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M. Amelia Santos et al. / Bioorg. Med. Chem. 14 (2006) 7539–7550
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(D2O, pD ca. 8): d 7.81 (d, J = 9.0 Hz, 2H, ArH), 7.548
(t, J = 7.8 Hz, 2H, ArH), 7.29 (t, J = 7.5 Hz, 1H, ArH),
7.17 (d, J = 8.1 Hz, 2H, ArH), 7.11 (d, J = 9.0 Hz, 2H,
ArH), 3.91 (s, 4H, CH2CO2H); m/z (FAB): 366
(M+H), 388 (M+Na).
tion mixture was stirred at 60 ꢁC overnight. The solvent
was evaporated, the residue put into a 5% NaOH solu-
tion (40 mL) which was extracted with ethyl acetate
(4· 40 mL), and the organic phase was dried over anhy-
drous Na2SO4. After evaporation of the solvent, the res-
idue was acidified with an HCl saturated methanolic
solution and recrystallized with ethyl ether, producing
the pure di-hydrochloride salt of the product as a yellow
hygroscopic solid (2.00 g, 74% yield). 1H NMR (D2O): d
7.40 (t, J = 8.1 Hz, 2H, ArH), 7.15–7.07 (m, 3H, ArH),
3.52 (br s, 8H, PipH), 3.33 (t, J = 8.4 Hz, 2H, NH2CH2
CH2CH2Pip), 3.10 (t, J = 7.6 Hz, 2H, NH2CH2CH2
CH2Pip), 2.18 (q, J = 7.5 Hz, 2H, NH2CH2CH2CH2Pip);
m/z (FAB): 220 (M+H).
6.2.28.
N-((Benzyloxycarbamoyl)methyl)-N-(4-pheno-
xybenzenesulfonyl)aminoacetic acid (B3b). A procedure
similar to that of A5b was followed with B3a. From
recrystallization with ethyl ether/n-hexane, the pure
product was obtained as a pale hygroscopic solid (73%
yield); 1H NMR (D2O, pD ca. 8):
d 7.74 (d,
J = 8.7 Hz, 2H, ArH), 7.43 (t, J = 7.5 Hz, 2H, ArH),
7.34–7.23 (m, 8H, ArH), 7.10 (d, J = 8.1 Hz, 2H,
ArH), 7.02 (d, J = 8.4 Hz, 2H, ArH), 4.68 (s, 2H,
CH2Ph), 3.73 (s, 2H, CH2CONH), 3.66 (s, 2H,
CH2CO2H); m/z (FAB): 471 (M+H).
6.3.3. N-Benzyl-N-(3-(4-phenyl-piperazine-1-yl)propylac-
etamide)aminoacetic acid (C1a). 3-(4-Phenyl-piperazine-
1-yl)-propylamine di-hydrochloride (1.01 g, 3.45 mmol)
was neutralized by stirring with KOH (0.39 g,
6.90 mmol) in dry methanol (50 mL) for 30 min. The
solid was filtered off, the solvent evaporated and the
residue dissolved in dry methanol/acetonitrile 1:1
(50 mL). To a suspension of BIDA anhydride hydro-
chloride (1.00 g, 4.14 mmol) in dry acetonitrile
(40 mL) was added TEA (0.57 mL, 4.14 mmol) and
the mixture stirred for 30 min. After cooling this solu-
tion with an ice-water bath, the amine solution was
dropwise added and the solution stirred for 4 h at
0 ꢁC. The reaction mixture was filtered, evaporated,
and dried under vacuum. The crude material was dis-
solved in water (40 mL) and washed with CH2Cl2 (4·
40 mL). The pH of the aqueous phase was raised up
to 7–8 with 2 M NaOH and then extracted with
CH2Cl2 (4· 40 mL). The organic phase was dried over
anhydrous Na2SO4 and after evaporation of the sol-
vent and vacuum drying, the pure product was ob-
tained as a hygroscopic white foam (1.23 g, 84%
yield). 1H NMR (D2O): d 7.51 (s, 5H, CH2PhH),
7.41 (t, J = 8.1 Hz, 2H, ArH), 7.14–7.09 (m, 3H,
ArH), 4.48 (s, 2H, CH2Ph), 4.09 (s, 2H, CH2CONH),
3.88 (s, 2H, CH2CO2H), 3.82–3.67 (m, 4H,
NCH2CH2CH2Pip), 3.23–3.13 (m, 8H, PipH), 1.90
(q, J = 7.2 Hz, 2H, NCH2CH2CH2Pip); m/z (FAB):
425 (M+H).
6.2.29. N-((Hydroxycarbamoyl)methyl)-N-(4-phenoxy-
benzenesulfonyl)aminoacetic acid (B3). Following a pro-
cedure similar to that for B2 but with B3b, the pure
product was obtained as a white slightly hygroscopic
solid (80%); 1H NMR (D2O, pD ca. 8): d 7.85 (d,
J = 8.7 Hz, 2H, ArH), 7.49 (t, J = 7.2 Hz, 2H, ArH),
7.30 (t, J = 7.2 Hz, 1H, ArH), 7.20–7.15 (2d, 4H,
ArH), 3.83 (s, 2H, CH2CONHOH), 3.81 (s, 2H,
CH2CO2H); m/z (FAB): 381 (M+H). Elem. Anal. calcd
(C16H16N2O7S): C, 50.52; H, 4.24; N; 7.36, S, 8.43%.
Found: C, 50.55; H, 4.45; N, 7.22; S, 8.17%.
6.3. Synthesis of the compounds C
6.3.1. N-Benzyl-iminodiacetic anhydride. To a suspension
of N-benzyliminodiacetic acid (BIDA) (0.500 g,
2.24 mmol) in dry dichloromethane (50 mL) was added
oxalyl chloride (0.25 mL, 2.80 mmol) and the reaction
mixture was left under reflux for 3 h. After cooling
down, the solid was filtered and washed with dry dichlo-
romethane to yield the pure hydrochloric salt of the
1
product as a white solid (0.505 g, 93% yield). H NMR
(CD3CN): d 7.54–7.47 (m, 5H, PhH), 4.26 (s, 2H,
CH2Ph), 3.98 (s, 4H, CH2CO); IR (KBr, cmꢀ1): 1794,
1737 (mC@O).
6.3.2. 3-(4-Phenyl-piperazine-1-yl)-propylamine. To a
solution of N-(3-bromopropyl)phthalimide (3.30 g,
12.3 mmol) in dry acetonitrile (40 mL) were added
phenylpiperazine (1.88 mL, 12.3 mmol) and TEA
(1.88 mL, 13.5 mmol). The mixture was left reacting un-
der reflux for 7 h. After cooling down, the yellow solid
formed was filtered and washed with acetonitrile, yielding
the pure N-(3-(4-phenyl-piperazine-1-yl)propyl)phthali-
mide (3.34 g, 78% yield). Mp 132–134 ꢁC. 1H NMR
(CDCl3): d 7.84 (m, 2H, ArH), 7.68 (m, 2H, ArH), 7.23
(t, J = 8.1 Hz, 2H, ArH), 6.84 (m, 3H, ArH), 3.80 (t,
J = 6.9 Hz, 2H, NCH2CH2CH2Pip), 3.04 (t, J = 8.8 Hz,
4H, 3,5-PipH), 2.54 (t, J = 8.2 Hz, 4H, 2,6-PipH), 2.48
(t, J = 7.5 Hz, 2H, NCH2CH2CH2Pip), 1.91 (q,
J = 7.0 Hz, 2H, NCH2CH2CH2Pip); m/z (FAB): 349 (M).
6.3.4. N-Benzyl-N-(3-(4-phenyl-piperazine-1-yl)propylac-
etamide)aminoacetohydroxamic acid (C1). A procedure
similar to that for A1 was followed with C1a. Here,
the crude product from evaporation of the reaction mix-
ture was dissolved in CH2Cl2 (50 mL), the solution
washed with water (4· 30 mL), dried over anhydrous
Na2SO4 and the solvent evaporated. To the residue,
THF was added leading to the precipitation of the pure
product as a white solid (0.410 g, 48% yield). Mp 126–
127 ꢁC; 1H NMR (D2O, pD ca. 3): d 7.54 (s, 5H,
CH2PhH), 7.46 (t, J = 7.8 Hz, 2H, ArH), 7.23–7.18 (m,
3H, ArH), 4.57 (s, 2H, CH2Ph), 4.19 (s, 2H, CH2CON-
HOH), 4.13 (s, 2H, CH2CONHCH2), 3.54 (br s, 8H,
PipH), 3.26–3.23 (m, 4H, NCH2CH2CH2Pip), 1.95 (q,
J = 6.9 Hz, 2H, NCH2CH2CH2Pip); m/z (FAB): 440
(M+H). Elem. Anal. calcd (C24H33N5O3Æ0.8H-
ClÆ0.2THF): C, 61.65; H, 7.39; N, 14.50%. Found: C,
61.77; H, 7.22; N, 14.54%.
To a solution of the former product (3.23 g, 9.24 mmol)
in 2:3 H2O/THF (40 mL) was added a 40% aqueous
solution of methylamine (12 mL, 0.14 mol) and the reac-