NOVEL SYNTHETIC ROUTE TO FLUOXETINE
3419
(2.1 g, 90%). Mp 73–75 ꢂC (lit.[11] 83 ꢂC). dH (CDCl3): 7.39–7.29 (m, 5H), 5.29 (dd,
J ¼ 9.8 and 3.1 Hz, 1H), 3.54–3.43 (m, 1H), 3.29–3.21 (m, 1H), 3.04 (s, 3H),
2.31–2.1 (m, 2H); dC (CDCl3): 154.31, 139.14, 128.76, 128.47, 125.75, 78.34,
46.46, 36.72, 29.72. Elemental analysis calculated for C11H13NO2: C, 69.09; H,
6.85; N, 7.32. Found: C, 69.21; H, 7.02; N, 7.29.
3-Isocyanatopropiophenone (11)
A 500-mL round-bottomed flask equipped with a magnetic stirring bar and a
500-mL addition funnel was charged with 50 mL DCE and 9.5 mL ethyl chlorofor-
mate (1 equiv), and the mixture was stirred in an ice bath. In a separate flask, 17.82 g
2 (0.1 mol) was suspended in 200 mL DCE, and 10.1 g TEA (1 equiv) was added over
10 min. The resulting hazy solution was charged into the addition funnel and added
to the ice-cooled DCE solution of ethylchloroformate over 20 min. Copious white
solids precipitated during the addition as TEA ꢀ HCl formed. After stirring for
another 15 min, the salt (12.6 g, 92%) was filtered off using a medium-porosity glass
frit. The filtrate at this stage was a DCE solution of the mixed carboxylic carbonic
anhydride 9 [dH (CDCl3): 7.99 (dm, J ¼ 7.8 Hz, 2H), 7.59 (tm, 7.5 Hz, 1H), 7.48
(tm, J ¼ 7.2 Hz, 2H), 4.33 (q, J ¼ 7.2 Hz, 2H), 3.37 (t, J ¼ 6.6 Hz, 2H), 2.93
(t, J ¼ 6.6 Hz, 2H), 1.37 (t, J ¼ 7.2 Hz, 3H); dC (CDCl3): 197.13, 167.66, 149.01,
136.45, 133.59, 128.86, 128.24, 65.84, 33.04, 28.62, 14.07].
The filtrate was charged into a clean, dry, 500-mL round-bottomed flask
equipped with a magnetic stirring bar. The flask was equipped with a clean 50-mL
addition funnel, and stirring was initiated with ice cooling. The addition funnel
was charged with a solution of 8.1 g NaN3 (125 mmol, 1.25 equiv) in 50 mL H2O,
1
which was added dropwise over 15 min. After stirring with ice cooling for 1 h, H
NMR showed the reaction was complete and the acyl azide 10 had completely
formed [dH (CDCl3): 3.33 (t, J ¼ 6.6 Hz, 2H), 2.79 (t, J ¼ 6.4 Hz, 2H)].
The mixture was poured into a separatory funnel, and the phases were split.
The organic phase was washed with a mixture of 100 mL saturated aqueous
NaHCO3 and 100 mL brine. The organic phase was dried over anhydrous MgSO4
and filtered into a dry, 500-mL round-bottomed flask equipped with a magnetic
stirring bar. The mixture was heated at 75 ꢂC overnight. The solvent was rotary-
evaporated to leave 14.64 g of a light orange liquid. The title compound was
obtained as a pale yellow oil (12.03 g, 69%) after reduced pressure distillation
(0.1 torr) of the crude product. The oil solidified when refrigerated. dH (CDCl3):
7.96 (dm, J ¼ 7.0 Hz, 2H), 7.59 (tm, J ¼ 7.3 Hz, 1H), 7.48 (tm, J ¼ 7.0 Hz, 2H),
3.74 (t, J ¼ 5.9 Hz, 2H), 3.27 (t, J ¼ 6.4 Hz, 2H); dC (CDCl3): 197.07, 136.61,
133.78, 128.97, 128.22, 123.51, 39.53, 38.16. Elemental analysis calculated for
C10H9NO2: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.36; H, 5.16; N, 7.86.
Racemic 3-(Methylamino)-1-phenyl-1-propanol (12)
An oven-dried, 1-L, round-bottomed flask equipped with a magnetic stirring
bar, a 200-mL addition funnel, and an N2 bubbler was charged with 3.38 g LAH
(0.089 mol, 3 equiv). The addition funnel was charged with 200 mL THF, which
was added in a gentle stream to the stirred solid over 20 min. Next, the addition funnel