4458 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 25
Zou et al.
7.31-7.21(m, 4H), 7.06-6.90 (m, 6H), 6.62 (d, J ) 8.1 Hz, 2H),
5.34 (s, 1H), 3.65-3.43 (m, 3H), 3.17 (m, 2H), 2.47 (t, J ) 7.5
Hz, 2H), 2.35 (t, J ) 7.5 Hz, 2H), 2.20-1.74 (m, 8H), 1.63-
1.52 (m, 4H).
4-(p-Nitr op h en yl)bu ta n ol (15). To a solution of 4-(p-
nitrophenyl)butyric acid 14 (3.14 g, 15 mmol) in dry THF (40
mL), 10 mL of BH3‚SMe2 (2.0 M in THF, 20 mmol) was added
dropwise at room temperature under argon. The solution was
stirred for 1 h after the addition was complete, and MeOH
(20 mL) was then carefully added to destroy the excess of BH3‚
SMe2. All solvents were removed in vacuo. The residue was
diluted with H2O (20 mL) and extracted with CHCl3 (3 × 20
mL). The combined organic layer was dried (MgSO4), After
removal of the solvent, the crude product was purified by flash
chromatography [hexanes/ethyl acetate (5:1)] to give 2.87 g
N -[3-(3-Iod o-4-a m in op h e n yl)p r op yl]-3r-[b is(4′-flu o-
r op h en yl)m eth oxy]tr op a n e (8a ). ICl (285 mg, 1.75 mmol)
in 5 mL of glacial acetic acid was added very slowly to a
solution of amine 7a (737 mg, 1.59 mmol) in 35 mL of glacial
acetic acid at room temperature over a period of 3 h. Acetic
acid was then removed in vacuo. The residue was diluted with
H2O (50 mL), basified to pH 9 with NH4OH, and extracted
with CHCl3 (3 × 25 mL). The combined organic layer was dried
over anhydrous MgSO4 and concentrated. The residue was
purified by flash column chromatography (10% CMA) to
1
(98%) of pure product 15 as a colorless oil. H NMR (CDCl3):
δ 8.15 (d, J ) 8.7 Hz, 2H), 7.33 (d, J ) 8.7 Hz, 2H), 3.68 (t, J
) 6.3 Hz, 2H), 2.76 (t, J ) 7.4 Hz, 2H), 1.82-1.20 (m, 5H). IR:
3500-3100 (br), 1599 cm-1
.
1
produce 697 mg (74.5%) of 8a as an oil. H NMR (CDCl3): δ
7.47 (s, 1H), 7.35-7.25 (m, 4H), 7.03-6.95 (m, 5H), 5.36 (s,
1H), 3.94 (br, s, 2H), 3.56 (t, J ) 4.8 Hz, 1H), 3.18 (br s, 2H),
2.44 (t, J ) 7.5 Hz, 2H), 2.36 (t, J ) 7.5 Hz, 2H), 2.15-1.73
1-Br om o-4-(4-n itr op h en yl)bu ta n e (16). 4-(4-Nitrophen-
yl)butanol (15) (2.87 g, 14.7 mmol) was dissolved in acetonitrile
(50 mL). Triphenylphosphine (5.78 g, 22.1 mmol) was added,
followed by addition of carbon tetrabromide (7.31 g, 22.1
mmol). The reaction mixture was stirred at room temperature
for 1 h, then basified with 15% NaOH to pH 9. The mixture
was then poured into a separatory funnel, and the aqueous
layer was extracted with ether (3 × 50 mL). The combined
organic layer was dried (MgSO4) and concentrated. The residue
was purified by flash column chromatography [hexanes/ethyl
acetate (10/1)] to give 3.57 g (94%) of compound 16 as an oil.
1H NMR (CDCl3): δ 8.15 (d, J ) 8.7 Hz, 2H), 7.33 (d, J ) 8.7
Hz, 2H), 3.43 (t, J ) 8.7 Hz, 2H), 3.68 (t, J ) 6.3 Hz, 2H), 2.76
(t, J ) 7.4 Hz, 2H), 2.00-1.76 (m, 4H). EIMS m/z: 257 (M+),
259 (M+).
(m, 10H). IR: 3373 (br), 1605 (m) cm-1
.
N-[3-(3-Iod o-4-a zid op h en yl)p r op yl]-3r-[b is(4′-flu or o-
p h en yl)m eth oxy]tr op a n e (9a ). To a solution of compound
8a (325 mg, 0.55 mmol) in a mixture of acetic acid (2 mL) and
H2O (6 mL) was added NaNO2 (53.4 mg, 0.77 mmol), and the
mixture was stirred at 0 °C for 30 min. NaN3 (54 mg, 0.83
mmol) was added, and the mixture was stirred for another 30
min at 0 °C. The mixture was diluted with water (30 mL),
basified with saturated NaHCO3 solution to pH 9, and
extracted with CHCl3. The combined organic layer was dried
over MgSO4 and concentrated. The residue was purified by
column chromatography (3% CMA) to yield 271 mg (80%) of
9a as an oil. The product was converted to its oxalate salt and
recrystallized from acetone to give the oxalate salt of 9a as a
(R)-(-)-An h yd r oecgon in e Meth yl Ester (19). (-)-Co-
caine HCl salt (20.0 g, 58.6 mmol) was dissolved in 6 N HCl
(130 mL), and the mixture was heated to reflux for 6 h.27 The
solution was then cooled to room temperature and extracted
with ether (2 × 100 mL). The aqueous phase was concentrated
and then lyophilized to dryness. POCl3 (80 mL) was added to
the residue, and the mixture was stirred at reflux for 4 h. The
excess POCl3 was removed under reduced pressure, and the
resulting dark oil was cooled to -40 °C and carefully treated
with anhydrous MeOH (100 mL). The mixture was then
warmed to room temperature and concentrated under reduced
pressure. The residue was dissolved in water (150 mL), and
the resulting solution was adjusted to pH 9 with NH4OH,
extracted with CHCl3, and dried over K2CO3. After removal
of the solvents, the residue was distilled under reduced
1
crystalline product, mp 105 °C (dec). H NMR: δ 7.62 (s, 1H),
7.18-7.30 (m, 5H), 6.94-7.04 (m, 5H), 5.36 (s, 1H), 3.56 (t, J
) 4.8 Hz, 1H), 3.20 (br s, 2H), 2.58 (t, J ) 7.5 Hz, 2H), 2.36 (t,
J ) 7.5 Hz, 2H), 1.73-2.15 (m, 10H). 13C NMR: δ 26.0, 29.7,
32.3, 35.6, 51.0, 58.2, 69.4, 79.3, 87.5, 115.0, 115.2, 118.1, 128.2,
129.5, 138.4, 139.1, 139.7, 140.6, 160.3, 163.5. IR: 2117(s),
1603(m), 1069 cm-1. Anal. (C29H29N4OF2I‚1/2C2H2O4‚C3H6O‚
H2O) C, H, N.
N-[3-(4-Isot h iocya n a t op h en yl)p r op yl]-3r-[b is(4′-flu o-
r op h en yl)m eth oxy]tr op a n e (10a ). Amine 8a (585 mg, 1.27
mmol) was dissolved in a mixture of CHCl3 (76 mL) and
aqueous NaHCO3 solution (479 mg in 32 mL of H2O), and the
mixture was vigorously stirred. Freshly distilled CSCl2 (0.126
mL, 1.65 mmol) was added dropwise at 0 °C. After the addition,
the reaction mixture was allowed to stir for 3 h. The two layers
were separated, and the aqueous layer was extracted with
CHCl3 (3 × 25 mL). The combined organic layer was dried over
MgSO4 and concentrated. The residue was purified by flash
column chromatography (2% CMA) to provide 515 mg (80%)
of product 10a as an oil, which was converted to its HCl salt
in HCl-saturated 2-PrOH and recrystallized from acetone to
give 10a ‚HCl, mp 205.5-207 °C. 1H NMR: δ 7.21-7.30 (m,
4H), 7.10-7.18 (m, 4H), 6.94-7.02 (m, 4H), 5.36 (s, 1H), 3.57
(t, J ) 4.8 Hz, 1H), 3.24 (br s, 2H), 2.64 (t, J ) 7.5 Hz, 2H),
2.40 (t, J ) 7.5 Hz, 2H), 1.80-2.17 (m, 10H). 13C NMR: δ 26.0,
29.6, 33.2, 35.6, 51.2, 58.5, 69.4, 79.6, 115.1, 115.4, 125.7, 128.4,
128.8, 129.5, 138.5, 141.6, 160.4, 163.6. IR: 2103.8 (s, br), 1603
(m), 1069 cm-1. EIMS m/z: 504 (M+). Anal. (C30H30N2OFS‚
HCl) C, H, N.
N-[4-(4-Isoth iocya n a top h en yl)bu tyl]-3r-[bis(4′flu or o-
p h en yl)m eth oxy]tr op a n e (10b). Compound 10b was pre-
pared as described above for 10a from amine 8b (541 mg, 1.14
mmol) to give 562 mg (95%) of product, which was converted
the HCl salt and recrystallized from acetone, mp 166-168 °C.
1H NMR: δ 7.22-7.30 (m, 4H), 7.10-7.15 (m, 4H), 6.93-7.01-
(m, 4H), 5.35 (s, 1H), 3.52 (t, J ) 4.6 Hz, 1H), 3.13 (br s, 2H),
2.60 (t, J ) 7.5 Hz), 2.31 (t, J ) 7.5 Hz, 2H), 2.03 (m, 2H),
1.78-1.91 (m, 6H), 1.43-1.63 (m, 4H). 13C NMR: δ 26.2, 28.5,
29.2, 35.5, 35.9, 52.0, 58.1, 69.8, 79.3, 115.1, 115.4, 125.6, 128.3,
128.6, 129.5, 138.7, 142.2, 160.4, 163.6. IR: 2099.4 (s, br),
1602.6 (m), 1069 cm-1. EIMS: m/z 518(M+). Anal. (C30H32N2-
OF2S‚HCl‚1/2C3H6O) C, H, N.
1
pressure to afford 7.80 g (73.5%) of 19 as a clear oil. H NMR
(CDCl3): δ 6.87 (m, 1H, H-3), 3.77 (m, 1H, H-1), 3.75 (s, 3H,
CO2CH3), 3.23 (m, 1H, H-5), 2.62 (m, 1H, H-4ax), 2.34 (s, 3H,
NCH3), 2.13 (m, 1H, H-4eq), 1.86 (m, 4H, H-6 and H-7).
2â-Ca r bom eth oxy-3â-(4-ch lor op h en yl)tr op a n e (20). A
solution of anhydroecgonine methyl ester (19, 2.81 g, 15.5
mmol) in anhydrous ether (90 mL) was added slowly to a
solution of (4-chlorophenyl)magnesium bromide (1 M in ether,
31 mL, 31 mmol) in anhydrous ether (90 mL) at -40 °C under
argon.28 The reaction mixture was stirred for 2 h at -40 °C,
then cooled to -78 °C, quenched with trifluoroacetic acid (10
mL), and allowed to warm to room temperature. The yellow
mixture was then diluted with H2O, basified with NH4OH to
pH 9, and extracted with CHCl3. The combined organic layer
was dried over K2CO3, concentrated, and purified by column
chromatography (Et2O/Et3N, 95:5) to give 2.23 g (49%) of the
â-isomer 20 as a white solid, mp 118.5-119.5 °C (lit.28 120-
121 °C). [R]25D -42.0° (c 1, MeOH) (lit.31 [R]21D -44.0°). 1H NMR
(CDCl3): δ 7.30-7.15 (m, 4H), 3.54 (m, 1H), 3.47 (s, 3H), 3.38
(m, 1H), 3.00-2.87 (m, 2H), 2.55 (m, 1H), 2.18 (s, 3H), 2.18-
2.05 (m, 1H), 1.74-1.58 (m, 4H). EIMS m/z: 293 (M+).
Nor -2â-car bom eth oxy-3â-(4-ch lor oph en yl)tr opan e (21).
2â-Carbomethoxy-3â-(4-chlorophenyl)tropane 20 (1.44 g, 4.91
mmol) was dissolved in 20 mL of 1,2-dichloroethane. To the
solution was added Na2CO3 (2.09 g, 19.65 mmol) and 1-chlo-
roethyl chloroformate (ACE-Cl, 2.11 mL, 19.7 mmol), and the
mixture was stirred at reflux for 3 h. After cooling to room
temperature, the reaction mixture was filtered, and the filtrate
was concentrated under reduced pressure. To the residue was