Methylamine Ephedrine

In this thiamine pyrophosphate-mediated process, ben2aldehyde (29), added to fermenting yeast, reacts with acetaldehyde (qv) (30), generated from glucose by the biocatalyst, to yield (R)-l-phen5l-l-hydroxy-2-propanone (31). The en2ymatically induced chiral center of (31) helps in the asymmetric reductive (chemical) condensation with methylamine to yield (lR,23)-ephedrine [299-42-3] (32). Substituted ben2aldehyde derivatives react in the same manner (80). 

The (ZZ-ephedrine was resolved into its components by the use of d-and Z-mandelic acids. In 1921 Neuberg and Hirsch showed that benz-aldehyde was reduced by yeast, fermenting in suerose or glueose solution to benzyl aleohol and a phenylpropanolone, which proved to be Z-Ph. CHOH. CO. CH3. This ean be simultaneously, or consecutively, eondensed with methylamine and then eonverted to Z-ephedrine by reduction, e.g., with aluminium amalgam in moist ether, or by hydrogen in presenee of platinic oxide as catalyst (Knoll, Hildebrant and Klavehn ). 

The second method consists of the fermentation of glucose by yeast carboligase in the presence of benzaldehyde, which during the process turns into ( )-l-phenyl-2-keto-propanol (11.3.5). This is reduced by hydrogen in the presence of methylamine, to give the desired ephedrine (11.3.4) [54,55]. 

Pyruvate decarboxylase (PDC, E.C. 4.1.1.1) accepts other substrates besides pyruvate, its natural reactant As early as 1921, Neubergand Hirsch described the reaction of yeast with benzaldehyde and pyruvate to phenylacetylcarbinol (2-keto-3-hydroxy-propylbenzene) (Neuberg, 1921) in a carboligase side reaction which yields ephedrine after reaction with methylamine and catalytic hydrogenation (Figure 7.37). 

Couturier (94) obtained a rather good yield of cK-ephedrine by reacting a diketone, phenylpropanedione, with methylamine in the presence of Raney nickel. Schwoegler and Adkins (93), on reducing acetonylacetone in ammonia, received a 28% yield of 2,5-dimethylpyrrolidine and a 59% yield of 2,5-dimethylpyrrole. From acetylacetone a quantitative yield of acetamide was obtained. 

The methyl phenyl di-ketone, sometimes called 1-phenyl, 1,2-propanedione, which would be the di-ketone used for condensation with methylamine and the subsequent hydrogenation in the presence of a catalyst to produce ephedrine, is known, as are certain other diketones. 

The most stringent section of the law is aimed primarily at production of meth, LSD, MDA and MDMA, PCP, and the barbiturates. Of those chemicals relevant to this book, it lists phenylacetone, methylamine, phenylacetic acid, ephedrine, pseudoephedrine, norpseudoephedrine, phenylpropanolamine, isosafrole, safrole, piperonal, benzyl cyanide, chlorephedrine, thionyl chloride, and N-methyl derivatives of ephedrine. 

The reasons for the popularity of this method are twofold. Firstly, this method does not require the use of methylamine because the methylamino group is already incorporated in the ephedrine molecule. Secondly,... 

As these alkaloids are not only used in chemistry as chiral auxiliaries, starting materials, and catalysts, but also in medicine, so technical syntheses have been developed and all of these compounds are commercially available. The standard materials ( )-(l/ ,2,S )-ephedrine [(-)-3) and ( —)-(lff,25,)-norephedrine [(-)- ] are produced in a technical process on multikilogram scale by reductive amination (with methylamine or ammonia, respectively) of (—)-(f )-l -hydroxy- Tphenyl-2-acetone with a platinum catalyst1. The ketone is in turn obtained by a biotechnological procedure from cultures of selected yeast strains (Saccharomyces sp.)2. 

It was shown that f -ephedrine is a secondary amine, containing an alcoholic hydroxyl group, as indicated by the formation of a nitrosamine and a dibenzoyl derivative. The presence of a methyl group is evident from the appearance of methylamine by oxidative or degradative reac-... 

The ephedrine synthesis described by Manske and Johnson (74) and by Skita and Keil (77) in 1929 is founded on a different reaction. If a mixture of o -phenylpropane-a,/S-dione and methylamine, in absolute alcohol is hydrogenated catalytically in the presence of platinum oxide (Manske) or colloidal platinum (Skita), dl-ephedrine, with a little dJr -ephedrine is obtained. The reaction has been further elaborated by Coles, Manske, and Johnson (76), by Skita, Keil and coworkers (78, 79, 262, 263) and by Couturier (265). Manske and Johnson (75) synthesized some ephedrine homologs and resolved racemic ephedrine by means of d-and f-mandelic acid. The pure I form of this acid is prepared easily with the aid of natural ephedrine, as confirmed by Jarowski and Hartung (268). 

Fourneau and Benoit (55) investigated the action of methylamine on several forms of phenylpropylene oxide. A complicated mixture of ephedrines and isoephedrines was obtained. 

A very ingenious direct synthesis of i-ephedrine, avoiding the laborious resolution of the racemic mixture, has been devised by Hildebrandt and Klavehn (271) and described by Kamlet (272). Neuberg and Hirsch (273) in 1921 demonstrated that when equal mols of acetaldehyde and benzaldehyde are added to a carbohydrate solution actively fermenting by yeast, levorotatory l-phenyl-2-ketopropanol-l, C H5-CH(OH)CO-CHi, is formed. This compound on reaction with methylamine and catalytic reduction yields 1-ephedrine directly. 

One of the older syntheses of ephedrine originates from Aladar Skita (1876-1953) in 1929 (Fig. 6.44). Methyl phenyl diketone is catalytically hydrogenated in presence of methylamine. Thus, ephedrine is produced in a single step, devoid of the other diastereomers of pseudoephedrine (the R,R- and S,S- enantiomers). [100]... 

The sympathomimetic ephedrine is produced using benzaldehyde as the starting material. Benzaldehyde is converted biotechnically using Carl Neuberg s synthesis (1921) with acetaldehyde which arises from fermentation of molasses to produce optically active phenylacetylcarbinol ((-)- -hydroxy-1-phenylacetone), which is transformed into L-(—)-ephedrine by catalytic hydrogenation in the presence of methylamine. 

Scheme 38.2 Synthesis of ephedrine by fermentation reaction on benzaldehyde, followed by reductive condensation with methylamine...

Horak and Gasperik used a method for the determination of ephedrine based on the liberation, by alkaline hydrolysis, of methylamine, which can be determined on the semi-micro scale in the Kjeldahl apparatus and the authors claimed good results when this method was used for the determination of ephedrine hydrochloride in pharmaceutical injections and tablets. 

The protonated molecules of phenylpropanolamines were shown to dissociate in a distinct way as outlined in detail for ephedrine (Scheme 4.1a). " In one route, the precursor ion at m/z 166 eliminated water (-18 Da) to generate the ion at m/z 148, which subsequently expelled methylamine (-31 Da) to yield the product ions at m/z 117 and 115, representing the cations of allyl-benzene and prop-2-ynyl-benzene, respectively. Alternatively, a second dissociation route starting also... 

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