Synthesis of ephedrine from phenylalanine

Natural Products pp Cite as. Ephedrine is an alkaloid derived from various plants in the genus Ephedra family Ephedraceae. The alkaloid is comparable in actions to adrenaline. It has many medicinal and pharmaceutical applications; it is a bronchodilator to relieve shortness of breath, chest tightness, wheezing, and cough associated with bronchial asthma.

Amino acids such as phenylalanine and tyrosine serve as the precursors for a large number of alkaloids, including ephedrine, capsaicin, and colchicines. Although ephedrine is produced by chemical synthesis or enzymatic methods, it is also obtained from Ephedra species.

This chapter provides general information about Ephedraephedrine, and its derivatives, discusses methods to analyze them, and finally presents achievements in this area of science.

Indole - 3 - acetic acid. Skip to main content. Advertisement Hide. Reference work entry First Online: 15 May This is a preview of subscription content, log in to check access. Herbalgram —57 Google Scholar. Chen KK, Kao CH Ephedrine and pseudoephedrine, their isolation, constitution, isomerism, properties, derivatives and synthesis. Chevallier A The encyclopedia of medicinal plants. Dollery C Therapeutic drugs.

An In-Depth Analysis Of L-Tyrosine.

Fukushim K Bioactivity of Ephedra : integrating cytotoxicity assessment with real-time biosensing. Dissertation, University of Maryland Google Scholar. Khimiya prirodnykh soedinenii — Google Scholar. Horikawa K, Mohri T, Tanaka Y, Tokiwa H Moderate inhibition of mutagenicity and carcinogenicity of benzo[a]pyrene, 1,6-dinitropyrene and 3,9-dinitrofluoranthene by Chinese medicinal herbs.

Mutagenesis — CrossRef Google Scholar. Ethnopharmacology — CrossRef Google Scholar. Shoyakugaku Zasshi — Google Scholar. Khanam S General study of formation of secondary metabolites. Department of Pharmacognosy. Bangalore, pp 18—22 Google Scholar. Pain — CrossRef Google Scholar. Talanta — CrossRef Google Scholar. Flora China — Google Scholar. Marchei E, Pellegrini M, Pacifici R, Zuccaro P, Pichini S A rapid and simple procedure for the determination of ephedrine alkaloids in dietary supplements by gas chromatography-mass spectrometry.Post a Comment.

Ephedraceae Pakistani Ephedra.

synthesis of ephedrine from phenylalanine

Chemical Structure. Thus, we have:. Foder et al. Special Features. Identification Tests. Add to it ml of ether and shake vigorously, the ethereal layer becomes purple and the aqueous layer turns blue.

CROSS REFERENCE TO RELATED APPLICATIONS

Allow it to stand for 12 hours and evaporate the chloroform, when crystals of ephedrine HCl are obtained, and. It is widely employed as an anorexic. It is also used in the optical resolution of externally compensated acids. E -N-[4-Hydroxymethoxyphenyl -methyl]methylnoenamide.

synthesis of ephedrine from phenylalanine

It is phenolic in nature. The residue is extracted once again with successive quantities of warm acetone or ethanol until and unless the marc is completely free from any pungent principles. Characteristic Features. However, its pungency is destroyed by oxidation. It has bp 0. It is used as a topical analgesic. It is often employed as a tool in neurobiological research.

It is used in creams to counter neuralgia caused by herpes infections and in other pain-relieving formulations. However, the acid part of the resulting amide structure is of polypeptide origin having essentially a branched-chain fatty acyl-CoA which is produced by chain extension of isobutyryl-CoA.

The aforesaid source of reactions are as given under:. The AlkaloidsAcademic Press. Email This BlogThis! Share to Twitter Share to Facebook. Follow us Facebook Twitter rss email.Background: The medicinal herb, Pinellia ternatais purported to be an anti-emetic with analgesic and sedative effects. Alkaloids are the main biologically active compounds in P.

However, how ephedrine is synthesized in plants is uncertain. Only the phenylalanine ammonia lyase PAL and relevant genes in this pathway have been characterized. Genomic information of P. Results: We analyzed the transcriptome of the tuber of P. Most known genes involved in benzoic acid biosynthesis were identified in the unigene dataset of P.

Also, 14, simple sequence repeats SSRs were identified from 12, unigenes. Twenty primer pairs for SSRs were randomly selected for the validation of their amplification effect.

Phenylalanine and tyrosine metabolism

Conclusion: RNA-seq data was used for the first time to provide a comprehensive gene information on P. These data will advance molecular genetics in this valuable medicinal plant. Pinellia ternata Thunb. The alkaloids isolated from the tubers of P. Due to overexploitation and lack of large-scale plantings, P.

Secondary metabolites of P. Ephedrine accumulates primarily in mature tubers and is of great interest to researchers Wu et al.

synthesis of ephedrine from phenylalanine

Ephedrine and other phenylpropylamino alkaloids, such as, 1S, 2S -pseudoephedrine, S -cathinone, 1R, 2S -norephedrine, and 1S, 2S -pseudonorephedrine are particularly produced by plants in the genus Ephedra and by Catha edulis.

In addition, dietary supplements that contain ephedrine are illegal in the United States for its serious side effects. Despite these limitations, ephedrine still is listed on the WHO Model List of Essential Medicines, and has been used to prevent low blood pressure, asthma, narcolepsy, and obesity.

This motivates efforts to increase the production of ephedrine in planta. Further, to obtain purified extracts of ephedrine from plant, it is paramount to understand the structurally-related metabolites on the ephedrine pathway.

This knowledge will provide information on potentially unforeseen byproducts and on how intermediates on the pathway can be chemically separated by chromatographic techniques.

Therefore, a complete understanding of the biosynthesis of phenylpropylamino alkaloids still needs to be fully elucidated Groves et al. Phenylpropylamino alkaloid biosynthesis begins with L-phenylalanine Phe Hagel et al. Recent studies suggest that Phe-derived benzoic acid is an intermediate in the formation of phenylpropylamino alkaloids Krizevski et al.

Proposed pathways for the biosynthesis of ephedrine in P. RNA-sequencing RNA-seq is a particularly effective technology for gene discovery, especially in non-model species for which reference genome sequences are not available. As mentioned above, the biosynthesis of ephedrine and other phenylpropylamino alkaloids is still largely unknown. Recently, candidate genes potentially involved in phenylpropylamino alkaloids biosynthesis in C.

Here, we characterized the transcriptome of the tuber of P. Based on the transcriptome sequences, SSR markers were predicted in P. No specific permits were required for the described field studies. No specific permissions were required for these locations and activities. The location is not privately-owned or protected in any way and the field studies did not involve endangered or protected species. Subsequently, mRNA was fragmented into smaller pieces — bpwhich were used for first-strand cDNA synthesis with reverse transcriptase and random hexamer-primer.

Methods for Synthesis of Methamphetamine

These cDNA fragments underwent an end-repair process and poly A was added and then ligated with the Illumina paired-end sequencing adaptors. Ligation products were purified with magnetic beads and separated by agarose gel electrophoresis.

Transcripts de novo assembly was carried out using two short read assembly programs: Trinity Grabherr et al. Clean reads were de novo assembled with Trinity with the fixed default k-mer size of Ephedrine is a medication and stimulant.

Common side effects include trouble sleeping, anxiety, headache, hallucinationshigh blood pressurefast heart rateloss of appetite, and inability to urinate. Ephedrine was first isolated in and came into commercial use in Both ephedrine and pseudoephedrine increase blood pressure and act as bronchodilatorswith pseudoephedrine having considerably less effect.

Ephedrine may decrease motion sicknessbut it has mainly been used to decrease the sedating effects of other medications used for motion sickness. Ephedrine promotes modest short-term weight loss[12] specifically fat loss, but its long-term effects are unknown.

Ephedrine also decreases gastric emptying. Methylxanthines such as caffeine and theophylline have a synergistic effect with ephedrine with respect to weight loss. This led to creation and marketing of compound products. It is a popular supplement taken by bodybuilders seeking to cut body fat before a competition. Because of ephedrine's structural similarity to methamphetamine, it can be used to create methamphetamine using chemical reduction in which ephedrine's hydroxyl group is removed; this has made ephedrine a highly sought-after chemical precursor in the illicit manufacture of methamphetamine.

The most popular method for reducing ephedrine to methamphetamine is similar to the Birch reductionin that it uses anhydrous ammonia and lithium metal in the reaction. The second-most popular method uses red phosphorus and iodine in the reaction with ephedrine. Moreover, ephedrine can be synthesized into methcathinone via simple oxidation. Ephedrine may be quantified in blood, plasma, or urine to monitor possible abuse by athletes, confirm a diagnosis of poisoning, or assist in a medicolegal death investigation.

Many commercial immunoassay screening tests directed at the amphetamines cross-react appreciably with ephedrine, but chromatographic techniques can easily distinguish ephedrine from other phenethylamine derivatives. Ephedrine should not be used in conjunction with certain antidepressants, namely norepinephrine-dopamine reuptake inhibitors NDRIsas this increases the risk of symptoms due to excessive serum levels of norepinephrine.

Bupropion is an example of an antidepressant with an amphetamine-like structure similar to ephedrine, and it is an NDRI. Its action bears more resemblance to amphetamine than to fluoxetine in that its primary mode of therapeutic action involves norepinephrine and to a lesser degree dopamine, but it also releases some serotonin from presynaptic clefts.

It should not be used with ephedrine, as it may increase the likelihood of side effects. Contraindications for the use of ephedrine include: closed-angle glaucomaphaeochromocytomaasymmetric septal hypertrophy idiopathic hypertrophic subaortic stenosisconcomitant or recent previous 14 days monoamine oxidase inhibitor MAOI therapy, general anaesthesia with halogenated hydrocarbons particularly halothanetachyarrhythmias or ventricular fibrillation, or hypersensitivity to ephedrine or other stimulants.There've been a lot of synthesis methods proposed on UseNet for synthesizing methamphetamine.

Thus far, I haven't seen one that I imagine would work. One, from Phrack magazine, is the "tried and true method" for prepping meth from Vick's nasal inhalers. Vick's nasal inhalers contain "l-desoxyephedrine," another name for "l-methamphetamine. The d- isomer is the one that everyone wants and that Uncle Sam has declared is just too cool for anyone except doctors.

The procedure described would extract the l-meth froom the inhalers and collect it and that's it. I'm sorry, but the Isomer Fairy can't wave her magick wand and reverse the chirality of the molecule. The only way to change between the two isomers is to oxidize the l-meth into phenylacetone, condense it with methylamine, then reduce it.

You'll get l-meth and that's that. A more credible souding one mentions that "methamphetamine is prepared by the calalytic reduction of pseudoephedrine in acetic acid" blahblahblah and then goes on to describe, not catalytic reduction via acetic acid, but reduction with sodium borohydride. I'm sorry to say that no method attempting to directly reduce pseudo ephedrine's hydroxyl group is going to work. You can't expose it to a strong acid, or a weak acid, or sodium borohydride, or even lithium aluminum hydride and expect it to reduce at all.

This is because the hydroxyl group the OH in ephedrine is on a very acidic carbon the first carbon away from the ring and a hydroxyl group is very basic. If the hydroxyl were on the second carbon from the ring the carbon with the amine group, the NH2 or NHCH3there might be some chance, but it's not and there's not. You're not getting a basic group off an acidic carbon without a fight, and acids, borohydride, and LiAlhydride aren't gonna fight that hard. One of the easiest ways to make methamphetamine is from amphetamine.

Of course, this assumes you have amphetamine in the first place, but let's just pretend you have some and you want to spice it up a bit. The difference between amphetamine and methamphetamine is the addition of a single methyl group CH3 to the amino group sticking off the middle carbon atom in the chain.

Fortunately, substituting amines is really simple. Vaporize your amine your amphetamine with a bunch of vaporized chloromethane CH3Cl, a solvent and some gaseous pyridine. The hydrogen joins the liberated chlorine, and the resulting HCl is soaked up by the pyridine.

The pyridine is optional. Adding it drives the reaction a bit by pulling the excess HCl out of the equation, but it's not neessary. Assuming you don't have amphetamine lying around, an easy synthesis with a very high yield is to reduce the condensation product of phenylacetone and methylamine. The benefit of this method is that different amines can be used to produce novel N-alkyl amphetamines ethamphetamine, tert-butylamphetamine, etc.This is the U.

National Stage of International Application No. PR, filed Aug. The present invention relates to new environments in which to conduct certain classes of chemical reactions. The present invention particularly relates to new methods and environments for the synthesis of useful pharmaceutical compounds such as ephedrine. A range of important classes of pharmaceutical compounds, food additives and other biologically active compounds are based on chiral alkyl amines.

Many of these compounds are commercially important and are synthesised for use in pharmaceutical compositions and in other applications. Physicochemical methods for production of enantiomerically pure compounds usually involve multi-step synthesis incorporating one or more steps which are asymmetric, and laborious purification procedures.

Such methods are not only tedious, but frequently provide relatively poor yields. Alternatively enantiomerically-pure starting materials can be used, together with enantioselective reaction steps; however, such pure starting materials are available only for a very limited number of desired compounds. In recent years, intense efforts have been directed towards development of methods which are highly selective, provide a good rate of transformation, and enable easy, non-chromatographic separation and purification of the product.

It has also been considered particularly desirable for the reactions to be carried out in non-aqueous solvents, since these are particularly convenient for large scale reactions and purifications. These compounds are adrenergic sympathomimetic agents and have antihistamine activity; 1-ephedrine is widely used as a bronchodilator, while d-pseudoephedrine is widely used as a decongestant. Compounds of these groups are present in a very wide range of prescription and over-the-counter pharmaceutical formulations.

The production of 1-phenylacetylcarbinol, a precursor of 1-ephedrine, by catalysis using whole baker's yeast cells in aqueous medium was one of the first microbial biotransformation processes to be used commercially Neuberg and Hirsch, ; see also Hildebrandt and Klavehn, This reaction involves the yeast-induced condensation of benzaldehyde with acetyl-coenzyme A.

The reaction has been widely investigated, and has been shown to be mediated by the enzyme pyruvate decarboxylase Groger, Schmander and Mothes, It has also been shown that the reaction has a relatively broad specificity for the substrate, enabling a variety of substituted aromatic aldehydes to be converted to the corresponding substituted optically-active phenylacetylcarbinols Long, James and Ward, Although this yeast-catalysed system has been widely exploited, this has normally utilised aqueous systems, which are inconvenient for large-scale extraction and purification, which require organic solvents.

Additionally, fermentation systems present the disadvantage that purification of the desired product can be difficult, and yields tend to be low; while the yield and convenience of the reaction can be improved by utilising immobilised cells, or cells which have been selected or genetically, modified, this adds significantly to the cost of the process. The use of purified enzymes is normally prohibitively expensive, and again without the use of immobilised enzymes the yields tend to be low and purification difficult.

This reaction results in superior conversion of the aromatic aldehydes to the desired carbinol when compared with the corresponding reaction conducted in conventional organic solvents.

Based on experiments with other ketones and aldehydes, it was believed that reductive amination of the carbinol could not be conducted in any mediums other than conventional organic solvents. Accordingly, the difficulty still remained that the intermediate had to be converted into 1-ephedrine using conventional techniques in conventional organic solvents. It has now surprisingly been found by the present applicant that reductive amination of the ketone precursor for ephedrine can be conducted in the presence of supercritical fluids or liquefied gases such as supercritical carbon dioxide or liquefied petroleum gas.

These reagents are especially advantageous to use as the reaction medium in large scale reactions since the purification and processing of the products is simpler than comparable reactions conducted in standard organic or aqueous solvents. Similarly, the applicant has found that particular ketone precursors for compounds structurally related to ephedrine can be subjected to reductive amination to form the target amines in supercritical fluids or liquefied gases.

Since carbon dioxide is non-toxic and can be readily recycled, this method avoids the problems associated with reactions involving organic solvents. According to one aspect of the present invention there is provided a method for the formation of an amine of formula VI :. Preferably, the reductant is H 2 and the reduction is conducted in the presence of a suitable catalyst so that R 6 is R 3.This is the U.

National Stage of International Application No. PR, filed Aug. The present invention relates to new environments in which to conduct certain classes of chemical reactions. The present invention particularly relates to new methods and environments for the synthesis of useful pharmaceutical compounds such as ephedrine. A range of important classes of pharmaceutical compounds, food additives and other biologically active compounds are based on chiral alkyl amines.

Many of these compounds are commercially important and are synthesised for use in pharmaceutical compositions and in other applications. Physicochemical methods for production of enantiomerically pure compounds usually involve multi-step synthesis incorporating one or more steps which are asymmetric, and laborious purification procedures.

Such methods are not only tedious, but frequently provide relatively poor yields. Alternatively enantiomerically-pure starting materials can be used, together with enantioselective reaction steps; however, such pure starting materials are available only for a very limited number of desired compounds. In recent years, intense efforts have been directed towards development of methods which are highly selective, provide a good rate of transformation, and enable easy, non-chromatographic separation and purification of the product.

It has also been considered particularly desirable for the reactions to be carried out in non-aqueous solvents, since these are particularly convenient for large scale reactions and purifications. These compounds are adrenergic sympathomimetic agents and have antihistamine activity; 1-ephedrine is widely used as a bronchodilator, while d-pseudoephedrine is widely used as a decongestant.

Compounds of these groups are present in a very wide range of prescription and over-the-counter pharmaceutical formulations. The production of 1-phenylacetylcarbinol, a precursor of 1-ephedrine, by catalysis using whole baker's yeast cells in aqueous medium was one of the first microbial biotransformation processes to be used commercially Neuberg and Hirsch, ; see also Hildebrandt and Klavehn, This reaction involves the yeast-induced condensation of benzaldehyde with acetyl-coenzyme A.

The reaction has been widely investigated, and has been shown to be mediated by the enzyme pyruvate decarboxylase Groger, Schmander and Mothes, It has also been shown that the reaction has a relatively broad specificity for the substrate, enabling a variety of substituted aromatic aldehydes to be converted to the corresponding substituted optically-active phenylacetylcarbinols Long, James and Ward, Although this yeast-catalysed system has been widely exploited, this has normally utilised aqueous systems, which are inconvenient for large-scale extraction and purification, which require organic solvents.

Additionally, fermentation systems present the disadvantage that purification of the desired product can be difficult, and yields tend to be low; while the yield and convenience of the reaction can be improved by utilising immobilised cells, or cells which have been selected or genetically, modified, this adds significantly to the cost of the process.

The use of purified enzymes is normally prohibitively expensive, and again without the use of immobilised enzymes the yields tend to be low and purification difficult. This reaction results in superior conversion of the aromatic aldehydes to the desired carbinol when compared with the corresponding reaction conducted in conventional organic solvents. Based on experiments with other ketones and aldehydes, it was believed that reductive amination of the carbinol could not be conducted in any mediums other than conventional organic solvents.

Accordingly, the difficulty still remained that the intermediate had to be converted into 1-ephedrine using conventional techniques in conventional organic solvents. It has now surprisingly been found by the present applicant that reductive amination of the ketone precursor for ephedrine can be conducted in the presence of supercritical fluids or liquefied gases such as supercritical carbon dioxide or liquefied petroleum gas.

These reagents are especially advantageous to use as the reaction medium in large scale reactions since the purification and processing of the products is simpler than comparable reactions conducted in standard organic or aqueous solvents.


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