1256 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 8
Yasunaga et al.
6-F lu or o-8-ch r om a n ol (5c). Baeyer-Villiger oxidation
was carried out under Canan Koch’s conditions.18 To a cooled
(ice bath) solution of 10c (4.90 g, 25.2 mmol) and m-chlorop-
erbenzoic acid (mCPBA; 80% purity, 10.9 g, 50.5 mmol) in CH2-
Cl2 (100 mL) was added trifluoroacetic acid (TFA; 1.94 mL,
25.2 mmol), and the mixture was allowed to warm up to room
temperature. After stirring overnight (14 h), the resulting
suspension was diluted with CH2Cl2 (100 mL) and cooled to 0
°C. To the cooled suspension was added slowly chilled 5%
aqueous Na2SO3 (100 mL), and the mixture was vigorously
stirred until the exothermic reaction ceased. The precipitate
formed was removed by filtration and washed with CH2Cl2,
then the filtrate was separated, and the organic phase was
washed with saturated NaHCO3 solution followed by brine,
dried, and concentrated (ca u tion : prior to concentration the
absence of oxidative species should be confirmed with a test
strip). To a solution of the residual material in MeOH (60 mL)
was added dropwise 1 N NaOH (55 mL), and the mixture was
stirred at room temperature for 1 h. The mixture was then
acidified with 1 N HCl to form a precipitate which was
collected, washed with water, and then recrystallized from
hexane-EtOAc (4:1) to give 5c as a yellow solid (3.10 g, 73%):
1H NMR (90 MHz, CDCl3) δ 6.48 (1H, dd, J ) 9.7, 3.0 Hz,
C5-H), 6.31 (1H, dd, J ) 9.2, 3.0 Hz, C7-H), 5.61 (1H, s, OH),
4.21 (2H, t, J ) 5.3 Hz, C2-H2), 2.74 (2H, t, J ) 6.6 Hz, C4-
H2), 2.14-1.88 (2H, m, C3-H2); MS(EI) m/e 168 (M+).
5.21 (1H, s, OH), 4.24 (2H, t, J ) 5.2 Hz, C2-H2), 2.74 (2H, t,
J ) 6.7 Hz, C4-H2), 2.04-1.99 (2H, m, C3-H2); MS(EI) m/e 168
(M+).
7-F lu or o-8-ch r om a n ol (5h ): prepared as an oil from
5-fluoro-4-chromanone (8h ) by a procedure similar to that
described for 5e; 1H NMR (500 MHz, CDCl3) δ 6.60 (1H, dd, J
) 9.9, 8.5 Hz, C6-H), 6.50 (1H, dd, J ) 8.5, 6.1 Hz, C6-H),
5.25 (1H, s, OH), 4.25 (2H, t, J ) 5.3 Hz, C2-H2), 2.74 (2H, t,
J ) 6.4 Hz, C4-H2), 2.04-1.99 (2H, m, C3-H2); MS(EI) m/e 168
(M+).
Syn th esis of 3a -e,g,h : Gen er a l P r oced u r e. The syn-
thesis of N-[2-[(6-fluorochroman-8-yl)oxy]ethyl]-4-(4-methox-
yphenyl)butylamine fumarate (2:1) (3c) is typical. A mixture
of 5c (1.68 g, 10 mmol), 1,2-dibromoethane (17.2 mL, 200
mmol), 3 N NaOH (6.7 mL, 20.1 mmol), and Bu4N+HSO4- (170
mg, 0.50 mmol) was vigorously stirred at 70 °C for 2 h.
Another portion of 3 N NaOH (3.3 mL, 9.9 mmol) was added,
and the reaction mixture was stirred for 1 h at the same
temperature. After cooling, CH2Cl2 (50 mL) was added to the
mixture and the organic phase was separated, washed suc-
cessively with 1 N NaOH, 1 N HCl, water, and brine, then
dried, and concentrated. The residual solid material was
recrystallized from MeOH to give 8-(2-bromomethoxy)-6-
fluorochroman (13c) as a brownish solid (2.22 g, 81%): 1H
NMR (500 MHz, CDCl3) δ 6.49 (1H, dd, J ) 9.8, 3.0 Hz, C5-
H), 6.42 (1H, dd, J ) 8.5, 3.0 Hz, C7-H), 4.28 (2H, t, J ) 6.7
Hz, OCH2), 4.22 (2H, t, J ) 5.3 Hz, C2-H2), 3.64 (2H, t, J )
6.7 Hz, CH2Br), 2.76 (2H, t, J ) 6.7 Hz, C4-H2), 2.02-1.97
(2H, m, C3-H2); MS(EI) m/e 274 (M+), 276 (M+ + 2).
6-Ch lor o-8-ch r om a n ol (5d ): prepared from 6-chloro-4-
chromanone (8d ) by a procedure similar to that described for
1
5c; H NMR (90 MHz, CDCl3) δ 6.73 (1H, d, J ) 2.8 Hz, C5-
H), 6.57 (1H, d, J ) 2.8 Hz, C7-H), 5.23 (1H, s, OH), 4.22 (2H,
t, J ) 5.4 Hz, C2-H2), 2.73 (2H, t, J ) 6.3 Hz, C4-H2), 2.13-
1.87 (2H, m, C3-H2); MS(EI) m/e 184 (M+).
The bromide 13c (550 mg, 2.0 mmol), 4-(4-methoxyphenyl)-
butylamine (14; 1.08 g, 6.0 mmol), K2CO3 (415 mg, 3.0 mmol),
and CH3CN (20 mL) were mixed and refluxed for 5 h. Acetone
(40 mL) was added to the mixture, and insoluble material was
removed by filtration. The filtrate was concentrated and
purified by column chromatography eluted with CHCl3-MeOH
(100:1) to give the free base of 3c as a slightly yellow oil (553
mg, 1.48 mmol, 74%). This was treated with fumaric acid (83
mg, 0.72 mmol) in EtOH and recrystallized from EtOH-Et2O
to give 3c as white crystals (520 mg, 60% from 13c): mp 138-
141 °C. Anal. (C22H28FNO3‚0.5C4H4O4) C, H, N, F.
8-[2-[[4-(4-Meth oxyph en yl)bu tyl]am in o]eth oxy]-6-ch r o-
m a n ol F u m a r a te (2:1) (3f). 8-(2-Bromoethoxy)-6-methoxy-
chroman (13e) was obtained from 5e as described for 13c. A
mixture of 13e (400 mg, 1.39 mmol) and 48% HBr (8 mL, 71
mmol) was heated to reflux for 30 min. After that period, the
mixture was poured into ice-water and extracted with EtOAc.
The organic phase was dried and concentrated; then the
residue was separated by column chromatography eluted with
CHCl3. The first fraction was collected and purified by
recrystallization from i-Pr2O-hexane to give 8-(2-bromoet-
hoxy)-6-chromanol (13f) as amber crystals (52 mg, 14%): 1H
NMR (90 MHz, CDCl3) δ 6.36-6.27 (1H, m, C5-H), 6.22-6.14
(1H, m, C7-H), 4.38-4.12 (4H, m, OCH2, C2-H2), 3.63 (2H, t,
J ) 6.8 Hz, CH2Br), 2.73 (2H, t, J ) 6.5 Hz, C4-H2), 2.10-
1.86 (2H, m, C3-H2); MS(EI) m/e 272 (M+), 274 (M+ + 2).
The bromide 13f (50 mg, 0.183 mmol) and the amine 14 (164
mg, 0.915 mmol) were dissolved in CH3CN (1 mL), and the
solution was stirred at 75 °C for 2.5 h. The mixture was
concentrated and purified by preparative TLC (Kieselgel
60F254; Merck) developed twice with CHCl3-MeOH-ammonia
(85:15:1.5) to give the free base of 3f as an oil (34 mg, 0.092
mmol, 50%). This was treated with fumaric acid (5.3 mg, 0.046
mmol) in acetone and recrystallized from acetone to give 3f
as white crystals (35 mg, 44% from 13f): mp 175-176 °C.
Anal. (C22H29NO4‚0.5C4H4O4‚0.25H2O) C, H, N.
8-Meth oxy-1,5-ben zod ioxep in -2-on e (11e). To a solution
of 6-methoxy-4-chromanone (8e; 4.45 g, 25.0 mmol) in CH2Cl2
(50 mL) were added mCPBA (80% purity, 7.01 g, 32.5 mmol)
and TFA (285 mg, 2.50 mmol), and the mixture was stirred at
room temperature for 15 h. Na2HPO4 (3.55 g, 25.0 mmol) and
Na2SO3 (3.15 g, 25.0 mmol), both well ground, were added
successively to the mixture, and the suspension was vigorously
stirred for 2 h. Insoluble materials were filtered off, and the
filtrate was quickly washed with chilled NaHCO3 solution and
brine, then dried, and concentrated. The residual solid mate-
rial was recrystallized from i-Pr2O to give 11e as yellow
granules (2.70 g, 55%): 1H NMR (90 MHz, CDCl3) δ 7.12-
7.01 (1H, m, C6-H), 6.76-6.62 (2H, m, C7-H, C9-H), 4.50 (2H,
t, J ) 6.8 Hz, C4-H2), 3.79 (3H, s, OCH3), 2.85 (2H, t, J ) 6.8
Hz, C3-H2); MS(EI) m/e 194 (M+).
6-Meth oxy-4-oxo-8-ch r om a n ol (12e). To a cooled (ice
bath) suspension of AlCl3 (3.43 g, 25.8 mmol) in DCE (25 mL)
was added 11e (2.50 g, 12.9 mmol), and the reaction vessel
was shielded from light. The mixture was stirred at room
temperature for 3 days, poured into ice-water, and then
extracted with EtOAc. The organic phase was washed with
water and brine, dried, and concentrated to give solid material,
which was purified by column chromatography eluted with
CHCl3-MeOH (100:0 to 100:1) to give 12e as a yellow solid
(1.21 g, 48%): 1H NMR (90 MHz, CDCl3) δ 6.88 (1H, d, J )
3.0 Hz, C5-H), 6.76 (1H, d, J ) 3.0 Hz, C7-H), 5.52 (1H, br s,
OH), 4.59 (2H, t, J ) 6.4 Hz, C2-H2), 3.78 (3H, s, OCH3), 2.83
(2H, t, J ) 6.4 Hz, C3-H2); MS(FAB) m/e 194 (M+), 195 (M+
1).
+
6-Meth oxy-8-ch r om a n ol (5e). A mixture of 12e (970 mg,
5.0 mmol), 10% Pd-C (194 mg), and glacial acetic acid (20
mL) was stirred under 4 atm of H2 at room temperature for
48 h. The mixture was filtered on a Celite pad, and the filtrate
was concentrated. The residue was purified by column chro-
matography eluted with CHCl3 to give 5e as an oil (610 mg,
68%): 1H NMR (90 MHz, CDCl3) δ 6.37 (1H, d, J ) 3.1 Hz,
C5-H), 6.14 (1H, d, J ) 3.1 Hz, C7-H), 5.59 (1H, s, OH), 4.17
(2H, t, J ) 5.2 Hz, C2-H2), 3.71 (3H, s, OCH3), 2.73 (2H, t, J
) 6.5 Hz, C4-H2), 2.12-1.86 (2H, m, C3-H2); MS(EI) m/e 180
(M+).
Recep tor Bin d in g Assa ys. 5-HT1A receptor binding as-
says were performed according to the method of Peroutka with
[3H]-8-OH-DPAT on rat hippocampus.19 Adrenaline R1 and
dopamine D2 receptor binding assays were performed accord-
ing to the reported method with [3H]prazosin on rat cortex and
[3H]spiperone on rat striatum, respectively.20,21
Clon in g a n d Exp r ession of Hu m a n 5-HT1A Recep tor .
Human 5-HT1A receptor genes22 were amplified from human
placenta genomic DNA by the PCR using oligonucleotides: 5′-
TTAGATCTCGAATCTTCGCGCTGCTTTTTCTTCCCTCC-3′
and 5′-AAAGATCTAGTGAATGGGACGGATCCTGTAGCCT-
5-F lu or o-8-ch r om a n ol (5g): prepared as an oil from
7-fluoro-4-chromanone (8g) by a procedure similar to that
described for 5e; 1H NMR (500 MHz, CDCl3) δ 6.67 (1H, dd, J
) 8.5, 4.5 Hz, C7-H), 6.48 (1H, dd, J ) 8.5, 8.1 Hz, C6-H),