Journal of Medicinal Chemistry
Article
Step k: (6bR,10aS)-8-[3-(4-Fluorophenoxy)propyl]-3-methyl-
2,3,6b,7,8,9,10,10a-octahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]-
quinoxaline (41). cis-23 (100 mg, 0.26 mmol) was dissolved in
ethanol and resolved by HPLC using a Chiral AD-H column (2.0 cm
× 25 cm) eluting with ethanol containing 0.1% diethylamine. The
corresponding peak was collected, concentrated, and dried under
vacuum to give the title compound (35 mg, 35% yield) as a pale-yellow
oil. 1H NMR (CDCl3, 400 MHz) δ 7.00−6.90 (m, 2H), 6.87−6.78 (m,
2H), 6.65 (t, J = 7.6 Hz, 1H), 6.51 (d, J = 7.3 Hz, 1H), 6.41 (dd, J =
8.0, 1.0 Hz, 1H), 3.97 (t, J = 6.4 Hz, 2H), 3.66−3.54 (m, 1H),
3.37−3.09 (m, 4H), 2.87 (s, 3H), 2.94−2.77 (m, 2H), 2.75−2.60 (m,
1H), 2.58−2.39 (m, 2H), 2.36−2.19 (m, 1H), 2.06−1.83 (m, 5H). 13C
NMR (DMSO-d6, 126 MHz) δ 156.4 (d, JCF = 236 Hz), 155.0, 137.7,
134.8, 129.6, 119.7, 115.7 (d, JCF = 23 Hz), 115.6 (d, JCF = 8 Hz),
112.3, 108.6, 66.4, 64.1, 56.1, 54.5, 50.0, 48.8, 43.8, 41.1, 37.1, 26.4,
24.5. MS (ESI) m/z 382.2 [M + H]+. HRMS (ESI) m/z calcd for
C23H29FN3O [M + H]+, 382.2295; found, 382.2294. UPLC purity,
98.4%; retention time, 2.08 min (method A).
The combined organic phase was dried over Na2SO4, concentrated
under vacuum, and further purified by flash column chromatography
using 25% ethyl acetate in hexanes to give 2,3,4,5-tetrahydro-1H-l-
1
benzazepinamine 26c (1.63 g, 68% yield) as a light-yellow solid. H
NMR (CDCl3, 300 MHz) δ 7.28 (dd, J = 1.4, 8.0 Hz, 1H), 7.21 (td, J
= 8.0, 1.4 Hz, 1H), 7.10 (dd, J = 1.1, 7.4 Hz, 1H), 6.91 (td, J = 7.3, 1.5
Hz, 1H), 3.78 (br, 2H), 3.22−3.18 (m, 2H), 2.82−2.70 (m, 2H),
1.92−1.78 (m, 2H), 1.72−1.50 (m, 2H).
A mixture of 4-piperidone hydrochloride monohydrate (1.54 g, 10
mmol) and 26c (1.62 g, 10 mmol) in 2-propanol (50 mL) was refluxed
for 2 h and then cooled to room temperature. Concentrated HCl (0.82
mL, 10 mmol) was added, and the resulting mixture was refluxed for 3
h before being cooled to room temperature. The solid was filtered,
rinsed with cold 2-propanol (2 × 20 mL), and dried under vacuum to
give the title compound (1.88 g, 71% yield) as a hydrochloride salt. A
small amount (20 mg) of the hydrochloride salt was converted into
free base form by basifying with 1N NaOH, followed by extraction
with CHCl3, washing with brine, and drying under vacuum to give the
title compound as a white foamy solid. 1H NMR (CDCl3, 300 MHz) δ
7.25 (dd, J = 1.0, 7.4 Hz, 1H), 6.98 (t, J = 7.4 Hz, 1H), 6.92 (d, J = 6.3
Hz, 1H), 4.05 (t, J = 1.6 Hz, 2H), 4.02−3.92 (m, 2H), 3.25 (t, J = 5.6
Hz, 2H), 3.20−3.05 (m, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.20−2.00 (m,
4H), 1.83 (m, 1H). MS (ESI) m/z 227.2 [M + H]+.
Step b and c: (cis)-4,5,6,7,9,10,12,12a-Octahydro-pyrido-
[3′,4′:4,5]pyrrolo[3,2,1-jk][1]benzazepine-11(8aH)-carboxylic Acid,
1,1-Dimethylethyl Ester (cis-28c). Sodium cyanoborohydride (0.94
g, 15 mmol) was added in small portions to a solution of 27c
hydrochloride salt (1.32 g, 5.0 mmol) in TFA (15 mL) at 0 °C. After
stirring at room temperature for 2 h, the mixture was carefully treated
with 6 N HCl (10 mL) and refluxed for 1 h. The mixture was basified
with 50% NaOH and extracted with CH2Cl2 (3 × 20 mL). The
combined organic phase was dried over MgSO4 and concentrated
under vacuum to give (cis)-4,5,6,7,8a,9,10,11,12,12a-decahydro-pyrido-
[3′,4′:4,5]pyrrolo[3,2,1-jk][1]benzazepine (1.0 g, 88% yield) as a
yellow oil. MS (ESI) m/z 229.2 [M + H]+.
Representative Synthetic Procedures of Tetracyclic Deriva-
tives Shown in Table 3 via Scheme 3. 4-((8aS,12aR)-
4,5,6,7,9,10,12,12a-Octahydroazepino[3,2,1-hi]pyrido[4,3-b]-
indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone (62, X = CH2,
R4 = R5 = H, m = 2, n = 1, a = R, b = S). Step a: 4,5,6,7,9,10,11,12-
Octahydroazepino[3,2,1-hi]pyrido[4,3-b]indole (27c). Sodium azide
(1.95 g, 30 mmol) was added in small portions to a solution of 3,4-
dihydro-(2H)-naphthalenone (2.92 g, 20 mmol) in CH3SO3H (50
mL) at 0 °C. The mixture was stirred at 0 °C for 15 min, then 1 h at
room temperature and then poured into ice (400 mL). The mixture
was basified until pH >8 with 1 N NaOH at 0 °C and extracted with
ether (3 × 100 mL). The combined organic phase was dried over
MgSO4, concentrated under vacuum, and then purified by silica gel
flash column chromatography eluting with 50% ethyl acetate in
hexanes to give 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g,
1
84% yield) as a white solid. H NMR (CDCl3, 300 MHz) δ 8.10 (br,
1H), 7.22 (d, J = 7.0 Hz, 2H), 7.13 (td, J = 7.6, 1.5 Hz, 1H),), 6.99 (d,
J = 8.1 Hz, 1H), 2.80 (t, J = 7.6 Hz, 2H), 2.36 (t, J = 7.1 Hz, 2H),
2.32−2.18 (m, 2H).
First, 1N NaOH (10 mL) was added to a solution of (cis)-
4,5,6,7,8a,9,10,11,12,12a-decahydropyrido[3′,4′:4,5]pyrrolo[3,2,1-jk]-
[1]benzazepine (1.0 g, 4.38 mmol) and di-tert-butyl dicarbonate (1.05
g, 4.8 mmol) in 1,4-dioxane (20 mL), and the mixture was then stirred
for 2 h at room temperature. After the solvent was removed under
reduced pressure, the residue was treated with ethyl acetate (30 mL).
The solution was washed with brine (30 mL), dried over MgSO4,
concentrated under vacuum, and then purified by flash column
chromatography using 20% ethyl acetate in hexanes to give the title
A solution of 1,3,4,5-tetrahydro-2H-1-benzazepin-2-one (2.71 g,
16.8 mmol) in THF (40 mL) was added dropwise to a suspension of
lithium aluminum hydride (1.27 g, 33.4 mmol) in ether (150 mL) at
room temperature. The mixture was refluxed for 16 h. Saturated
potassium sodium tartrate salt solution (15 mL) was added to the
mixture which was cooled with an ice−water bath. The mixture was
stirred for 2 h and the two layers were separated. The aqueous layer
was extracted with ether (2 × 25 mL). The combined organic phase
was dried over anhydrous Na2SO4, concentrated in vacuum, and
purified by flash column chromatography eluting with 30% ethyl
acetate in hexanes to give 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g,
97% yield) as a yellow liquid. 1H NMR (CDCl3, 300 MHz) δ 7.11 (d, J
= 7.4 Hz, 1H). 7.04 (td, J = 7.5, 1.5 Hz, 1H), 6.82 (td, J = 7.3, 1.1 Hz,
1H), 6.74 (dd, J = 7.7, 1.1 Hz, 1H), 3.78 (br, 1H), 3.10−3.00 (m, 2H),
2.82− 2.72 (m, 2H), 1.86−1.72 (m, 2H), 1.70−1.58 (m, 2H).
A solution of NaNO2 (1.35 g, 19.6 mmol) in water (4.0 mL) was
added dropwise to a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine
(2.40 g, 16.3 mmol) in acetic acid (10 mL) at 0−10 °C. The mixture
was stirred at 5 °C for 10 min, then at room temperature for 1 h, and
then extracted with CH2Cl2 (3 × 20 mL). The combined organic
phase was dried over MgSO4, concentrated under vacuum, and then
purified by silica gel flash column chromatography to give 1-nitroso-
2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91% yield) as a brown
liquid. 1H NMR (CDCl3, 300 MHz) δ 7.48−7.40 (m, 1H), 7.40−7.32
(m, 2H), 7.32−7.25 (m, 1H), 3.92 (br, 2H), 2.82−2.70 (m, 2H),
1.85−1.70 (m, 4H).
1
compound (1.2 g, 83% yield) as a white solid. H NMR (CDCl3, 500
MHz) δ 6.95 (d, J = 7.2 Hz, 1H), 6.90 (d, J = 7.5 Hz, 1H), 6.68 (t, J =
7.4 Hz, 1H), 3.65−3.55 (m, 1H), 3.48−3.29 (m, 3H), 3.29−3.20 (m,
1H), 3.12−2.71 (m, 2H), 2.71−2.50 (m, 2H), 2.08−1.83 (m, 4H),
1.83−1.62 (m, 1H), 1.62−1.07 (m, 11H). MS (ESI) m/z 329.2 [M +
H]+.
Steps d and e: (8aS,12aR)-4,5,6,7,8a,9,10,11,12,12a-Decahydro-
pyrido[3′,4′:4,5]pyrrolo[3,2,1-jk][1]benzazepine (29c). (8aS,12aR)-
4,5,6,7,9,10,12,12a-Octahydro-pyrido[3′,4′:4,5]pyrrolo[3,2,1-jk][1]-
benzazepine-11(8aH)-carboxylic acid, 1,1-dimethylethyl ester (0.24 g,
0.73 mmol), which was obtained by chiral separation of cis-28c on a
Chiracel OD column eluting with 2% 2-propanol in hexane, was stirred
in 20% TFA in CH2Cl2 (10 mL) at room temperature for 2 h before
the solution was basified with saturated ammonium hydroxide until
pH > 10. The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 20 mL). The combined organic phase was
washed with brine (20 mL), dried over MgSO4, concentrated, and
dried under vacuum to give the title compound (0.16 g, 94% yield) as
1
a white foamy solid. H NMR (CDCl3, 500 MHz) δ 6.96−6.87 (m,
A solution of 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60
g, 14.7 mmol) in THF (40 mL) was added dropwise under nitrogen
atmosphere to a suspension of lithium aluminum hydride (0.56 g, 14.7
mmol) in THF (10 mL) cooled with an ice-bath such that the
temperature did not rise above 15 °C. The mixture was stirred at room
temperature for an hour, quenched with saturated potassium sodium
tartrate salt solution (15 mL), and extracted with ether (3 × 20 mL).
2H), 6.69 (t, J = 7.4 Hz, 1H), 4.57−3.58 (br, 1H) 3.35−3.19 (m, 3H),
3.10 (dd, J = 12.7, 6.3 Hz, 1H), 3.03−2.78 (m, 3H), 2.71−2.59 (m,
1H), 2.58−2.44 (m, 2H), 2.10−1.67 (m, 5H), 1.65−1.40 (m, 1H). MS
(ESI) m/z 229.2 [M + H]+.
4-((8aS,12aR)-4,5,6,7,9,10,12,12a-Octahydroazepino[3,2,1-hi]-
pyrido[4,3-b]indol-11(8aH)-yl)-1-(4-fluorophenyl)-1-butanone (62).
To a solution of 29c (0.23 g, 1.0 mmol) in 1,4-dioxane (7.0 mL) were
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dx.doi.org/10.1021/jm401958n | J. Med. Chem. 2014, 57, 2670−2682