Received 12th December 2011, Accepted 21st January 2012 First published on the web 23rd February 2012 DOI: 1F.1BC9/b00000F00A
A novel and straightforward synthesis of pseudoephedrine from
readily available N-methylamphetamine is presented. This
practical synthesis is expected to be a disruptive technology
replacing the need to find an open pharmacy.
Pseudoephedrine, active ingredient of Sudafed®, has long
been the most popular nasal decongestant in the United States
due to its effectiveness and relatively mild side effects . In
recent years it has become increasingly difficult to obtain
psuedoephedine in many states because of its use as a
precursor for the illegal drug N-methylamphetamine (also
known under various names including crystal meth, meth, ice,
etc.)[1,2]. While in the past many stores were able to sell
pseudoephedrine, new laws in the United States have
restricted sales to pharmacies, with the medicine kept behind
the counter. The pharmacies require signatures and
examination of government issued ID in order to purchase
pseudoephedrine. Because the hours of availability of such
pharmacies are often limited, it would be of great interest to
have a simple synthesis of pseudoephedrine from reagents
which can be more readily procured.
A quick search of several neighborhoods of the United States revealed that while pseudoephedrine is difficult to obtain, N-methylamphetamine can be procured at almost any time on short notice and in quantities sufficient for synthesis of useful amounts of the desired material. Moreover, according to government maintained statistics, Nmethylmphetamine is becoming an increasingly attractive starting material for pseudoephedrine, as the availability of Nmethylmphetamine has remained high while prices have dropped and purity has increased . We present here a convenient series of transformations using reagents which can be found in most well stocked organic chemistry laboratories to produce psuedoephedrine from N-methylamphetamine.
While N-methylamphetamine itself is a powerful decongestant, it is less desirable in a medical setting because of its severe side effects and addictive properties . Such side effects may include insomnia, agitation, irritability, dry mouth, sweating, and heart palpitations. Other side effects may include violent urges or, similarly, the urge to be successful in business or finance.
In our search for sources of N-methylamphetamine we have found that, similar to research grade chemicals purchased from the major chemical supply houses, the purity of the reagent varies greatly between suppliers and even between batches despite the above cited overall increase in purity. Unfortunately, and again similar to suppliers of fine chemicals, relative cost is not strongly correlated to sample quality. We therefore found it necessary to purify the starting material before use. This may be accomplished by precipitating the amphetamine from isopropanol with HCl followed by deprotonation with sodium hydroxide and extraction into chloroform, which after removal of the solvent in vacuo yields N-methylamphetamine, 1. In the majority of the samples obtained for this study, 1 was greater than 95% enantiomerically pure, with the S enantiomer being the major isomer present. This is consistent with reduction of commercially available ephedrine or pseudoephedrine as the origin of the casually procured material used in this study.
Scheme 1 Synthesis of pseudoephedrine from N-methylamphetamine.
The synthetic procedure is shown in scheme 1. The
chromium tricarbonyl coordination compound 2 was formed
in 96% yield by heating the purified starting material and
chromium hexacarbonyl in dibutyl ether solution according to
the procedure described by Blagg and Davies . While in
the cited work a single equivalent of nBuLi was used to
deprotonate a similar chromium complex, in the case of 2 two
equivalents of nBuLi were required due to the presence of the
relatively acidic amine proton. After successful formation of
the dianion 3, which was not isolated but taken on
immediately in the same reaction vessel, a single hydroxy
group was introduced at the alpha position by addition of one
equivalent of oxodiperoxymolybdenum(pyridine)(HMPA),
commonly known as MoOPH. The series of transformations
producing 4 from 2 went in 87% yield overall. Chromium was de-complexed from the newly formed alcohol 4 by
exposing the reaction mixture to air. After washing the
resulting solution with dilute NaOH and DI water crude
pseudoephedrine 5 was obtained. Purification was
accomplished by recrystallization of the material from toluene
followed by precipitation from isopropanol with HCl to obtain
the final product 5*HCl in 93% yield from 4. The
hydrochloride and sulfate salts are the most commonly
encountered forms of pseudoephedrine in pharmaceutical
preparations and thus 5*HCl can be used as-obtained from the
This synthesis follows that of Blagg and Davies, who used N,N-dimethylamphetamine as the starting material and produced the (1S,2S)-diasteromer of N,N-dimethyl pseudoephedrine exclusively. This, as discussed in their publication, is likely due to coordination of lithium in the intermediate complex by the nitrogen atom. In the current study both the alpha carbon and the nitrogen atom are deprotonated and it was thought that charge repulsion may decrease, or even reverse, the diastereoselectivity of the reaction. On the contrary, the selectivity was retained in this reaction, resulting in pure (1S,2S)-pseudoephedrine.
We have demonstrated here a simple series of transformations which allow pseudoephedrine to be obtained in a more straightforward manner than is the current norm. We expect that the simultaneous trends of restricting pseudoephedrine sales while N-methylamphetamine becomes less expensive and of higher purity will make the methods presented here increasingly attractive. Future work will focus on increasing yields and decreasing reaction times. It was also suggested to one of us that a “green chemistry” approach, that is, elimination of toxic and environmentally detrimental solvents and reagents, should be a high priority . We agree and plan to look for alternative reagents to replace the chromium based material as well as the ether solvents.
Notes and references
* [email protected]
a Institute for Theoretical Experiments
b Department of Chemistry, Miskatonic University
1 L. Hendeles and R. C. Hatton, J. Allergy Clin. Immunol., 2006, 279- 280.
2 http://www.justice.gov/ndic/pubs38/38661/meth.htm accessed Feb. 23rd 2012.
3 F. Romanelli and K. M. Smith, Pharmacotherapy, 2006, 1148-1156.
4 J. Blagg and S. G. Davies, J. Chem. Soc. Chem. Commun., 1985, 653-654.
5 Private communication.