1.0 equiv.) and 2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic
acid, HCl salt (2, 256 mg, 0.86 mmol, 1.0 equiv.) in DCM (20 mL),
Et3N (0.48 mL, 3.4 mmol, 4.0 equiv.) was added to form a
clear homogenous solution. The reaction solution was stirred at
room temperature overnight. The DCM layer was extracted with
water (40 mL) twice. The aqueous layers were combined and the
pH adjusted to 2.0 with concentrated HCl. The precipitate was
collected by filtration, washed with water and dried to afford the
title com◦pound as a white solid (0.19 g, 0.39 mmol, 45%).30 Mp:
160–162 C. 1H NMR (500 MHz, d6-DMSO) d 10.85 (s, 1H), 8.60
(s, 1H), 8.11 (d, J = 6.4 Hz, 1H), 8.03 (s, 1H), 7.62 (dd, J = 6.8,
1.8 Hz, 1H), 7.34 (ddd, J = 6.9, 5.0, 1.9 Hz, 1H), 7.30 (t, J = 8.6
Hz, 1H), 4.37 (ddd, J = 9.9, 8.2, 4.9 Hz, 1H), 3.19–3.05 (m, 1H),
2.91 (dd, J = 13.9, 10.1 Hz, 1H). 13C NMR (126 MHz, d6-DMSO)
d 173.2, 167.8, 157.0 (d, JC–F = 243.5 Hz, 1C), 154.3, 141.9, 136.2
(d, JC–F = 3.6 Hz, 1C), 134.9, 133.8, 132.0, 130.4 (d, JC–F = 7.3 Hz,
1C), 121.5, 119.9, 117.5, 116.3 (d, JC–F = 21.9 Hz, 1C), 107.4 (d,
JC–F = 20.8 Hz, 1C), 54.2, 35.4. HRMS-ESI (m/z): [M+H]+ calcd
A mixture of 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-
dichloro-benzoyl chloride (11, 5.5 g, 12.4 mmol, 1.0 equiv.) and
2-amino-3-(3-bromo-4-fluoro-phenyl)-propionic acid, HCl salt
(2, HCl salt, 3.7 g, 12.4 mmol, 1.0 equiv.) was suspended in
dry THF (200 mL). PhN(CH3)2 (5 mL, 37.5 mmol, 3.0 equiv.)
was added drop wise over 5 min to form a clear solution. After
stirring at room temperature for 2 h, THF was evaporated under
reduced pressure and the residue was re-dissolved in EtOAc. The
organic layer was washed with 1 M HCl and brine, dried over
MgSO4, filtered and concentrated under reduced pressure. The
i
crude product thus obtained was recrystallized from hot PrOAc
to afford the title compound as a white solid (5.6 g, 8.6 mmol,
70%). Mp: 144–145 ◦C. 1H NMR (600 MHz, d6-DMSO) d 13.10
(s, 1H), 11.69 (s, 1H), 9.11 (s, 1H), 8.42 (t, J = 8.5 Hz, 2H),
7.90–7.83 (m, 2H), 7.67 (s, 1H), 7.63 (dd, J = 6.8, 1.9 Hz, 1H),
7.36–7.24 (m, 2H), 4.60 (ddd, J = 10.2, 7.9, 5.1 Hz, 1H), 3.20 (dd,
J = 13.9, 4.9 Hz, 1H), 2.99 (dd, J = 13.9, 10.3 Hz, 1H). 13C NMR
(151 MHz, d6-DMSO) d 171.9, 165.9, 157.1 (d, JC–F = 243.8 Hz,
1C), 154.7, 147.9, 137.5, 135.7 (d, JC–F = 3.5 Hz, 1C), 135.0, 133.9,
132.5, 130.3 (d, JC–F = 7.3 Hz, 1C), 130.2, 129.0, 128.6, 127.5,
for C17H13N2O5FCl2Br 492.9363; found, 492.9355. [a]20 = +11.3◦
D
(c = 0.02, MeOH).
125.2, 119.5, 119.3, 116.4 (d, JC–F = 22.0 Hz, 1C), 107.5 (d, JC–F
=
2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-ben-
zoic acid (6). In a 3-necked, round-bottom flask equipped for
mechanical stirring and fitted with a pH meter was placed a
mixture of 2-amino-4,5-dichloro-benzoic acid (3, 40 g, 0.19 mol,
1.0 equiv.) and benzo[1,2,5]thiadiazole-4-sulfonyl chloride (4, 45 g,
0.19 mol, 1.0 equiv.) suspended in 700 mL H2O. Under vigorous
stirring, aqueous Na2CO3 (2.0 M) was added with a syringe pump
to adjust and maintain the pH at 8.0 0.2. The reaction took
about 16 h to complete (about 1.2 equivalents of Na2CO3 were
needed). Concentrated HCl was carefully added upon stirring to
adjust pH < 2.0. The precipitated solid was collected by filtration,
washed with water and dried under reduced pressure. The crude
product was stirred in hot EtOAc (ca. 1 g/2 mL EtOAc, 50 ◦C) for
20 min. and cooled to room temperature. The solid was collected
by filtration to give the pure title compound (66 g, 0.16 mol, 85%).
Mp: 237–239 ◦C. 1H NMR (500 MHz, d6-DMSO) d 11.93 (br. s,
1H), 8.44 (ddd, J = 9.7, 8.0, 0.9 Hz, 2H), 7.92 (s, 1H), 7.89 (d,
J = 8.8, 7.1 Hz, 1H), 7.72 (s, 1H). 13C NMR (125.7 MHz, d6-
DMSO): d 165.9, 153.3, 146.6, 137.6, 134.8, 130.9, 130.8, 127.9,
127.2, 125.9, 123.4, 117.5, 116.0. IR (dry film, cm-1): 3108 (br. m),
1675 (s), 1375 (s), 1244 (s), 1157 (s). HRMS-ESI (m/z): [M - H]-
calcd for C13H7Cl2N3O4S2 401.9171; found, 401.9177.
20.8 Hz, 1C), 54.0, 34.8. HRMS-ESI (m/z): [M+H]+ calcd for
C22H15N4O5S2FCl2Br 646.9023; found, 646.9015. [a]20 = -79.9◦
D
(c = 0.38, MeOH).
Acknowledgements
We wish to thank Dr Jiejun Wu, Ms. Heather McAllister and Ms.
Bita Naderi for analytical support; and Dr Daniel J. Pippel for
proof-reading this manuscript.
Notes and references
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2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-ben-
zoyl chloride (11). 2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-
4,5-dichloro-benzoic acid (6, 5 g, 12.4 mmol, 1.0 equiv.) was
suspended in 40 mL CH2Cl2 and DMF (48 mL, 5 mol%). Oxalyl
chloride (1.3 mL, 14.9 mmol, 1.2 equiv.) was added drop wise at
room temperature. After stirring at room temperature for 16 h,
the precipitated solid was collected by filtration and washed with
DCM to afford the pure title compound (5.5 g, 12.4 mmol, 100%).
Mp: 210–212 ◦C. 1H NMR (600 MHz, d6-DMSO) d 11.61 (s, 1H),
8.47 (ddd, J = 9.7, 8.0, 0.9 Hz, 2H), 7.92 (s, 1H), 7.91 (dd, J =
8.8, 7.1 Hz, 1H), 7.73 (s, 1H). 13C NMR (151 MHz, d6-DMSO) d
167.5, 154.7, 148.0, 138.6, 136.4, 132.5, 132.5, 129.0, 128.7, 127.6,
125.2, 118.9, 117.2.
2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-
benzoylamino]-3-(3-bromo-4-fluoro-phenyl)-propionic acid (1).
This journal is
The Royal Society of Chemistry 2011
Org. Biomol. Chem., 2011, 9, 2654–2660 | 2659
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