Synthesis of NMP, a Fluoxetine (Prozac) Precursor, in the Introductory Organic Laboratory
Daniel M. Perrine,* Nathan R. Sabanayagam, and Kristy J. Reynolds Department ofChemistry, Loyola College in Maryland, 4501 N. Charles St., Baltimore, MD 21210-2699
The majority of our organic chemistry students have as their goal a career in the health sciences, and theybecome more engaged in a laboratory experiment when it involves structures with a potential pharmacological application. With this in mind, we have devised a synthesis of 4 (see scheme), the immediateprecursor of one of the most widely used (and most profitable) drugs of all time: (±)-N-methyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine (5), an antidepressant with the nonproprietary nameof fluoxetine and marketed by Eli Lilly under the trade name Prozac (1, 2). Prozac was introduced in 1986 as the first in a new class of antidepressants, the selective serotonin reuptake inhibitors(SSRIs), which are much less toxic than drugs in earlier antidepressant classes such as the tricyclics. There are a number of syntheses of Prozac reported in the literature, includingenantioselective syntheses by Corey (3) and Sharpless (4). Our modified procedure relies on these methods and on Molloy’s original patent (5), in which Prozac was formed from 4, “N-methyl-Prozac” (NMP), using thevon Braun demethylation reaction. NMP is of interest in itself because it is nearly as active an SSRI as fluoxetine (5), is the subject of an Eli Lilly patent in its own right (6 ), and is almostcertainly a prodrug for Prozac, being metabolized to it in vivo. The synthesis of 4 summarized here is used in the second semester of our introductory organic chemistry course. It requires twoperiods. In the first, shorter period, students reduce 3-dimethylaminopropiophenone, 1, with NaBH4 to form the alcohol 2; in the second, longer session, this product is coupled in an SNAr reaction with...