A Simple and Convenient Synthesis of From N-Methylamphetamine by O. Hai, and I. B. Hakkenshit

Pseudoephedrine, active ingredient of Sudafed®, has long HCl followed by deprotonation with sodium hydroxide been the most popular nasal in the United and extraction into chloroform, which after removal of the States due to its effectiveness and relatively mild side solvent in vacuo yields N-methylamphetamine, 1. In the effects1. In recent years it has become increasingly difficult majority of the samples obtained for this study, 1 was greater to obtain psuedoephedine in many states because of its use than 95% enantiomerically pure, with the S being as a precursor for the illegal N-methylamphetamine the major isomer present. This is consistent with reduction of (also known under various names including crystal meth, commercially available or pseudoephedrine as the meth, ice, etc.)1,2. While in the past many stores were able origin of the casually procured material used in this study. 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, N-methylmphetamine is becoming an increasingly attractive starting material for pseudoephedrine, as the availability of N-methylmphetamine has remained high while prices have dropped and purity has increased2. We present here a convenient series of transformations using reagents which can be found in most well stocked organic chemistry laboratories to produce Scheme 1 Synthesis of pseudoephedrine from N-methylamphetamine. psuedoephedrine from N-methylamphetamine.

While N-methylamphetamine itself is a powerful The synthetic procedure is shown in scheme 1. The decongestant, it is less desirable in a medical setting because chromium tricarbonyl coordination compound 2 was formed 3 of its severe side effects and addictive properties . Such in 96% yield by heating the purified starting material and side effects may include insomnia, agitation, irritability, chromium hexacarbonyl in dibutyl ether solution according dry mouth, sweating, and heart . Other side to the procedure described by Blagg and Davies4. While effects may include violent urges or, similarly, the urge to be in the cited work a single equivalent of nBuLi was used to successful in business or finance. deprotonate a similar chromium complex, in the case of 2 In our search for sources of N-methylamphetamine we have two equivalents of nBuLi were required due to the presence found that, similar to research grade chemicals purchased of the relatively acidic proton. After successful from the major chemical supply houses, the purity of formation of the dianion 3, which was not isolated but taken the reagent varies greatly between suppliers and even on immediately in the same reaction vessel, a single hydroxy between batches despite the above cited overall increase group was introduced at the alpha position by addition in purity. Unfortunately, and again similar to suppliers of of one equivalent of oxodiperoxymolybdenum(pyridine) fine chemicals, relative cost is not strongly correlated to (HMPA), commonly known as MoOPH. The series of sample quality. We therefore found it necessary to purify transformations producing 4 from 2 went in 87% yield the starting material before use. This may be accomplished overall. Chromium was de-complexed from the newly by precipitating the from isopropanol with formed alcohol 4 by exposing the reaction mixture to air.

12 | Annals of Improbable Research | May–June 2013 | vol. 19, no. 3 www.improbable.com After washing the resulting solution with dilute NaOH and less expensive and of higher purity will make the methods DI water crude pseudoephedrine 5 was obtained. Purification presented here increasingly attractive. Future work will was accomplished by recrystallization of the material from focus on increasing yields and decreasing reaction times. toluene followed by precipitation from isopropanol with It was also suggested to one of us that a “green chemistry” HCl to obtain the final product5 *HCl in 93% yield from 4. approach, that is, elimination of toxic and environmentally The hydrochloride and sulfate salts are the most commonly detrimental solvents and reagents, should be a high priority5. encountered forms of pseudoephedrine in pharmaceutical We agree and plan to look for alternative reagents to replace preparations and thus 5*HCl can be used as-obtained from the chromium based material as well as the ether solvents. the precipitation. This synthesis follows that of Blagg and Davies, who Notes used N,N- as the starting material 1. “Oral : An Ineffective Replacement for and produced the (1S,2S)-diasteromer of N,N-dimethyl Pseudoephedrine?” L. Hendeles and R.C. Hatton, Journal pseudoephedrine exclusively. This, as discussed in their of and Clinical Immunology, vol. 118, 2006, publication, is likely due to coordination of lithium in the pp. 279–80. intermediate complex by the nitrogen atom. In the current 2. http://www.justice.gov/ndic/pubs38/38661/meth.htm study both the alpha carbon and the nitrogen atom are accessed Feb. 23rd 2012. deprotonated and it was thought that charge repulsion may decrease, or even reverse, the diastereoselectivity of the 3. “Clinical Effects and Management of reaction. On the contrary, the selectivity was retained in this Abuse,” F. Romanelli and K.M. Smith, Pharmacotherapy, reaction, resulting in pure (1S,2S)-pseudoephedrine. vol. 26, no. 8, August 2006, pp. 1148-56. We have demonstrated here a simple series of 4. “Stereospecific Conversion of N,N-dimethylamphetamine transformations which allow pseudoephedrine to be obtained into N-methylpseudoephedrine,” Julian Blagg and Stephen in a more straightforward manner than is the current norm. G. Davies, Journal of the Chemical Society, Chemical We expect that the simultaneous trends of restricting Communications, vol. 10, 1985, pp. 653-4. pseudoephedrine sales while N-methylamphetamine becomes 5. Private communication.

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