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iloperidone was treated with isopropyl alcohol (1.0 L) and
stirred for 10−15 min. Isopropyl alcohol was distilled under
vacuum at temperature not more than 55 °C to obtain the
residue.18 To the obtained residue was added isopropyl alcohol
(9.7 L), and the mixture was heated to reflux temperature (80−
85 °C) till clear solution was obtained. The obtained clear
solution was gradually cooled to 25−30 °C and stirred for 60
min. The precipitate obtained was filtered and washed with
isopropyl alcohol (1 L). Weight of wet product was 1.85 kg.
Obtained wet product was dried under vacuum at 50−55 °C
for 6−7 h. Dry weight of 1 was 1.68 kg (95% yield). HPLC
purity:17 99.85%. FT-IR (KBr, λmax, cm−1): 3031, 2949, 2779,
2746, 2822, 1669, 1614, 1585, 1510, 1462, 1448, 1415, 1380,
1313, 1262, 1221, 1177, 1150, 1123, 1077, 1034, 997, 985, 955,
884, 876, 853, 812, 781, 643, 610, 569, 475. 1H NMR (CDCl3):
δ 2.03−2.10 (m, 6H), 2.12−2.18 (m, 2H), 2.55−2.56 (s, 3H),
2.58−2.60 (t, 2H), 3.02−3.09 (m, 3H), 3.91 (s, 3H), 4.10−4.19
(t, 2H), 6.91−6.93 (d, 1H), 7.01−7.06 (dd, 1H), 7.21−7.24
(dd, 1H), 7.51−7.52 (d, 1H), 7.53−7.56 (dd, 1H), 7.69−7.65
(dd, 1H). 13C NMR (CDCl3): 26.02, 26.40, 30.36, 34.34, 53.36,
54.90, 55.80, 67.16, 97.04, 97.31, 110.20, 111.02, 111.98,
112.23, 117.12, 122.36, 122.46, 123.06, 130.11, 149.00, 152.66,
160.91, 162.60, 163.53, 163.66, 165.09, 198.59. MS (ESI, m/z):
427.2 [M + H].+ Anal. Calcd (%) for C24H27FN2O4 (426.48):
C, 67.54; H, 6.33; found (%): C, 67.24; H, 6.18.
(200 mL). The dichloromethane layer was then concentrated
by rotary evaporation to obtain a residue (35 g). To the
obtained residue was added isopropyl alcohol (400 mL), and
the mixture was refluxed for 25 min. Finally the mixture was
cooled to 0−5 °C and stirred for 60 min. The precipitated
product was filtered under suction and washed with isopropyl
alcohol (20 mL). The obtained wet material (30 g) was dried
under vacuum at 50−55 °C to furnish 10 (28 g). HPLC
purity:17 99.85%; FT-IR (KBr, λmax, cm−1): 3081, 2958, 2938,
1671, 1586, 1513, 1462, 1450, 1417, 1345, 1273, 1220, 1147,
1
1050, 1031, 1022, 875, 807, 795; H NMR (CDCl3): δ 2.38−
2.46 (m, 2H), 2.56 (s, 6H), 3.91 (s, 6H), 4.32 (t, 4H, J = 6.2
Hz), 6.94 (d, 2H, J = 8.1 Hz), 7.53−7.56 (m, 2H), 7.53−7.56
(m, 2H); MS (ESI, m/z): 373 [M + H].+
Synthesis of 1-[3-(4-Acetyl-2-methoxyphenoxy)propyl]-4-
(6-fluorobenzo[d]isoxazol-3-yl) Piperidine 1-Oxide (11).
Iloperidone (1; 10 g, 23 mmol) was charged to 30% hydrogen
peroxide (170 mL) and stirred for 30 min at 25−30 °C, and
then the temperature of the reaction mass was raised to 40−45
°C and maintained for 70−75 h. The progress of the reaction
was monitored by TLC (ethyl acetate/toluene/acetone; 2:6:2);
after completion of reaction, it was cooled to 0−5 °C and the
reaction mass was basified to pH between 8 and 9. The
obtained precipitate was stirred for 30 min at 0−5 °C and
filtered. The obtained wet material was dried under vacuum at
50−55 °C to furnish crude 9. The obtained crude product was
recrystallized from isopropyl alcohol thrice to yield white solid
11 (1.5 g). HPLC purity:17 98.27%; FT-IR (KBr, λmax, cm−1):
3083, 2958, 2878, 1655, 1606, 1584, 1509, 1467, 1419, 1348,
1273, 1223, 1182, 1143, 1121, 1032, 971, 957, 881, 857, 813,
Synthesis of Related Substances. Synthesis of 1-[4-(3-
Bromopropoxy)-3-methoxyphenyl]ethanone (6). To a stirred
solution of 1-(4-hydroxy-3-methoxyphenyl)ethanone (2) (15 g,
90 mmol) were charged N,N-dimethylformamide (50 mL),
potassium carbonate (15 g, 108 mmol), and 1,3-dibromopro-
pane (3) (55 g, 272 mmol) at 25−30 °C. The reaction mixture
was then maintained at 25−30 °C for 8−10 h. Progress of the
reaction was monitored by HPLC; after completion of the
reaction, the reaction mixture was quenched with water (500
mL) and product was extracted twice with toluene (150 mL).
The combined toluene layers were washed twice with water
(125 mL). The toluene layer was concentrated By rotary
evaporation to obtain a residue (15 g). The obtained residue
was purified by column chromatography using 3% ethyl acetate
in heptane. The fractions containing the desired product were
combined and concentrated to obtain a solid which was finally
crystallized from cyclohexane (125 mL) to obtain pure 6 (8 g).
HPLC purity:17 99.6%; FT-IR (KBr, λmax, cm−1): 3073, 3008,
2958, 2932, 2841, 1669, 1595, 1586, 1521, 1466, 1448, 1419,
1
802; H NMR (CDCl3): δ 1.89−1.93 (m, 2H), 2.31−2.40 (m,
2H), 2.55 (s, 3H), 2.60−2.72 (m, 2H), 3.29−3.52 (m, 2H),
3.29−3.52 (m, 2H), 3.29−3.52 (m, 2H), 3.29−3.52 (m, 1H),
3.85 (s, 3H), 4.23 (t, 2H, J = 6.0 Hz), 7.11 (d, 1H, J = 8.4 Hz),
7.30−7.36 (m, 1H), 7.62−7.65 (m, 1H), 7.71−7.74 (dd, J = 9.3
and 2.0 Hz, 1H), 8.02−8.07 (dd, J = 8.7 and 5.4 Hz, 1H); MS
(ESI, m/z): 443 [M + H]+.
Synthesis of 1-[4-(3-Hydroxypropoxy)-3-methoxyphenyl]-
ethanone (12). To a stirred solution of 1-(4-hydroxy-3-
methoxyphenyl)ethanone 2 (10 g, 60 mmol), acetonitrile (100
mL), and potassium carbonate (20.8 g, 150 mmol) was charged
3-bromopropan-1-ol (17 g 122 mmol) at room temperature.
The reaction temperature was raised to 60−65 °C and
maintained for 26−28 h. The progress of the reaction was
monitored by TLC (chloroform/methanol, 9.5:0.5). Upon
completion of reaction, the reaction mixture was cooled to
room temperature and filtered. The obtained filtrate was
concentrated by rotary evaporation to obtain a residue that was
finally recrystallized from toluene to furnish pure 12 (15 g).
HPLC purity:17 98.88%; FT-IR (KBr, λmax, cm−1): 3011, 2955,
2923, 2842, 1663, 1590, 1552, 1501, 1470, 1422, 1349, 1262,
1
1383, 1350, 1274, 1224, 1182, 1145, 1039, 1022, 873, 807; H
NMR (CDCl3): δ 2.36−2.45 (m, 2H), 2.57 (s, 3H), 3.63 (t,
2H, J = 6.3 Hz), 3.91 (s, 3H), 4.23 (t, 2H, J = 5.9 Hz), 6.92 (d,
1H, J = 8.4 Hz), 7.53−7.58 (m, 1H), 7.53−7.58 (m, 1H); MS
(ESI, m/z): 287 [M + H]+.
Synthesis of 1,1′-{Propane-1,3-diylbis[oxy(3-methoxy-4,1-
phenylene)]} Diethanone (10). To a stirred solution of 1-(4-
hydroxy-3-methoxyphenyl) ethanone (2) (20 g, 120 mmol),
N,N-dimethyl formamide (200 mL), and potassium carbonate
(32 g, 232 mmol) was charged 1-[4-(3-chloropropoxy)-3-
methoxyphenyl] ethanone (4) (29.3 g, 120 mmol) at 25−30
°C. The reaction mixture was then stirred for 2 h at 25−30 °C,
and then the temperature of the reaction mass was raised to
70−75 °C and maintained for 18−20 h. The progress of the
reaction was monitored by TLC (heptane:ethyl acetate; 4:6);
after completion of reaction, it was cooled to room temperature
and quenched with water (200 mL). The desired product was
extracted twice using dichloromethane (150 mL). Finally the
combined dichloromethane layer was washed twice with water
1
1211, 1175, 1143, 1075, 1043, 852, 806, 762, 721; H NMR
(CDCl3) δ 2.13−2.18 (m, 2H), 2.55 (s, 3H), 3.78 (t, 2H, J =
6.2 Hz), 3.91 (s, 3H), 4.25 (t, 2H, J = 6.0 Hz), 4.39 (t, 1H, J =
6.8 Hz), 6.92 (d, 1H, J = 8.1 Hz), 7.53−7.58 (m, 1H), 7.53−
7.58 (m, 1H); MS (ESI, m/z): 225 [M + H]+.
Synthesis of 3-(4-Acetyl-2-methoxyphenoxy)propyl-4-(6-
fluorobenzo[d]isoxazol-3-yl) Piperidine-1-carboxylate (13).
To a stirred solution of 1-[4-(3-chloropropoxy)-3-
methoxyphenyl]ethanone (4, 20 g, 82.5 mmol), N,N-dimethyl
formamide (240 mL), and potassium carbonate (28.5 g, 206
mmol) was charged 6-fluoro-3-piperidin-4-yl-1,2 benzisoxazole
hydrochloride (5, 24.3 g, 94.74 mmol) at 25−30 °C. The
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dx.doi.org/10.1021/op400335p | Org. Process Res. Dev. 2014, 18, 342−348