Synthesis of Chiral Histamine H3-Receptor Ligands
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 7 1199
amount of 5 was 1.50 g (2.40 mmol). A white hygroscopic foam
was obtained (it is not possible to measure the melting point)
(yield 1.55 g, 1.95 mmol, 81%): 1H NMR data identical to those
of compound 9.
120.71 (d, Im-5-CH), 130.24 (s, Im-4-C), 137.06 (d, Im-2-CH);
[R]D 2.48 ( 0.03 (SD) (23.8 °C, H2O, c ) 1); [R]20 2.9 (H2O, c )
0.01).36 HRMS: m/z 142.1061, calcd for (M +DH)+ C6H11N3O
142.0980. Anal. (C6H11N3O‚2HCl) C, H, N: calcd, 19.63; found,
18.62.
2-(S)-(Tr ip h en ylm eth yla m in o)-3-[1-(tr ip h en ylm eth yl)-
im id a zol-4(5)-yl]p r op yl 4-Iod oben zyl Eth er (14). Com-
pound 14 was made according to general method 3 (yield 1.02
g, 1.21 mmol, 38%): mp 84 °C; 1H NMR (CDCl3) δ 2.17 (q, J AB
) 14.3 Hz, J AE ) 7.0 Hz, 1H, Im-CHAH), 2.50 (broad s, 1H,
NH), 2.61 (q, J AB ) 14.3 Hz, J BE ) 4.6 Hz, 1H, Im-CHHB),
2.72 (q, J CD ) 9.0 Hz, J CE ) 6.2 Hz, 1H, -O-CHCH), 2.88 (m,
1H, HNCHE), 3.12 (q, J CD ) 9.0 Hz, J DE ) 3.7 Hz, 1H, -O-
CHHD), 4.04 (d, 1H, J MN ) 12.2 Hz, -O-CHMH-(4-I-phenyl)),
4.10 (d, J MN ) 12.2 Hz, 1H, -O-CHHN-(4-I-phenyl)), 6.32 (s,
1H, Im-5-H), 6.88 (d, J 2,3 ) J 5,6 ) 8.3 Hz, 2H, 4-I-phenyl-2,6-
H), 7.05-7.50 (m, 31H, phenyl-H, Im-2-H), 7.56 (d, J 2,3 ) J 5,6
) 8.3 Hz, 2H, 4-I-phenyl-3,5-H).
2-(S)-Am in o-3-(1H-im idazol-4(5)-yl)pr opyl Meth yl Eth er
Dih yd r och lor id e (21). Compound 21 was made according to
general method 4. The amount of 15 was 1.95 g (3.05 mmol).
White crystals were obtained after recrystallization from
ethanol/ether (yield 560 mg, 2.45 mmol, 80%): mp 181 °C; 1H
NMR (D2O) δ 3.10 (d, 2H, J ) 6.9 Hz, Im-CH2), 3.31 (s, 3H,
CH3), 3.46 (q, J AB ) 11.1 Hz, J AC ) 6.2 Hz, 1H, H3C-O-CHAH),
3.57 (q, J AB ) 11.1 Hz, J BC ) 3.4 Hz, 1H, H3C-O-CHHB), 3.71
(m, 1H, H2NCHC), 7.34 (s, 1H, Im-5-H), 8.61 (s, 1H, Im-2-H);
13C NMR (D2O) δ, 27.32 (t, Im-CH2), 52.98 (d, H2N-CH), 61.70
(t, O-CH3), 73.07 (t, O-CH2), 120.67 (d, Im-5-CH), 130.43 (s,
Im-4-C), 137,14 (d, Im-2-CH); [R]D 8.64 ( 0.06 (SD) (23.4 °C,
H2O, c ) 1). HRMS: m/z 156.1175, calcd for (M + H)+
C7H13N3O 156.1137. Anal. (C7H13N3O‚2HCl) C, H, N: calcd,
18.42; found, 17.73.
2-(R)-Am in o-3-(1H-im id a zol-4(5)-yl)p r op yl Cycloh exyl-
m eth yl Eth er Dih yd r och lor id e (22). Compound 22 was
made according to general method 4, starting from 840 mg
(1.16 mmol) of 7. White crystals were obtained after recrys-
tallization from ethanol/ether (yield 230 mg, 0.74 mmol,
64%): mp 246 °C; 1H NMR (D2O) δ 0.88-0.97 (m, 2H,
cyclohexyl-H), 1.10-1.28 (m, 3H, cyclohexyl-H), 1.60-1.70 (m,
6H, cyclohexyl-H), 3.20 (m, 2H, Im-CH2), 3.32-3.39 (m, 2H,
cyclohexyl-CH2-O-), 3.59 (q, J AB ) 11.1 Hz, J AC ) 5.8 Hz, 1H,
cyclohexylmethyl-O-CHAH), 3.71 (q, J AB ) 11.1 Hz, J BC ) 3.7
Hz, 1H, cyclohexylmethyl-O-CHHB), 3.81 (m, 1H, H2NCHC),
7.42 (s, 1H, Im-5-H), 8.69 (d, J ) 1.2 Hz, 1H, Im-2-H); 13C NMR
(D2O) δ 27.45 (t, cyclohexyl-4-CH2), 28.19 (t, cyclohexyl-3,5-
CH2), 28.99 (t, Im-CH2), 32.20 (t, cyclohexyl-2,6-CH2), 39.91
(t, cyclohexyl-1-CH), 53.03 (d, H2N-CH), 71.41 (t, cyclohexyl-
CH2-O), 80.19 (t, O-CH2-CH), 120.62 (d, Im-5-CH), 130.33 (s,
Im-4-C), 137.01 (d, Im-2-CH); [R]D -11.77 ( 0.07 (SD) (23.3
°C, H2O, c ) 1), HRMS: m/z 238.1930, calcd for (M + H)+
C13H23N3O 238.1919. Anal. (C13H23N3O‚2HCl‚0.5H2O) C, H, N.
2-(S)-(Tr ip h en ylm eth yla m in o)-3-[1-(tr ip h en ylm eth yl)-
im id a zol-4(5)-yl]p r op yl Meth yl Eth er (15). Compound 15
was made according to general method 3. A yellowish solid
foam was obtained (yield 0.99 g, 1.55 mmol, 48%): mp 110
1
°C; H NMR (CDCl3) δ 2.15 (q, J AB ) 14.2 Hz, J AE ) 7.2 Hz,
1H, Im-CHAH), 2.50 (broad s, 1H, NH), 2.60 (m, 2H, Im-CHHB,
-O-CHCH), 2.82 (m, 1H, HNCHE), 3.00 (s, 4H, CH3 and -O-
CHHD), 6.33 (s, 1H, Im-5-H), 7.07-7.53 (m, 31H, phenyl-H,
Im-2-H).
3-[1-(Tr ip h en ylm eth yl)im id a zol-4(5)-yl]p r op yl Ben zyl
Eth er (16). Compound 16 was made according to general
method 3. The amount of 6 was 2.00 g (5.43 mmol). The eluent
for column chromatography was ethyl acetate:CH2Cl2 (1:1).
Light-yellow crystals were obtained (yield 1.56 g, 3.40 mmol,
1
63%): mp 86 °C; H NMR (CDCl3) δ 1.94 (m, 2H, CH2-CH2-
CH2), 2.64 (t, J ) 7.6 Hz, 2H, Im-CH2), 3.49 (t, J ) 6.4 Hz,
2H, O-CH2), 4.45 (s, 2H, phenyl-CH2), 6.51 (s, 1H, Im-5-H),
7.11-7.34 (m, 21H, phenyl-H, Im-2-H).
3-[1-(Tr ip h en ylm eth yl)im id a zol-4(5)-yl]p r op yl 4-Br o-
m oben zyl Eth er (17). Compound 17 was made according to
general method 3. The amount of 6 was 2.00 g (5.43 mmol).
The eluent for column chromatography was ethyl acetate:
CH2Cl2 (1:1). A light-yellow oil was obtained (yield 1.83 g, 3.40
mmol, 63%): 1H NMR (CDCl3) δ 1.94 (m, 2H, CH2-CH2-CH2),
2.63 (t, J ) 7.5 Hz, 2H, Im-CH2), 3.47 (t, J ) 6.4 Hz, 2H,
O-CH2), 4.39 (s, 2H, 4-Br-phenyl-CH2), 6.51 (s, 1H, Im-5-H),
2-(S)-Am in o-3-(1H-im id a zol-4(5)-yl)p r op yl Cycloh exyl-
m eth yl Eth er Dih yd r och lor id e (23). Compound 23 was
made according to general method 4. The amount of 11 was
960 mg (1.33 mmol). White crystals were obtained after
recrystallization from ethanol/ether (yield 170 mg, 0.55 mmol,
42%): mp 255 °C; 1H and 13C NMR data were identical to those
of compound 22; [R]D 11.93 ( 0.03 (SD) (24.2 °C, H2O, c ) 1).
HRMS: m/z 238.1947, calcd for (M + H)+ C13H23N3O 238.1919.
Anal. (C13H23N3O‚2HCl‚0.13H2O) C, H: calcd, 8.31; found,
7.60; N.
7.11-7.34 (m, 18H, phenyl-H, Im-2-H), 7.42 (d, J 2,3 ) J 5,6
8.4 Hz, 2H, 4-Br-phenyl-3,5-H).
)
3-[1-(Tr ip h en ylm eth yl)im id a zol-4(5)-yl]p r op yl 4-Iod o-
ben zyl Eth er (18). Compound 18 was made according to
general method 3. The amount of 6 was 6.0 g (16.3 mmol).
The eluent for column chromatography was ethyl acetate:
CH2Cl2 (1:1). A light yellow oil was obtained (yield 5.27 g, 9.02
mmol, 55%): 1H NMR (CDCl3) δ 1.93 (m, 2H, CH2-CH2-CH2),
2.63 (t, J ) 7.5 Hz, 2H, Im-CH2), 3.47 (t, J ) 6.4 Hz, 2H,
O-CH2), 4.39 (s, 2H, 4-I-phenyl-CH2), 6.51 (s, 1H, Im-5-H), 7.04
(d, J 2,3 ) J 5,6 ) 8.4 Hz, 2H, 4-I-phenyl-2,6-H), 7.12-7.35 (m,
16H, phenyl-H, Im-2-H), 7.62 (d, J 2,3 ) J 5,6 ) 8.3 Hz, 2H, 4-I-
phenyl-3,5-H).
2-(S)-Am in o-3-(1H-im id a zol-4(5)-yl)p r op a n ol Dih yd r o-
ch lor id e (19). Compound 19 was made according to general
method 4. The amount of 5 was 2.00 g (3.20 mmol). White
crystals were obtained after recrystallization from ethanol/
ether (yield 560 mg, 2.62 mmol, 82%): mp 200 °C (lit. 196-
198 °C36); 1H and 13C NMR data were identical to those of
compound 20; [R]D -2.65 ( 0.04 (SD) (23.3 °C, H2O, c ) 1);
[R]D -2.9 (H2O, c ) 0.01).36 HRMS: m/z 142.0969, calcd for
(M + H)+ C6H11N3O 142.0980. Anal. (C6H11N3O‚2 HCl‚0.4H2O)
C: calcd, 32.56; found, 34.36; H, N.
2-(R)-Am in o-3-(1H-im idazol-4(5)-yl)pr opyl Ben zyl Eth er
Dih yd r och lor id e (24). Compound 24 was made according to
general method 4. The amount of 8 was 2.00 g (2.79 mmol).
The product was recrystallized from 2-propanol/ether, yielding
very hygroscopic crystals. The crystals were transferred into
a flask with absolute ethanol, and the solvent was removed
at first with a rotavapor and then with high vacuum, yielding
a white, hygroscopic foam. The product was stored under Ar
1
(yield 310 mg, 1.02 mmol, 37%): mp 74.5 °C; H NMR (D2O)
δ 3.17 (m, 2H, Im-CH2), 3.60 (q, J AB ) 11.0 Hz, J AC ) 5.4 Hz,
1H, benzyl-O-CHAH), 3.73 (q, J AB ) 11.0 Hz, J BC ) 3.4 Hz,
1H, benzyl-O-CHHB), 3.79 (m, 1H, H2NCHC), 4.57 (d, J MN
)
11.8 Hz, 1H, phenyl-CHHN), 4.66 (d, J MN ) 11.7 Hz, 1H,
phenyl-CHHN), 7.28 (s, 1H, Im-5-H), 7.43 (m, 5H, phenyl-H),
8.63 (s, 1H, Im-2-H); 13C NMR (D2O) δ, 27.68 (t, Im-CH2), 53.11
(d, H2N-CH), 70.18 (t, benzyl-O-CH2), 75.91 (t, phenyl-CH2-
O), 120.30 (d, Im-5-CH), 131.05 (s, Im-4-C), 131.38 (d, phenyl-
4-CH), 131.48 (d, phenyl-2,6-CH), 131.65 (d, phenyl-3,5-CH),
137.27 (d, Im-2-CH), 139.80 (d, phenyl-1-C); [R]D -16.43 ( 0.03
(SD) (24.4 °C, H2O, c ) 1). HRMS: m/z 232.1465, calcd for (M
+ H)+ C13H17N3O 232.1450. Anal. (C13H17N3O‚2HCl‚1.5H2O)
C, H, N.
2-(R)-Am in o-3-(1H-im id a zol-4(5)-yl)p r op a n ol Dih yd r o-
ch lor id e (20). Compound 20 was made according to general
method 4. The amount of starting material 3 was 2.51 g (4.01
mmol). White crystals were obtained (yield 720 mg, 3.36 mmol,
1
84%): mp 196-197 °C (lit. 196-198 °C36); H NMR (D2O) δ
3.20 (m, 2H, Im-CH2), 3.72 (m, 2H, HO-CH2), 3.84 (m, 1H, NH2-
CH), 7.46 (s, 1H, Im-5-H), 8.72 (s, 1H, Im-2-H); 13C NMR (D2O)
δ 27.03 (t, HO-CH2), 54.66 (d, H2N-CH), 62.95 (t, Im-CH2),
2-(S)-Am in o-3-(1H-im idazol-4(5)-yl)pr opyl Ben zyl Eth er
Dih yd r och lor id e (25). Compound 25 was made according to
general method 4. The amount of 12 was 1.60 g (2.23 mmol).