DiscoVery of Lorcaserin
Journal of Medicinal Chemistry, 2008, Vol. 51, No. 2 311
raphy (tR ) 13.7 min, 5% isopropanol in hexane with 0.2%
diethylamine at a flow rate of 10 mL/min on a 20 mm × 250 mm
Chiracel OD chiral column) and then deprotected under standard
conditions. 1H NMR (400 MHz, DMSO-d6) δ 7.2 (m, 3 H), 3.3–3.0
(m, 7 H), 1.9–1.6 (m, 2 H), 0.91 (t, J ) 7 Hz, 3 H). MS calculated
for C12H16ClN + H, 210; observed, 210.
(1S)-8-Chloro-2,3,4,5-tetrahydro-1-ethyl-1H-3-benzazepine
(7ff). (1R,S)-N-Trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-ethyl-
1H-3-benzazepine (6y and 6z) was separated by chiral chromatog-
raphy (tR ) 20.2 min, 5% isopropanol in hexane with 0.2%
diethylamine at a flow rate of 10 mL/min on a 20 mm × 250 mm
Chiracel OD chiral column) and then deprotected under standard
conditions. 1H NMR (400 MHz, DMSO-d6) δ 7.2 (m, 3 H), 3.3–3.0
(m, 7 H), 1.9–1.6 (m, 2 H), 0.91 (t, J ) 7 Hz, 3 H). MS calculated
for C12H16ClN + H, 210; observed, 210.
7-methoxy-2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine via method
C as a white solid. H NMR (400 MHz, CDCl3) δ 7.05 (s, 1 H),
6.59 (s, 1 H), 3.80 (s, 3 H), 3.0–2.8 (m, 6 H), 2.62 (m, 1 H), 2.16
(bs, 1 H), 1.24 (d, J ) 7 Hz, 3 H). MS calculated for C12H16ClNO
+ H, 226; observed, 226.
1
(1R)-8-Chloro-7-methoxy-2,3,4,5-tetrahydro-1-methyl-1H-3-
benzazepine (7v). (1R,S)-8-Chloro-7-methoxy-2,3,4,5-tetrahydro-
1-methyl-1H-3-benzazepine (7t) was separated by chiral chroma-
tography (tR ) 42 min, 5% isopropanol in hexane with 0.2%
diethylamine at a flow rate of 9 mL/min on a 20 mm × 250 mm
1
Chiracel OD chiral column). H NMR (400 MHz, CDCl3) δ 7.05
(s, 1 H), 6.59 (s, 1 H), 3.80 (s, 3 H), 3.0–2.8 (m, 6 H), 2.62 (m, 1
H), 2.16 (bs, 1 H), 1.24 (d, J ) 7 Hz, 3 H). MS calculated for
C12H16ClNO + H, 226; observed, 226.
(1S)-8-Chloro-7-methoxy-2,3,4,5-tetrahydro-1-methyl-1H-3-
benzazepine (7u). (1R,S)-8-Chloro-7-methoxy-2,3,4,5-tetrahydro-
1-methyl-1H-3-benzazepine (7t) was separated by chiral chroma-
tography (tR ) 47 min, 5% isopropanol in hexane with 0.2%
diethylamine at a flow rate of 9 mL/min on a 20 mm × 250 mm
Method B. Preparation of (1R,S)-7,8-Dichloro-2,3,4,5-tet-
rahydro-1-methyl-1H-3-benzazepine (7p). (1R,S)-N-Trifluoro-
acetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1 H-3-benzazepine (0.900
g, 2.67 mmol) was dissolved in acetonitrile (30 mL), treated with
N-chlorosuccinimide (0.357 g, 2.67 mmol), and stirred overnight
at 70 °C. The product mixture was diluted with water (100 mL)
and extracted twice with EtOAc (100 mL), and the combined
organic phases were washed with brine (100 mL), dried with
Na2SO4, and concentrated. Flash chromatography (20% EtOAc in
hexane, silica) resulted in 0.399 g of a clear oil. The trifluoroacetyl-
protected intermediate was dissolved in methanol (20 mL), treated
with 15% aqueous NaOH (20 mL), and stirred overnight at 20 °C.
The product mixture was diluted with water (100 mL) and extracted
twice with EtOAc (100 mL), and the combined organic phases were
washed with brine (100 mL), dried with Na2SO4, and concentrated
1
Chiracel OD chiral column). H NMR (400 MHz, CDCl3) δ 7.05
(s, 1 H), 6.59 (s, 1 H), 3.80 (s, 3 H), 3.0–2.8 (m, 6 H), 2.62 (m, 1
H), 2.16 (bs, 1 H), 1.24 (d, J ) 7 Hz, 3 H). MS calculated for
C12H16ClNO + H, 226; observed, 226.
Method C. Preparation of (1R,S)-8-Chloro-7-fluoro-2,3,4,5-
tetrahydro-1-methyl-1H-3-benzazepine (7w). A solution of (1R,S)-
N-trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-ben-
zazepine (2.5 g, 8.5 mmol) in 1,2-dichloroethane (15 mL) was
treated with Selectfluor (3.9 g, 11 mmol) and trifluoromethane-
sulfonic acid (8 mL, 90 mmol) and stirred 60 h at 75 °C. The
product mixture was poured into water (200 mL) and extracted
with EtOAc (200 mL), and the organic phase was washed with
saturated aqueous NaHCO3 (2 × 100 mL) and brine (100 mL),
dried with Na2SO4, and concentrated. The crude product was
purified by flash chromatography (6% EtOAc in hexane, silica),
resulting in 1.6 g of a white solid. MS calculated for C13H12ClF4NO
+ H, 310; observed, 310. A solution of the trifluoroacetyl-protected
intermediate (160 mg, 0.22 mmol) was dissolved in methanol (3
mL), treated with 15% aqueous NaOH (2 mL), and stirred for 3.5 h
at 25 °C. The product mixture was concentrated, extracted three
times with CH2Cl2 (5 mL), dried with Na2SO4, and concentrated
1
to give 0.306 g of a yellow solid. H NMR (400 MHz, CDCl3) δ
7.20 (s, 1 H), 7.16 (s, 1 H), 3.05–2.86 (m, 6 H), 2.71 (dd, J ) 7,
13 Hz, 1 H), 1.83 (bs, 1 H), 1.33 (d, J ) 7 Hz, 3 H). MS calculated
for C11H13Cl2N + H, 230; observed, 230.
(1R)-7,8-Dichloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine (7q). 7q was obtained from (1R)-N-trifluoroacetyl-8-chloro-
2,3,4,5-tetrahydro-1-methyl-1 H-3-benzazepine via method B as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 1 H), 7.16 (s,
1 H), 3.05–2.86 (m, 6 H), 2.71 (dd, J ) 7, 13 Hz, 1 H), 1.83 (bs,
1 H), 1.33 (d, J ) 7 Hz, 3 H). MS calculated for C11H13Cl2N + H,
230; observed, 230.
1
to give 93 mg of a clear oil. H NMR (400 MHz, CDCl3) δ 7.11
(1S)-7,8-Dichloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine (7r). 7r was obtained from (1S)-N-trifluoroacetyl-8-chloro-
2,3,4,5-tetrahydro-1-methyl-1H-3-benzazepine via method B as a
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.20 (s, 1 H), 7.16 (s,
1 H), 3.05–2.86 (m, 6 H), 2.71 (dd, J ) 7, 13 Hz, 1 H), 1.83 (bs,
1 H), 1.33 (d, J ) 7 Hz, 3 H). MS calculated for C11H13Cl2N + H,
230; observed, 230.
(m, 1 H), 6.85 (m, 1 H), 3.05–2.95 (m, 3 H), 2.95–2.80 (m, 3H),
2.68 (m, 1 H), 2.38 (bm, 1 H), 1.31 (m, 3 H). MS calculated for
C11H13ClFN + H, 214; observed, 214.
(1R,S)-8-Chloro-9-fluoro-2,3,4,5-tetrahydro-1-methyl-1H-3-
benzazepine (7aa). The minor regioisomer was obtained from
(1R,S)-N-trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-
3-benzazepine via method C as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.06 (dd, J ) 8, 8 Hz, 1 H), 6.75 (d, J ) 8 Hz, 1 H),
3.58 (m, 1 H), 3.25–3.15 (m, 3 H), 2.93 (d, J ) 13 Hz, 1 H),
2.75–2.60 (m, 3H), 1.96 (bs, 1 H), 1.33 (d, J ) 8 Hz, 3 H). MS
calculated for C11H13ClFN + H, 214; observed, 214.
(1S)-8-Chloro-9-fluoro-2,3,4,5-tetrahydro-1-methyl-1H-3-ben-
zazepine (7bb). The minor regioisomer was obtained from (1S)-
N-trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-ben-
zazepine via method C as a colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.06 (dd, J ) 8, 8 Hz, 1 H), 6.75 (d, J ) 8 Hz, 1 H),
3.58 (m, 1 H), 3.25–3.15 (m, 3 H), 2.93 (d, J ) 13 Hz, 1 H)
2.75–2.60 (m, 3H), 1.96 (bs, 1 H), 1.33 (d, J ) 8 Hz, 3 H). MS
calculated for C11H13ClFN + H, 214; observed, 214.
Method D. Preparation of (1R,S)-6,8-Dichloro-2,3,4,5-tet-
rahydro-1-methyl-1H-3-benzazepine (7cc) from 2,4-Dichlo-
rophenethylamine via the Friedel–Crafts Route. (2R,S)-2-
Chloro-N-(2,4-dichlorophenethyl)propanamide (8cc). A solution
of 2-(2,3-dichlorophenethylamine (2.0 g, 10.5 mmol) in dichlo-
romethane (50 mL) was treated with diisopropylethylamine (1.63
g, 12.6 mmol) and 2-chloropropionyl chloride (1.12 mL, 11.6 mmol)
sequentially, and the mixture was stirred at 20 °C for 1 h. The
mixture was diluted with dichloromethane (50 mL), washed with
10% aqueous HCl and brine (20 mL), dried with MgSO4, and
concentrated. Flash chromatography (30% ethyl acetate in hexanes)
(1R,S)-8,9-Dichloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine (7x). The minor regioisomer was obtained from (1R,S)-N-
trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine via method B as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J ) 8 Hz, 1 H), 7.16 (d, J ) 8 Hz, 1 H), 4.17 (m, 1 H),
3.55 (m, 2 H), 3.5–3.3 (m, 2 H), 3.2–3.0 (m, 2 H), 1.43 (d, J ) 7
Hz, 3 H). MS calculated for C11H13Cl2N + H, 230; observed, 230.
(1R)-8,9-Dichloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine (7y). The minor regioisomer was obtained from (1R)-N-
trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine via method B as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J ) 8 Hz, 1 H), 7.16 (d, J ) 8 Hz, 1 H), 4.17 (m, 1 H),
3.55 (m, 2 H), 3.5–3.3 (m, 2 H), 3.2–3.0 (m, 2 H), 1.43 (d, J ) 7
Hz, 3 H). MS calculated for C11H13Cl2N + H, 230; observed, 230.
(1S)-8,9-Dichloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine (7z). The minor regioisomer was obtained from (1S)-N-
trifluoroacetyl-8-chloro-2,3,4,5-tetrahydro-1-methyl-1H-3-benza-
zepine via method B as a colorless oil. 1H NMR (400 MHz, CDCl3)
δ 7.40 (d, J ) 8 Hz, 1 H), 7.16 (d, J ) 8 Hz, 1 H), 4.17 (m, 1 H),
3.55 (m, 2 H), 3.5–3.3 (m, 2 H), 3.2–3.0 (m, 2 H), 1.43 (d, J ) 7
Hz, 3 H). MS calculated for C11H13Cl2N + H, 230; observed, 230.
(1R,S)-8-Chloro-7-methoxy-2,3,4,5-tetrahydro-1-methyl-1H-
3-benzazepine (7t). 7t was obtained from (1R,S)-N-trifluoroacetyl-