Synthesis of Thrombin Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 7 1171
(1{5}). Compound 1{5} (28 mg, 64%) was collected as a white
powder according to the method for preparing 1{2} using 11{5}
(24 mg, 0.084 mmol) instead of 11{2}. 1H NMR (300 MHz, CD3-
OD): δ 1.04-1.17 (t, J ) 7.1 Hz, 3H), 1.76-2.00 (m, 1H), 2.05-
2.44 (m, 3H), 3.47-3.80 (m, 2H), 3.81-4.01 (m, 1H), 4.38-
4.62 (m, 2H), 5.45-5.82 (m, 1H), 7.18-7.24 (m, 2H), 7.30-
7.35 (m, 2H), 7.60 (d, J ) 8.2 Hz, 2H), 7.77 (d, J ) 8.2 Hz,
2H). 13C NMR (75.5 MHz, CD3OD):17 δ 11.6, 28.0, 32.6, 42.5,
42.3, 53.1, 116.2, 116.4, 124.8, 126.9, 127.9, 128.0, 128.2, 129.0,
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 2-(4-Ca r ba m -
im id oylb en zyla m id e) 1-[(3,5-Dim et h oxyp h en yl)et h yl-
a m id e] (1{11}). Compound 1{11} (21 mg, 50%) was collected
as a white powder according to the method for preparing 1{2}
1
using 11{11} (25 mg, 0.074 mmol) instead of 11{2}. H NMR
(300 MHz, CD3Cl3): δ 1.10 (t, J ) 7.1 Hz, 3H), 1.80-1.90 (m,
1H), 2.17-2.20 (m, 1H), 2.23-2.39 (m, 2H), 3.55-3.66 (m, 1H),
3.88-4.05 (m, 1H), 4.45 (d, J ) 16.1 Hz, 1H), 4.60 (d, J ) 16.1
Hz, 1H), 6.76-7.79 (m, 1H), 6.42-6.47 (m, 1H), 6.52-6.56 (m,
2H), 7.55 (d, J ) 8.5 Hz, 2H), 7.78 (d, J ) 8.5 Hz, 2H). 13C
NMR (75.5 MHz, CDCl3): δ 12.0, 32.6, 42.4, 45.0, 46.8, 53.1,
54.9, 99.5, 106.3, 127.0, 127.9, 128.0, 137.9, 140.4, 144.6, 146.3,
161.5, 168.5, 175.7. HRMS m/z: 451.2342 [(M + H)+ calcd for
129.8, 131.1, 137.3, 140.3, 146.2, 156.4, 159.9, 160.5, 167.1,
+
176.2. HRMS m/z: 409.2032 [(M + H)+ calcd for C23H26FN4O2
409.2040].
,
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
im id oylben zyla m id e) 2-[Eth yl-(2-m eth oxyp h en yl)a m id e]
(1{6}). Compound 1{6} (37 mg, 59%) was collected as a white
powder according to the method for preparing 1{2} using 11{6}
(36 mg, 0.12 mmol) instead of 11{2}. 1H NMR (300 MHz, CD3-
Cl3): δ 1.01-1.18 (m, 3H), 1.76-1.82 (m, 1H), 1.83-2.20 (m,
3H), 3.40-3.58 (m, 1H), 3.60-3.70 (m, 1H), 3.82 (s, 3H), 3.86-
4.01 (m, 1H), 4.40-4.61 (m, 2H), 5.50-5.63 (m, 1H), 6.90-
7.21 (m, 3H), 7.22-7.40 (m, 1H), 7.60 (d, J ) 8.4 Hz, 2H), 7.79
(d, J ) 8.4 Hz, 2H). 13C NMR (75.5 MHz, CDCl3): δ 12.0, 28.1,
32.5, 42.5, 43.5, 53.1, 54.9, 111.8, 120.7, 126.8, 127.9, 127.9,
C
25H31N4O4+, 451.2345].
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
im id oylben zyla m id e) 2-[Eth yl(4-m eth oxyp h en yl)a m id e]
(1{12}). Compound 1{12} (47 mg, 67%) was collected as a
white powder according to the method for preparing 1{2} using
11{12} (40 mg, 0.13 mmol) instead of 11{2}. 1H NMR (300
MHz, CD3Cl3): δ 1.14 (t, J ) 7.1 Hz, 3H), 1.78-1.82 (m, 1H),
2.05-2.20 (m, 1H), 2.21-2.30 (m, 2H), 3.58-3.70 (m, 2H),
3.93-4.01 (m, 1H), 4.42 (d, J ) 15.9 Hz, 1H), 4.58 (d, J ) 15.9
Hz, 1H), 5.78-5.82 (m, 1H), 7.10 (d, J ) 8.9 Hz, 2H), 7.19 (d,
J ) 8.9 Hz, 2H), 7.58 (d, J ) 8.4 Hz, 2H), 7.79 (d, J ) 8.4 Hz,
2H). 13C NMR (75.5 MHz, CDCl3): δ 11.9, 28.0, 32.6, 42.4, 45.3,
53.2, 54.7, 114.3, 127.4, 127.9, 128.0, 129.2, 135.6, 137.9, 141.9,
146.2, 159.3, 167.8, 175.8. HRMS m/z: 421.2244 [(M + H)+
calcd for C24H29N4O3+, 421.2240].
2-[1-(2-Meth yl-2,3-d ih yd r oin d ol-1-yl)m eth a n oyl]cyclo-
p en t -2-en eca r b oxylic Acid 4-Ca r b a m im id oylb en zyl-
a m id e (1{13}). Compound 1{13} (4.5 mg, 12%) was prepared
from 11{13} (0.18 g, 0.62 mmol) according to the method for
the preparation of 1{7}. 1{13} was produced as a white
powder. 1H NMR on diastereomers (300 MHz, CDCl3): δ 1.18-
1.25 (m, 3H), 2.05-2.20 (m, 1H), 2.21-2.39 (m, 1H), 2.43-
2.78 (m, 3H), 2.97-3.07 (m, 1H), 3.95-4.04 (m, 1H), 4.21-
4.38 (m, 1H), 4.53-4.61 (m, 1H), 4.70-4.82 (m, 1H), 6.30-
6.47 (m, 1H), 7.02-7.17 (m, 1H), 7.19-7.25 (m, 2H), 7.40 (s,
2H), 7.49-7.60 (m, 2H), 7.90-8.04 (m, 1H). 13C NMR (75.5
MHz, CDCl3): δ 20.7, [27.3 and 27.6],18 [32.8 and 32.9],18 35.8,
42.4, 53.5, [56.9 and 57.7],18 117.5, 124.3, 125.2, 125.3, 126.7,
128.0, 128.7, 129.3, 130.3, 139.7, 146.3, 157.6, 168.7, 175.4.
+
HRMS m/z: 421.2247 [(M + H)+ calcd for C24H29N4O3
421.2240].
,
{[5-(4-Ca r b a m im id oylb en zylca r b a m oyl)cyclop en t -1-
en eca r bon yl]-o-tolyla m in o}a cetic Acid (1{7}). Compound
1{7} (0.034 g, 23%) was prepared from 11{7} (0.10 g, 0.27
mmol) according to the method for the preparation of 1{3} but
using DCC (0.062 g, 0.30 mmol) and HOBt (0.30 mL, 1 M
solution, 0.30 mmol) in warm THF (50 °C) instead of HATU
in DMF. Purification was achieved using preparative HPLC
(Kromasil C-18; methanol/water, 1:1, + 0.1% TFA). 1{7} was
1
produced as a white powder. H NMR (250 MHz, CD3OD): δ
1.81-1.96 (m, 1H), 2.0-2.12 (m, 1H), 2.38-2.43, (m, 5H),
3.60-3.79 (m, 1H), 3.81-3.87 (d, J ) 16.8 Hz, 0.5H),18 3.90-
3.97 (d, J ) 16.8 Hz, 0.5 H), 4.39-4.60 (m, 2H), 4.58-4.64 (d,
J ) 16.8 Hz, 0.5H),18 4.70-4.76 (d, J ) 16.8 Hz, 0.5H),18 5.41-
5.08 (m, 1H), 7.12-7.35 (m, 3H), 7.39-7.48 (m, 1H), 7.52-
7.78 (m, 4 H). 13C NMR (62.9 MHz, CD3OD): δ 16.1, 27.3 (d),
32.9 (d), 42.5 (d), 51.2 (d), 53.0 (d), 126.9, 127.0, 127.8, 128.0,
128.5, 128.6, 128.8, 129.7, 131.2, 131.5, 142.4, 142.5, 163.7,
174.6, 176.8, 180.4. HRMS m/z: 435.2037 [(M + H)+ calcd for
127.0, 127.5, 127.7, 127.8, 127.9, 138.2, 144.3, 166.4, 166.7,
178.5. HRMS m/z: 403.2131 [(M + H)+ calcd for C24H27N4O2
403.2133].
,
+
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
im id oylb en zyla m id e) 2-[(5-Ch lor o-2-m et h ylp h en yl)-
C
24H27N4O4+, 435.2032].
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
eth yla m id e (1{14}). Compound 1{14} (38 mg, 60%) was
collected as a white powder according to the method for
preparing 1{2} using 11{14} (37 mg, 0.11 mmol) instead of
11{2}. 1H NMR (300 MHz, CD3OD): δ 1.02-1.19 (m, 3H),
1.78-1.93 (m, 1H), 1.98-2.43 (m, 6H), 3.18-3.23 (m, 1H),
[3.43-3.52 and 4.62-3.75 (m, 1H)],18 [3.82-3.98 and 4.05-
4.19 (m, 1H),18 4.38-4.62 (m, 2H), [5.38-5.44 and 5.54-5.62
(m, 1H)],18 7.22-7.40 (m, 3H), 7.45-7.60 (m, 2H), 7.72-7.82
(m, 2H). 13C NMR (75.5 MHz, CD3OD): δ 11.2, 16.2, 28.0, 32.9,
42.4, 43.9, 53.4, 124.3, 126.8, 127.8, 127.9, 128.0, 128.2, 128.7,
129.9, 132.4, 140.4, 145.5, 150.1, 162.0, 165.2, 175.9. HRMS
m/z: 439.1885 [(M + H)+ calcd for C24H28ClN4O2+, 439.1901].
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
im id oylb en zyla m id e) 2-[E t h yl-(3-et h ylp h en yl)a m id e]
(1{19}). Compound 1{19} (50 mg, 60%) was collected as a
white powder according to the method for preparing 1{2} using
0 °C DMF and BOP-Cl instead of 50 °C THF and DCC/HOBt
and using 11{19} (53 mg, 0.17 mmol) instead of 11{2}. 1H
NMR (300 MHz, CDCl3): δ 1.11 (t, J ) 7.0 Hz, 3H), 1.22 (t, J
) 7.6 Hz, 3H), 1.78-1-92 (m, 1H), 2.02-2.38 (m, 3H), 2.58-
2.67 (q, J ) 7.6 Hz, 2H), 3.58-3.70 (m, 2H), 3.93-4.02 (m,
1H), 4.43 (d, J ) 16.1 Hz, 1H), 4.60 (d, J ) 16.1 Hz, 1H), 5.58-
5.62 (m, 1H), 7.02-7.10 (m, 3H), 7.12-7-16 (m 1H), 8.60 (d,
J ) 8.2 Hz, 2H), 8.78 (d, J ) 8.2 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3): δ 11.9, 15.0, 28.1, 28.4, 32.6, 42.6, 45.0, 53.2, 125.1,
126.9, 127.0, 127.7, 127.9, 128.0, 129.1, 137.9, 140.7, 142.9,
146.0, 146.2, 160.1, 167.1, 175.7. HRMS m/z: 419.2443 [(M +
H)+ calcd for C25H31N4O2+, 419.2447].
im id oylb en zyla m id e) 2-[(3-Ch lor op h en yl)et h yla m id e]
(1{9}). Compound 1{9} (65 mg, 72%) was collected as a white
powder according to the method for preparing 1{2} using 11{9}
(51 mg, 0.12 mmol) instead of 11{2}. 1H NMR (300 MHz, CD3-
Cl3): δ 1.10 (t, J ) 7.1 Hz, 3H), 1.78-1.83 (m, 1H), 2.17-2.21
(m, 1H), 2.25-2.30 (m, 2H), 3.57-3.63 (m, 1H), 3.77-3.81 (m,
1H), 3.97-4.03 (m, 1H), 4.44 (d, J ) 15.1 Hz, 1H), 4.60 (d, J
) 15.1 Hz, 1H), 5.62-5.65 (m, 1H), 7.22-7.42 (m, 4H), 7.58
(d, J ) 8.2 Hz, 2H), 7.78 (d, J ) 8.2 Hz, 2H). 13C NMR (75.5
MHz, CDCl3): δ 11.9, 28.1, 32.7, 42.5, 45.1, 53.2, 126.6, 127.5,
127.9, 128.0, 128.2, 130.3, 134.5, 137.7, 141.0, 144.4, 146.2,
160.2, 167.1, 169.2, 175.7. HRMS m/z: 425.1751 [(M + H)+
calcd for C23H26ClN4O2+, 425.1744].
Cyclop en t-2-en e-1,2-d ica r boxylic Acid 1-(4-Ca r ba m -
im id oylb en zyla m id e) 2-[E t h yl(3-flu or op h en yl)a m id e]
(1{10}). Compound 1{10} (27 mg, 44%) was collected as a
white powder according to the method for preparing 1{2} using
11{10} (34 mg, 0.11 mmol) instead of 11{2}. 1H NMR (300
MHz, CD3Cl3): δ 1.10 (t, J ) 7.1 Hz, 3H), 1.78-1.82 (m, 1H),
2.18-2.21 (m, 1H), 2.35-3.39 (m, 2H), 3.58-3.65 (m, 1H),
3.76-3.81 (m, 1H), 3.97-4.03 (m, 1H), 4.44 (d, J ) 16.1 Hz,
1H), 4.60 (d, J ) 16.1 Hz, 1H), 5.61-5.64 (m, 1H), 7.01-7.10
(m, 1H), 7.16-7.21 (m, 2H), 7.37-7.43 (m, 1H), 7.57 (d, J )
8.4 Hz, 2H), 7.76 (d, J ) 8.4 Hz, 2H). 13C NMR (75.5 MHz,
CDCl3):17 δ 11.8, 28.0, 32.7, 42.5, 45.1, 53.1, 114.0, 114.3, 115.5,
124.0, 127.9, 130.4, 130.5, 140.9, 146.2, 164.5, 175.0. HRMS
m/z: 409.2032 [(M + H)+ calcd for C23H26FN4O2+, 409.2040].