140
E. Rivero-Buceta et al. / European Journal of Medicinal Chemistry 106 (2015) 132e143
evaporated to dryness. The residue was purified by CCTLC using a
gradient of dichloromethane:methanol (10:1) to dichlor-
omethane:methanol:ammonia (10:1:0.2) as eluent to yield 482 mg
(94%) of 15 as a yellow oil. MS (ESþ): m/z 483 (M þ H)þ. 1H NMR
4.1.14. 1,3,5-Tris(2,3,4-trihydroxybenzamidoethylaminomethyl)-
2,4,6-triethylbenzene (20)
Following the general deprotection procedure, the OBn deriva-
tive 19 (119 mg, 0.23 mmol) gave 45 mg (96%)þof 20 as a white solid;
m.p. 164e166 ꢀC. MS (ESþ): m/z 835 (M þ 1) . 1H NMR (400 MHz,
(400 MHz, CDCl3) d: 2.85 (br s, 2H, CH2NH2), 3.35 (m, 2H, CH2NH),
5.06 (s, 2H, CH2Ar), 5.15 (s, 2H, CH2Ar), 5.16 (s, 2H, CH2Ar), 6.87 (d,
J ¼ 9.0 Hz,1H, Ar), 7.28e7.46 (m, 15H, Ar), 7.84 (d, J ¼ 8.9 Hz,1H, Ar),
CD3OD)
d
: 1.19 (t, J ¼ 7.3 Hz, 9H, CH3CH2), 2.91 (q, J ¼ 7.3 Hz, 6H,
CH2CH3), 3.50 (m, 6H, CH2), 3.81 (m, 6H, CH2), 4.22 (s, 6H, CH2NH),
6.39 (d, J ¼ 8.8 Hz, 3H, Ar), 7.22 (d, J ¼ 8.8 Hz, 3H, Ar). 13C NMR
8.22 (t, J ¼ 5.4 Hz, 1H, NH). 13C NMR (100 MHz, CDCl3)
d 41.2 (CH2),
42.2 (CH2), 70.6 (CH2), 75.4 (CH2), 76.8 (CH2), 108.8 (CH), 119.4 (C),
126.6 (CH), 127.3e126.6 (CH), 135.9 (C), 136.1 (C), 136.9 (C), 140.8
(C), 151.5 (C), 155.4 (C), 165.0 (C]O).
(100 MHz, CD3OD) d: 16.6 (CH3), 25.7 (CH2), 37.5 (CH2), 43.3 (CH2),
50.2 (CH2), 108.2 (C), 108.4 (CH), 120.0 (CH), 128.9 (C), 134.1 (C),
149.4 (C), 151.4 (C), 150.7 (C), 173.2 (C]O). Anal. Calcd for
C42H54N6O12: C, 60.42; H, 6.52; N, 10.07. Found: C, 60.21; H, 6.75; N,
9.94.
4.1.11. N-(4-aminobutyl)-2,3,4-tris(benzyloxy)benzamide (16)
In a procedure analogous to that described for compound 15, a
solution of 14 (198 mg, 0.45 mmol) in dichloromethane (6.7 mL)
4.1.15. 1,3,5-Tris(2,3,4-tribenzyloxybenzamidobutylaminomethyl)-
2,4,6-triethylbenzene (21)
To a solution of the tris bromo derivative 18 [7] (29 mg,
0.07 mmol) in dichloromethane (0.5 mL), the aminobutyl derivative
was treated with
a solution of butane-1,4-diamine (270 ml,
2.67 mmol) in dichloromethane (2.2 mL) to yield 205 mg (89%) of
16 as a colorless oil. MS (ESþ): m/z 512 (M þ H)þ. 1H NMR
16 (133 mg, 0.26 mmol) and triethylamine were added (36
ml,
(300 MHz, CDCl3) d: 1.29 (m, 4H, CH2), 1.92 (br s, 2H, NH2), 2.63 (t,
0.47 mmol). The reaction mixture was stirred at room temperature
for 2 h, diluted with dichloromethane (15 mL) and washed with
brine (3 ꢁ 15 mL). The organic phase was dried over anhydrous
MgSO4, filtered, and evaporated. The residue was purified by CCTLC
using dichloromethane:methanol (10:1) as eluent to yield 51 mg
(46%) of 21 as a yellow oil. MS (ESþ): m/z 866 (1/2M þ 1)þ. 1H NMR
J ¼ 6.4 Hz, 2H, CH2NH2), 3.25 (m, 2H, CH2NH), 5.07 (s, 2H, CH2Ar),
5.14 (s, 2H, CH2Ar), 5.16 (s, 2H, CH2Ar), 6.88 (d, J ¼ 9.0 Hz, 1H, Ar),
7.31e7.45 (m, 15H, Ar), 7.90e7.94 (m, 2H, Ar, NH). 13C NMR (75 MHz,
CDCl3) d: 26.6 (CH2), 30.4 (CH2), 39.3 (CH2), 41.5 (CH2), 70.8 (CH2),
75.7 (CH2), 77.2 (CH2), 109.1 (CH), 119.5 (C), 126.8 (CH), 127.5 (CH),
128.2 (CH), 128.4 (CH), 128.6e128.7 (CH), 136.2 (C), 136.4 (C), 137.1
(C), 141.0 (C), 151.7 (C), 155.6 (C), 164.8 (C]O).
(400 MHz, CDCl3)
d
: 1.15 (t, J ¼ 6.2 Hz, 9H, CH3CH2), 1.37 (m, 6H,
CH2), 1.64 (m, 6H, CH2), 2.88 (m, CH2CH3, CH2NH), 3.20 (m, 6H,
CH2NH), 3.93 (br s, 6H, CH2NH), 5.05 (s, 6H, CH2Ar), 5.12 (s, 6H,
CH2Ar), 5.14 (s, 6H, CH2Ar), 6.86 (d, J ¼ 7.8 Hz, 3H, Ar), 7.26e7.42 (m,
45H, Ar), 7.86 (d, J ¼ 7.8 Hz, 3H, Ar), 7.94 (m, 3H, NH). 13C NMR
4.1.12. Piperazin-1-yl-(2,3,4-tris(benzyloxy)phenyl)methanone (17)
In a procedure analogous to that described for compound 15, a
solution of 14 (198 mg, 0.45 mmol) in dichloromethane (6.7 mL)
was treated with a solution of piperazine (235 mg, 2.67 mmol) in
dichloromethane (2.2 mL) to yield a residue that was purified by
CCTLC using dichloromethane:methanol (20:1) as eluent to afford
225 mg (99%) of 17 as a yellow oil. MS (ESþ): m/z 509 (M þ H)þ. 1H
(75 MHz, CDCl3) d: 17.1 (CH3), 24.2 (CH2), 25.0 (CH2), 27.2 (CH2), 39.1
(CH2), 46.63 (CH2), 49.5 (CH2), 71.09 (CH2), 75.91 (CH2), 77.59 (CH2),
109.1 (CH), 119.7 (CH), 127.8 (CH), 128.4 (CH), 128.6 (CH), 128.8 (CH),
128.9 (CH), 129.0 (CH), 129.1 (CH), 136.4 (C), 137.3 (C), 141.3 (C),
152.0 (C), 156.0 (C), 165.3 (C]O).
NMR (300 MHz, CDCl3) d: 2.67 (m, 3H, CH2), 2.86 (m, 1H, CH2), 3.12
4.1.16. 1,3,5-Tris(2,3,4-trihydroxybenzamidobutylaminomethyl)-
2,4,6-triethylbenzene (22)
(m, 2H, CH2), 3.72 (m, 2H, CH2), 4.88 (d, J ¼ 10.6 Hz, 1H, CH2Ar),
5.04e5.20 (m, 5H, CH2Ar), 6.81 (d, J ¼ 8.5 Hz, 1H, Ar), 6.97 (d,
J ¼ 8.6 Hz, 1H, Ar), 7.24e7.48 (m, 15H, Ar). 13C NMR (75 MHz, CDCl3)
Following the general deprotection procedure, the OBn deriva-
tive 21 (50 mg, 0.023 mmol) gave a crude product which was then
purified on a Biotage HPFC system (High Performance Flash Chro-
matography) on reverse phase using water:acetonitrile (100:0 to
70:30) as eluent to afford 7 mg (27%) of 22 as a white amorphous
d: 42.6 (CH2), 45.4 (CH2), 45.9 (CH2), 47.9 (CH2), 71.0 (CH2), 75.2
(CH2), 76.3 (CH2), 109.8 (CH), 122.7 (C), 124.3 (CH), 127.4 (CH),
128.0e128.8 (CH), 136.5 (C), 137.1 (C), 137.3 (C), 141.2 (C), 149.5 (C),
154.0 (C), 167.4 (C]O).
solid. MS (ESþ): m/z 920 (M þ H)þ. 1H NMR (300 MH, CD3OD)
d:
1.18 (t, J ¼ 7.5 Hz, 9H, CH3CH2), 1.72 (m, 6H, CH2), 1.85 (m, 6H, CH2),
2.87 (q, J ¼ 7.3 Hz, 6H, CH2CH3), 3.32 (m, 6H, CH2NH), 3.40 (m, 6H,
CH2NH), 3.48 (m, 6H, NHCH2CH2), 4.32 (s, 6H, CH2NH), 6.35 (d,
J ¼ 8.8 Hz, 3H, Ar), 7.09 (d, J ¼ 8.8 Hz, 3H, Ar). 13C NMR (100 MHz,
4.1.13. 1,3,5-Tris(2,3,4-tribenzyloxybenzamidoethylaminomethyl)-
2,4,6-triethylbenzene (19)
To a solution of the tris bromo derivative 18 [7] (50 mg,
0.11 mmol) in dichloromethane (1 mL) the aminoethyl derivative 15
CD3OD) d: 16.3 (CH3), 24.1 (CH2), 25.3 (CH2), 27.7 (CH2), 38.9 (CH2),
(231 mg, 0.47 mmol) and Et3N (65
ml, 0.47 mmol) were added. The
45.9 (CH2), 108.0 (C), 108.6 (CH), 119.1 (CH), 128.8 (C), 134.0 (C),
reaction mixture was stirred at 30 ꢀC overnight, diluted with
dichloromethane (15 mL) and washed with brine (3 ꢁ 15 mL). The
organic phase was dried over anhydrous MgSO4, filtered, and
evaporated to dryness. The residue was purified by CCTLC using
dichloromethane:methanol:ammonia (15:1:0.4) as eluent to yield
106 mg (57%) of 19 as a colorless oil. MS (ESþ): m/z 1647 (M þ H)þ.
149.3 (C), 150.9 (C), 151.4 (C), 172.2 (C]O). Anal. Calcd for
C48H66N6O12: C, 66.73; H, 7.24; N, 9.14. Found: C, 66.97; H, 7.16; N,
9.08.
4.1.17. 1,3,5-Tris[(4-(2,3,4-tribenzyloxyphenylcarbonyl)piperazin-1-
yl)methyl]-2,4,6-triethylbenzene (23)
To a solution of the tris bromo derivative 18 [7] (43 mg,
0.10 mmol) in dichloromethane (1 mL), the piperazinyl derivative
1H NMR (400 MHz, CDCl3)
d: 1.14 (t, J ¼ 7.2 Hz, 9H, CH3CH2),
2.63e2.69 (m, 12H, CH2CH3, CH2), 3.36 (m, 6H, CH2), 3.61 (s, 6H,
CH2NH), 5.04 (s, 6H, CH2Ar), 5.09 (s, 6H, CH2Ar), 5.14 (s, 6H, CH2Ar),
6.86 (dd, J ¼ 9.2, 0.5 Hz, 3H, Ar), 7.22e7.41 (m, 45H, Ar), 7.88 (dd,
J ¼ 8.9, 0.7 Hz, 3H, Ar), 8.01 (t, J ¼ 5.2 Hz, 3H, NH). 13C NMR
17 (198 mg, 0.39 mmol) and Et3N were added (54 ml, 0.39 mmol).
The reaction mixture was stirred at room temperature overnight,
diluted with dichloromethane (15 mL) and washed with brine
(3 ꢁ 15 mL). The organic phase was dried over anhydrous MgSO4,
filtered, and evaporated. The residue was purified by CCTLC using
dichloromethane:methanol (30:1) to yield 127 mg (75%) of 23 as a
yellow oil. MS (ESþ): m/z 1725 (M þ 1)þ, 863 (1/2M þ 1)þ. 1H-RMN
(100 MHz, CDCl3) d: 17.0 (CH3), 22.6 (CH2), 39.5 (CH2), 47.5 (CH2),
49.4 (CH2), 70.8 (CH2), 75.6 (CH2), 109.1 (CH), 119.9 (C), 126.7 (CH),
127.5 (CH), 128.1e128.8 (CH), 134.0 (C), 136.2 (C), 137.1 (C), 141.1 (C),
142.1 (C), 151.7 (C), 155.6 (C), 164.9 (C]O).