Synthesis of Dextromethorphan

The alkaloid dextromethorphan is an antitussive drug manufactured by Lonza in enantiomerically pure form. While early synthesis involved the tedious resolution of an octahydroi-soquinoline intermediate with mandelic acid, a more recent process takes advantage of the catalytic reduction of a C-N double bond promoted by a chiral Ir/ferrocenylphosphine complex [70]. 

It must be noted that transition metal-catalyzed stereoselective reductions of C-N double bonds are much less frequent than those of C-C and C-O bonds, and only very recently industrial applications of this type of process have been reported. In consideration of the ubiquitous presence of nitrogen-bearing stereocenters in a number of biologically active substances, it can be safely anticipated that extension of this reaction to chiral drugs manufacturing will become increasingly popular in the near future. 

In the catalytic Lonza process reported in Fig. 23, the unstable imine 67 was prepared in two steps from 2-cyclohexen-l -yl ethylamine and 4-methoxyphenylacetic acid via amide formation and Bischler-Napieralski cyclization to the hexahydroisoquinoline. To obtain more 

Working with a substrate/catalyst ratio = 1500, amine 69 was obtained in 89% e.e. From this, an established reaction sequence led to the desired compound 70. 

The synthesis of enantiomerically pure (1S,2R)- -aminoindanol became a subject of frontline industrial research activity after the Merck group discovered a series of HIV-protease inhibitors that contained this moiety. Merck s discovery eventually led to the development of indinavir sulfate as one of the leading drugs for the treatment of AIDS, and, as a consequence, to an industrially feasible, large-scale preparation of (1S,27 )-1-aminoindanol in enantiomeric pure form [71,72]. 

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The synthesis of dextromethorphan is an outgrowth of early efforts to synthesize the morphine skeleton. /V-Methy1morphinan(40) was synthesized in 1946 (58,59). The 3-hydroxyl and the 3-methoxy analogues were prepared by the same method. Whereas the natural alkaloids of opium are optically active, ie, only one optical isomer can be isolated, synthetic routes to the morphine skeleton provide racemic mixtures, ie, both optical isomers, which can be separated, tested, and compared pharmacologically. In the case of 3-methoxy-/V-methylmorphinan, the levorotatory isomer levorphanol [77-07-6] (levorphan) was found to possess both analgesic and antitussive activity whereas the dextrorotatory isomer, dextromethorphan (39), possessed only antitussive activity. Dextromethorphan, unlike most narcotics, does not depress ciUary activity, secretion of respiratory tract fluid, or respiration. 

Figure 23. Stereoselective synthesis of dextromethorphan. Reagents a, 4-methoxyphenylacetyl chloride b, POCl3 c, Ir(COD)BF4, H2, toluene, H20, NaOH, BtqNX.

Uses. In many cases cyanoacetic acid, cyanoacetates, or cyanoacetamide can be used alternatively. The traded cyanoacetic acid is mainly iatended for the synthesis of the cough remedy dextromethorphan [125-71-3] (31) (61) (see Expectorants, antitussives, and related agents) and of the fungicide cymoxanil [57966-95-7] (32) (62) (see Fungicides,agricultural). 

The Grewe synthesis of /V-methylmorphinan [3882-38-0] (40), which paved the way for the preparation of dextromethorphan and numerous analogues, follows standard reactions to 2-meth5l-l-benzyl-l,2,3,4,5,6,7,8-octahydroisoquinoline. Cyclization of this compound with phosphoric acid gave a mixture of isomers from which /V-methylmorphinan was separated. 

SCHEME 29.26. Enantioselective hydrogenation in the synthesis of naturally occurring isoquinoline alkaloids (e.g., morphoHne, laudanosine, and dextromethorphan). 

The synthesis (60) and potent antitussive activity (61) of dimemorfan [36309-01-0] (41), D-3-methyl-/V-methylmorphinan, have been reported. This compound, prepared by a modification of the Grewe process, differs from dextromethorphan only by having a methyl group, rather than a methoxy group, in the 3 position. 

Grewe (1946) introduced a vital alkylation reaction via a very specific stereo-selective (trans) synthesis followed by acid-catalyzed intramolecular, aromatic substitution, which caused the B/C-c/s CfD-trans ring fusions found to be common in either morphine or its natural congeners. This study has paved the way for an altogether new morphinan analogues known as benzomorphans . A few classical examples of this group of compoimds are listed below, viz., levorphanol tartrate dextromethorphan hydrobromide butorphanol tartrate ... 

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