0-08-052349-1.00032-9)

(Direct link to the publisher's page: https://doi.org/10.1016/B978-0-08-052349-1.00032-9).



1b) Sasai, H. (2014). 2.13 The Henry (Nitroaldol) Reaction. Comprehensive Organic Synthesis II, 543–570. doi:10.1016/b978-0-08-097742-3.00214-7. Download from the site https://sci-hub.se/: using provided DOI number (10.1016/b978-0-08-097742-3.00214-7)



2. Three examples of the nitroalkenes preparations (condensation of aromatic aldehyde and nitro alkane).

​

2a Organic Syntheses, Coll. Vol. 4, p.573 (1963); Vol. 35, p.74 (1955). DOI:10.15227/orgsyn.035.0074; (Conditions: Catalyst: butyl amine; solvent: toluene; rfl., ~5 h, yield: >~80-90%). Download directly from the address: https://www.orgsyn.org/Content/pdfs/procedures/CV4P0573.pdf



2b J. Chem Sci 135, 20 (2023). DOI:10.1007/s12039-023-02144-7 (Conditions: Catalyst: ammonium acetate; no solvent; 2h ~100oC, yields: >~80-90%). Download directly from the address: https://doi.org/10.1007/s12039-023-02144-7 (open access article).



2c Catherine B. Gairaud et al. The Synthesis of w-Nitrostyrenes. The Journal Of Organic Chemistry 1953 18 (1), 1-3. DOI: 10.1021/Jo01129a001 (Conditions: Catalyst: ammonium acetate; solvent: acetic acid; 2h. ~120oC, isolated yield: >~55%) .

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/Jo01129a001).



3. Organic Syntheses, Coll. Vol. 4, p.573(1963). o-Methoxyphenylacetone. DOI:10.15227/orgsyn.035.0074.

Download directly from the address: https://orgsyn.org/Content/pdfs/procedures/CV4P0573.pdf



4. R. V. Heinzelman. Physiologically Active Secondary Amines. β-(o-Methoxyphenyl)-isopropyl-N-methylamine and Related Compounds. Journal of the American Chemical Society 1953 75 (4), 921-925. DOI: 10.1021/ja01100a043

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/ja01100a043)



5. Examples of complete nitro alkene reduction



Four examples of nitro alkane reduction to the saturated primary amine, using LiAlH4.



5a Beng-Thong Ho et al. Analogs of a-methylphenethylamine (amphetamine). I. Synthesis and pharmacological activity of some methoxy and/or methyl analogs. Journal of Medicinal Chemistry 1970 13 (1), 26-30 DOI: 10.1021/jm00295a007

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/jm00295a007).



5b Alejandra Gallardo-Godoy et al. Sulfur-Substituted α-Alkyl Phenethylamines as Selective and Reversible MAO-A Inhibitors:Biological Activities, CoMFA Analysis, and Active Site Modeling. Journal of Medicinal Chemistry 2005 48 (7), 2407-2419. DOI: 10.1021/jm0493109

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/jm0493109).



5c Danielle M. Schultz, et al. ‘Hybrid’ benzofuran–benzopyran congeners as rigid analogs of hallucinogenic phenethylamines, Bioorganic & Medicinal Chemistry, Volume 16, Issue 11, 2008, 6242-6251. DOI 10.1016/j.bmc.2008.04.030

Download from the site https://sci-hub.se/, using DOI number (10.1016/j.bmc.2008.04.030).

5d Michael P. Johnson et al. Synthesis and pharmacological examination of 1-(3-methoxy-4-methylphenyl)-2-aminopropane and 5-methoxy-6-methyl-2-aminoindan: similarities to 3,4-(methylenedioxy)methamphetamine (MDMA). Journal of Medicinal Chemistry 1991. 34 (5), 1662-1668 DOI: 10.1021/jm00109a020

One example of catalytic hydrogenation of nitro alkene to the saturated primary amine.



5e Masahiko Kohno et al. Synthesis of Phenethylamines by Hydrogenation of β-Nitrostyrenes, Bulletin of the Chemical Society of Japan, Volume 63, Issue 4, April 1990, Pages 1252–1254, https://doi.org/10.1246/bcsj.63.1252

Download from the site https://sci-hub.se/, using DOI number (10.1246/bcsj.63.1252).



One example of nitro alkene reduction to the saturated primary amine, using NaBH4/CuCl2.



5f d’Andrea L, et al.. One-pot Reduction of Nitrostyrenes to Phenethylamines using Sodium Borohydride and Copper(II) chloride. ChemRxiv. 2023; doi:10.26434/chemrxiv-2023-nwn3x-v4 This content is a preprint and has not been peer-reviewed. (Open access)

Download from the site https://chemrxiv.org/engage/chemrxiv/article-details/6509cee9b927619fe76fde7a

Chapter B.



A General, Two-Step Procedure for The Preparation of Various Amphetamines via Reduction of Oximes

​

The procedure is applicable to the amphetamine itself, as well as to the various analogues, substituted on the benzene ring. The analogues require appropriately substituted phenylacetone (BMK)​

Introduction

The procedure involves two steps: 1. Oxime preparation and 2. Oxime reduction.

Carbonyl compounds, aldehydes and ketones, readily react with hydroxylamine (in the form of hydrochloride salt) to form oximes. These compounds are usually solid, stable, easy to isolate, purify and handle. While not particularly reactive, oximes can be reduced to primary amines, using reducing agents such as LiAlH4 (LAH), metallic sodium in alcohols (anhydrous ethanol, propanol), catalytic hydrogenation and, less commonly, other reagents.

Oximes from adehydes (aldoximes) and ketones (ketoximes) have long been used as immediate precursors to primary amines, thus affording these compounds from carbonyl compounds, in a two-step procedure.

The overall synthesis is summarized in Scheme 4, and exemplified on the preparation of amphetamine from BMK. This approach, involving sodium/propanol reduction, (also including amphetamine racemate separation), was published recently.1

​

Scheme 4. A general procedure for the synthesis of amphetamine and analogues, via the reduction of oxime intermediate

1. The first step: oxime formation. The condensation proceeds rapidly and quantitatively, in the presence of a mild base, which liberates free hydroxylamine from its hydrochloride salt. (Free hydroxylamine is unstable, unlike its salt. Both are very toxic and should be handled with care).

General conditions include (among others): Na2CO3, ethanol, water;2a dil. NaOH, water, ethanol;2b and sodium acetate, methanol.2c

This step should not be particularly hazardous on any scale.

2. The second step: oxime reduction to the primary amine (e.g. amphetamine and its analogues). General conditions include, among others: a) catalytic hydrogenation (hydrogen and a catalyst),3a, 3b b) sodium metal/alcohol (ethanol, propanol)1, 3c, 3d c) LiAlH4 in ethers.3e, 3f, 3g and others d), e), f).

a) Known procedures for catalytic hydrogenation3a,3b require high pressures (>100 atm), and special equipment (hydrogenation bombs, hydrogen tank, pressure gauges and regulators etc.). The usual catalyst is Raney nickel since palladium catalysts are often prone to catalyst poisoning (inactivation). In general, the hydrogenation does not appear to be convenient on substantial scales (e.g. >50-100 g). (Better and more cost-effective procedures might exist).

b) Procedures using metallic sodium in alcohols1,3c,3d (ethanol, propanol) require large excess of sodium (10 eq), which is added gradually to the reaction mixture. (An inconvenient and hazardous process on large scales). Also, anhydrous alcohols are required and the method poses a serious risk of explosion, as sodium reacts violently with alcohol (and explosively with water, in the case of accident). In addition, highly flammable and explosive hydrogen gas is evolved. In general, the known, specific protocols are impractical, expensive and very hazardous for larger scales, e.g. >20-50 g. (More convenient and less hazardous modifications might be developed).

c) Procedures using LiAlH4 in ethers (diethyl ether, THF) are generally more convenient, though requiring large volumes of solvent (diethyl ether). Many examples have been reported in the literature, and three references are cited.3e-3g Given the required volumes of solvent, the scalability of the method is probably limited to 50-100 g of amphetamine per batch, if not less.

Other methods to reduce oximes to primary amines have been reported in the scientific literature, but are less well studied, may fail altogether or result in low yields and side products. (Some could be improved by further experiments and optimization). These are as follows:

d) General method for oxime reduction using NaBH4 and hydrated NiCl2 in methanol.3h

The method has been applied to the reduction of various oximes to the primary amines, thought not to amphetamine or its analogues. The yields are generally >90%, however the serious drawback is the use of large excess of NaBH4 (10 eq) and 2 eq of NiCl2 x 6 H2O, per 1 eq of an oxime. Though modifications are possible, in its present form it has no production potential.

e) General method for oxime reduction using ammonium formate and powdered metallic magnesium as a catalyst.3i

The method has been applied to the reduction of various oximes to the primary amines, thought not to amphetamine or its analogues. The yields are generally >80%. It uses 3 eq of HCO2NH4 and 4 eq of Mg powder per 1 eq of the oxime, effecting the complete conversion in <1 h. The method, if reproducible, might have a moderate production potential. The possible drawbacks are the properties of the commercial Mg powder (available from various suppliers) and the isolation procedure (amphetamine, which is relatively volatile, would have to be distilled). In general, it is probably worthwhile experimenting.

f) General method for oxime reduction using metallic zinc and acetic acid or aluminum amalgam.

Although effective for some activated oximes,3j, 3k zinc apparently affords only low yields of the amines from ordinary ketoximes, likely including amphetamines. Also, side products may arise.Aluminum foil, covered with a very thin film of amalgam, efficiently reduced an activated oxime,3l however reductions of ordinary ketoximes (including the amphetamine precursor) seem to provide lower yields, and there might be side products. In addition, the procedure uses highly toxic mercury (II) chloride (HgCl2). Thus, it posses a real risk of contamination and intoxication with elemental mercury and its compounds, and should be avoided for any products intended for consumption.



In conclusion, the original reaction, Scheme below, is erroneous. The correct procedures are discussed in Chapter B, above and shown in Scheme 4. Thus, the original Scheme should be corrected accordingly and possibly modified and expanded ​

Original Scheme:

​

References for Chapter B



1. Recent complete synthesis of amphetamine (and methamphetamine):

Kristýna Dobšíková et al. Conformational analysis of amphetamine and methamphetamine: a comprehensive approach by vibrational and chiroptical spectroscopy. Analyst, 2023,148, 1337-1348. DOI https://doi.org/10.1039/D2AN02014A.(Open access article). The detailed synthetic procedure for the amphetamine synthesis is presented in a separate file, (supplementary information, at the address: https://www.rsc.org/suppdata/d2/an/d2an02014a/d2an02014a1.pdf (Short description: The experiment involves the oxime preparation, followed by the reduction to racemic amphetamine, using Na/propanol. Yield: ~8.5 g, ~85% over two steps). Also included are the procedures for the racemic amphetamine separation (tartaric acid method) and the synthesis of methamphetamine, in two steps, from amphetamine).



2. General methods for oxime preparation ( from ketones and hydroxylamine hydrochloride)



2a Org. Synth. 2010, 87, 36. DOI: 10.15227/orgsyn.087.0036 (Conditions: Na2CO3,, ethanol, water)

https://www.orgsyn.org/Content/pdfs/procedures/v87p0036.pdf

2b Org. Synth. 2011, 88, 33-41. DOI: 10.15227/orgsyn.088.0033 (Conditions: dil. NaOH, water, ethanol)

https://www.orgsyn.org/Content/pdfs/procedures/v88p0033.pdf

2c Org. Synth. 2023, 100, 248–270. DOI: 10.15227/orgsyn.100.0248 (Conditions: sodium acetate, methanol)

https://www.orgsyn.org/Content/pdfs/procedures/v100p0248.pdf

3. General methods for reduction of oximes to primary amines



Catalytic reductions (hydrogen and a catalyst)



3a Fred W. Hoover et al.. Synthesis of 2-Amino-1-Phenyl-1-Propanol and its Methylated Derivatives. The Journal of Organic Chemistry 1947 12 (4), 506-509. DOI: 10.1021/jo01168a003

Download from the site https://sci-hub.se/ using DOI number 10.1021/jo01168a003



3b R. V. Heinzelman. Physiologically Active Secondary Amines. β-(o-Methoxyphenyl)-isopropyl-N-methylamine and Related Compounds. Journal of the American Chemical Society 1953 75 (4), 921-925. DOI: 10.1021/ja01100a043

Download from the site https://sci-hub.se/ using DOI number 10.1021/ja01100a043



Reduction using sodium metal/alcohols



3c Vogel's Textbook of Practical Organic Chemistry Fifth Edition, Longman Scientific & Technical, 1989. ISBN 0-582-46236-3, p. 776.(download from https://archive.org/details/TextbookOfPracticalOrganicChemistry5thEd ) .



3d Xing Fan, et al. Efficient synthesis and identification of novel propane-1,3-diamino bridged CCR5 antagonists with variation on the basic center carrier. European Journal of Medicinal Chemistry,Volume 45, Issue 7, 2010, 2827. DOI: 10.1016/j.ejmech.2010.03.003

Download from the site https://sci-hub.se/ using DOI number 10.1016/j.ejmech.2010.03.003



Reductions using LiAlH4 (LAH)



3e Organic Syntheses, Coll. Vol. 10, p.305 (2004); DOI:10.15227/orgsyn.079.0130

https://www.orgsyn.org/Content/pdfs/procedures/V79P0130.pdf

3f Kulkarni, Mahesh R.; et al.. Discovery of tetrahydrocarbazoles as dual pERK and pRb inhibitors. European Journal of Medicinal Chemistry (2017), 134, 366-378 DOI:10.1016/j.ejmech.2017.02.062

Download from the site https://sci-hub.se/, using DOI number 10.1016/j.ejmech.2017.02.062 .

3g Ricci, Antonio et al.. Electron Paramagnetic Resonance (EPR) Study of Spin-Labeled Camptothecin Derivatives: A Different Look of the Ternary Complex. Journal of Medicinal Chemistry (2011), 54(4), 1003-1009. DOI: 10.1021/jm101232t. Download from the site https://sci-hub.se/, using DOI number (10.1021/jm101232t ).



Other reagents for oxime reduction



3h Ipaktschi, J. Reduction von Oximen mit Natriumboranat in Gegenwart von Übergangsmetallverbindungen. Chem. Ber., 1984 117: 856-858. https://doi.org/10.1002/cber.19841170237

Download from the site https://sci-hub.se/, using DOI number 10.1002/cber.19841170237.



3i K. Abiraj et al. Magnesium‐Catalyzed Proficient Reduction of Oximes to Amines Using Ammonium Formate. Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 2004, 34:4, 599-605. DOI: 10.1081/SCC-120027707 Download from the site https://sci-hub.se/, using DOI number 10.1081/SCC-120027707.



3j https://www.orgsyn.org/Content/pdfs/procedures/CV5P0373.pdf



3k https://www.orgsyn.org/Content/pdfs/procedures/CV3P0513.pdf



3l https://www.orgsyn.org/Content/pdfs/procedures/CV5P0032.pdf

Chapter C.



A General, One-Step Procedure for the Preparation of Various

Amphetamines via Catalytic Hydrogenation.

​

Most ketones, including phenylacetone (BMK), can be directly converted to the corresponding primary amines, using reaction known as reductive alkylation (i.e. reductive amination). The reaction involves initial addition of ammonia to a carbonyl group and the reversible formation of unstable imine, which is not isolated. The imine is then reduced to amine, using hydrogen in the presence of a catalyst (Raney nickel, PtO2 etc). Formation of a secondary amine is largely suppressed by the presence of ammonia, in large excess. The early procedures involved very high pressures (~350 atm, ~150oC), which is inconvenient and highly hazardous, also requiring special equipment.1 Later modifications enabled much lower pressures and temperatures, making the reaction practical to perform.2,3 While the yields tend to be moderate, partially due to the formation of secondary amines as side products, the reaction can be economical on large scales. The obtained primary amine is purified by distillation under the reduced pressure.​

The general procedure is illustrated on a catalytic reductive alkylation of phenylacetone (BMK) with ammonia, Scheme 5:

Scheme 5. General procedure for the synthesis of amphetamines, via catalytic reductive alkylation of ammonia

The dedicated, low pressure hydrogenation equipment is mandatory. (Many are readily available, since they are used in food industry). Also, the apparatus can be constructed, according to the instructions in Organic Syntheses (with significant modifications, using modern parts and materials).4 The shaking system, shown in Fig. 5 is to be replaced by a powerful magnetic stirrer and the hydrogenation vessel should be made of non-magnetic stainless steel (for non-corrosive solutions only). (Typically, it is made of glass). Note that all operations with gaseous hydrogen, particularly under the pressure, are inherently highly hazardous in many ways (e.g. leaks and explosive ignition). Also,improper catalyst handling, in contact with air, will result in spontaneous ignition. Additionally, it is mandatory to use high-pressure, commercial hydrogen tanks, as hydrogen source, and the dedicated, reducing pressure-regulators for hydrogen.​

Fig. 5 Home-made hydrogenation apparatus

​

In conclusion, this general method is feasible for the production of amphetamine and its analogues, providing that the specialized hydrogenation equipment is available. Some additional experiments and modifications of the procedure are necessary, including catalyst variations.​

References for Chapter C



1. Organic Syntheses, Coll. Vol. 3, p.717 (1955). DOI:10.15227/orgsyn.023.0068

Download from the site https://www.orgsyn.org/Content/pdfs/procedures/CV3P0717.pdf



2. Elliot R. Alexander et al.. A Low Pressure Reductive Alkylation Method for the Conversion of Ketones to Primary Amines. Journal of the American Chemical Society 1948 70 (4), 1315-1316. DOI: 10.1021/ja01184a007

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/ja01184a007)



3. R. V. Heinzelman. Physiologically Active Secondary Amines. β-(o-Methoxyphenyl)-isopropyl-N-methylamine and Related Compounds. Journal of the American Chemical Society 1953 75 (4), 921-925. DOI: 10.1021/ja01100a043

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/ja01100a043)



4. Org. Synth. CV1P0061. Apparatus for Catalytic Reduction. DOI: 10.15227/orgsyn.008.0010.

Download from the site https://www.orgsyn.org/Content/pdfs/procedures/CV1P0061.pdf

Chapter D.



Preparation of Various Amphetamines via two-step Leuckart reaction

​

Leuckart, also known as Leuckart-Wallach reaction, involves a two step procedure, reduction and hydrolysis, as detailed below. The reaction has been reviewed.1a,1b

In the first step, carbonyl compounds (aldehydes or ketones) are reductively converted to the corresponding formamides, using reagents such as aqueous ammonium formate,2 dry ammonium formate, mixtures containing free formic acid, and/or formamide, neat formamide etc. The use of formamide/water, instead of ammonium formate has been optimized for amines other then amphetamine.3

In the second step, the obtained formamide (which is stable, but usually not isolated) is acid-hydrolyzed to the amine salt, while the free amine is isolated by basification of the mixture. Basic formamide hydrolysis is much slower and offers no advantages, however it may be used, if the reaction is performed in steel reactors which are not acid-resistant.

Many variants exist, including some more recent modifications (e.g. special catalysts,4 microwave radiation (MW) 5 etc). However, those newer procedures, while useful and efficient, cannot be practically applied on large scales, e.g. >50-100 g. This is due either to the catalyst cost and air sensitivity, or to the lack of necessary equipment, such as powerful microwave sources. (Direct exposure to powerful, unprotected sources of MW is highly hazardous. Although it is not an ionizing radiation, it causes rapid internal heating, organ damage and death).

The classical Leuckart reaction applied to amphetamine preparation, is shown in Scheme 6.​

Scheme 6. Amphetamine preparation using Leuckart reaction.


Although the reaction is time-consuming, laborious (involving several operational steps) and requires high temperatures, it is cost-effective and suitable for large-scale productions. In addition, no special equipment is required. Thus, it has been used extensively in laboratory, mainly for various amphetamine analogues (and many other, unrelated primary amines), industrially and also by various groups operating outside legal frameworks.


In conclusion, this general method is quite often practiced in the production of amphetamine and its analogues, mainly substituted on the aromatic ring. Corrections/additions:

There is an error in the second part of the original reaction Scheme, below, because hydrogen peroxide (H2O2), is never used in Leuckart procedure, as far as it is known. Instead, the reagent in question is hydrochloric acid, i.e. HCl/H2O. In addition, the Scheme may be further modified, based on the Scheme 6 and discussion in Chapter D, above. ​

Original Scheme:

​

References for Chapter D

1. Reviews

1a. M. L. Moore, Org. React. 5, 301-330 (1949); https://onlinelibrary.wiley.com/doi/10.1002/0471264180.or005.07;

https://doi.org/10.1002/0471264180.or005.07 Download from the site

1b. Umar, Q. et al. A Brief Review: Advancement in the Synthesis of Amine through the Leuckart Reaction. Reactions 2023, 4, 117-147. https://doi.org/10.3390/reactions4010007 (Open access)

Ammonium formate generated in situ

2a. A. W. Ingersoll. α-Phenylethylamine. Org. Synth. 1937, 17, 76. DOI: 10.15227/orgsyn.017.0076

https://www.orgsyn.org/Content/pdfs/procedures/CV2P0503.pdf

2b. R. V. Heinzelman. Physiologically Active Secondary Amines. β-(o-Methoxyphenyl)-isopropyl-N-methylamine and Related Compounds. Journal of the American Chemical Society 1953 75 (4), 921-925. DOI: 10.1021/ja01100a043

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/ja01100a043)


3. Carlson, Rolf at al. An Optimized Procedure for the Reductive Amination of Acetophenone by the Leuckart Reaction, Acta Chemica Scandinavica, 1993: 47: 1046-1049. DOI number: 10.3891/acta.chem.scand.47-1046. http://actachemscand.org/doi/10.3891/acta.chem.scand.47-1046 (Open access)


Use of a special catalyst

4. Kitamura et al. Catalytic Leuckart−Wallach-Type Reductive Amination of Ketones. The Journal of Organic Chemistry 2002 67 (24), 8685. DOI: 10.1021/jo0203701.

Download from the site https://sci-hub.se/, using provided DOI number (10.1021/jo0203701)



Use of microwave radiation

5. Loupy et al. Towards the rehabilitation of the Leuckart reductive amination reaction using microwave technology. Tetrahedron Letters, Volume 37, 1996, 8177. DOI: 10.1016/0040-4039(96)01865-5

Download from the site https://sci-hub.se/, using provided DOI number (10.1016/0040-4039(96)01865-5)

Chapter E.



Separation of (+)S and (-)R enantiomers of amphetamine

​

On a preparative scale, amphetamine is always obtained as racemic mixture, which is optically inactive (composed of equal amounts of S and R enantiomer). In the case of amphetamine, dextro form, i.e (+)S enantiomer is very significantly stronger stimulant of central nervous system (CNS) then (-)R enantiomer, and has less side effects.

Since the amphetamine has been used as a prescription drug for decades (e.g. drug Adderall1), there has been a need to use the more active enantiomer, i. e. (+)S amphetamine. Hence, the efficient methods for enantiomer separation were developed. (However, for the optimal pharmacological activity, Adderall contains both enantiomers, in the ratio (+)S/ (-)R = 75:25).

At present, the main practical, large-scale separation of amphetamine enantiomers consists of a fractional crystallization of the salts, obtained from naturally occurring, optically active, acids. (Numerous other optically active amines, unrelated to amphetamine are also obtained analogously). Usually, these acids are L-(+) tartaric acid and its derivatives, and L-(-) malic acid. In general, however only one, pure enantiomer of the amine can be isolated, while the opposite one is obtained by using the opposite enantiomer of the acid, e.g. D-(-) tartaric acid. Since those acids do not occur naturally, they themselves need to be enantioseparated, and thus are far more expensive. (In recent years, numerous enzymatic enantioseparations have become industrially viable, but they require careful choice of the enzyme strains, reaction conditions etc., and are often unsuitable for simple separations. However, many simple, preparative examples are known, e.g. the one desrbied in Vogel2).

In the case of amphetamine itself, the desired (+)S amphetamine (i.e. dextroamphetamine) requires L-(+) tartaric acid and the separation is relatively simple, as elaborated below. It should be noted that, in general, the yields are not high, being in the range ~50-60%, resulting in overall yields of only ~25% (if the opposite enantiomer is discarded). While the separation must be performed with methamphetamine, since levomethamphetamine is practically inactive, in the case of amphetamine, enantioseparation is not always mandatory, depending on the specific compound and the intended use (as noted above, Adderall is an S/R mixture in 75/25 ratio).

Separation of dextramphetamine has been achieved decades ago (Temmler, GB 508757, 1939; Nabenhauer, US 2276508, 1942 to SK&F).3 Similar separation method, by the fractional crystallization of diastereoisomeric salts, has been published in a very recent scientific paper4 and is presented in the Scheme 7, below.

It is also noteworthy that monitoring the enatioseparation is not a straightforward procedure, although it was practiced using manual polarimeters, since 19th century. (Using polarimeters, the enantiopurity of a known compound, can be calculated from simple equation, not shown here. However, other optically active compounds must not be present). Other methods, particular HPLC equipment with chiral columns, have been used extensively in recent years, and they do allow for the presence of other optically active compounds. However, the equipment is quite expensive.

View attachment G09DPhZORt.png​

Scheme 7. Separation procedure of the racemic amphetamine to the pure (+)S and (-)R enantiomers.

References for Chapter E

1. https://www.drugs.com/tips/adderall-patient-tips

2. Vogel's Textbook Of Practical Organic Chemistry, 5th Ed. Longman Scientific & Technical. Longman Group UK Limited. ©Longman Group UK Limited I989. ISBN 0-582-46236-3. Page: 812.

3. In general, integral texts of the patents can be downloaded free of charge and anonymously, from the sites of various National Patent offices. The German patent office is a particularity rich, providing millions of patents from the countries worldwide. If the patent number and the country code is known (eg. US2276508), the search of the patent database is very simple, as well as the download of the full text, as pdf file. (More advanced search options are also available). The relevant address for searching is:

DEPATISnet | Basic search

DEPATISnet wird Ihnen vom Deutschen Patent- und Markenamt (DPMA) zur Verfügung gestellt und ermöglicht Ihnen die Durchführung von Online-Recherchen zu Patentveröffentlichungen aus aller Welt, die sich im Datenbestand des amtsinternen deutschen Patentinformationssystems DEPATIS befinden.

depatisnet.dpma.de

4Kristýna Dobšíková et al. Conformational analysis of amphetamine and methamphetamine: a comprehensive approach by vibrational and chiroptical spectroscopy. Analyst, 2023,148, 1337-1348.

DOI: https://doi.org/10.1039/D2AN02014A.(Open access article).

The detailed synthetic procedure for the amphetamine synthesis and enantiomer resolution is presented in a separate file, supplementary information, at the address: https://www.rsc.org/suppdata/d2/an/d2an02014a/d2an02014a1.pdf (The reference is also cited in chapter B).

​

Notes on the Pharmacological Activity of Amphetamine and its Synthetic Derivatives, as well as Some Endogenous Physiologicaly Active Amines, Including Various Neurotransmitters

​

A comprehensive presentation of amphetamine pharmacology can be found in ref. 1. It also encompasses the pharmacological comparison of amphetamine, endogenous cathecolamines, various analogues, as well as 2-phenylethyl amine (which are all very different).
​

References for Notes

1a. Goodman&Gilman's The Pharmacological Basis of Therapeutcs, 14th Ed. Editors: Laurence L. Brunton, PhD, Björn C. Knollmann, MD, PhD. Copyright © 2023 by McGraw Hill LLC. ISBN: 978-1-26-425808-6

Download from: https://libgen.is/ (and other domains if any) and the mirror links therein (some may not work). Search the site using ISBN 978-1-26-425808-6

1b. Martindale The Complete Drug Reference. Thirty-eighth Edition. ISBN 978 0 85711 139 5, ISSN 0263-5364. Published by Pharmaceutical Press 1 Lambeth High Street, London SE1 7JN, UK ©Pharmaceutical Press 2014

Download from: https://libgen.is/(https://libgen.rs/ and other domains if any) and the mirror links therein (some may not work). Search the site using ISBN 978-0-85711-139-5 or "Martindale: The Complete Drug Reference"

​