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Vol. 53, No. 8
NMR (300 MHz, DMSO-d6) d 1.58—1.73 (4H, m), 2.23—2.30 (2H, m),
3.86—3.92 (2H, m), 5.06 (2H, s), 6.85 (2H, d, Jꢁ9.2 Hz), 6.93 (2H, d,
Jꢁ9.2 Hz), 7.10—7.18 (1H, m), 7.22—7.30 (2H, m), 7.38—7.47 (1H, m);
MS (FAB) m/z 317 (M)ꢃ.
7.41—7.47 (1H, m), 7.80 (2H, d, Jꢁ6.3 Hz), 8.79 (2H, d, Jꢁ6.4 Hz), 8.96
(1H, t, Jꢁ6.3 Hz); MS (FAB) m/z 367 (MꢀH)ꢀ. Anal. Calcd for
C21H19N2O3F·0.95HCl: C, 62.90; H, 5.01; N, 6.99; F, 4.74; Cl, 8.40. Found:
C, 63.12; H, 5.04; N, 7.16; F, 4.56; Cl, 8.44.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}hexanoic Acid (9c) Compound
9c was prepared from 8 by a procedure similar to that described for 9a.
Compound 9c was obtained as a colorless powder (92% in 2 steps): 1H-
NMR (300 MHz, DMSO-d6) d 1.33—1.46 (2H, m), 1.49—1.60 (2H, m),
1.62—1.73 (2H, m), 2.18—2.26 (2H, m), 3.84—3.91 (2H, m), 5.06 (2H, s),
6.84 (2H, d, Jꢁ9.2 Hz), 6.93 (2H, d, Jꢁ9.2 Hz), 7.10—7.18 (1H, m), 7.22—
7.30 (2H, m), 7.38—7.47 (1H, m), 11.99 (1H, br s); MS (FAB) m/z 331
(M)ꢃ.
3-{4-[(3-Fluorobenzyl)oxy]phenyl}-N-(pyridin-4-ylmethyl)propanam-
ide Hydrochloride (6b) Compound 6b was prepared from 5b by a proce-
dure similar to that described for 6a. Compound 6b was obtained as a color-
less solid (70%): mp 176—177 °C; 1H-NMR (400 MHz, DMSO-d6) d
2.48—2.54 (2H, m), 2.80 (2H, t, Jꢁ7.5 Hz), 4.49 (2H, d, Jꢁ3.8 Hz), 5.11
(2H, s), 6.94 (2H, d, Jꢁ8.8 Hz), 7.11—7.19 (3H, m), 7.25—7.32 (2H, m),
7.41—7.47 (1H, m), 7.70 (2H, d, Jꢁ6.4 Hz), 8.68—8.74 (1H, m), 8.76 (2H,
d, Jꢁ6.3 Hz); MS (FAB) m/z 365 (MꢀH)ꢀ. Anal. Calcd for
C22H21N2O2F·HCl: C, 65.91; H, 5.53; N, 6.99; F, 4.74; Cl, 8.84. Found: C,
65.62; H, 5.55; N, 6.95; F, 4.75; Cl, 8.60.
4-{4-[(3-Fluorobenzyl)oxy]phenyl}-N-(pyridin-4-ylmethyl)butanamide
Hydrochloride (6c) Compound 6c was prepared from 5c by a procedure
similar to that described for 6a. Compound 6c was obtained as a colorless
solid (42%): mp 109—112 °C; 1H-NMR (400 MHz, DMSO-d6) d 1.76—
1.88 (2H, m), 2.23 (2H, t, Jꢁ7.8 Hz), 2.48—2.55 (2H, m), 4.50 (2H, d,
Jꢁ5.9 Hz), 5.10 (2H, s), 6.93 (2H, d, Jꢁ8.8 Hz), 7.09—7.19 (3H, m),
7.24—7.30 (2H, m), 7.41—7.47 (1H, m), 7.82 (2H, d, Jꢁ6.3 Hz), 8.68 (1H,
t, Jꢁ5.9 Hz), 8.82 (2H, d, Jꢁ6.9 Hz); MS (FAB) m/z 379 (MꢀH)ꢀ. Anal.
Calcd for C23H23N2O2F·HCl: C, 66.58; H, 5.83; N, 6.75; F, 4.58; Cl, 8.54.
Found: C, 66.44; H, 5.91; N, 6.73; F, 4.42; Cl, 8.52.
4-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(pyridin-4-ylmethyl)butanam-
ide Hydrochloride (10a) Compound 10a was prepared from 9a by a pro-
cedure similar to that described for 6a. Compound 10a was obtained as a
1
colorless powder (77%): mp 144—146 °C; H-NMR (400 MHz, DMSO-d6)
d 1.90—2.00 (2H, m), 2.80—2.41 (2H, m), 3.91 (2H, t, Jꢁ6.3 Hz), 4.52
(2H, d, Jꢁ5.9 Hz), 5.07 (2H, s), 6.85 (2H, d, Jꢁ9.3 Hz), 6.94 (2H, d,
Jꢁ9.3 Hz), 7.11—7.18 (1H, m), 7.23—7.30 (2H, m), 7.39—7.47 (1H, m),
7.83 (2H, d, Jꢁ6.4 Hz), 8.73—8.83 (3H, m); MS (FAB) m/z 395 (MꢀH)ꢀ.
Anal. Calcd for C23H23N2O3F·HCl: C, 64.11; H, 5.61; N, 6.50; F, 4.41; Cl,
8.23. Found: C, 63.99; H, 5.63; N, 6.51; F, 4.29; Cl, 8.26.
5-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(pyridin-4-ylmethyl)pen-
tanamide Hydrochloride (10b) Compound 10b was prepared from 9b by
a procedure similar to that described for 6a. Compound 10b was obtained as
N-(4-{4-[(3-Fluorobenzyl)oxy]phenyl}butyl)-2-pyridin-4-ylacetamide
1
a beige powder (79%): mp 110—112 °C; H-NMR (400 MHz, DMSO-d6) d
Oxalate (6d) To
a mixture of pyridin-4-ylmethylamine (108 mg,
1.66—1.72 (4H, m), 2.26—2.34 (2H, m), 3.88—3.93 (2H, m), 4.51 (2H, d,
Jꢁ5.9 Hz), 5.06 (2H, s), 6.85 (2H, d, Jꢁ8.8 Hz), 6.93 (2H, d, Jꢁ8.8 Hz),
7.11—7.18 (1H, m), 7.23—7.29 (2H, m), 7.39—7.46 (1H, m), 7.83 (2H, d,
Jꢁ6.8 Hz), 8.69—8.74 (1H, m), 8.81 (2H, d, Jꢁ6.9 Hz); MS (FAB) m/z 409
(MꢀH)ꢀ. Anal. Calcd for C24H25N2O3F·HCl: C, 64.79; H, 5.89; N, 6.30; F,
4.27; Cl, 7.97. Found: C, 64.68; H, 5.83; N, 6.21; F, 4.27; Cl, 8.09.
6-{4-[(3-Fluorobenzyl)oxy]phenoxy}-N-(pyridin-4-ylmethyl)hexan-
amide Hydrochloride (10c) Compound 10c was prepared from 9c by a
procedure similar to that described for 6a. Compound 10c was obtained as a
beige powder (68%): mp 125—127 °C; 1H-NMR (400 MHz, DMSO-d6) d
1.36—1.46 (2H, m), 1.55—1.73 (4H, m), 2.22—2.28 (2H, m), 3.89 (2H,
t, Jꢁ6.3 Hz), 4.51 (2H, d, Jꢁ5.8 Hz), 5.06 (2H, s), 6.84 (2H, d, Jꢁ
9.2 Hz), 6.93 (2H, d, Jꢁ9.2 Hz), 7.11—7.18 (1H, m), 7.22—7.30 (2H, m),
7.39—7.46 (1H, m), 7.82 (2H, d, Jꢁ6.3 Hz), 8.66—8.72 (1H, m), 8.80
(2H, d, Jꢁ6.3 Hz); MS (FAB) m/z 423 (MꢀH)ꢀ. Anal. Calcd for
C25H27N2O3F·HCl: C, 65.42; H, 6.15; N, 6.10; F, 4.14; Cl, 7.72. Found: C,
65.27; H, 6.14; N, 6.09; F, 4.21; Cl, 7.69.
(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)amine (11) To a mixture
of 4-[(3-fluorobenzyl)oxy]phenol 8 (655 mg, 3.0 mmol) and K2CO3 (829 mg,
6.0 mmol) in MeCN (10 ml) was added 2-(3-bromopropyl)-1H-isoindole-
1,3(2H)-dione (1.05 g, 3.90 mmol) at room temperature. The mixture was
stirred at 80 °C. H2O was added to the mixture. The precipitate was collected
by filtration, washed with H2O and dried in vacuo to give 2-(3-{4-[(3-fluo-
robenzyl)oxy]phenoxy}propyl)-1H-isoindole-1,3(2H)-dione as a light brown
powder (1.21 g, 99%). The mixture of 2-(3-{4-[(3-fluorobenzyl)oxy]phe-
noxy}propyl)-1H-isoindole-1,3(2H)-dione (1.21 g, 2.98 mmol) and hy-
drazine hydrate (448 mg, 8.94 mmol) in MeOH (10 ml) and CHCl3 (20 ml)
was stirred at room temperature for overnight. The precipitate was filtered
and washed with CHCl3. The filtrate was washed with aqueous NaOH and
brine and dried, concentrated in vacuo. The residue was purified by column
chromatography on silica gel (CHCl3 : MeOHꢁ88 : 12) to give 11 as a beige
solid (539 mg, 66%): 1H-NMR (300 MHz, CDCl3) d 1.85—1.96 (2H, m),
2.87—2.93 (2H, m), 3.97—4.04 (2H, m), 5.01 (2H, s), 6.83 (2H, d,
Jꢁ9.2 Hz), 6.89 (2H, d, Jꢁ9.2 Hz), 6.96—7.04 (1H, m), 7.12—7.21 (2H,
m), 7.21—7.28 (1H, m); MS (FAB) m/z 276 (MꢀH)ꢀ.
1.00 mmol), 1-hydroxybenzotriazole (HOBt) (68 mg, 0.50 mmol), 1-ethyl-3-
(3-dimethylaminopropyl)-carbodiimide hydrochloride (WSC·HCl) (211 mg,
1.10 mmol) and THF (6 ml) was added 5d (302 mg, 1.00 mmol) at room
temperature. The mixture was stirred for 3 h. The reaction mixture was
quenched by saturated NaHCO3. The mixture was partitioned between
CHCl3 and aqueous NaOH. The organic layer was dried and concentrated in
vacuo to give light yellow solid. The residue was purified by column chro-
matography on silica gel (CHCl3 : MeOHꢁ98 : 2—96 : 4) to afford a free
base of 6d (371 mg). The compound was dissolved in MeOH. To the mix-
ture was added oxalic acid (94 mg, 1.04 mmol). The mixture was concen-
trated in vacuo, the residue was recrystallized from AcOEt–CH3CN (5 : 1) to
give 6d as a colorless powder (284 mg, 59%): mp 128—130 °C; 1H-NMR
(400 MHz, DMSO-d6) d 1.49—1.47 (4H, m), 2.16—2.22 (2H, m), 2.48—
2.54 (2H, m), 4.29 (2H, d, Jꢁ5.9 Hz), 5.09 (2H, s), 6.92 (2H, d, Jꢁ8.3 Hz),
7.10 (2H, d, Jꢁ8.3 Hz), 7.12—7.18 (1H, m), 7.24—7.30 (4H, m), 7.40—
7.49 (1H, m), 8.34—8.44 (1H, m), 8.47—8.53 (2H, m); MS (FAB) m/z 393
(MꢀH)ꢀ. Anal. Calcd for C24H25N2O2F·(CO2H)2: C, 64.72; H, 5.64; N,
5.81; F, 3.94. Found: C, 64.65; H, 5.57; N, 5.75; F, 4.06.
4-({4-[(3-Fluorobenzyl)oxy]phenyl}sulfanyl)-N-(pyridin-4-ylmethyl)-
butanamide Hydrochloride (6e) Compound 6e was prepared from 5e by
a procedure similar to that described for 6a. Compound 6e was obtained as a
1
colorless powder (57%): mp 101—103 °C; H-NMR (400 MHz, DMSO-d6)
d 1.72—1.82 (2H, m), 2.36 (2H, t, Jꢁ7.3 Hz), 2.87 (2H, t, Jꢁ7.3 Hz), 4.50
(2H, d, Jꢁ5.4 Hz), 5.12 (2H, s), 7.00 (2H, d, Jꢁ8.8 Hz), 7.13—7.19 (1H,
m), 7.25—7.35 (4H, m), 7.41—7.48 (1H, m), 7.82 (2H, d, Jꢁ6.9 Hz),
8.70—8.77 (1H, m), 8.81 (2H, d, Jꢁ6.3 Hz); MS (FAB) m/z 411 (MꢀH)ꢀ.
Anal. Calcd for C23H23N2O2SF·HCl: C, 60.11; H, 5.57; N, 6.10; F, 4.13; Cl,
7.71; S, 6.98. Found: C, 59.91; H, 5.44; N, 6.07; F, 3.92; Cl, 7.65; S, 6.98.
4-{4-[(3-Fluorobenzyl)oxy]phenoxy}butanoic Acid (9a) To a mixture
of 4-[(3-fluorobenzyl)oxy]phenol 8 (436 mg, 2.00 mmol), K2CO3 (332 mg,
2.40 mmol) in CH3CN (10 ml) was added ethyl 4-bromobutanoate (0.315 ml,
2.20 mmol) at room temperature. The mixture was stirred at 80 °C for 26 h.
The mixture was partitioned between CHCl3 and aqueous NaOH. The or-
ganic layer was dried and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (hexane : AcOEtꢁ1 : 0—4 : 1) to give
N-(3-{4-[(3-Fluorobenzyl)oxy]phenoxy}propyl)-2-pyridin-4-ylacet-
amide Hydrochloride (12) Compound 12 was prepared from 11 by a pro-
cedure similar to that described for 6a. Compound 12 was obtained as a
slightly pink powder (93%): mp 143—145 °C; 1H-NMR (400 MHz, DMSO-
d6) d 3.33—3.40 (2H, m), 3.91 (2H, t, Jꢁ5.6 Hz), 4.47 (2H, d, Jꢁ5.3 Hz),
5.07 (2H, s), 6.55—6.65 (1H, m), 6.88 (2H, d, Jꢁ9.3 Hz), 6.92—6.97 (3H,
m), 7.11—7.18 (1H, m), 7.23—7.29 (2H, m), 7.40—7.47 (1H, m), 7.84 (2H,
d, Jꢁ6.3 Hz), 8.81 (2H, d, Jꢁ6.4 Hz); MS (FAB) m/z 395 (MꢀH)ꢀ. Anal.
Calcd for C23H23N2O3F·HCl: C, 64.11; H, 5.61; N, 6.50; F, 4.41; Cl, 8.23.
Found: C, 64.01; H, 5.53; N, 6.47; F, 4.30; Cl, 8.09.
ethyl 4-{4-[(3-fluorobenzyl)oxy]phenoxy}butanoate as
a colorless oil
(630 mg, 95%). The mixture of the intermediate (620 mg, 1.87 mmol) in 1 M
NaOH (2.8 ml, 2.8 mmol) and EtOH (5 ml) was stirred at room temperature
for 4 h. The mixture was concentrated in vacuo. 1 M HCl was added to the
residue. The precipitate was collected to afford 9a as a colorless powder
(537 mg, 94%): 1H-NMR (300 MHz, DMSO-d6) d 1.84—1.95 (2H, m),
2.32—2.40 (2H, m), 3.87—3.94 (2H, m), 5.06 (2H, s), 6.85 (2H, d,
Jꢁ9.1 Hz), 6.93 (2H, d, Jꢁ9.1 Hz), 7.10—7.18 (1H, m), 7.22—7.30 (2H,
m), 7.38—7.47 (1H, m), 12.11 (1H, s); MS (FAB) m/z 304 (M)ꢃ.
5-{4-[(3-Fluorobenzyl)oxy]phenoxy}pentanoic Acid (9b) Compound
9b was prepared from 8 by a procedure similar to that described for 9a.
Compound 9b was obtained as a colorless powder (92% in 2 steps): 1H-
(2-{4-[(3-Fluorobenzyl)oxy]phenoxy}ethyl)amine (13) A mixture of
tert-butyl(2-bromoethyl)carbamate (1.0 g, 4.5 mmol), 4-[(3-fluorobenzyl)-