Highly Selective h5-HT1D Receptor Agonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 24 4993
ide-potassium hydroxide under high vacuum to leave 12.7 g
(60%) of 4-(imidazol-1-yl)phenylhydrazine dihydrochloride: 1H
NMR (360 MHz, DMSO-d6) δ 7.20 (2H, d, J ) 9.0 Hz), 7.73
(2H, d, J ) 9.0 Hz), 7.91 (1H, t, J ) 1.5 Hz), 8.23 (1H, t, J )
1.7 Hz), 9.71 (1H, t, J ) 1.3 Hz).
4-(Imidazol-1-yl)phenylhydrazine dihydrochloride was re-
acted with 9, using a method similar to that described for 10a ,
to give 10b as a foamy brown solid in 34% yield: 1H NMR
(250 MHz, DMSO-d6) δ 1.36 (2H, m), 1.67-1.85 (4H, m), 2.30
(2H, t, J ) 6.8 Hz), 2.70 (4H, m), 4.54 (1H, d, J ) 4.2 Hz),
7.08 (1H, t, J ) 1.1 Hz), 7.23-7.28 (2H, m), 7.44 (1H, d, J )
8.6 Hz), 7.65 (1H, t, J ) 1.2 Hz), 7.68 (1H, d, J ) 2.1 Hz), 8.12
(1H, t, J ) 1.1 Hz), 10.99 (1H, s); MS (ES+) m/z 325 (M + H)+,
210, 163, 154.
heated at reflux for 2.5 h, cooled to room temperature, and
quenched by the successive addition of water (10 mL), 15%
aqueous NaOH (15 mL), and water (30 mL). The resulting
mixture was filtered to remove a granular precipitate, and the
filtrate was cooled to 0 °C before di-tert-butyl dicarbonate (41.3
g) was added. After 2 h at room temperature, the solvent was
evaporated and the residue was partitioned between 2 N
aqueous NaOH and dichloromethane. The organic phase was
washed with brine, dried (Na2SO4), and evaporated. Flash
chromatography of the residue (silica gel, CH2Cl2-MeOH-
NH3(aq); 89:10:1) gave 47.7 g (91%) of 12 as a colorless oil:
1H NMR (250 MHz, DMSO-d6) δ 1.38 (9H, s), 1.49 (2H, m),
1.64 (2H, m), 1.94 (2H, m), 2.66 (3H, s), 2.84 (2H, m), 3.44
(2H, s), 3.70 (1H, m), 7.20-7.35 (5H, m).
1-{3-[5-(1,2,4-Tr ia zol-1-yl)-1H-in d ol-3-yl]p r op yl}p ip er i-
d in -4-ol (10c). This was prepared from 4-(1,2,4-triazol-1-yl)-
phenylhydrazine (prepared in a similar way to 4-(imidazol-1-
yl)phenylhydrazine described above) and 9, using a method
similar to that described for 10a , to give 10c in 65% yield: 1H
NMR (250 MHz, DMSO-d6) δ 1.28-1.46 (2H, m), 1.64-2.04
(6H, m), 1.95 (2H, m), 2.30 (2H, t, J ) 6.8 Hz), 2.72 (4H, br t),
3.35-3.50 (1H, m), 4.53 (1H, d, J ) 4.2 Hz), 7.25 (1H, d, J )
2.2 Hz), 7.44-7.54 (2H, m), 7.92 (1H, d, J ) 1.7 Hz), 8.18 (1H,
s), 9.18 (1H, s), 11.06 (1H, s); MS (ES+) m/z 326 (M + H)+.
1-{3-[5-(1,2,4-Tr ia zol-4-yl)-1H-in d ol-3-yl]p r op yl}p ip er i-
d in -4-on e (11a ). To a stirred solution of 10a (105 mg, 0.322
mmol) in a mixture of anhydrous DMSO (3 mL) and anhydrous
triethylamine (314 µL, 2.25 mmol) was added portionwise,
under nitrogen, solid sulfur trioxide pyridine complex (185 mg,
1.16 mmol) over 7 min. The mixture was stirred at room
temperature for 55 min, then diluted with water (20 mL),
basified with saturated aqueous K2CO3 and extracted with
ethyl acetate (3 × 70 mL). The organic extracts were combined,
washed with brine (20 mL), dried (Na2SO4), and evaporated.
Flash chromatography of the residue (silica gel, CH2Cl2-
MeOH-NH3(aq); 90:10:1) afforded 72 mg (69%) of 11a as a
waxy solid: 1H NMR (250 MHz, CDCl3) δ 1.96 (2H, qn, J )
7.3 Hz), 2.42-2.62 (6H, m), 2.72-2.90 (6H, m), 7.13-7.19 (2H,
m), 7.50 (1H, d, J ) 8.5 Hz), 7.57 (1H, d, J ) 2.0 Hz), 8.42
(1H, br s), 8.48 (2H, s). MS (ES+) m/z 324 (M + H)+.
1-{3-[5-(Im id a zol-1-yl)-1H-in d ol-3-yl]p r op yl}p ip er id in -
4-on e (11b). This was prepared from 10b, using a method
similar to that described for 11a , in 61% yield as a cream
solid: 1H NMR (250 MHz, CDCl3) δ 1.96 (2H, qn, J ) 7.5 Hz),
2.46 (4H, t, J ) 6.1 Hz), 2.56 (2H, t, J ) 7.4 Hz), 2.76 (4H, t,
J ) 6.1 Hz), 2.84 (2H, t, J ) 7.5 Hz), 7.13 (1H, d, J ) 2.2 Hz),
7.18-7.23 (2H, m), 7.30 (1H, t, J ) 1.2 Hz), 7.44 (1H, d, J )
8.5 Hz), 7.58 (1H, d, J ) 2.1 Hz), 7.84 (1H, t, J ) 1.0 Hz), 8.41
(1H, br s); MS (ES+) m/z 323 (M + H)+.
1-{3-[5-(1,2,4-Tr ia zol-1-yl)-1H-in d ol-3-yl]p r op yl}p ip er i-
d in -4-on e (11c). This was prepared from 10c, following a
procedure similar to that described for 11a , in 74% yield as a
pale yellow solid: mp 158-161 °C (EtOAc); 1H NMR (360 MHz,
CDCl3) δ 1.96 (2H, qn, J ) 7.3 Hz), 2.46 (4H, t, J ) 6.1 Hz),
2.55 (2H, t, J ) 7.2 Hz), 2.75 (4H, t, J ) 6.1 Hz), 2.86 (2H, t,
J ) 7.5 Hz), 7.12 (1H, d, J ) 2.2 Hz), 7.40-7.48 (2H, m), 7.88
(1H, s), 8.12 (1H, s), 8.20 (1H, br s), 8.53 (1H, s); MS (ES+)
m/z 324 (M + H)+.
4-[N -(t er t -Bu t yloxyca r b on yl)m e t h yla m in o]p ip e r i-
d in e (13). A solution of 12 (42.7 g, 140 mmol) in methanol
(500 mL) was shaken under hydrogen over palladium hydrox-
ide on carbon (5 g) at 50 psi for 4 h. More catalyst (5 g) was
added, and the mixture was shaken under hydrogen at 40 psi
overnight. The catalyst was filtered off, and the filtrate was
evaporated to give 27.38 g (91%) of 13 as a colorless solid: 1H
NMR (250 MHz, DMSO-d6) δ 1.39 (9H, s), 1.47-1.60 (4H, m),
2.50 (2H, m), 2.65 (3H, s), 3.00 (2H, m), 3.82 (1H, m).
4-Met h yla m in o-1-{3-[5-(1,2,4-t r ia zol-4-yl)-1H -in d ol-3-
yl]p r op yl}p ip er id in e (14). This was prepared from 13, using
a method similar to that described for 9 and 10a , to afford 14
as a brown solid in 47% yield over two steps: 1H NMR (360
MHz, DMSO-d6) δ 1.16-1.24 (3H, m), 1.73-1.90 (6H, m), 2.25
(6H, m), 2.70 (2H, t), 2.78 (2H, m), 7.28 (2H, m), 7.46 (1H, d),
7.77 (1H, d), 9.01 (2H, s), 11.08 (1H, s); MS (ES+) m/z 677 (2M
+ H)+, 339 (M + H)+, 201, 170, 114.
3-[5-(1,2,4-Tr ia zol-4-yl)-1H-in d ol-3-yl]p r op a n -1-ol (15a )
and 3-(3-h ydr oxypr opyl)-1H-in dol-5-yl-N-m eth ylm eth an e-
su lfon a m id e (15b) were synthesized by literature proce-
dures.27,28
(S)-4-[3-(3-Hyd r oxyp r oyl)-1H-in d ol-5-ylm eth yl]-1,3-ox-
a zolid in -2-on e (15c). A mixture of (S)-4-(3-iodo-4-aminoben-
zyl)-1,3-oxazolidin-2-one26 (800 mg, 2.51 mmol), 1,5-bis-
(triethylsilyl)pent-4-yn-1-ol (1.169 g, 3.77 mmol), lithium
chloride (107 mg, 2.51 mmol), sodium carbonate (1.33 g, 12.6
mmol), and triphenylphosphine (0.1573 g, 0.60 mmol) in
anhydrous DMF (30 mL) was degassed by bubbling through
nitrogen for 30 min. Palladium acetate (67.3 mg, 0.30 mmol)
was then added, and the mixture was heated at 100 °C, under
nitrogen, for 16.5 h. The solvent was evaporated, and the
residue was partitioned between water (75 mL) and ethyl
acetate (125 mL). The aqueous layer was further extracted
with ethyl acetate (2 × 125 mL), and the combined organic
extracts were washed with brine (50 mL), dried (MgSO4), and
evaporated. The residue was dissolved in 5 N aqueous HCl
(25 mL) and ethanol (25 mL) and allowed to stand at room
temperature for 30 min. The mixture was basified to pH 10
with saturated aqueous K2CO3, diluted with water (25 mL),
and extracted with ethyl acetate (2 × 125 mL). The combined
organic extracts were washed with brine (30 mL), dried
(MgSO4), and evaporated. The residue was purified by flash
chromatography (silica gel, CH2Cl2-MeOH-NH3(aq); 95:5:0.5)
to afford 0.420 g (61%) of 15c as a thick brown oil: 1H NMR
(360 MHz, DMSO-d6) δ 1.78 (2H, q, J ) 7.9 Hz), 2.69 (2H, t,
J ) 7.4 Hz), 2.77 (1H, dd, J ) 13.5 and 7.1 Hz), 2.89 (1H, dd,
J ) 13.5 and 4.6 Hz), 3.46 (2H, q, J ) 5.3 Hz), 3.98-4.08 (2H,
m), 4.18-4.28 (1H, m), 4.42 (1H, t, J ) 5.1 Hz), 6.92 (1H, dd,
J ) 8.3 and 1.5 Hz), 7.06 (1H, d, J ) 2.1 Hz), 7.24 (1H, d, J )
8.3 Hz), 7.35 (1H, s), 7.77 (1H, s), 10.66 (1H, s); MS (ES+) m/z
275 (M + H)+.
1-Ben zyl-4-[N-(ter t-b u t yloxyca r b on yl)m et h yla m in o]-
p ip er id in e (12). To a stirred solution of 4-amino-1-benzylpi-
peridine (40 g, 0.21 mol) in anhydrous dichloromethane (500
mL) was added di-tert-butyl dicarbonate (50.4 g, 0.23 mmol),
and the mixture was stirred at room temperature for 18 h.
The solvent was removed, and the residue was triturated with
diethyl ether. The solid was collected by filtration to give 60.29
g (99%) of 1-benzyl-4-[N-(tert-butyloxycarbonyl)amino]piperi-
1
dine as a white solid: mp 135-138 °C; H NMR (360 MHz,
3-[5-(1,2,4-Tr ia zol-1-ylm eth yl)-1H-in d ol-3-yl]p r op a n -1-
ol (15d ). This was prepared from 2-iodo-4-(1,2,4-triazol-1-
ylmethyl)aniline,29 using a procedure similar to that described
for 15c, in 56% yield as a beige solid: 1H NMR (360 MHz,
DMSO-d6) δ 1.74-1.82 (2H, m), 2.66-2.70 (2H, m), 3.43-3.49
(2H, m), 4.41-4.44 (1H, m), 5.42 (2H, s), 7.01-7.04 (1H, m),
7.11-7.12 (1H, m), 7.28-7.30 (1H, m), 7.51 (1H, s), 7.93 (1H,
s), 8.60 (1H, s), 10.79 (1H, s).
CDCl3) δ 1.44 (9H, s), 1.53 (2H, m), 1.92 (2H, s), 2.12 (2H, m),
2.83 (2H, m), 3.51 (2H, s), 4.42 (1H, s), 7.22-7.32 (5H, m).
To a cooled (-5 °C) and stirred solution of lithium aluminum
hydride (1 M solution in THF; 258 mL) in anhydrous THF (250
mL) under nitrogen was added a solution of 1-benzyl-4-[N-
(tert-butyloxycarbonyl)amino]piperidine (50 g, 172 mmol) in
anhydrous THF (750 mL) over 20 min. The mixture was then