Prodrugs for Amidines
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 19 3999
206 (27), 178 (12), 177 (43), 139 (11), 112 (25), 111 (20), 95
(100), 83 (32), 75 (19), 57 (17). Anal. (C13H8F2O3) C, H.
(EI+, relative intensity) 210 (M+ - HCl, 4), 139 (26), 122 (13),
109 (8), 76 (13), 75 (11), 65 (27), 64 (17), 63 (100), 50 (10), 43
(13).
To a suspension of bis-amidine 1 (0.5 g, 0.0026 mol) in DMF
(10 mL) at room temperature was added a solution of carbon-
ate 21 (0.87 g, 0.0035 mol). The resulting solution was stirred
for 16 h. Ice water (40 mL) was added to the mixture, filtered,
washed with water (3 × 30 mL) and ether (30 mL), and dried
in a vacuum for 24 h to furnish 4-fluorophenyl carbamate 8
(0.92 g, 61%) as a yellow solid: mp >300 °C; TLC (Rf) 0.45
(CHCl3, MeOH, NH4OH, 4:1:0.2, v/v); IR (KBr) 3465-3000,
1667, 1621, 1491, 1260, 1187, 1139, 1078, 969, 859, 793, 665
1-Acetoxyeth yl 4-Nitr op h en yl Ca r bon a te (17). To a
solution of 1-chloroethyl 4-nitrophenyl carbonate (2.0 g, 0.0082
mol) in glacial acetic acid (50 mL) at room temperature was
added mercuric acetate (3.8 g, 0.012 m) and the mixture was
stirred for 40 h. Water (100 mL) was then added to the mixture
and extracted with ether (2 × 75 mL). The ethereal phase was
washed with NaOH (0.5 N, 30 mL), satd NaCl (30 mL), and
water (2 × 50 mL) and dried (anhydrous Na2SO4). The solution
was filtered, concentrated under reduced pressure, and puri-
fied by silica gel column chromatography to afford pure
carbonate 17 (1.9 g, 89%) as a colorless liquid: TLC (Rf) 0.65
(CHCl3); IR (film) 1779, 1749, 1615, 1592, 1528, 1491, 1266,
1
cm-1; H NMR (DMSO-d6) 9.31 (s, 4H), 8.12 (d, 4H, J ) 8.73
Hz, Ar-CH), 7.98 (d, 4H, J ) 8.57 Hz), 7.33 (s, 2H), 7.22 (d,
8H, J ) 6.5 Hz); 13C NMR (DMSO-d6) 162.1, 161.9, 157.8,
156.5, 154.2, 153.4, 152.6, 147.8, 133.0, 132.4, 132.6, 128.8,
128.5, 127.8, 123.5, 123.4, 123.3, 116.0, 115.9, 115.6, 115.5,
115.4, 115.2; MS m/z (FAB, m-nitrobenzoic acid) 581 (M + 1),
469, 443, 426, 357, 331. Anal. (C32H22N4O5F2‚0.5H2O) C, H,
N.
1
1110, 1070, 857 cm-1; H NMR (CDCl3) 8.29 (d, 2H, J ) 9.05
Hz), 7.41 (d, 2H, J ) 9.04 Hz), 6.84 (q, 1H, J ) 10.95 Hz),
2.14 (s, 3H), 1.62 (d, 3H, 5.4 Hz); 13C NMR (CDCl3) 169.1,
155.3, 150.7, 145.8, 125.5, 121.9, 92.5, 20.96, 19.61; MS m/e
(EI+, relative intensity) 210 (M+), 166 (4), 122 (5), 87 (33), 63
(6), 50 (3), 43 (100).
2,5-Bis[4-(N-(4-m et h oxyp h en oxy)ca r b on yla m id in o)-
p h en yl]fu r a n (9). Bis(4-m eth oxyp h en yl) Ca r bon a te (22).
Reaction of 4-methoxyphenol with 4-methoxyphenyl chloro-
formate in pyridine/CH2Cl2 followed by aqueous workup as
described above gave carbonate 22, after silica gel column
chromatography, in 93% yield as a white solid: mp 95 °C; TLC
(Rf) 0.53 (100% CHCl3); IR (KBr) 3076, 2958, 2848, 1772, 1610,
1514, 1470, 1286, 1242, 1182, 1028, 894, 836, 776, 726, 534
cm-1; 1H NMR (CDCl3) 7.16 (d, 4H, J ) 9.05 Hz), 6.88 (d, 4H,
J ) 9.04 Hz), 3.78 (s, 6H); 13C NMR (CDCl3) 157.7, 153.0,
144.8, 122.0, 114.7, 55.8; MS m/e (EI+, relative intensity, %)
274 (M+, 100), 230 (33), 215 (29), 187 (12), 124 (16), 123 (46),
107 (10), 95 (12), 77 (13), 64 (7), 52 (5), 41 (6). Anal. (C15H14O5)
C, H.
A mixture of bis-amidine 1 (0.4 g, 0.0013 mol), diisopropy-
lethylamine (0.35 g, 0.0026 mol), and THF/CH3CN (1:1 mix-
ture, 15 mL) was stirred at room temperature. A solution of
carbonate 17 (0.71 g, 0.00264 mol) in THF (5 mL) was then
added and stirring was continued for 24 h. Solvents were
removed under reduced pressure at 40 °C, triturated with
anhydrous ether (20 mL), filtered, washed with ether (2 × 25
mL), dried in air, and crystallized from CHCl3-ether to yield
1-acetoxyethyl carbamate 10 as a yellow solid in 71% yield
(0.52 g): mp 165-167 °C dec; TLC (Rf) 0.5 (CHCl3, MeOH,
NH4OH, 4:1:0.2, v/v); IR (KBr) 3690-2900 (br), 3458 (s), 3324
(s), 3131 (s), 2945 (s), 1734, 1667, 1640, 1607, 1562, 1488, 1412,
1362, 1279, 1243, 1147, 1117, 1089, 1057, 1022, 992, 932, 885,
842, 797, 597, 566 cm-1; 1H NMR (DMSO-d6) 9.33 (s, 4H), 8.09
(d, 4H, J ) 8.54 Hz), 7.96 (d, 4H, J ) 8.54 Hz), 7.34 (s, 2H),
6.79 (q, 2H, J ) 10.87 Hz), 2.03 (s, 6H), 1.55 (d, 6H, J ) 5.39
Hz); 13C NMR (DMSO-d6) 168.9, 166.8, 161.5, 152.6, 133.1,
132.6, 128.6, 123.4, 110.8, 89.2, 20.8, 19.6; MS m/z (FAB,
thioglycerol) 565 (M + 1), 479, 461, 435, 375, 357, 331, 314,
288, 271. Anal. (C28H28N4O9) C, H, N.
2,5-B is [4-(N -e t h o x y c a r b o n y lo x y a m id in o )p h e n y l]-
fu r a n (11). Na OH m eth od : To a suspension of the bis-
amidoxime (2,5-bis[4-(N-hydroxyamidino)phenyl]furan) (0.86
g, 0.0028 mol) and CH2Cl2 (15 mL) was added a solution of
ethyl chloroformate (1.22 g, 0.011 mol) in CH2Cl2 (15 mL) and
the mixture stirred for 10 min. NaOH (1 N, 12 mL) was then
added dropwise and stirred at room temperature for 6 h. Ice
water (10 mL) was added and the solid was filtered, washed
with water (3 × 30 mL), dried in air, and crystallized from
ethanol to give pure ethyl carbonate 11 (0.67 g, 50% yield) as
a white solid.
To a suspension of bis-amidine 1 (0.7 g, 0.0016 mol) in DMF
(10 mL) at room temperature was added carbonate 22 (1.39
g, 0.0051 mol) and the mixture stirred for 24 h. Anhydrous
ether (25 mL) was then added to the precipitated product,
stirred for a few minutes, filtered, washed with ether (3 × 15
mL), and dried under vacuum in a desiccator for 48 h to
furnish 4-methoxyphenyl carbamate 9 (0.9 g, 65%) as a yellow
solid: mp >300 °C; TLC (Rf) 0.68 (CHCl3, MeOH, NH4OH, 4:1:
0.2, v/v); IR (KBr) 3450-3100, 3010, 2934, 2836, 1683, 1484,
1256, 1184, 1142, 1078, 1033, 1010, 967, 928, 850, 801, 774,
1
753, 696, 659, 607, 583, 559, 531 cm-1; H NMR (DMSO-d6)
9.26 (s, 4H), 8.11 (d, 4H, J ) 8.54 Hz), 7.98 (d, 4H, J ) 8.53
Hz), 7.34 (s, 2H), 7.09 (d, 4H, J ) 9.04 Hz), 6.93 (d, 4H, J )
9.03 Hz), 3.75 (s, 6H), 2.88 (s, 3H, DMF), 2.72 (s, 3H, DMF);
13C NMR (DMSO-d6) 166.62, 156.3, 152.6, 145.1, 133.0, 132.6,
128.5, 123.4, 122.7, 114.1, 110.7, 55.4, 35.74 (DMF), 30.74
(DMF); MS m/z (FAB, thioglycerol) 605 (M + 1), 481, 429, 323,
303, 289, 273, 257, 247, 229. Anal. (C34H28N4O7‚1DMF) C, H,
N.
Ca r bon a te m eth od : Eth yl 4-Nitr op h en yl Ca r bon a te
(13). Reaction of 4-nitrophenol with ethyl chloroformate in
pyridine/CH2Cl2 as described above, gave carbonate 13 as
colorless crystals in 92% yield by silica gel chromatographic
purification and 82% by crystallization: mp 70-71 °C; TLC
(Rf) 0.48 (100% CHCl3); IR (KBr) 3124, 3092, 3010, 2920, 2866,
1772, 1622, 1600, 1536, 1278, 1112, 1060, 1006, 908, 860, 774,
2,5-Bis[4-(1-a cetoxyeth oxyca r bon yla m id in o)p h en yl]-
fu r a n (10). 1-Ch lor oeth yl 4-Nitr op h en yl Ca r bon a te (16).
To an ice-cold solution of 4-nitrophenol (2.0 g, 0.015 mol) and
triethylamine (1.6 g, 0.016 mol) (or pyridine) in CH2Cl2 (20
mL) at 0-5 °C was added a solution of 1-chloroethyl chloro-
formate (2.1 g, 19 mmol) in CH2Cl2 (10 mL) and the mixture
stirred for 15 min and then at room temperature overnight
(16 h). The mixture was extracted with CH2Cl2 (50 mL),
washed successively with water (50 mL), NaOH (0.5 N, 50 mL),
satd NaCl solution (50 mL), and water (3 × 50 mL), and dried
(Na2SO4). The CH2Cl2 solution was filtered and evaporated
under reduced pressure and the residue was purified by silica
gel column chromatography using chloroform (100%) as eluent
to furnish pure carbonate 16 as a white solid: mp 70-71 °C
(lit.21 mp 69-70 °C); TLC (Rf) 0.75 (CHCl3); IR (KBr) 3116,
3084, 2999, 2932, 2864, 2364, 2330, 1779, 1626, 1525, 1355,
732, 662, 527, 502 cm-1 1H NMR (CDCl3) 8.29 (d, 2H, J )
;
9.05 Hz), 7.38 (d, 2H, J ) 9.05 Hz), 4.36 (q, 2H, J ) 14.28
Hz), 1.38 (t, 3H, J ) 7.07 Hz); 13C NMR (CDCl3) 155.8, 152.6,
145.6, 125.5, 122.0, 65.7, 14.3; MS m/e (EI+, relative intensity,
%) 212 (M+, 1.4), 211 (1), 139 (100), 109 (60), 89 (100), 93 (13),
81 (11), 65 (21), 63 (13).
Reaction of the bis-amidoxime with carbonate 13 in DMF
at room temperature gave the bis-ethoxycarbonyloxy deriva-
tive in 85% yield as a white solid: mp >300 °C dec. The
physical data for compound 11 obtained by both methods were
identical. TLC (Rf) 0.5 (CHCl3, MeOH, NH4OH, 4:1:0.2, v/v);
IR (KBr) 3700-3100, 3056, 2989, 2937, 2915, 2890, 1770, 1668,
1635, 1481, 1414, 1370, 1266, 1208, 1124, 1035, 1013, 939, 857,
834, 775, 686 cm-1; 1H NMR (DMSO-d6) 7.91 (d, 4H, J ) 7.21
Hz), 7.78 (d, 4H, J ) 7.20 Hz), 7.24 (s, 2H), 6.89 (s, 4H), 4.20
1245, 1101, 914, 863, 779, 677 cm-1 1H NMR (CDCl3) 8.31
;
(dd, 2H, J ) 5.08, 2.07 Hz), 7.43 (dd, 2H, J ) 4.76, 2.22 Hz),
6.50 (q, 1H, J ) 11.67 Hz), 1.93 (d, 3H, J ) 5.87 Hz); 13C NMR
(CDCl3) 155.2, 150.6, 145.9, 125.6, 121.9, 85.4, 25.3; MS m/e