to a residue, to which was added 200 mL of ether and 200
mL of water. The layers were separated and the aqueous
layer was washed with 100 mL of ether. The ether layers
were combined, dried with MgSO4, and evaporated to give
4, an oil (39.17 g, 89% yield). By HPLC at 260 nm, the
product was 92% pure. 1H NMR (CDCl3) 7.31 (m, 5H), 4.83
(q, 1H, J ) 4.9, 3.3 Hz), 3.64 (m, 1H), 3.46 (m, 1H), 3.25
(s, 1H), 2.14 (m, 1H), 2.00 (m, 1H). 13C NMR (CDCl3) 148.4,
128.4, 127.6, 125.6, 70.9, 41.5, 41.1.
mmol) were added in portions. To the mixture was added 1
mL of acetone, 25 mL of water, and 25 mL of ether. The
layers were separated, and the ether layer was washed with
three 25 mL portions of water and evaporated to an oil, 2.38
g (93%). Gradient HPLC revealed a purity of 92% by area,
1
retention time 27.4 min. H NMR (CDCl3) 7.45 (d, J ) 7,
2H), 7.3 (m, 10H), 6.9 (d, J ) 7, 2H), 5.3 (m, 1H), 4.9 (m,
1H), 2.8 (m, 2H), 2,6 (m, 2H), 2.4 (s, 3H), 2.3 (m, 1H), 2.1
(m, 1H), 1.8 (m, 2H). 13C NMR (CDCl3) 160.50, 145.03,
144.95, 140.93, 140.73, 122.77, 122.74, 128.13, 128.08,
127.86, 127.84, 126.86, 126.83, 126.71, 126.67, 125.83,
125.76, 125.56, 125.48, 124.45 (q, J ) 270), 124.42 (q, J )
270), 122.61 (q, J ) 31), 122.58 (q, J ) 31), 115.77, 78.51,
78.32, 75.48, 75.12, 56.81, 56.53, 54.15, 53.88, 41.95, 41.80,
36.42, 36.20, 34.68, 34.64. 19F NMR (CDCl3) -61.84,
-61.87. LC/MS 178, 282, 322, 444 (M + 1).
N-Methyl-N-[4-(trifluoromethyl)phenyl]-γ-[4-(trifluo-
romethyl)phenoxy]benzenepropanamine (7). Fluoxetine
HCl (2.0 g, 5.8 mmol) and potassium carbonate (1.9 g, 13.7
mmol) were mixed in 10 mL of DMSO and warmed to 50
°C. 4-Fluorobenzotrifluoride (1.5 mL, 11.8 mmol) was added
and the mixture was stirred at 100 °C for 3 h. An additional
0.9 mL of 4-fluorobenzotrifluoride (7.1 mmol) was added,
and the mixture was stirred for an additional 46 h. After
cooling, toluene and water, 20 mL each, were added, and
the layers were separated. The organic layer was washed
with 20 mL portions of water, 5% HCl, and water. The
solvent was evaporated to give an oil which was purified by
preparative HPLC, Zorbax RX-C8, 2.1 × 25 cm, eluted at
22 mL/min with 15% water (containing 0.07% TFA) and
85% acetonitrile. The last peak was collected and the eluent
was concentrated in vacuo and the residue was extracted with
methylene chloride. The organic layer was washed with water
and evaporated to an oil. Gradient HPLC analysis showed a
purity of 98.5%. HPLC/MS showed ions 188, 254, 270, 310,
N,N-Bis-[γ-[4-(trifluoromethyl)phenoxy]-γ-phenylpro-
pyl]-methylamine (12). Fluoxetine HCl (2.6 g, 7.5 mmol)
was treated with 50% NaOH to pH 12 in 13 mL of ether
and 13 mL of water. The layers were separated, and the ether
layer was evaporated in vacuo to an oil. This fluoxetine free
base, crude chlorocompound, 16 (0.96 g, 0.3 mmol), sodium
iodide (0.04 g, 0.3 mmol), and 5 mL of DMF were combined
and heated at 80 °C for 16 h. Most of the DMF was removed
by evaporation in vacuo, and the resultant oil was treated
with 5 mL of ethyl acetate and 5 mL of water at pH 12. The
ethyl acetate layer was washed twice with water and
evaporated in vacuo to an oil, 2.14 g. A portion of the crude
oil (0.5 g) was purified by flash chromatography using the
Biotage Flash 40 system with a 8 cm pre-packed silica gel
column with 30% ethyl acetate in heptane with 1% NH4OH
as the eluent. Combination and concentration of fractions
1
351, and 454 (M + 1). H NMR (CDCl3) 7.5 (m, 9H), 7.0
(d, J ) 7, 2H), 6.7 (d, J ) 7, 2H), 5.25 (m, 1H), 3.7 (m,
2H), 3.0 (s, 3H), 2.25 (m, 2H). 13C NMR (CDCl3) 160.18,
150.87, 140.35, 128.79, 127.92, 126.76 (q, J ) 3.5), 126.40
(q, J ) 3.6), 125.51, 125.50 (q, 270), 125.0 (q, 270), 122.87
(q, J ) 32), 117.33 (q, J ) 32), 115.57, 110.96, 77.69, 48.52,
39.22, 35.67. 19F NMR (CDCl3) -60.94, -61.74.
Tetrahydro-3-methyl-6-phenyl-2H-1,3-oxazine (9). Com-
pound 3 (0.50 g, 3 mmol) was combined with 0.23 mL (3
mmol) of 37% aqueous formaldehyde and 10 mL of ethanol.
After stirring at room temperature for 1.5 h, the solvent was
evaporated to give a colorless oil. 1H NMR (CDCl3) 7.3 (m,
5H), 4.6 (d, d J ) 1.5, 9.2, 1H), 4.46 (d, d J ) 2.3, 11.4,
1H), 4.22 (d, J ) 9.2, 1H), 3.08 (m,d J ) 2.1, 12.7, 1H),
2.86 (d,t J ) 3.0, 12.5, 1H), 2.48 (s, 3H), 2.09 (d,q J ) 4.4,
13.2, 1H), 1.63 (m,d J ) 2.4, 12.5, 1H). 13C NMR (CDCl3)
142.16, 128.33, 127.51, 125.17, 89.31, 86.44, 52.40, 39.54,
30.13. GC/MS, retention 13.6 min, m/e 43, 58, 71, 72, 73,
104, 105, 117, 132, 177.
N-[γ-[4-(Trifluoromethyl)phenoxy]-γ-phenylpropyl]-r-
[2-(methylamino)ethyl]-benzenemethanol (11). Fluoxetine
hydrochloride (2.0 g, 5.8 mmol), 3-chloropropiophenone
(0.97 g, 5.8 mmol), and triethylamine (1.7 mL, 12.2 mmol)
were combined with 15 mL of ether and stirred overnight.
Another 0.4 mL of triethylamine and 15 mL of acetonitrile
were added, and the mixture was distilled until the temper-
ature reached 40 °C. After 1 h, the mixture was cooled and
filtered, and the filtrate was evaporated to a residue. This
was dissolved in 15 mL of methanol and cooled in an ice
bath; water (1 mL) and sodium borohydride (0.29 g, 7.5
1
provided an oil, 0.08 g, 91.3% pure by gradient HPLC. H
NMR (CDCl3) 7.46 (d, 4H), 7.33 (m, 10H), 6.91 (d, 4H),
5.29 (m, 2H), 2.65 (m, 2H), 2.45 (m, 2H), 2.29 (s, 3H), 2.17
(m, 2H), 1.98 (m, 2H). 13C NMR (CDCl3) 160.6, 141.2,
128.7, 127.8, 126.7, 125.7, 124.4 (q, J ) 271), 122.7 (q, J
) 32.7), 115.7, 78.1, 53.7, 42.2, 36.6. 19F NMR (CDCl3)
-61.89. LC/MS 322, 587 (M + 1).
N-(3-Phenylpropyl)-N-methyl-γ-[4-(trifluoromethyl)-
phenoxy]-benzenepropanamine (13). Fluoxetine HCl (2.0
g, 5.8 mmol) was dissolved in 10 mL of water, and 20 mL
of ether was added followed by 5 N NaOH until the pH was
12. The layers were separated and the ether layer was washed
with water, dried over sodium sulfate, and evaporated to an
oil. The residue was dissolved in 15 mL of toluene and
combined with sodium iodide (0.07 g, 0.5 mmol), tetrabutyl-
ammonium hydrogen sulfate (0.01 g, 0.3 mmol). 1-Chloro-
3-phenylpropane (0.8 mL, 5.7 mmol) was added, and the
mixture was refluxed for 2 days. Additional toluene and 10
mL of water was added, and the layers were separated. The
organic solution was evaporated to an oil and was purified
by preparative HPLC, Zorbax RX-C8, 2.1 × 25 cm, eluted
at 22 mL/min with 40% water (containing 0.07% TFA) and
60% acetonitrile. The main peak was collected, and the eluent
was concentrated in vacuo. Ether and aqueous NaOH,
sufficient to achieve a pH of 12, were added to the residue,
and the layers were separated. The ether layer was washed
518
•
Vol. 4, No. 6, 2000 / Organic Process Research & Development