J. B. Baell et al. / Bioorg. Med. Chem. 12 (2004) 4025–4037
4035
1
61 ꢂC (glass); H NMR (300 MHz, CDCl3) d ppm: 1.39
calcd for C34H36N6O5S (M+Hþ) 641.2546, found
641.2534.
(s, 9H), 1.48 (s, 9H), 1.49 (s, 9H), 1.86 (s, 2H), 2.02 (p,
2H, J ¼ 6:9 Hz), 3.15 (s, 2H), 3.61 (q, 2H, J ¼ 6:9 Hz),
3.97 (q, 4H, J ¼ 6:0 Hz), 4.75 (s, 1H), 5.05 (s, 1H), 5.60
(s, 1H), 6.73–7.76, 6.93–7.16, 7.29–7.46 (m, 15H), 7.79
(dd, 1H, J ¼ 0:6, 8.7 Hz); 13C NMR (75 MHz, CDCl3) d
ppm: 28.2, 28.4, 28.5, 28.7, 32.0, 37.5, 39.0, 51.6, 66.3,
66.5, 79.2, 83.0, 110.8, 112.3, 114.0, 117.9, 118.4, 122.7,
123.1, 124.7, 128.7, 128.9, 129.1, 129.6, 129.7, 131.5,
134.5, 144.3, 152.9, 153.7, 154.6, 155.9, 156.0, 157.6,
157.9, 163.4, 169.6; ATR IR(neat) cmꢁ1: 3330, 2977,
2930, 1720, 1642,1614; HRMS calcd for C49H60N6O10S
(M+Hþ) 925.4170, (M+Naþ) 947.3989, found 925.4138,
947.4002.
5.20. N-((4-(3-((Aminoiminomethyl)amino)propoxy)phen-
yl)methyl)-2-(3-aminopropoxy)-N-(6-phenoxy-2-benzo-
thiazolyl)benzamide (4b)
The substituted guanidine (21b) (55.1 mg, 59.6 lmol)
was treated with TFA (0.18 mL, 2.4 mmol) in DCM
(3 mL) for 6 h. The reaction was concentrated under
reduced pressure and then exposed to high vacuum to
remove any remaining TFA. The dirty green product
was dissolved in water, centrifuged and the supernatant
decanted. Freeze-drying of the supernatant afforded 4b
1
(44.9 mg, 79%) as a hygroscopic white solid. H NMR
ppm: 2.06 (p, 4H,
5.18. Carbamic acid, ((3-(4-(((2-methoxybenzoyl)(6-(4-
(benzyloxy)phenoxy)-2-benzothiazolyl)amino)methyl)-
phenoxy)propyl)carbonimidoyl)bis-, bis(tert-butyl) ester
(21c)
(300 MHz, methanol-d4)
d
J ¼ 6:6 Hz), 3.06 (t, 2H, J ¼ 7:2 Hz), 3.39 (t, 2H,
J ¼ 6:75 Hz), 4.03 (t, 2H, J ¼ 5:85 Hz), 4.17 (t, 2H,
J ¼ 5:55 Hz), 5.43 (s, 2H), 6.83 (m, 2H), 6.94–7.20 (m,
9H), 7.30–7.60 (m, 5H), 7.84 (d, J ¼ 9:0 Hz); 13C NMR
(75 MHz, methanol-d4) d ppm: 29.0, 30.5, 39.4, 40.4,
53.7, 66.9, 67.7, 112.6, 114.5, 116.3, 120.5, 120.6, 123.2,
124.4, 125.4, 126.4, 130.0, 130.5, 131.4, 131.7, 134.1,
The title compound was prepared from 12c in a manner
similar to that described for the synthesis of 21a to give
21c (0.123 g, 42%) as a clear amorphous solid. mp 55–
1
56 ꢂC (glass); H NMR (300 MHz, CDCl3) d ppm: 1.49
136.7, 146.4, 156.7, 159.9, 172.6; ATR IR(neat) cmꢁ1
:
(s, 9H), 2.05 (p, 2H, J ¼ 6:0 Hz), 3.61 (t, 2H,
J ¼ 6:0 Hz), 3.74 (s, 3H), 3.97 (t, 2H, J ¼ 5:9 Hz), 5.06
(s, 2H), 5.60 (s, 1H), 6.70–7.74 (m, 20H); 13C
NMR (75 MHz, CDCl3) d ppm: 28.4, 28.7, 32.3, 39.3,
51.8, 55.8, 66.5, 70.8, 79.5, 83.3, 109.7, 111.2, 114.3,
116.2, 117.7, 120.6, 121.0, 122.5, 124.7, 127.7, 128.2,
128.6, 128.8, 128.9, 129.4, 131.7, 134.8, 137.1, 144.1,
151.1, 153.3, 155.1, 155.2, 155.5, 156.2, 158.1, 163.7,
169.9; ATR IR(neat) cmꢁ1: 3330, 3328, 3014, 3043,
2956, 2927, 2869, 1626, 1591, 1152, 1246; HRMS
calcd for C49H53N5O9S (M+Hþ) 888.3642, found
888.3633.
3355, 3172, 2962, 1671, 1595 ; MS m=z 625 (M+Hþ), 739
(M+TFAþ); MS (ESI)) m=z 851 (M+2TFA)Hꢁ);
HRMS calcd for C34H36N6O4S (M+Hþ) 625.2597,
(M+TFA+Hþ) 739.2527, found 625.2587, 739.2517.
5.21. N-((4-(3-((Aminoiminomethyl)amino)propoxy)phen-
yl)methyl)-N-(6-(4-hydroxyphenoxy)-2-benzothiazolyl)
2-methoxybenzamide (4c)
The title compound was prepared from 21c in a manner
similar to that described for the synthesis of 4a, this time
using a reaction time of 6 h to give 4c (16.9 mg, 70%) as a
hygroscopic white solid. 1H NMR (300 MHz, methanol-
d4) d ppm: 2.02 (p, 2H, J ¼ 6:3 Hz), 3.39 (t, 2H,
J ¼ 6:8 Hz), 3.79 (s, 3H), 4.04 (t, 2H, J ¼ 6:0 Hz), 6.76–
7.75 (m, 15H); 13C NMR (75 MHz, methanol-d4) d ppm:
30.5, 40.5, 53.5, 57.1, 66.9, 110.7, 113.4, 116.2, 118.2,
119.3, 121.1, 122.7, 124.1, 127.5, 130.2, 130.4, 131.6,
134.0, 136.6, 145.7, 151.7, 115.9, 157.8, 158.3, 160.3,
172.6; 13C NMR (acetone-d6) d ppm: 39.9, 52.8, 56.8,
66.3, 110.5, 112.9, 115.7, 117.7, 118.6, 122.1, 122.2,
123.6, 126.0, 129.8, 129.9, 130.9, 133.2, 135.9, 145.2,
150.9, 155.3, 156.9, 157.2, 159.5, 170.7; ATR IR(neat)
cmꢁ1: 3353, 3190, 2922, 2857, 1657, 1631, 1599; MS m=z
598 (M+Hþ); MS (ESI-) m=z 596 (M)Hꢁ); HRMS calcd
for C32H31N5O5S (M+Hþ) 598.2124, found 598.2115.
5.19. N-((4-(3-((Aminoiminomethyl)amino)propoxy)phen-
yl)methyl)-2-(3-aminopropoxy)-N-(6-(4-hydroxyphen-
oxy)-2-benzothiazolyl)benzamide (4a)
The substituted guanidine (21a) (0.153 g, 149 lmol) was
treated with thioanisole (0.87 mL, 7.5 mmol) in TFA
(3 mL) for 8 h.38 The reaction was concentrated under
reduced pressure and triturated repeatedly with 2:1 ethyl
acetate:hexane, 2:1 ether:hexane and then hexane.
De-ionised water was added and the resulting mixture
was centrifuged to remove water insoluble components.
The supernatant was decanted and freeze-dried to afford
4a (78 mg, 79%) as a hygroscopic white solid. 1H
NMR (300 MHz, methanol-d4) d ppm: 1.99 (p, 2H,
J ¼ 6:0 Hz), 2.02 (p, 2H, J ¼ 6:0 Hz), 3.01 (t, 2H,
J ¼ 7:3 Hz), 3.35 (t, 2H, J ¼ 6:9 Hz), 3.99 (t, 2H,
J ¼ 5:9 Hz), 4.14 (t, 2H, J ¼ 5:7 Hz), 4.51 (s, 2H), 6.81–
7.17 (m, 9H), 7.34 (d, 2H, J ¼ 2:4 Hz), 7.48–7.52 (m,
2H), 7.71–7.73 (dd, 2H, J ¼ 0:44, 8.8 Hz); 13C NMR
(75 MHz, methanol-d4) d ppm: 29.0, 30.5, 39.4, 40.4,
53.7, 66.9, 67.7, 110.6, 114.5, 116.3, 118.1, 119.4, 122.7,
123.2, 124.2, 126.4, 130.0, 130.5, 131.4, 134.1, 136.6,
145.6, 151.6, 156.0, 156.7, 158.5, 160.5, 172.6; ATR
IR(neat) cmꢁ1: 3359, 3200, 2930, 1673, 1599; HRMS
5.22. 2-(3-Aminopropoxy)-N-((4-(3-aminopropoxy)phen-
yl)methyl)-N-(6-(4-hydroxyphenoxy)-2-benzothiazolyl)-
benzamide (4d)
The amine (20a) (57 mg, 62.2 mol) obtained using the
same hydrazinolysis procedure described above in the
preparation of 21a, was treated with thioanisole
(0.36 mL, 3.1 mmol) in TFA (0.8 mL) for 3 h. The
reaction mixture was then concentrated under reduced