Synthesis of R- and S- Fluoxetine, Norfluoxetine and Related Compounds from Styrene Oxide

Solvent-Dependent Mixed Complex Formation—NMR Studies and Asymmetric Addition Reactions of Lithioacetonitrile to Benzaldehyde Mediated by Chiral Lithium Amides

“…NMR Studies of LiÀ1: Addition of nBu[ 6 Li] to acetonitrile in THF or DEE at À 78 8C resulted in several signals in the 13 C and 6 Li NMR spectra at À 90 8C. These signals are probably from mixed dimers and tetramers of nBuLi and lithioacetonitrile.…”

“…Two 6 Li NMR signals at d 0.84 and d 0.97 of equal intensity, independent of concentration (0.02 to 0.20 m), were observed at À 90 8C. To establish that these two lithium signals arose from a single complex, we performed a 6 Li, 6 Li EXSY experiment at À 90 8C. From the cross-peak-todiagonal-peak intensities, the rate constant for the lithium exchange was determined to be 0.47 AE 0.03 s À1 , corresponding to a DG = (176 K) of 10.4 AE 0.1 kcal mol À1 .…”

“…[12] It was shown that lithiophenylacetonitrile was present as an N-metalated ketenimine in a homo-dimer solvated by N,N,N',N'-tetramethylethylene diamine (TME-DA), as in Scheme 2. Detailed solution studies of lithiophenylacetonitrile by NMR spectroscopy by Collum et al with 6 Li, 15 N scalar couplings showed an N-lithiated ketenimine dimer to be present in diethyl ether (DEE)/toluene and a TMEDA-solvated dimer to be present in toluene. [13] No 6 Li, 15 N couplings were resolved for solutions in tetrahydrofuran.…”

“…Detailed solution studies of lithiophenylacetonitrile by NMR spectroscopy by Collum et al with 6 Li, 15 N scalar couplings showed an N-lithiated ketenimine dimer to be present in diethyl ether (DEE)/toluene and a TMEDA-solvated dimer to be present in toluene. [13] No 6 Li, 15 N couplings were resolved for solutions in tetrahydrofuran. They also observed that a mixed dimer was formed between doubly labeled [ 6 Li, 15 Scheme 2.…”

Sequential Metabolism of Secondary Alkyl Amines to Metabolic-Intermediate Complexes: Opposing Roles for the Secondary Hydroxylamine and Primary Amine Metabolites of Desipramine, (S)-Fluoxetine, and N-Desmethyldiltiazem

“…The (S)-enantiomers of fluoxetine and norfluoxetine were prepared from commercially available (S)-3-chloro-1-phenylpropanol by conversion to the corresponding 3-iodo compound and subsequent displacement with ammonia or methylamine, respectively (Corey and Reichard, 1989). Subsequent O-arylation of 4-chlorotrifluoromethylbenzene was accomplished using sodium hydride in DMSO (norfluoxetine) (Mitchell and Koening, 1995) or in dimethylacetamide (fluoxetine) (Kamal et al, 2002). The tartrate salts of norfluoxetine enantiomers were prepared by the method described previously (Hilborn et al, 2001).…”