Pseudoephedrine reductions

Because of their limited effects on allergic symptoms, decongestants often are used in combination with antihistamines.8 Many antihistamines are available in fixed-dose combinations with pseudoephedrine, which enhances the reduction in nasal congestion and allows for the patient convenience of one tablet. Optimally, therapy should be initiated with an antihistamine alone, adding the adrenergic agent only if nasal congestion does not resolve with antihistamine monotherapy. Use of separate antihistamine and pseudoephedrine also permits independent dose titration.4,11,12... 

Cervinka and co-workers have extensively investigated the asymmetric reduction of prochiral ketones with LAH modified with alkaloids and related amino alcohols. Most of this work has been reviewed in detail by Morrison and Mosher (1) and will not be discussed extensively here. Modification of LAH was effected with (-)-quinine (65), (- )-cinchonidine (66), (- )-ephedrine (67), (-)-A-ethyl-ephedrine (68), (-)- l-phenyl-2-dimethylaminoethanol (69), (+ )-quinidine (70), (+ )-cinchonine (71), and (+ )-pseudoephedrine (72). 

Pseudoephedrine. Same as above, except that it is better suited to the reduction to methyl-amphetamine. 

Table 1. Reduction of (S)-2-[(Ethoxycarbonyl)amino]propiophenone (74) to Ephedrine (75a) and Pseudoephedrine (76 b)...

This operation is necessary to hydrolyze the pseudoephedrine aminal which forms as a direct product of the reduction, in addition to the desired aldehyde. The use of the additional 700 mL of 1 N aqueous hydrochloric acid solution was found to be crucial for this hydrolysis reaction. 

Although initially available as an injectable solution for the treatment of obesity, D-metham-phetamine hydrochloride is currently available as conventional and prolonged release tablets. Illicit methamphetamine is synthesized from the precursors phenylacetone and iV -methylformamide (dl mixture) or alternatively from ephedrine or pseudoephedrine by red phosphorus/acid reduction. 

In this enantiodifferentiating photoreduction, the chiral amine plays two roles, as a chiral inductor and as an electron donor. Irradiation of 25 (Scheme 10) in a hexane slurry of unmodified NaY zeolite gave only the intramolecular hydrogen abstraction product 26. However, photolysis of 25 coimmobilized with ephedrine, pseudoephedrine, or norephedrine in NaY supercages afforded the reduction product 27 along with 26. It is clear that the immobilized amine plays the decisive role in the photoinduced electron-transfer reduction of 25, since 27 was not formed in unmodified or (— )-diethyl tartrate-modified zeolites. Consequently, the ee of obtained 27 was independent of the loading level of the chiral inductor. 

The strategy presented above with phenyl cyclohexyl ketone has been established to be general by investigating a number of aryl alkyl ketones and diaryl ketones [281,283]. The best cases of % ee are summarized in Schemes 14 and 15. 2-Ethoxybenzophenone 32 gives intramolecular cyclization product 33 as the only product in solution as well as within NaY. However, in NaY in the presence of chiral amines, intermolecular reduction product 34, in addition to 33, was obtained (Scheme 16). More importantly, with pseudoephedrine and (l/ ,2/ )-... 

Reduction of pseudoephedrine amides with metal amide-borane complexes, and lithium amidotrihydroborate (LAB) in particular, furnishes the corresponding primary alcohols in high yield. In the initial report, LAB was prepared by deprotonation of the commercial, solid reagent borane-ammonia complex, using slightly less than 1 equiv of butyllithium as base (eq 11). In... 

Pseudoephedrine is an orally active sympathomimetic amine exerting its decongestant action by acting directly on a-adrenergic receptors in the respiratory tract mucosa producing vasoconstriction resulting in shrinkage of swollen nasal mucous membranes, reduction of tissue hyperemia, edema, and nasal... 

Reduction of one carbonlyl group leads to the formation of either (-)-norephedrine (phenylpropanolamine is the name used to refer to the synthetic mixture of norephedrine), or norpseudoephedrine (called cathine). N-methy-lation of (-)-norephedrine results in the formation of (+)-ephedrine. N-methy-lation of cathine leads to the formation of (+)-pseudoephedrine (8). 

Either (-)-ephedrine or (+)-pseudoephedrine can be used to make methamphetamine by reductive dehalogenation using red phosphorus as a catalyst. If (-)-ephedrine is used as the starting material, the process will generate (+)-methamphetamine. If psuedoephedrine is used, the result will be dextromethamphetamine (136). As this synthetic route has become nearly universal, both state and federal governments have enacted laws limiting the amount of pure ephedrine or pseudoephedrine that can be purchased. 

Ephedrine and pseudoephedrine are structurally mirror images of each other. This is possible because they have a chiral center, the isopropyl carbon to which the nitrogen atom is attached. If the reduction is done in such a manner that the chiral nature of the substance is not jumbled (i.e. racemization), then ephedrine and pseudoephedrine give rise to "1" and "d" methamphetamine, respectively. The "1" form is several times more potent than the "d" form. Meth produced from phenylacetone is a racemic mixture, meaning that it is a 50-50 mix of the "1" and "d" forms of meth. Obviously, a batch of pure "1" form is most desirable, a racemic mixture is OK, and pure... 

What then if you are starting with pseudoephedrine, and you want as a result a racemic mixture for a product, but aren t using the palladium black or hydroiodic acid routes This problem can be sidestepped by dissolving the pseudoephedrine (hydrochloride or sulfate) in some concentrated hydrochloric acid, and boiling it under reflux for a couple hours. The result is a 50-50 mix of ephedrine and pseudoephedrine which upon reduction will give a racemic meth mixture. 

This method of making crank is based on the research of Gary Small and Arlene Minnella as published in the Journal of Organic Chemistry, Volume 40, pages 3151 to 3152 (1975). The article is titled "Lithium-Ammonia Reduction of Benzyl Alcohols to Aromatic Hydrocarbons. An Improved Procedure." It results in the 100% conversion of ephedrine, pseudoephedrine or PPA in a reaction time of 10 minutes or so. 

This method of directly reducing ephedrine, pseudoephedrine, or phenylpropanolamine to meth or benzedrine uses hydrazine hydrate as the reducing agent. The Wolff-Kishner reduction is generally used to deoxygenate ketones to the corresponding hydrocarbon, but in this case, it can be used on these particular substances to reduce them. No doubt, this is because the benzyl alcohol grouping has a ketone nature due to tautomerism. 

This method is very similar to the indirect reduction of ephedrine. The difference in this case is that here the chlorination and reduction are done simultaneously in a "one pot" process. This has the obvious advantages of being quicker and using fewer chemicals. This method has the further advantage of using ephedrine, pseudoephedrine, or PPA in their... 

Catalytic reduction from the exo-face gave achiral 68 ready for desymmetrisation. Elimination with the chiral base (simply the sodium salt 69 of pseudoephedrine 53) gave a single enantiomer of 66 ready for conjugate addition of the pyridine and conversion into epibatidine 70. 

The. V-alkylation of ephedrine is a convenient method for obtaining tertiary amines which are useful as catalysts, e.g., for enantioselective addition of zinc alkyls to carbonyl compounds (Section D. 1.3.1.4.), and as molybdenum complexes for enantioselective epoxidation of allylic alcohols (Section D.4.5.2.2.). As the lithium salts, they are used as chiral bases, and in the free form for the enantioselective protonation of enolates (Section D.2.I.). As auxiliaries, such tertiary amines were used for electrophilic amination (Section D.7.I.), and carbanionic reactions, e.g., Michael additions (Sections D. 1.5.2.1. and D.1.5.2.4.). For the introduction of simple jV-substituents (CH3, F.t, I-Pr, Pretc.), reductive amination of the corresponding carbonyl compounds with Raney nickel is the method of choice13. For /V-substituents containing further functional groups, e.g., 6 and 7, direct alkylations of ephedrine and pseudoephedrine have both been applied14,15. 

Make pseudoephedrine from phenylpropanolamine using reductive amina-tioii. As suggested in Problem 11(d), use one equivalent of ll2C=0 lo avoid (limeihylation. 

In 8 healthy subjects a single 150-mg oral dose of phenylpropanolamine decreased the clearance of theophylline (given as a single 4-mg/kg intravenous dose of aminophylline 1 hour after the phenylpropanolamine) by 50%. Such a large reduction in clearance would be expeeted to result in some increase in serum theophylline levels, but so far no studies of this potentially clinically important interaction seem to have been earried out in patients. Be alert for evidence of toxicity if both drugs are used. More study is needed. See also Pseudoephedrine and related drugs + Caffeine , p.1276. 

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