4402 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 21
Kreimeyer et al.
as described for 14a starting with the appropriate nitro
derivative (11c, 11d ).
Compound 15e was prepared as described for the conversion
of 14a to 15c starting from 14b: yield 88 mg (72%), white
solid: mp 215-217 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.49
(s, 1H, NH amide), 10.37 (br, s, 1H, OH), 7.92 (d, J ) 8.6, 1H,
H-5), 7.37 (t, J ) 8.0, 1H, H-5′), 7.30 (d, J ) 1.9, 1H, H-8),
7.20 (dd, J ) 8.6, 1.9, 1H, H-6), 7.10 (br, d, J ) 7.7, 1H, H-6′),
7.01 (m, 1H, H-4′′), 6.95 (pt, J ) 2.2, 1.3, 1H, H-2′), 6.90 (dd,
J ) 8.3, 1.7, 1H, H-6′′), 6.86 (dd, J ) 8.0, 1.4, 1H, H-3′′), 6.82
(dd, J ) 8.0, 1.3, 1H, H-4′), 6.63 (m, 1H, H-5′′), 5.48 (t, J )
7-Ch lor o-4-h ydr oxy-3-[3-(2-am in oph en oxy)ph en yl]qu in -
olin -2(1H)-on e (14b). Yield 1.21 g (87%), white solid: mp 278
1
°C; H NMR (200 MHz, DMSO-d6) δ 11.55 (s, 1H, NH), 7.91
(d, 1H, J ) 8.3, H-5), 7.33 (t, 1H, J ) 7.8, H5′), 7.30 (d, 1H, J
) 1.9, H-8), 7.2 (dd, 1H, J ) 8.8, 1.9, H-6), 7.3 (d, 1H, J ) 7.8,
H-6′), 6.85 (m, 5H), 6.54 (m, 1H, H-5′′), 4.90 (br, s, 2H, NH2);
MS (FAB) m/z 379 [MH]+. Anal. (C21H15ClN2O3) C, H, N.
7-Ch lor o-4-h ydr oxy-3-[3-(3-am in oph en oxy)ph en yl]qu in -
olin -2(1H)-on e (14c). Yield 0.14 g (45%), white solid: mp
242-244 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.51 (s, 1H,
NH), 7.92 (d, 1H, J ) 8.8, H-5), 7.53 (pt, 1H, J ) 8.0, 7.7, H-5′),
7.30 (d, 1H, J ) 1.9, H-8), 7.20 (dd, 1H, J ) 8.8, 1.9, H-6),
7.10 (d, 1H, J ) 7.7, H-6′), 7.0 (m, 2H, H2′,H5′′), 6.9 (ddd, 1H,
J ) 8.0, 2.2, 1.1, H4′), 6.3 (dd, 1H, J ) 8.0, 1.9, H6′′), 6.24 (pt,
1H, J ) 2.2, 1.9, H-2′′), 6.2 (ddd, 1H, J ) 8.0, 1.9, 0.8, H4′′),
6.5, 1H, NHCH2CH2SO2F), 4.14 (m, 2H, NHCH2CH2SO2F),
+
3.68 (m, 2H, NHCH2CH2SO2F); MS (FAB) m/z 489 [MH]
.
Anal. (C23H18ClFN2O5S) C, H, N.
2-Ch lor o-N-[3-[3-(7-ch lor o-4-h yd r oxy-2-oxo-1,2-d ih y-
d r oqu in olin -3-yl)p h en oxy]p h en yl]a ceta m id e (15f). Com-
pound 15f was prepared as described for the conversion of 12
to 13b starting from 14c: yield 58 mg (64%), white solid; mp
222-224 °C; 1H NMR (300 MHz, DMSO-d6) δ 11.49 (s, 1H,
NH, Ar), 10.37 (s, 1H, NH, amide), 7.92 (d, J ) 8.5, 1H, H-5),
7.39 (m, 2H, H-5′, H-8), 7.31 (m, 3H, H-6, H-6′, H-5′′), 7.19
(m, 2H, H-4′ or H-4′′, H-2′), 7.05 (br, t, J ) 2.5, 1H, H-2′′),
76.95 (ddd, J ) 8.0, 2.5, 0.5, 1H, H-4′ or H-4′′), 6.78 (m, 1H,
H6′′), 4.22 (s, 2H, CH2); MS (FAB) m/z 455 [MH]+. Anal.
(C23H16Cl2N2O4) C, H, N.
4-Ch lor o-2-n itr oben zoic Am id e (17). Compound 17 was
synthesized according to a reported procedure starting from
4-chloro-2-nitrobenzoic acid (6.05 g, 30 mmol).53 The crude
product was purified by silica gel chromatography using 5%
methanol in CH2Cl2 as eluent to give 5.86 g (97%) of 17 as a
white solid: mp 171 °C (lit. 172 °C53); 1H NMR (200 MHz,
CDCl3) δ 8.20 (s, 1H, NH2), 8.13 (d, 1H, J ) 2.2, H-3), 7.86
(dd, 1H, J ) 8.4, 2.2, H-5), 7.77 (s, 1H, NH2), 7.66 (d, 1H, J )
8.4, H-6); MS (EI) m/z 200 [M+]. Anal. (C7H5ClN2O3) C, H, N.
4-Ch lor o-2-n itr oben zon itr ile (18). Compound 18 was
prepared according to the method of Campagna et al.27 starting
from 17 (4.01 g, 20 mmol). Workup was performed by precipi-
tation of the product with ice, filtration, and redissolution of
the residue in CH2Cl2 (100 mL). After extraction with water
(2 × 50 mL), the organic layer was dried (MgSO4), filtrated,
and evaporated to dryness. The crude product was purified
by silica gel chromatography (hexane-ethyl acetate, 8:2, as
eluent): yield 3.30 g (90%), white solid; mp 98 °C (lit. 93-97
°C54); 1H NMR (200 MHz, CDCl3) δ 8.33 (d, 1H, J ) 1.8, H-6),
7.90 (d, 1H, J ) 8.0, H-3), 7.82 (dd, 1H, J ) 8.0, 1H, H-5); MS
(EI) m/z 182 [M+]. Anal. (C7H3ClN2O2) C, H, N.
2-Am in o-4-ch lor oben zon itr ile (19). Amine 19 was syn-
thesized according to the procedure of Lamara et al.54 using
12 equiv of a solution of 20% TiCl3 in hydrochloric acid to
reduce 0.91 g (5 mmol) of 18. Purification by silica gel
chromatography (hexane-ether, 6:4, as eluent) gave 617 mg
(81%) of 19 as a white solid: mp 156 °C (lit. 156-158 °C55);
1H NMR (200 MHz, DMSO-d6) δ 7.41 (d, J ) 8.4, 1H, H-6),
6.82 (d, J ) 2.2, 1H, H-3), 6.59 (dd, J ) 8.4, 2.2, 1H, H-5),
6.33 (s, 2H, NH2), MS (EI) m/z 152 [M+]. Anal. (C7H5ClN2) C,
H, N.
5.19 (br, s, 2H, NH2); MS (FAB) m/z 379 [MH]+. Anal. (C21H15
-
ClN2O3) C, H, N.
7-Ch lor o-4-h yd r oxy-3-(3-isoth iocya n a top h en yl)qu in o-
lin -2(1H)-on e (15a ). Treatment of 14a (0.14 g, 0.5 mmol)
under the conditions described for the conversion of 12 to 13a
gave 15a as a pale yellow solid (0.10 g, 62%): mp 227-229
1
°C; H NMR (300 MHz, DMSO-d6) δ 11.64 (s, 1H, NH), 7.97
(d, 1H, J ) 8.6, H-5), 7.46 (pt, 1H, J ) 8.0, 7.7, H-5′), 7.41 (t,
1H, J ) 1.7, H-2′), 7.40 (m, 2H, H-4′, H-6′), 7.33 (d, 1H, J )
2.0, H-8), 7.22 (dd, 1H, J ) 8.6, 2.0, H-6′); IR (neat) 2108 (NCS);
MS (FAB) m/z 329 [MH]+. Anal. (C16H9ClN2O2S) C, H, N.
2-Ch lor o-N-[3-(7-ch lor o-4-h yd r oxy-2-oxo-1,2-d ih yd r o-
qu in olin -3-yl)p h en yl]a ceta m id e (15b). Treatment of 14a
(0.11 g, 0.4 mmol) under the conditions described for the
conversion of 12 to 13b gave 15b as a white solid (52.3 mg,
1
36%): mp > 310 °C; H NMR (300 MHz, DMSO-d6) δ 11.50
(s, 1H, NH, Ar), 10.31 (s, 1H, NH amide), 7.93 (d, 1H, J ) 8.8,
H-5), 7.60 (d, 1H, J ) 7.7, H-4′), 7.55 (br, s, 1H, H-2′), 7.33 (t,
1H, J ) 8.0, H-5′), 7.30 (d, 1H, J ) 2.2, H-8), 7.20 (dd, 1H, J
) 8.0, 1.4, H-6′), 7.09 (br, d, 1H, J ) 7.1, H-6), 4.25 (s, 2H,
CH2); MS (FAB) m/z 363 [MH]+. Anal. (C17H12Cl2N2O3) C, H,
N.
3-[3-(7-Ch lor o-4-h yd r oxy-2-oxo-1,2-d ih yd r oqu in olin -3-
yl)a n ilin o]eth ylsu lfon yl F lu or id e (15c). The reactive agent
ethenesulfonyl fluoride was obtained as described in the
literature25 with one difference: the procedure using triethyl-
amine instead of MgO was successful for converting 2-chloro-
ethanesulfonyl fluoride into ethenesulfonyl fluoride. To a
solution of 14a (0.14 g, 0,5 mmol) in DMF (0.6 mL) was first
added TFA (0.038 mL, 0.5 mmol) and then ethenesulfonyl
fluoride (0.062 mL, 0.75 mmol). The reaction mixture was
stirred overnight, and after addition of water (5 mL) and ethyl
acetate (10 mL), the organic layer was washed with water (2
× 15 mL), dried (MgSO4), filtrated, and evaporated to dryness.
Silica gel chromatography (toluene-ethyl acetate-methanol,
5:4:1, as eluent) of the crude product gave 0.14 g (69%) of 15c
as a white solid: mp 274-276 °C; 1H NMR (200 MHz, DMSO-
d6) δ 11.52 (s, 1H, NH, Ar), 10.10 (s, 1H, NHCH2CH2SO2F),
7.89 (d, 1H, J ) 8.0, H-5), 7.29 (d, 1H, J ) 2.0, H-8), 7.20 (dd,
1H, J ) 8.0, 2.0, H-6), 7.15 (t, 1H, J ) 7.6, H-5′), 6.60 (m, 3H),
4.10 (m, 2H, NH-CH2-CH2-SO2F), 3.62 (m, 2H, NH-CH2-CH2-
SO2F); MS (FAB) m/z 397 [MH]+. Anal. (C17H14Cl2FN2O4S) C,
H, N.
4-Am in o-7-ch lor o-3-(3-p h en oxyp h en yl)qu in olin -2(1H)-
on e (3). Compound 3 was prepared as described by Carling
et al.22 starting from 19 (0.31 g, 2 mmol) and crude 3-phenoxy-
phenylacetic chloride (4 mmol). The obtained intermediate was
not isolated but directly treated with sodium hydride in DMF
to yield compound 3, which was purified by silica gel chroma-
tography (CH2Cl2-methanol, 95:5, as eluent): yield 0.32 g
(51%), white solid; mp 196 °C (lit. 196-197 °C22); the spectro-
2-Ch lor o-N-[2-[3-(7-ch lor o-4-h yd r oxy-2-oxo-1,2-d ih y-
d r oqu in olin -3yl)p h en oxy]p h en yl]a ceta m id e (15d ). Treat-
ment of 14b (0.15 mg, 0.4 mmol) with chloroacetic anhydride
(0.068 g, 0.4 mmol) as described for the preparation of 13b
gave 15d (0.053 g, 29%) as a white powder: mp 153-155 °C;
1H NMR (300 MHz, DMSO-d6) δ 11.52 (s, 1H, NH Ar), 10.37
(br, s, 1H, OH), 9.82 (s, 1H, NH amide), 8.00 (m, 1H, H-3′′),
7.93 (d, J ) 8.5, 1H, H-5), 7.41 (pt, J ) 8.0, 7.7; 1H, H-5′),
7.30 (d, J ) 1.9, 1H, H-8), 7.20 (m, 2H, H-6, H-6′), 7.11 (m,
2H, H-6′′, H-4′′), 7.07 (br, s, 1H, H-2′), 6.98 (m, 2H, H-5′′, H-4′),
copic data are as published by Carling et al.22 Anal. (C21H15
ClN2O2) C, H, N.
-
2-Ch lor o-N-[7-ch lor o-2-oxo-3-(3-p h en oxyp h en yl)-1,2-
d ih yd r oqu in olin -4-yl]a ceta m id e (20). To a solution of 3
(0.109 g, 0.3 mmol) in THF (10 mL) with triethylamine (0.21
mL, 1.5 mmol) was added chloroacetic chloride (0.12 mL, 1.5
mmol), and the mixture was heated to reflux for 1 h. It was
evaporated, and the residue was dissolved in ethyl acetate (20
mL). The organic layer was washed with water (2 × 20 mL),
dried (Na2SO4), filtrated, and removed under vacuum. The
crude product was purified on silica gel (toluene-ethyl acetate,
6:4, as eluent) to give 20 as a white solid (40 mg, 30%): mp
4.36 (s, 2H, CH2); MS (FAB) m/z 455 [MH]+. Anal. (C23H16
-
Cl2N2O5) C, H, N.
2-[2-[3-(7-Ch lor o-4-h yd r oxy-2-oxo-1,2-d ih yd r oqu in olin -
3-yl)ph en oxy]ph en yl]an ilin o]eth ylsu lfon yl Flu or ide (15e).