Synthesis of NMP, a Fluoxetine (Prozac) Precursor, in the Introductory Organic Laboratory

Abstract

A synthesis of the immediate precursor of the widely used antidepressant fluoxetine (Prozac) is described. The procedure is short, safe, and simple enough to serve as a laboratory exercise for undergraduate students in the second semester of introductory organic chemistry and is one which will be particularly interesting to those planning a career in the health sciences. The compound synthesized is (±)-N,N-dimethyl-3-(p-trifluoromethylphenoxy)-3-phenylpropylamine, or "N-methyl Prozac" (NMP). The synthesis of NMP requires one two-hour period and a second three-hour period. In the first period, a common Mannich base, 3-dimethylaminopropiophenone, is reduced with sodium borohydride to form (±)-3-dimethylamino-1-phenylpropanol. In the second period, potassium t-butoxide is used to couple (±)-3-dimethylamino-1-phenylpropanol with p-chlorotrifluoromethylbenzene to form NMP, which is isolated as its oxalate salt. All processes use equipment and materials that are inexpensive and readily available in most undergraduate laboratories. Detailed physical data are given on NMP, including high-field DEPT 13C NMR.