July 2012
CNS‐Agent Precursor: A Simple and Efficient Synthesis of an Antipsychotic
831
Drug Fluanisone
under reduced pressure. The crude product was purified by column
chromatography using 60–120 mesh silica gel while eluting with
ethyl acetate–hexane mixture in 1:1 ratio. The pure product was
obtained as yellow syrup and yield 0.33 g (80%).
IR (neat): υ 3070, 3032, 2929, 2861, 1641, 1604, 1507,
1453, 1389, 1343, 1295, 1223, 1156, 1075, 1027, 994, 916,
835, 772, 737, 697 cm−1 1H NMR (CDCl3): δ 2.20–2.32
(m, 1H), 2.42–2.55 (m, 1H), 4.20–4.32 (m, 2H), 4.45 (t, 1H,
J = 6.5 Hz), 5.00 (t, 2H, J = 6.5 Hz), 5.67–5.80 (m, 1H),
7.00 (t, 2H, J = 7.0 Hz), 7.20–7.35 (m, 7H).; EIMS m/z: 279
(m+ Na), 198, 150, 120, 91.
;
IR (neat): υ 2927, 2861, 1598, 1499, 1442, 1348, 1228,
1154, 1099, 1051, 972, 836, 746, 698 cm−1 1H NMR
;
(CDCl3): δ 1.30–1.40 (m, 2H), 1.55–1.65 (m, 2H), 3.00–3.15
(m, 2H), 3.20–3.40 (m, 6H), 3.80 (s, 3H), 4.00 (t, 2H, J = 6.5
Hz), 4.10–4.25 (m, 2H), 4.36 (d, 1H, J = 6.0 Hz), 6.70–7.00
(m, 6H), 7.15–7.35 (m, 7H); 13C NMR (75 MHz, CDCl3): δ
164.3, 154.5, 138.8, 138.1, 128.9, 127.8, 127.2, 123.4, 122.5,
121.2, 115.8, 115.3, 111.8, 80.9, 70.9, 61.5, 55.4, 52.2, 49.8,
44.7, 41.6, 35.6, 23.4.; EIMS m/z: 448 (m+), 385, 341, 302,
289, 259, 235, 230, 228, 200, 174, 172, 138, 116.
1‐(4‐Fluorophenyl)‐4‐[4‐(2‐methoxyphenyl)‐piperazin‐1‐yl]‐
butan‐1‐ol(8). A mixture of compound 7 (0.33 g) in methanol
(5 mL), 10% of Pd/C (35 mg) was added and stirred under
hydrogen atmosphere for 10 h at room temperature. After the
completion of the reaction as indicated by TLC, the reaction
mixture was filtered on celite bed, and the cake was washed
with methanol (2 × 5 mL). The combined filtrates were
concentrated under reduced pressure to afford the crude product,
which was purified by column chromatography using 60–120
mesh silica gel while eluting with ethyl acetate–hexane mixture
in 1:1 ratio. The pure product was obtained as yellow syrup and
yield 0.23 g (90%).
4‐(Benzyloxy)‐4‐(4‐fluorophenyl)‐butan‐1‐ol (5).
To a
stirred mixture of compound 4 (0.5 g, 1.9 mmol) in dry THF
(10 mL), BH3·DMS (1.12 mL, 11.85 mmol) was added at 0°C
and continued stirring at room temperature for 1.5 h. Then, the
reaction mixture was cooled to 0°C, and methanol (1 mL) was
added and followed by 3N NaOH (0.7 g in 6‐mL water) and
30% H2O2 (7 mL) and continued stirring for 1 h. Then, the
reaction mixture was extracted with ethyl acetate (2 × 10 mL),
and organic layer was washed with brine, dried over Na2SO4,
and concentrated under reduced pressure. The crude product
was purified by column chromatography using 60–120 mesh
silica gel while eluting with ethyl acetate–hexane mixture in 3:7
ratio. The pure product was obtained as yellow syrup and yield
0.4 g (75%).
IR (neat): υ 3395, 3064, 3032, 2937, 2866, 1650, 1604,
1507, 1453, 1390, 1344, 1296, 1222, 1156, 1060, 835, 737,
698 cm−1 1H NMR (CDCl3): δ 1.55–1.90 (m, 4H), 3.60
;
(t, 2H, J = 6.5 Hz), 4.19–4.35 (m, 2H), 4.45 (d, 1H, J = 6.5 Hz),
7.02 (t, 2H, J = 7.0 Hz), 7.20–7.40 (m, 7H).; EIMS m/z: 297
(m+ Na), 167, 150, 149, 102, 91, 71.
IR (neat): υ 3411, 2925, 1597, 1499, 1440, 1231, 1172,
;
1112, 1037, 753 cm−1 1H NMR (CDCl3): δ 1.50–1.60
4‐(Benzyloxy)‐4‐(4‐fluorophenyl)‐butanal (6). To a stirred
mixture of compound 5 (0.3 g, 1 mmol) in dry DCM (10 mL),
pyridinium chlorochromate (PCC) (0.3 g, 1.6 mmol) was added
at room temperature and continued stirring for 2 h. The progress
of the reaction mixture was monitored by TLC. After the
complete conversion of the starting material as indicated by TLC,
the reaction mixture was filtered on celite bed, and the cake was
washed with DCM (2 × 10 mL). The combined filtrates were
washed with brine, dried over Na2SO4, and concentrated under
reduced pressure. The crude product was purified by column
chromatography using 60–120 mesh silica gel while eluting with
ethyl acetate–hexane mixture in 2:8 ratio. The pure product was
obtained as colorless liquid, yield, 0.27 g (90%).
(m, 2H), 1.65–1.75 (m, 2H), 3.02–3.20 (m, 2H), 3.24–3.40
(m, 6H), 3.80 (s, 3H), 4.00 (t, 2H, J = 6.5 Hz), 4.60 (t, 1H,
J = 6.5 Hz), 6.80–7.08 (m, 6H), 7.20–7.30 (m, 2H).; EIMS
m/z: 358, 333, 317, 301, 279, 277, 242, 239, 217, 195, 88.
1‐(4‐Fluorophenyl)‐4‐[4‐(2‐methoxyphenyl)‐piperazin‐1‐yl]‐
butan‐1‐one (1). To a stirred mixture of compound 8 (0.23 g,
0.64 mmol) in methylenedichloride (5 mL), Dess–Martin
periodinane (0.33 g, 0.77 mmol) and sodium bicarbonate (0.11 g,
1.28 mmol) were added under nitrogen atmosphere, and the
stirring was continued for 3 h at room temperature. After the
completion of the reaction as indicated by TLC, the reaction
mixture was quenched by adding ice, and the reaction mixture
was extracted with DCM (2 × 5 mL). The combined organic
layers were washed with brine, dried over Na2SO4, and
concentrated under reduced pressure to afford the crude product,
which was purified by column chromatography using 60–120
mesh silica gel while eluting with ethyl acetate–hexane mixture
in 2:8 ratio. The pure product was obtained as colorless syrup
and yield 0.21 g (92%).
IR (neat): υ 3064, 3032, 2926, 2857, 1724, 1604, 1508,
1454, 1391, 1345, 1296, 1222, 1157, 1092, 1030, 910, 837,
740, 698 cm−1 1H NMR (CDCl3): δ 1.90–2.10 (m, 2H), 2.50
;
(t, 2H, J = 6.5 Hz), 4.20 (d, 1H, J = 6.5 Hz), 4.25–4.32
(m, 1H), 4.40 (d, 1H, J = 6.0 Hz), 7.01 (t, 2H, J = 7.0 Hz),
7.20–7.30 (m, 7H), 9.65 (s, 1H).; EIMS m/z: 295 (m+ Na),
165, 147, 109, 100, 79, 71.
IR (neat): υ 2927, 2855, 1681, 1504, 1448, 1377, 1206, 1139,
1‐[4‐(Benzyloxy)‐4‐(4‐fluorophenyl)‐butyl]‐4‐(2‐methoxyphenyl)‐
piperazine (7). To a stirred mixture of compound 6 (0.25 g, 0.9
mmol) in methanol (10 mL), 1‐(2‐methoxyphenyl)‐piperazine
(0.17 g, 0.9 mmol) and acetic acid (1 mL) were added at 0°C,
and the resulting reaction mixture was stirred at room temperature
for 1 h. Then, the reaction mixture was cooled to 0°C, and
NaBH3CN (0.12 g, 1.8 mmol) was added and continued stirring at
room temperature for 3 h. The progress of the reaction mixture
was monitored by TLC. After the completion of the reaction as
indicated by TLC, the reaction mixture was quenched by adding
crushed ice. Then, the solvent was removed under reduced
pressure, and the residue was neutralized with sodium bicarbonate
solution and extracted with ethyl acetate (3 × 10 mL). The organic
layer was washed with brine, dried over Na2SO4, and concentrated
1024, 840, 802, 723 cm−1 1H NMR (CDCl3): δ 1.80–1.92
;
(m, 2H), 2.99 (t, 2H, J = 6.0 Hz), 3.20 (t, 2H, J = 6.0 Hz),
3.30–3.50 (m, 6H), 3.80 (s, 3H), 4.05 (t, 2H, J = 6.0 Hz),
6.60–7.12 (m, 6H), 7.90–8.01 (m, 2H). EIMS m/z: 356 (m+),
348, 317, 299, 279, 242, 237, 191, 165, 162, 157, 150.
Acknowledgments. B.N. is thankful to UGC‐New Delhi for
providing fellowship.
REFERENCES AND NOTES
[1] Fineberg, N. A.; Gale, T. M.; Kumar T. S. Psychopharmacology
2006, 20, 97.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet