In the Laboratory Notes for the Instructor page 1 MS 1997 0565 The Synthesis of NMP a Fluoxetine Prozac Precursor in the Introductory Organic Laboratory Daniel M Perrine 1 Nathan R Sabanayagam and Kristy J Reynolds Department of Chemistry Loyola College in Maryland 4501 N Charles St Baltimore MD 21210 2699 Background The principal synthetic pathways we considered to prepare this lab are sketched above We first attempted to simplify Corey s 1 enantioselective synthesis of fluoxetine which starts from commercially available 8 by dispensing with the chiral catalyst and substituting NaBH4 for BH3 which we felt was unsuitably hazardous for an introductory laboratory setting A question that may arise from the students or which can be posed to them is why in a period of only a few years several enantioselective syntheses of fluoxetine were published by such preeminent chemists as Brown 2 a Nobel laureate Corey a Nobel laureate to be and Sharpless 3 The answer lies in the fact that the activity of most drugs marketed as racemates actually likes predominately or exclusively with one of the enantiomers Ibuprofen Advil Nuprin etc is the most common example While marketed as the racemate it is known that the S form is the only active form and in Europe this form is marketed as dexibuprofen Seractil A contrasting example is found in the over the counter cough suppressant dextromethorphan the DM of Robitussin DM This is the exclusively dextrorotatory form and has no analgesic or narcotic properties while the antitussive properties are found equally in its enantiomer levomethorphan the levorotatory form is an opioid narcotic and a Schedule II drug 4 It was consequently expected that studies of the activity of the R versus the S form of fluoxetine would reveal significant differences in their respective activities At the same time that the enantioselective syntheses of Sharpless Brown and Corey were being developed and published workers at Eli Lilly Research Laboratories were testing this hypothesis To their surprise they found only a slight difference in activity between the enantiomers regardless of the species or pharmacological test there is little enantiospecificity regarding interactions of fluoxetine with the serotonin uptake carrier and all the in vitro and in vivo data indicate that the eudismic ratio of the fluoxetine enantiomers is near unity 5 The eudismic ratio is the ratio of affinities or activities of two enantiomers In any case we were quite satisfied to be able to find a route to the racemic material and it seemed an obvious thing to substitute the much safer and convenient NaBH4 for BH3 in the reduction of 8 But when we carried out this reaction we were surprised to find that GC MS showed that over 10 of our starting material 8 was converted to 12 and 14 with displacement of chlorine by hydride Several variations of concentration temperature and solvent did nothing to eliminate this undesirable side reaction This complication plus the drawback that 8 is in any case fairly expensive led us to direct our attention to the patent procedure of Molloy and Schmiegel 6 This begins with 1 which is quite inexpensive or can be made in a classic Mannich reaction 7 of acetophenone 15 with formaldehyde and dimethylamine Unfortunately for the goal of synthesizing Prozac itself Mannich reactions using primary amines usually form a mixture of products and this was the case when Mannich himself 8 and later Blicke and Burckhalter 9 attempted to synthesize 3 monomethylaminopropiophenone from methylamine and acetophenone As summarized in the Journal article for reasons of safety and economy we have modified the patent procedure in several ways Reduction of 1 to 2 by use of NaBH4 instead of borane was simpler safer and quicker By coupling with 3 which is very cheap instead of 7 which is very expensive we were able to eliminate one step in the patent procedure while avoiding the 1 Corresponding author In the Laboratory Notes for the Instructor page 2 MS 1997 0565 use of SOCl2 which is as disagreeable as it is toxic Additionally the lab now exemplified nucleophilic aromatic substitution which we thought was more interesting than the more ordinary Williamson ether synthesis The literature method for effecting this SNAr reaction 10 is to deprotonate 2 by heating it at 90 EC for several hours with NaH in N N dimethylacetamide DMAA We found that bringing the reaction to reflux for 30 minutes allowed the reaction time to be considerably shortened with no significant loss in yield and this can provide an interesting laboratory exercise for an advanced synthesis class But we felt that sodium hydride was too hazardous for a beginning lab even when used in an oil dispersion After exploring a few other combinations of solvents and bases 11 we settled on the use of Aldrich s 1 0 M solution of potassium tert butoxide in t butyl alcohol which is reasonably safe to use and can be dispensed from an automatic pippetor directly into the student flasks We tried using t butyl alcohol as the reaction solvent but found that an aprotic polar solvent like DMAA was indispensable Additionally DMAA is inexpensive and partitions cleanly into the aqueous phase of a water ether workup We then considered making our own solutions of K t butoxide in DMAA for student use but decided this was too inconvenient Our present procedure which represents a manageable compromise of the many factors involved is to distill off the t butyl alcohol thereby raising the temperature to the boiling point of the DMAA and shortening the reaction time while admittedly lowering the yield Notes for the Instructor These Notes are keyed to Ins within the Instructions to the Student document Ins 1 Ins 2 Ins 3 Ins 4 Ins 5 Ins 6 The toxicity of 2 and 4 is not known but is likely to be quite low While oxalic acid is poisonous in large quantities it occurs in the leaves of many edible plants particularly rhubarb It is probably a good idea in order to disabuse any student adventurers who might imagine that consuming their product would give them some sort of a high to emphasize that antidepressants are not euphorigenic i e they will not make you feel good if you are not already depressed any more than aspirin will make you feel better if you don t have a headache Even if a person is psychologically depressed antidepressant drugs begin to help only after they have been taken daily at their regular dosage which for fluoxetine is about 20 60 mg for a minimum of