J. Wrobel et al. / Bioorg. Med. Chem. 10 (2002) 639–656
651
Hz, 8H), 7.60 (s, 2H), 7.44 (t, J=7 Hz, 4H), 7.37 (t,
J=7 Hz, 4H), 4.5–4.7 (m, 6H), 4.34 (m, 2H), 1.18 (d,
J=6 Hz, 12H); MS (ES-POS): [M+Na] 921. Anal.
calcd for C50H46N2O10S.20.5H2O: C, 66.13; H, 5.22; N,
3.08. Found: C, 66.00; H, 5.08; N, 3.04.
compound (2, 50 mg, 66%):ÀESI: [MÀH]- 1066. 1H
NMR (DMSO-d6) d 10.55 (s, 2H), 8.21 (s, 2H), 8.14 (d,
J=8 Hz, 2H), 8.07 (s, 2H), 8.03 (s, 2H), 7.95 (d,
J=8 Hz, 2H), 7.61 (m, 4H), 3.31 (m, 8H), 3.06 (m, 8H),
2.58 (s, 6H).
This compound (18.7 g, 20.89 mmol) was dissolved in
200 mL of dry DMF under a nitrogen atmosphere. The
clear solution was cooled to 0 ꢁC in an ice bath and
piperidine (8.3 mL, 83.56 mmol) added in one portion.
The solution was allowed to gradually warm to room
temperature and after 3 h was diluted with 750 mL ethyl
acetate. The mixture was washed with brine (3Â). The
aqueous layer was then back extracted with ethyl ace-
tate (2Â) and the organiclayers were ocmbined. The
2,20-[(E)-1,2-Ethenediyl]bis[5-[3-[(1,1-dioxido-4-thiomor-
pholinyl)sulfonyl]-4-methoxybenzoyl]amino]benzenesulfo-
nic acid] (14). Using the same procedure as for
compound 2 above and starting from 3-(1,1-dioxo-1-
thiomorpholine-4-sulfonyl)-4-methoxy-benzoicacid ( 74)
the title compound was produced in 15% yield: ESI:
1
[MÀH]- 1031. H NMR (DMSO-d6) d 10.50 (s, 2H),
8.46 (d, 2H, J=2 Hz), 8.35 (dd, 2H, J=2 Hz, 9 Hz),
8.16 (d, 2H, J=2 Hz), 8.07 (s, 2H), 7.89 (dd, 2H, J=2
Hz, 9 Hz), 7.62 (d, 2H, J=9 Hz), 7.43 (d, 2H, J=9 Hz),
4.04 (s, 6H), 3.67 (br s, 8H), 3.25 (br s, 8H).
organiclayer was dried (MgSO ) and concentrated to a
4
small volume. Hexane (200 mL) was added with stirring
and the resulting precipitate was collected by filtration.
The compound was further dried, under vacuum, over-
night to afford the title compound (58, 7.3 g, 77%) as a
dark yellow solid: 1H NMR (DMSO-d6) d 7.48 (d,
J=8 Hz, 2H), 7.38 (s, 2H), 7.20 (d, J=2 Hz, 2H), 6.90
(dd, J=2 Hz, 8 Hz, 2H), 5.90 (br s, 4H), 4.53 (m, 2H),
1.17 (d, J=6 Hz); MS (ES-NEG): [MÀH] 453. Anal.
calcd for C20H26N2O6S2.1.2H2O: C, 50.45; H, 6.01; N,
5.88. Found: C, 50.44; H, 5.83; N, 5.87.
4-Allylsulfonylbenzoic acid (83, R=allyl). A solution of
commercially available 4-mercaptobenzoic acid (4 g,
26 mmol) in methylene chloride (200 mL) was treated
with triethylamine (4 g, 40 mol) at room temperature.
The resulting solution was cooled to 0 ꢁC and treated
with allyl bromide (10 g, 83 mmol) in methylene chloride
(5 mL) under a nitrogen atmosphere. The mixture was
stirred at 0 ꢁC for 2 h and at room temperature for an
additional 18 h. It was diluted with methylene chloride
(500 mL), washed with water, dried, and evaporated.
The crude product was recrystallized from methylene
chloride/ether/hexane (1:5:20, 25 mL) to afford 4-allyl-
thiobenzoicacid (3.5 g, 66% yield) as a pale solid: 1H
NMR (DMSO-d6) d 3.74 (d, J=7 Hz, 2H), 5.10 (d,
J=11, 17 Hz, 1H), 5.30 (d, J=11, 17 Hz, 1H), 5.85 (m,
1H), 7.39 (d, J=9 Hz, 2H), 7.83 (d, J=9 Hz); MS (ES-
Neg): [MÀH]À 194. Anal. HPLC: 94% purity.
2,20 -[(E)-1,2-Ethenediyl]bis[5-[4-(methylthio)-3-(4-mor-
pholinyl sulfonyl) benzoyl] amino]benzenesulfonic acid]
(2). To a solution of 4-methylsulfanyl-3-(morpholino-4-
sulfonyl)-benzoicaicd ( 72, X=SCH3, NRR00 =mor-
pholine, 2.96 g, 9.3 mmol) in 30 mL of dichloromethane
under nitrogen was added dimethylformamide (50 mL)
and the solution was cooled to 0 ꢁC in an ice water bath.
Oxalyl chloride (1.41 mL, 11 mmol) was added. After 2h
the mixture was concentrated to dryness and then
redissolved in 5 mL of dry tetrahydrofuran. This solu-
tion was added dropwise to a stirred suspension of
bis(1-methylethyl) 2,20-[(E)-1,2-ethenediyl]bis[5-amino-
benzenesulfonate] (58, 2.04 g, 4.5 mmol) and potassium
carbonate (2.57 g, 19 mmol) in 45 mL of dry THF. The
resulting mixture was stirred for 18 h, concentrated to
near dryness, and then partitioned between ethyl acetate
and water. The organicfraction was washed three times
with water followed by brine. The solvent was dried
(MgSO4) and concentrated. The residue was suspended
in 4:1 ethyl acetate/hexane (25 mL), filtered and dried to
afford 2,2-[(E)-1,2-ethenediyl]bis[5-[4-(methylthio)-3-(4-
morpholinyl sulfonyl) benzoyl] amino] benzenesulfonic
acid], bis(1-methylethyl) ester (4, 2.65 g, 55%) as a yel-
low solid: 1H NMR (DMSO-d6) d 10.87 (s, 2H), 8.54 (s,
2H), 8.47 (s, 2H), 8.24 (m, 4H), 7.92 (d, J=2 Hz, 2H),
7.82 (s, 2H), 7.73 (d, J=9 Hz, 2H), 4.95 (m, 2H), 4.78
(m, 2H), 3.89 (m, 4H), 3.60 (m, 8H), 3.58 (m, 4H), 3.12
(m, 8H), 1.97 (m, 4H), 1.68 (m, 4H), 1.18 (d, J=6 Hz,
A solution of this acid (730 mg) in methanol (50 mL)
was treated with Oxone1 (5 g) in water (50 mL) at 0 ꢁC.
The resulting white suspension was stirred at room
temperature for 48 h. The methanol was evaporated
and the residue was diluted with water and extracted
with methylene chloride. The methylene chloride
extract was washed with water, dried and evaporated to
give the title compound (83, R=allyl, 626 mg, 77%
1
yield) as a white solid: H NMR (DMSO-d6) d 4.20 (d,
J=7 Hz, 2H), 5.20 (d, J=17, 11 Hz, 1H), 5.30 (d, J=17,
11 Hz, 1H), 5.68 (m, 1H), 7.97 (d, J=9 Hz), 8.10 (d,
J=9 Hz). Anal. HPLC: 92.4% pure; MS (ES-Neg):
[MÀH]À 225.
2,20-[(E)-1,2-Ethenediyl]bis[5-[4-(2-propenylsulfonyl)ben-
zoyl]amino]benzenesulfonic acid (37). Commercially
available 4,40-diaminostilbene-2,20-disulfonicacid (2.0 g,
5.4 mmol) was suspended in water (16 mL) and treated
with 1 M tetra-N-butylammonium hydroxide solution
(11.2 mL, 11.2 mmol). The resulting solution was stirred
at rt for 1 h and then extracted with methylene chloride
(3Â50 mL). The methylene chloride extract was washed,
dried and evaporated to dryness to afford 2,20-[(E)-1,2-
ethenediyl]bis[5-aminobenzenesulfonicacid, bis(tetra- N-
butylammonium) salt (3.48 g, 75% yield) as an orange
solid: 1HNMR (CDCl3) d 0.90 (m, 24H), 1.25 (m, 16H),
1.45 (m, 16H), 3.00 (m, 16H), 6.57 (d, J=8 Hz, 2H),
.
12H); CHN, calcd for C44H52N4O14S6 2H2O: C, 48.51;
H, 5.18; N, 5.14. Found: C, 48.42; H, 5.29; N, 4.57.
This compound (70 mg, 0.07 mmol) was dissolved in
acetone (20 mL) and sodium iodide (120 mg, 0.80 mmol)
was added. The mixture was stirred at 60 ꢁC for 12 h. It
was filtered, washed several times with acetone, and fil-
tered again, to provide the bis(sodium) salt of the title