S. Mishra et al. / Bioorg. Med. Chem. 16 (2008) 5536–5546
5543
and N,N-di-isopropylethylamine (DIPEA) (0.95 mL;
5.5 mmol) and stirred overnight at room temperature.
The reaction mixture was diluted with DCM (150) and
washed with water (3 · 50 mL). Organic layer was dried
over Na2SO4 and concentrated under reduced pressure,
giving compound (3 ), which was purified by column
chromatography on silica gel (eluent; chloroform/meth-
anol 9:1) to give desired product as a white syrupy mass.
Yield 0.792 g (78%), 1H NMR (400 MHz, CDCl3)d 1.94
(m, 2H), 2.3 (m, 4H), 2.26 (s, 6H), 3.15 (t, J = 7.6 Hz,
2H), 4.25 (t, J = 5.6 Hz, 2H), 10.46 (s, 1H, carboxy).
13CNMR (400 MHz, CDCl3) d 175.1, 171.0, 64.4,
63.66, 43.06, 32.3, 30.2, 17.4. Anal. Calcd for
C9H17NO4: C, 53.19; H, 8.43; N, 6.89. Found C,
52.93; H, 8.65; N, 6.86. ESI-MS m/z [M + H]+ 204.10.
Ar-H), 7.5 (d, J = 8.6 Hz, 1H, Ar-H). 13C NMR
(400 MHz, CDCl3) d 171.4, 169.6, 152.4, 147.9, 143.5,
131.4, 130.5, 129.6, 129.2, 128.3, 125.6, 121.5, 120.1,
118.5, 64.2, 63.8, 49.03, 33.9, 33.6, 20.8. Anal. Calcd
for C22H25Cl4NO5: C, 50.31; H, 4.80; N, 2.67. Found
+
C, 50.42; H, 4.74; N, 2.65. ESI-MS m/z [MꢀCl]
488.11.
6.4. Succinamic acid 5-chloro-2-(2,4-dichloro-phenoxy)-
phenyl ester (7)
To a solution of succinamic acid (5) (0.234 g, 2 mmol) in
dry DMF (5 mL) was added CDI (0.324 g, 2 mmol) with
stirring at room temperature under N2. After evolution
of CO2 was complete (2 h), triclosan (4) (0.579 g,
2 mmol) was added and the reaction proceeded for an
additional 24 h. The mixture was concentrated in vacuo
to a white solid and washed with H2O followed by CCl4.
The resulting solid was purified on a silica gel column;
elution withEtOAc/methanol (9:1) gave 7as a white crys-
6.2. Pentanedioic acid 5-chloro-2-(2,4-dichloro-phenoxy)-
phenyl ester 2-dimethylamino-ethyl ester (5)
Mono-(dimethyl
aminoethyl)glutatrate
(2.03
g,
1
10 mmol) and CDI (2.03 g, 10 mmol) were suspended
in dichloromethane (10 mL) with stirring at 25 ꢁC under
nitrogen for 1 h. Triclosan (2.895 g; 10 mmol) was added
to this reaction mixture and stirred for another 3 h.
Completion of the reaction was monitored on TLC
and after completion the reaction mixture was poured
in water and extracted with DCM. Organic layer was
dried over Na2SO4, and concentrated in vacuum. The
crude product was chromatographed on silica gel col-
umn, eluted with chloroform/methanol (9:1), Yield
talline solid (0.529 g, 68% yield). H NMR (400 MHz,
CDCl3) d 2.55 (t, J = 6.8 Hz, 2H), 2.82–2.92 (m, 2H),
5.6 (d, J = 8.4 Hz, 2H), 6.67–6.90 (m, 2H, Ar-H), 7.15–
7.26 (m, 4H, Ar-H). 13C NMR (400 MHz, CDCl3) d
172.4, 169.9, 152.0, 148.1, 143.2, 131.0, 129.5, 128.5,
126.9, 125.5, 121.6, 120.9, 119.9, 118.4, 32.6, 29.9. Anal.
Calcd for C16H12Cl3NO4: C, 49.45; H, 3.11; N,
3.60. Found C, 49.45; H, 3.10; N, 3.56. ESI-MS m/z
+
[M+Na] 410, [M + K]+ 427.9.
1
2.554 g (54%). H NMR (400 MHz, CDCl3) d 1.9(m,
6.5. Pentanedioic acid mono-[5-chloro-2-(2,4-dichloro-
phenoxy)-phenyl] ester (8)
2H), 2.27 (s, 6H), 2.3–2.56 (m, 4H), 3.18 (t, J = 7.2 Hz,
2H), 4.16 (t, J = 5.6 Hz, 2H), 6.82 (m, 2H, Ar-H), 7.15
(m, 3H, Ar-H), 7.4 (d, J = 8.0 Hz, 1H, Ar-H). 13CNMR
(400 MHz, CDCl3) d 170.1, 169.8, 148.4, 144.1, 139.2,
127.9, 127.0, 126.7, 125.6, 124.4, 123.4, 121.8, 117.8,
117.5, 64.6, 63.7, 43.0, 32.5, 30.0, 17.4. Anal. Calcd for
C21H22Cl3NO5: C, 53.13; H, 4.67; N, 2.95. Found C,
Triclosan (1.158 g; 4 mmol), glutaric anhydride (0.684 g;
6 mmol) and 4-(dimethyl amino)pyridine (16 mg;
0.13 mmol) were dissolved in 20 mL of dry dichloro-
methane and left overnight at room temperature. The
reaction mixture was diluted with dichloromethane
(100 mL) and washed with water. The organic layer
was dried over sodium sulfate and solvent removed by
vacuum evaporation. The white solid was purified by sil-
ica gel chromatography (eluent: chloroform/methanol
+
53.17; H, 4.69; N, 2.95. ESI-MS m/z [M+H] 474.10.
6.3. (2-{4-[5-Chloro-2-(2,4-dichloro-phenoxy)-phenoxy-
carbonyl]-butyryloxy}-ethyl)-trimethyl-ammonium chlo-
ride (6)
1
10:1 to 5:1). Yield 0.900 g (56%), H NMR (400 MHz,
CDCl3) d 1.98 (m, 2H), 2.40 (J = 4.8 Hz, 2H), 2.55
(t, J = 7.2 Hz), 6.8 (m, 2H, Ar-H), 7.1–7.4 (m, 4H, Ar-
H), 10.6 (s, 1H, carboxy). 13C NMR (400 MHz, CDCl3)
d 176.5, 170.2, 150.8, 146.5, 141.6, 130.4, 129.4, 128,
126.9, 125.8, 124.3, 121.3, 120.5, 119.5, 32.8, 32.5,
19.2. Anal. Calcd for C17H13Cl3O5: C, 50.59; H,
3.25. Found C, 50.45; H, 3.34. ESI-MS m/z
[M+K]+439.2.
The dimethylaminoethyl-glutaryl esters of triclosan
(compound 5, 0.946 g; 2 mmol) dissolved in the mini-
mum amount of dry THF was treated with methyl io-
dide ( 0.71 g; 0.32 mL; 10 mmol). Although a solid
product separated in the very first few minutes, stirring
at room temperature continued for another 3 h. The
reaction mixture was left overnight at 4 ꢁC, and then
the precipitate was filtered off, washed with several por-
tions of dry ether followed by drying in vacuum. Iodide
salts were used in ion exchange without additional puri-
fication. Ion exchange chromatography on a Sephadex
column (chloride form, DEAE, A25) with methanol as
eluent afforded white (waxy) solid. The residue was fur-
ther purified by flash chromatography over silica Merck-
60, eluting with a gradient (from 1:9 to 4:6) of methanol
6.6. 4-Oxo-pentanoic acid 5-chloro-2-(2,4-dichloro-phen-
oxy)-phenyl ester (9)
To a solution of levulinic (0.255 mL, 2.5 mmol), a few
drops of DMF, and 20 mL CH2Cl2 were added followed
by oxalyl chloride (0.435 mL, 5.0 mmol) dropwise at
room temperature. After stirring at room temperature
for 1 h, the mixture was concentrated to dryness. Then
solution of triclosan (868 mg, 3 mmol), DIPEA
(0.522 mL, 3.0 mmol), and 10 mL CH2Cl2 was added
dropwise, and the reaction mixture was stirred at room
1
in ethyl acetate to provide 6 (1.001 g, 82% yield). H
NMR (400 MHz, CDCl3) d 1.9(m, 2 H), 2.4–2.6
(m, 4H), 3.2 (s, 9H), 3.27 (t, J = 7.8 Hz, 2H), 4.15
(t, J = 5.6 Hz, 2H), 6.9 (m, 2H, Ar-H), 7.2–7.3 (m, 3H,