N. Khorana et al. / Bioorg. Med. Chem. 11 (2003) 717–722
721
.
.
Thionyl chloride (0.5 mL) was added to a solution of
this alkenol (0.32 g, 2 mmol) in benzene (10 mL) and the
reaction mixture was heated at 70–80 ꢂC for 24 h. The
reaction mixture was poured into ice/H2O (100 mL),
and the aqueous solution was extracted with CH2Cl2
(2ꢃ25 mL). The combine organic fraction was washed
well with H2O (30 mL), and finally the CH2Cl2 was
evaporated under reduced pressure to give 0.26 g (72%)
of the alkenyl halide as an oil. This halide was used to
alkylate 32 as described above and the product was
converted to its HCl salt to give a 30% yield of Z12; mp
217–219 ꢂC after recrystalization from MeOH/anhy-
lute EtOH mixture. Anal. C23H24N2HCl 0.5H2O C, H,
N.
1-(3-(4-Fluorophenoxy)propyl)piperidine hydrochloride
(29). A mixture of 1-(3-chloropropoxy)-4-fluorobenzene
(0.57 g, 3.0 mmol), piperidine (0.26 g, 3.0 mmol),
K2CO3 (0.75 g, 5.6 mmol) and a catalytic amount of
NaI in MeCN (30 mL) was heated at reflux for 18 h.
After the reaction mixture was allowed to cool to room
temperature, it was extracted with Et2O (2ꢃ30 mL). The
combined ethereal extract was washed with H2O (30
mL), dried (MgSO4) evaporated to dryness under
vacuum, and the crude product was purified by column
chromatography (silica gel; CH2Cl2). Ethereal HCl was
added to a solution of the free base of 29 in anhydrous
Et2O to form the HCl salt. Recrystallization from
absolute EtOH/anhydrous Et2O afforded 0.33 g(40%)
of the title compound as a pale yellow powder; mp
136–138 ꢂC. Anal. (C14H20FNO.HCl 0.75H2O) C, H, N.
.
.
drous Et2O. Anal. C23H26N2 HCl 0.25H2O C, H, N.
(E)5-Methyl-2-(5-phenyl-2-pentenyl)-1,2,3,4-tetrahydro-
pyrido[4,3-b]indole hydrochloride (E12). A solution of
5-(phenyl)-2-pentyn-1-ol (0.50 g, 3.1 mmol; see 13 for
preparation) in dry THF (2 mL) was added in a drop-
wise manner over 15 min to a stirred suspension of
LiAlH4 (0.16 g, 4 mmol) in THF (20 mL) at 0 ꢂC. The
suspension was warmed to 67 ꢂC and allowed to stir for
24 h. The reaction mixture was cooled to room tem-
perature and excess LiAlH4 was destroyed by careful
addition of 15% NaOH. The resultingsolution was
extracted with Et2O (2ꢃ30 mL). The organic phase was
washed with H2O (30 mL), dried (MgSO4) and solvent
was evaporated in vacuo. The crude product was pur-
ified by column chromatography (silica gel; CH2Cl2) to
give 0.45 g (92%) of the alkenol. The alkenol was con-
verted to the correspondingchloro compound in 75%
yield as described for Z12, and the crude product was
allowed to react with 32 to afford the desired product in
32% yield after conversion to its HCl salt; mp
Radioligand binding assay
The radioligand binding studies were performed as pre-
viously described.15 Tritiated (+)lysergic acid diethyla-
mide (LSD) (0.5 nM) was used to label murine 5-HT5A
receptors (cell line generously donated by Dr. R. Hen)
and 1 mM LSD was used to determine nonspecific bind-
ing. Typically, 11 concentrations of test agent (10ꢀ10
–
10ꢀ5 M) were evaluated, except where the compound
displayed <30% inhibition at 10,000 nM in which case it
was not further examined. Data were analyzed using
GraphPad and represent the means and SEM of three
independent determinations run in triplicate.
225–227 ꢂC followingrecrystallization from MeOH/
.
.
anhydrous Et2O. Anal. C23H26N2HCl 0.25H2O C, H, N.
Acknowledgements
5-Methyl-2-(5-phenyl-2-pentynyl)-1,2,3,4-tetrahydropyr-
ido[4,3-b]indole hydrochloride (13). 4-Phenyl-1-butyne
(98%; 1.5 g, 11.5 mmol) was added slowly to a stirred
solution of Et2O (24 mL) and 2.5 M nBuLi in hexane
(4.6 mL, 12 mmol) at ꢀ10 ꢂC. A suspension of paraf-
ormaldehyde (0.8 g, excess) in THF (28 mL) was added
to the mixture, and the gelatinous mixture was allowed
to stir at 0 ꢂC for 45 min. The mixture was heated at
reflux for a further 90 min, allowed to cool to room
temperature, poured into ice/water (ca. 50 mL), and
extracted with Et2O (2ꢃ30 mL). The combined organic
extracts were dried (MgSO4) and the solvent was
removed in vacuo. The crude product was purified by
column chromatography (silica gel; CH2Cl2) to give
1.33 g(72%) of the pentynol as a yellow oil. Thionyl
chloride (0.5 mL) was added to the pentynol (0.32 g, 2
mmol) in benzene (10 mL), and the reaction mixture
was heated at 70–80 ꢂC for 24 h. The reaction mixture
was poured into ice/H2O (100 mL), and the aqueous
solution was extracted with CH2Cl2 (2ꢃ25 mL). The
combined organic fraction was washed well with H2O
(30 mL), and the CH2Cl2 was evaporated under reduced
pressure to give 0.35 g (99%) of the desired chloro
compound as an oil. The chloro compound was used to
alkylate 32 as described above and the product was
converted to its HCl salt to give a 24% yield of 13; mp
208–210 ꢂC after recrystalization from an EtOAc/abso-
N.K. was supported in part by a Royal Thai Govern-
ment scholarship.
References and Notes
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