Arch. Pharm. Chem. Life Sci. 2015, 348, 1–13
Fluorinated Benzoimidazole Derivatives as Anticoagulants
ARC HH PHARM
Archiv der Pharmazie
7
.21 (m, 1H, Ar-H), 7.22 (m, 1H, Ar-H), 7.30 (d, J ¼ 8.5 Hz, 2H, Ar-
3-({2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
ethyl-1H-benzoimidazole-5-carbonyl}-o-tolyl-amino)-
propionic acid (14b)
H), 7.41 (m, 1H, Ar-H), 7.50 (m, 1H, Ar-H), 7.61 (m, 1H, Ar-H),
8
.45 (s, 2H, N-H), 11.31 (s, 2H, N-H). HRMS (ESI) m/z: 565.2182
þ
1
2
[MþH] ; calcd. for C29
H
30ClFN
6
O
3
(MþH) 565.2125.
Yield: 75%; m.p. 237–239°C;
00 MHz) d: 1.33 (t, 3H, –CH ), 2.15 (s, 3H, –CH
J ¼ 7.2 Hz, 2H, –CH ), 4.23 (t, J ¼ 7.2 Hz, 2H, –CH
J ¼ 7.2 Hz, 2H, –CH ), 5.06 (d, J ¼ 7.2 Hz, 2H, –CH ), 7.06 (m, 1H,
H
NMR (DMSO-d
6
þ HCl,
5
3
3
), 2.61 (t,
3
-({2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
2
2
–), 4.47 (q,
ethyl-1H-benzoimidazole-5-carbonyl}-pyridin-2-yl-amino)-
propionic acid ethyl ester (13h)
Yield: 57%; m.p. 202–203°C; H NMR (DMSO-d
2
2
Ar-H), 7.11 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.13 (m, 1H, Ar-H), 7.25 (m,
1H, Ar-H), 7.46 (m, 1H, Ar-H), 7.62 (m, 1H, Ar-H), 7.65 (m, 1H,
Ar-H), 7.84 (d, J ¼ 8.5 Hz, 2H, Ar-H), 9.01 (s, 2H, N-H), 9.28 (s, 2H,
1
6
, 500 MHz) d:
), 2.69
–), 4.23 (q,
–), 4.71 (d,
1
.12 (t, J ¼ 7.2 Hz, 3H, –CH
3
), 1.24 (t, J ¼ 7.2 Hz, 3H, –CH
–), 3.97 (t, J ¼ 7.2 Hz, 2H, –NCH
–), 4.31 (q, J ¼ 7.2 Hz, 2H, –OCH
3
1
3
2
(
t, J ¼ 7.2 Hz, 2H, –CH
2
2
N-H). C NMR (DMSO-d
6
þ HCl, 125 MHz) d: 172.48, 168.39,
J ¼ 7.2 Hz, 2H, –NCH
2
2
163.56, 152.28, 148.62, 140.80, 140.41, 140.29, 134.80, 134.11,
132.21, 131.34, 129.67, 128.10, 126.98, 114.69, 113.90, 112.30,
2
2
H, –NCH –), 6.93 (m, 1H, Ar-H), 7.06 (m, 1H, Ar-H), 7.13 (d,
J ¼ 8.5 Hz, 2H, Ar-H), 7.42 (m, 1H, Ar-H), 7.50 (m, 1H, Ar-H), 7.54
111.69, 45.23, 40.41, 38.21, 31.77, 17.46, 13.92. HRMS (ESI) m/z:
þ
(
d, J ¼ 8.5 Hz, 2H, Ar-H), 7.63 (m, 1H, Ar-H), 8.40 (m, 1H, Ar-H).
517.2359 [MþH] ; calcd. for C28
H
29FN
O
6 3
(MþH) 517.2358.
þ
HRMS (ESI) m/z: 532.2511 [MþH] ; calcd. for C28
7 3
H30FN O
(
MþH) 532.2467.
3-[{2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
ethyl-1H-benzoimidazole-5-carbonyl}-(2-methoxy-phenyl)-
amino]-propionic acid (14c)
3-[{2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
1
2
ethyl-1H-benzoimidazole-5-carbonyl}-(5-methyl-pyridin-2-
yl)-amino]-propionic acid ethyl ester (13i)
Yield: 80%; m.p. 228–229°C;
500 MHz) d: 1.33 (t, 3H, –CH
3.72 (s, 3H, –OCH
), 4.09 (t, J ¼ 7.2 Hz, 2H, –CH
J ¼ 7.2 Hz, 2H, –CH ), 5.07 (d, J ¼ 7.2 Hz, 2H, –CH ), 6.81 (m, 1H,
H
NMR (DMSO-d
6
þ HCl,
3
), 2.61 (t, J ¼ 7.2 Hz, 2H, –CH
2
),
1
Yield: 52%; m.p. 180–181°C; H NMR (DMSO-d
6
, 500 MHz) d:
), 2.18
–), 3.98 (t, J ¼ 7.2 Hz,
–), 4.31 (q, J ¼ 7.2 Hz,
2
–), 6.84 (m, 1H, Ar-H), 7.06 (m,
3
2
–), 4.47 (q,
1
.12 (t, J ¼ 7.2 Hz, 3H, –CH
s, 3H, –CH
), 2.65 (t, J ¼ 7.2 Hz, 2H, –CH
–), 4.18 (q, J ¼ 7.2 Hz, 2H, –NCH
–), 4.70 (d, 2H, –NCH
3
), 1.24 (t, J ¼ 7.2 Hz, 3H, –CH
3
2
2
(
3
2
Ar-H), 6.93 (m, 1H, Ar-H), 7.08 (m, 1H, Ar-H), 7.15 (m, 1H, Ar-H),
7.22 (m, 1H, Ar-H), 7.46 (m, 1H, Ar-H), 7.67 (d, J ¼ 8.5 Hz, 2H, Ar-
H), 7.84 (d, J ¼ 8.5 Hz, 2H, Ar-H), 9.03 (s, 2H, N-H), 9.26 (s, 2H, N-
2
2
1
H, –NCH
H, –OCH
2
2
2
1
3
2
H, Ar-H), 7.15 (m, 1H, Ar-H), 7.42 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.49
H). C NMR (DMSO-d
6
þ HCl, 125 MHz) d: 172.56, 169.19,
(
1
m, 1H, Ar-H), 7.52 (m, 1H, Ar-H), 7.63 (m, 1H, Ar-H), 8.23 (m,
163.52, 154.25, 152.07, 148.62, 140.43, 134.34, 132.20, 130.70,
129.77, 129.44, 129.21, 126.04, 125.26, 120.84, 119.59, 114.70,
þ
H, Ar-H). HRMS (ESI) m/z: 546.2641 [MþH] ; calcd. for
C
29
H
32FN
7
O
3
(MþH) 546.2623.
113.42, 112.35, 112.14, 111.69, 55.64, 45.00, 40.35, 38.26,
þ
3
C
1.89, 13.93. HRMS (ESI) m/z: 533.2323 [MþH] ; calcd. for
General procedure for the synthesis of the target
compounds 14a–i
28
H
29FN
6
O
4
(MþH) 533.2307.
Compounds 13a–i (2 mmol) were added to a solution of
sodium hydroxide (0.24 g, 6.0 mmol) in water/ethanol (30 mL,
3-[{2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
ethyl-1H-benzoimidazole-5-carbonyl}-(3-methoxy-phenyl)-
amino]-propionic acid (14d)
2
:1 v/v) and kept stirring at room temperature for 2 h. The
1
2
mixture was then diluted with 50 mL of water and neutralized
with acetic acid. The precipitate was isolated and washed with
water to afford the zwitterionic title compounds 14a–i.
Yield: 71%; m.p. 232–234°C;
500 MHz) d: 1.35 (t, 3H, –CH
3.64 (s, 3H, –OCH
), 4.03 (t, J ¼ 7.2 Hz, 2H, –CH
J ¼ 7.2 Hz, 2H, –CH
H
NMR (DMSO-d
6
þ HCl,
3
), 2.55 (t, J ¼ 7.2 Hz, 2H, –CH
2
),
3
2
–), 4.50 (q,
), 6.72 (d,
2
–), 5.09 (d, J ¼ 7.2 Hz, 2H, –CH
2
3-({2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
J ¼ 8.5 Hz, 2H, Ar-H), 6.92 (m, 1H, Ar-H), 7.10 (d, J ¼ 8.5 Hz, 2H,
Ar-H), 7.51 (m, 1H, Ar-H), 7.66 (m, 1H, Ar-H), 7.72 (m, 1H, Ar-H),
7.82 (m, 1H, Ar-H), 7.87 (m, 1H, Ar-H), 9.03 (s, 2H, N-H), 9.28 (s,
ethyl-1H-benzoimidazole-5-carbonyl}-phenyl-amino)-
propionic acid (14a)
1
2
13
2
Yield: 73%; m.p. 240–242°C;
H
NMR (DMSO-d
6
þ HCl,
),
), 5.07
), 7.07 (m, 1H, Ar-H), 7.15 (m, 1H, Ar-H),
.23 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.24 (m, 1H, Ar-H), 7.45 (m, 1H, Ar-
2H, N-H). C NMR (DMSO-d
6
þ HCl, 125 MHz) d: 172.53,
5
00 MHz) d: 1.33 (t, 3H, –CH
3
), 2.53 (t, J ¼ 7.2 Hz, 2H, –CH
2
168.22, 163.57, 159.65, 152.19, 151.01, 148.62, 140.40, 134.42,
132.16, 129.97, 129.29, 126.06, 125.79, 120.46, 114.70, 114.49,
114.27, 113.81, 112.74, 112.33, 111.66, 55.23, 46.13, 40.38,
4
.04 (t, J ¼ 7.2 Hz, 2H, –CH –), 4.48 (q, J ¼ 7.2 Hz, 2H, –CH
2
2
(d, J ¼ 7.2 Hz, 2H, –CH
2
þ
7
38.17, 32.07, 13.96. HRMS (ESI) m/z: 533.2314 [MþH] ; calcd.
H), 7.64 (m, 1H, Ar-H), 7.68 (d, J ¼ 8.5 Hz, 2H, Ar-H), 7.81 (m, 1H,
for C28
H
29FN
O
6 4
(MþH) 533.2307.
1
3
Ar-H), 7.87 (m, 1H, Ar-H), 9.01 (s, 2H, N-H), 9.27 (s, 2H, N-H).
C
2
NMR (DMSO-d
6
þ HCl, 125 MHz) d: 172.25, 168.88, 163.32,
3-[{2-[(4-Carbamimidoyl-2-fluoro-phenylamino)-methyl]-1-
ethyl-1H-benzoimidazole-5-carbonyl}-(3-fluoro-phenyl)-
amino]-propionic acid (14e)
1
1
1
52.47, 151.00, 148.61, 140.27, 133.49, 132.46, 130.26, 130.03,
29.07, 126.06, 125.45, 116.46, 116.26, 114.68, 114.60, 114.47,
13.82, 112.53, 111.72, 4.67, 40.50, 38.23, 31.96, 13.88. HRMS
1
2
Yield: 75%; m.p. 236–237°C;
H
NMR (DMSO-d
6
þ HCl,
þ
(
5
ESI) m/z: 503.2175 [MþH] ; calcd. for C27
H
27FN
6
O
3
(MþH)
500 MHz) d: 1.36 (t, 3H, –CH
3
), 2.57 (t, J ¼ 7.2 Hz, 2H, –CH
2
),
03.2201.
4.06 (t, J ¼ 7.2 Hz, 2H, –CH
2
–), 4.50 (q, J ¼ 7.2 Hz, 2H, –CH
2
–),
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