Dopamine D4 Receptor Ligands
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3099
prepared according to procedure F using 6c (1.77 g, 11.5
mmol), 2,3-dimethoxyphenol (2.00 g, 7.70 mmol), EtOK (1.88
g, 15.4 mmol), and 18-crown-6 ether (1.02 g, 3.90 mmol) in
anhydrous toluene (30 mL), stirred for 72 h at reflux under
4.0 (m, 4H), 3.98 (m, 1H), 3.79 (m, 1H), 3.30 (m, 1H), 3.18 (m,
1H), 2.94 (m, 2H), 1.31 (m, 3H).
(()-2-(2-Eth oxyp h en oxym eth yl)-4-(4-n itr oben zyl)m or -
p h olin e Oxa lic Acid Sa lt (16). Compound 16 was prepared
according to procedure C using 16c (3.00 g, 11.0 mmol),
4-nitrobenzylbromide (2.37 g, 11.0 mmol), and K2CO3 (1.52 g,
11.0 mmol), stirred in DMF (30 mL) for 4 h at 80 °C. Yield
1.10 g (27%), mp 113-114 °C. 1H NMR (DMSO-d6): δ 8.23 (d,
2H, J ) 9.8 Hz), 7.33 (d, 2H, J ) 9.8 Hz), 6.92 (m, 2H), 6.85
(m, 2H), 4.0 (m, 1H), 3.93 (m, 2H), 3.83 (m, 3H), 3.74 (d, 1H,
J ) 11.0 Hz), 3.66 (d, 1H, J ) 11.0 Hz), 3.59 (m, 1H), 2.92 (d,
1H, J ) 9.6 Hz), 2.72 (d, 1H, J ) 9.6 Hz), 2.29 (m, 1H), 2.18
(t, 1H, J ) 9.6 Hz), 1.18 (t, 3H, J ) 5.8 Hz). Anal. (C20H24N2O5‚
C2H2O4‚0.4H2O) C, H, N.
2-Eth oxy-4-iod op h en ol (17b). Compound 17b was pre-
pared according to procedure D using 2-ethoxyphenol (17a )
(20.0 g, 144.0 mmol), NaI (21.7 g, 144.0 mmol), NaOH (5.80 g,
144.0 mmol), aqueous NaOCl (10.8 g, 4%, 267 mL), and EtOH
(500 mL), stirred 1.5 h at -10 °C. Aqueous Na2S2O3 (10%, 200
mL) was added, and the pH was adjusted to 7 with HCl (1 N).
The product was precipitated and was filtered. Yield 26.2 g
(69%), mp 88-91 °C. 1H NMR (DMSO-d6): δ 9.22 (s, 1H), 7.13
(m, 1H), 7.06 (m, 1H), 6.60 (m, 1H), 3.97 (m, 2H), 1.30 (m,
3H).
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N2. Yield 1.0 g (23%), mp 139-141 °C. H NMR (DMSO-d6):
δ 7.45 (s, 1H), 7.40 (d, 2H, J ) 7.0 Hz), 7.36 (d, 2H, J ) 7.0
Hz), 6.94 (t, 1H, J ) 7.3 Hz), 6.63 (m, 1H), 3.98 (m, 1H), 3.93
(m, 1H), 3.84 (m, 1H), 3.80 (m, 1H), 3.75 (s, 3H), 3.64 (m, 1H),
3.59 (s, 3H), 3.55 (s, 2H), 2.92 (d, 1H, J ) 9.6 Hz), 2.72 (d, 1H,
J ) 9.6 Hz), 2.29 (m, 1H), 2.18 (m, 1H). Anal. (C20H24ClNO4‚
C2H2O4‚0.7H2O) C, H, N.
4-Ch lor om or p h olin e (14b). Compound 14b was prepared
using morpholine (14a ) (19.7 g, 277.0 mmol) cooled to 10 °C
and aqueous NaOCl (10.8 g, 4%, 500 mL) was added, and the
mixture was stirred for 5 min. The compound was extracted
with diethyl ether (4 × 60 mL) and isolated as an oil. Yield
1
14.0 g (72%). H NMR (CDCl3): δ 3.73 (s, 4H), 3.16 (s, 4H).
4-Ch lor o-2-eth oxyp h en ol (14c). Compound 14c was pre-
pared using 2-ethoxyphenol (2.75 g, 19.9 mmol) cooled in TFA/
diethyl ether (2:1) (50 mL) at -60 °C. Compound 14b (2.66 g,
21.9 mmol) in diethyl ether (50 mL) was added and the
mixture stirred at -60 °C for 1 h. The ether phase was washed
with H2O (50 mL), separated, dried, and evaporated. The
compound was purified by vacuum distillation. Yield 2.03 g
(54%), bp 150 °C (0.40 mmHg). 1H NMR (DMSO-d6): δ 9.20
(s, 1H), 6.92 (s, 1H), 6.76 (m, 2H), 4.01 (m, 2H), 1.32 (m, 3H).
(()-2-(2-Eth oxy-4-iod op h en oxym eth yl)-oxir a n e (17c).
Compound 17c was prepared according to procedure A using
compound 17b (15.0 g, 56.8 mmol), epibromohydrin (23.0 g,
171.0 mmol), and K2CO3 (11.7 g, 85.2 mmol) in DME (200 mL),
stirred at reflux overnight. Yield 11.3 g (62%). 1H NMR
(CDCl3): δ 7.21 (m, 1H), 7.16 (m, 1H), 6.68 (m, 1H), 4.22 (m,
1H), 4.02 (m, 2H), 3.98 (m, 1H), 3.83 (s, 3H), 3.30 (m, 1H),
2.91 (m, 1H), 2.73 (m, 1H).
(()-4-(4-Ch lor ob en zyl)-2-(4-ch lor o-2-et h oxyp h en oxy-
m eth yl)m or p h olin e Oxa lic Acid Sa lt (14). P r oced u r e F .
A mixture of 6c (1.50 g, 5.80 mmol), 14c (1.50 g, 8.70 mmol),
EtOK (1.30 g, 11.6 mmol), and 18-crown-6 ether (0.30 g, 1.20
mmol) was stirred in anhydrous toluene (30 mL) at reflux for
34 h under N2. H2O (20 mL) was added, and the mixture was
shaken and separated. Drying and evaporation of the toluene
phase was followed by column chromatography on silica gel
with 4% EtOH in CH2Cl2 as eluent. The free base was
dissolved in diethyl ether and precipitated with oxalic acid to
give compound 14. Yield 0.65 g (28%), mp 88-90 °C. 1H NMR
(DMSO-d6): δ 7.38 (d, 2H, J ) 7.9 Hz), 7.33 (d, 2H, J ) 7.9
Hz), 6.97 (d, 1H, J ) 4.5 Hz), 6.93 (s, 1H), 6.87 (m, 1H), 3.96
(m, 2H), 3.86 (m, 1H), 3.80 (d, 1H, J ) 10.2 Hz), 3.75 (m, 1H),
3.53 (t, 1H, J ) 10.7 Hz), 3.43 (d, 1H, J ) 10.9 Hz), 3.25 (s,
2H), 2.72 (d, 1H, J ) 9.6 Hz), 2.62 (d, 1H, J ) 9.6 Hz), 2.11
(m, 1H,), 1.92 (t, 1H, J ) 9.6 Hz), 1.22 (t, 3H, J ) 9.6 Hz).
Anal. (C20H23Cl2NO3) C, H, N.
(()-2-[(2-E t h oxy-4-iod op h en oxy)m et h yl]m or p h olin e
(17d ). Compound 17d was prepared according to procedure
B using compound 17c (5.16 g, 16.1 mmol), aminohydrogen-
sulfate (11.3 g, 80.5 mmol), and NaOH (6.45 g, 161.0 mmol)
in 2-propanol/H2O (3:1) (200 mL), stirred at reflux for 8 h. The
product was isolated as an oil. Yield 3.96 g (67%). 1H NMR
(CDCl3): δ 7.23 (m, 1H), 7.18 (m, 1H), 6.71 (m, 1H), 4.41 (m,
1H), 4.20 (m, 1H), 4.06 (m, 3H), 3.81 (m,1H), 3.66 (m, 1H),
3.59 (m, 1H), 3.40 (m, 1H), 3.23 (m, 1H), 1.47 (m, 3H).
(()-4-(4-Ch lor ob e n zyl)-2-(2-e t h oxy-4-iod op h e n oxy-
m eth yl)m or p h olin e Oxa lic Acid Sa lt (17). Compound 17
was prepared according to procedure C using 17d (3.90 g, 10.7
mmol), 4-chlorobenzyl chloride (2.07 g, 12.9 mmol), and K2CO3
(8.13 g, 58.9 mmol) in EtOH (100 mL), stirred at reflux for 3
(()-4-(4-Ch lor ob en zyl)-2-(5-ch lor o-2-et h oxyp h en oxy-
m eth yl)m or p h olin e (15). Compound 15 was prepared ac-
cording to procedure F using 5-chloro-2-ethoxyphenol (1.70 g,
9.80 mmol), 6c (1.70 g, 6.60 mmol), t-BuOK (1.61 g, 13.2 mmol),
and 18-crown-6 ether (0.87 g, 3.30 mmol), stirred in anhydrous
DMF (30 mL) for 15 h at 100 °C under N2. Yield 1.29 g (33%),
1
h. Yield 1.58 g (11%), mp 86-90 °C. H NMR (DMSO-d6): δ
7.37 (m, 2H), 7.32 (m, 2H), 7.17 (m, 2H), 6.76 (m, 1H), 4.0 (m,
1H), 3.94 (m, 2H), 3.86 (m, 2H), 3.80 (d, 1H, J ) 10.3 Hz),
3.74 (m, 1H), 3.52 (m, 1H), 3.40 (m, 1H), 2.78 (d, 1H, J ) 9.7
Hz), 2.62 (m, 1H), 2.10 (t, 1H, J ) 9.7 Hz), 1.93 (t, 1H, J ) 9.7
Hz), 1.22 (t, 3H, J ) 5.47 Hz). Anal. (C20H23ClINO3‚0.3H2O)
C, H, N.
1
mp 85-87 °C. H NMR (CDCl3): δ 7.44 (s, 4H), 6.84 (m, 3H),
4.29 (m, 3H), 4.14 (m, 3H), 4.04 (m, 3H), 3.65 (d, 1H, J ) 10.4
Hz), 3.56 (d, 1H, J ) 10.4 Hz), 3.16 (m, 1H), 2.97 (m, 1H),
1.40 (t, 3H, J ) 5.8 Hz). Anal. (C20H23Cl2NO3) C, H, N.
(()-4-(2,4-Dich lor oben zyl)-2-(2-eth oxyph en oxym eth yl)-
m or p h olin e Oxa lic Acid Sa lt (18). Compound 18 was
prepared as procedure C by stirring 16d (0.27 g, 1.10 mmol),
2,4-dichloro-1-chloromethylbenzene (0.22 g, 1.10 mmol), and
K2CO3 (0.15 g, 1.10 mmol) in DMF (10 mL) for 3 h at 80 °C.
Yield 0.21 g (48%), mp 141-143 °C. 1H NMR (DMSO-d6): δ
7.60 (m, 1H), 7.53 (d, 1H, J ) 7.5 Hz), 7.42 (m, 1H), 6.93 (m,
2H), 6.86 (m, 2H), 4.0 (m, 1H), 3.94 (m, 2H), 3.87 (m, 3H), 3.66
(d, 1H, J ) 9.6 Hz), 3.58 (m, 2H), 2.91 (d, 1H, J ) 9.6 Hz),
2.71 (d, 1H, J ) 9.6 Hz), 2.29 (bt, 1H), 2.17 (t, 1H, J ) 9.6
Hz), 1.22 (t, 3H, J ) 6.3 Hz). Anal. (C22H27Cl2NO8) C, H, N.
(()-4-[4-(4-Ch lor ob en zyl)-m or p h olin -2-ylm et h oxy]-3-
eth oxyben zon itr ile Oxa lic Acid Sa lt (19). Compound 19
was prepared by using compound 17 as its free base (1.00 g,
2.10 mmol), tetrakis(triphenylphosphine)palladium(0) (0.35 g,
0.30 mmol), and Zn(CN)2 (0.17 g, 1.40 mmol) in anhydrous
DMF (15 mL), stirred for 4 h at 80 °C under N2, followed by
addition of H2O (20 mL). The precipitate and the mother liquor
were extracted with EtOAc (2 × 30 mL), dried, and evaporated
to dryness. The crude product was further purified by frac-
tional crystallization from EtOH and then triturated with
(()-4-Ben zyl-2-(2-et h oxyp h en oxym et h yl)m or p h olin e
(16b). Compound 16b was prepared according to procedure F
using 4-benzyl-2-chloromethylmorpholine (16a )35 (14.0 g, 62.0
mmol), 2-ethoxyphenol (12.8 g, 93.0 mmol), t-BuOK (15.1 g,
124.0 mmol), and 18-crown-6 ether (8.19 g, 31.0 mmol), stirred
in anhydrous DMF (140 mL) at 110 °C overnight under N2.
Yield 4.76 g (23%). 1H NMR (CDCl3): δ 7.38 (m, 5H), 6.94 (m,
4H), 4.10 (m, 2H), 4.06 (m, 2H), 3.98 (m, 2H), 3.81 (m, 1H),
3.58 (m, 1H), 3.04 (m, 1H), 2.76 (m, 1H), 2.29 (m, 1H), 2.11
(m, 1H), 1.64 (m, 1H), 1.41 (m, 3H).
(()-2-[(2-E t h oxyp h en oxy)m et h yl]m or p h olin e (16c).
Compound 16c was prepared by stirring a mixture of 16b (4.75
g, 14.5 mmol) and Pd/C (5%, 500 mg) in EtOH/concentrated
HCl (3:1) (40 mL) under an atmosphere of hydrogen. The
mixture was filtered and was evaporated. Aqueous sodium
hydroxide (50 mL, 4 N) was added, and the mixture was
extracted with toluene (2 × 40 mL). The product was isolated
as an oil. Yield 3.31 g (96%), mp 176-179 °C. 1H NMR (DMSO-
d6): δ 9.42 (s, 1H), 6.97 (m, 2H), 6.89 (m, 2H), 4.09 (m, 1H),