1
96
H. Stark et al. / Bioorg. Med. Chem. 9 (2001) 191±198
Table 4. Analytical data of prodrugs 2±6
Calculated
Found
H
ꢀ
No.
Formula
MW
Mp [ C]
C
H
N
C
N
.
O C
2
C
C
C
C
C
C
C
22
10
12
H
H
H
41
15
19
N
N
N
3
3
3
4
H
4
O
4
479.7
241.3
269.3
299.3
313.3
380.4
393.9
119
79
63
104
106
86±88
163
65.1
49.8
53.5
48.2
49.8
47.4
67.1
9.46
6.27
7.11
5.73
6.11
5.83
4.99
8.76
17.4
64.9
49.8
53.4
47.8
49.8
47.7
67.1
9.39
6.33
7.31
5.77
6.21
5.68
4.84
8.84
17.5
3
3
4
4
5
6
a
b
a
b
O
O
4
4
2.
15.6
14.0
13.4
11.0
10.7
15.8
13.7
13.6
10.8
10.7
8
9
H
13
N
3
O C
4
H
H
4
O
O
4
H
15
N
3
O C
2.
4
4
4
11
H
17
N
N
3
O C
4.
4
H
4
O
4.
0.5H
2
O
22
H
19
3
O
4.
0.25H
2
O
crystallized as salt of maleic acid in EtOH/Et O (yield:
2
ing to 3a with methyl chloroformate (2 mmol, 0.19 g).
Compound 4a was crystallized as salt of maleic acid in
20
1
0
.5 g, 65%). ꢀ =� 53.8 (c=1 g/100 mL in MeOH); H
D
20
NMR ([d ]DMSO) d 8.86 (s, 1H, Im-2-H), 7.72 (d**,
EtOH/Et O (yield: 0.4 g, 66%). ꢀ =+9.2 (c=1 g/
6
2
D
1
J=8.2 Hz, 1H, NH), 7.32 (s, 1H, Im-5-H), 6.04 (s, 2H,
Mal), 4.06 (m, 1H, CH), 2.72 (d, J=6.8 Hz, 2H, Im-
CH ), 1.99 (t, J=7.3 Hz, 2H, CO-CH ), 1.41 (m, 2H,
100 mL in MeOH); H NMR ([d ]DMSO) d 8.90 (s, 1H,
6
Im-2-H), 7.36 (s, 1H, Im-5-H), 7.16 (d**, J=8.1 Hz, 1H,
NH-CO), 6.06 (s, 2H, Mal), 3.81 (m, 1H, CH), 3.49 (s,
2
2
CO-CH -CH ), 1.23 (m, 24H, alkyl-H), 1.05 (d, J=
2
3H, O-Me), 2.73 (d, J=6.7 Hz, 2H, Im-CH ), 1.07 (d,
2
2
6
.6 Hz, 3H, CH-Me), 0.85 (t, J=7.0 Hz, 3H, CH -Me);
2
J=6.6 Hz, 3H, CH-Me); MS (70 eV), m/z (%) 183 (1)
+
+
MS (70 eV), m/z (%) 363 (2) [M ], 256 (3), 167 (6), 108
89), 82 (100).
[M ], 140 (12), 101 (16), 86 (100), 82 (16).
(
(
R)-(+)-N-(1-(1H-Imidazol-4-yl)-2-propyl)carbamate
ethylester (4b). The synthesis was performed according
to 3b with ethyl chloroformate (2 mmol, 0.19 g). Com-
pound 4b was crystallized as salt of maleic acid in
Dicarbamates
R)-(+)-N-(1-(1-(Methoxycarbonyl)-1H-imidazol-4-yl)-
-propyl)carbamate methylester (3a). A solution of
(
2
20
EtOH/Et O (yield: 0.4 g, 63%). ꢀ =+7.4 (c=1 g/
2
D
1
methyl chloroformate (4 mmol, 0.38 g) in 10 mL of ethyl
acetate was slowly added to 1 (2 mmol, 0.25 g) and Et N
100 mL in MeOH); H NMR ([d ]DMSO) d 8.91 (s, 1H,
6
Im-2-H), 7.35 (s, 1H, Im-5-H), 7.12 (d**, J=8.2 Hz,
NH-CO), 6.05 (s, 2H, Mal), 3.91 (q, J=7.0 Hz, 2H, O-
CH ), 3.81 (m, 1H, CH), 2.72 (d, J=6.7 Hz, 2H, Im-
2
3
(
acetate. After stirring for 3 h at ambient temp Et N hy-
4 mmol, 0.4 g) in 5 mL of MeOH and 10 mL of ethyl
.
3
drochloride was ®ltrated and the residue evaporated
under reduced pressure. The oily compound 3a was
CH ), 1.11 (t, J=7.0 Hz, 3H, O-CH -Me), 1.06 (d, J=
2
6.6 Hz, 3H, CH-Me); MS (70 eV), m/z (%) 197 (1) [M ],
154 (84), 109 (13), 86 (32), 81 (100).
2
+
crystallized as salt of maleic acid in EtOH/Et O at
2
ꢀ
�
5 C and was recrystallized in Et O (yield: 0.2 g, 41%).
2
20
1
ꢀ =+2.3 (c=1 g/100 mL in MeOH); H NMR
D
(
Acetyloxy)alkylcarbamate
(
[d ]DMSO) d 8.17 (d, J=1.0 Hz, 1H, Im-2-H), 7.31 (s,
6
1H, Im-5-H), 7.07 (d**, J=8.0 Hz, 1H, NH), 3.95 (s,
3H, Im-COO-Me), 3.75 (m, 1H, CH), 3.49 (s, 3H, NH-
(1-Chloroethyl)-(4-nitrophenyl)carbonate.30 a-Chloroethyl
chloroformate (35 mmol, 5 g) was added slowly at 0 C
ꢀ
to 4-nitrophenol (35 mmol, 4.87 g) and pyridine
COO-Me), 2.62 (d, J=6.8 Hz, 2H, Im-CH ), 1.02 (d,
2
J=6.6 Hz, 3H, CH-Me); MS (70 eV), m/z (%) 241 (1)
+
(35 mmol, 2,77 g) in 100 mL of CHCl . After 30 min at
3
0 C the mixture was stirred at ambient temp for 18 h.
+
ꢀ
Washing of the mixture (H O, 0.5% NaOH, H O),
[
M ], 210 (4) [M � MeO], 166 (16), 140 (100), 102 (17),
81 (45).
2
2
drying (Na SO ), and evaporation to dryness resulted in
2
4
ꢀ
(R)-(+)-N-(1-(1-(Ethoxycarbonyl)-1H-imidazol-4-yl)-2-
an oil, which slowly crystallized at � 5 C. Recrystalli-
zation in ethyl acetate/petrol ether gave 81% yield (7 g),
which can be used directly for further reactions. Mp.
70±71 C; H NMR ([d ]DMSO) d 8.35 (dd, J=9.0 Hz,
J=2.8 Hz, 2H, Ph-3-H, Ph-5-H), 7.62 (dd, J=9.0 Hz,
J=2.8 Hz, 2H, Ph-2-H, Ph-6-H), 6.61 (q, J=5.8 Hz,
propyl)carbamate ethylester (3b). The synthesis was
made according to 3a with ethyl chloroformate and
EtOH instead of MeOH. Crystallization was performed
ꢀ
1
3
6
2
D
0
4
4
3
in Et O (yield: 0.24 g, 44%). ꢀ =+1.8 (c=1 g/
2
1
1
00 mL in MeOH); H NMR ([d ]DMSO) d 8.16 (d,
6
J=1.0 Hz, 1H, Im-2-H), 7.29 (s, 1H, Im-5-H), 7.02 (d**,
J=8.1 Hz, NH), 4.39 (q, J=7.1 Hz, 2H, Im-COO-CH2),
1H, CH), 1.86 (d, J=5.7 Hz, 3H, Me); MS (70 eV), m/z
+
+
(%) 245 (1) [M ], 210 (8) [M � Cl], 166 (14), 139 (99),
122 (19), 109 (28), 93 (13), 81 (11), 76 (11); (C H
8
3.94 (q, J=7.1 Hz, 2H, NH-COO-CH ), 3.77 (m, 1H,
CH), 2.62 (d, J=6.4 Hz, 2H, Im-CH ), 1.33 (t, J=
2
9
ClNO5).
2
7.1 Hz, 3H, Im-COO-CH -Me), 1.13 (t, J=7.1 Hz, 3H,
NH-COO-CH -Me), 1.02 (d, J=6.5 Hz, 3H, CH-Me);
2
(1-(Acetoxy)ethyl)-(4-nitrophenyl)carbonate.30 The pro-
duct obtained above (28 mmol, 6.87g) in 50mL of acetic
acid was mixed with Hg(H CCOO) (34 mmol, 10.83 g)
2
+
MS (70 eV), m/z (%) 269 (2) [M ], 224 (5), 180 (17), 154
(
100), 116 (11), 81 (77).
3
2
and stirred for 18 h at ambient temp. After evaporation
to dryness the residue was dissolved in Et O, ®ltrated,
2
Monocarbamates
R)-(+)-N-(1-(1H-Imidazol-4-yl)-2-propyl)carbamate
methylester (4a). The synthesis was performed accord-
washed (H O, NaHCO , H O), dried (Na SO ), and
2
3
2
2
4
(
once more evaporated to dryness. The oil obtained
was puri®ed by column chromatography (eluent: