1924 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 12
Spicer et al.
7.7 Hz, 1 H, H-2), 7.64 (dd, J ) 8.5, 2.1 Hz, 1 H, H-6), 7.71 (d,
J ) 8.5 Hz, 1 H, H-5), 8.04 (br s, 1 H, H-8), 8.42 (dd, J ) 7.5,
1.7 Hz, 1 H, H-3), 8.52 (dd, J ) 8.0, 1.7 Hz, 1 H, H-1), 11.98
(s, 1 H, NH), 13.85 (br s, 1 H, COOH). Anal. (C16H13NO3) C,
H, N.
7.0, 1.4 Hz, 1 H, H-3), 9.62 (s, 1 H, H-9), and 16.34 (s, 1 H,
COOH). Anal. (C20H13NO2) C, H, N.
5-F lu or oa cr id in e-4-ca r boxylic a cid (2g) was prepared
by similar reduction of the known8 5-fluoro-9-oxoacridan-4-
carboxylic acid (1g) in 90% yield: mp (MeOH/H2O) 295-298
°C dec; 1H NMR [(CD3)2SO] δ 7.74-7.80 (m, 1 H, ArH), 7.90-
7.96 (m, 2 H, ArH), 8.19 (d, J ) 8.6 Hz, 1 H, ArH), 8.61 (dd, J
) 8.6, 1.2 Hz, 1 H, ArH), 8.81 (dd, J ) 7.0, 1.0 Hz, 1 H, ArH),
9.65 (s, 1 H, H-9). Anal. (C14H8FNO2) C, H, N, F.
A hot suspension of 1u (1.00 g, 3.75 mmol) in 50% aqueous
EtOH was treated with sufficient Et3N to obtain a clear
solution. Portions of aluminum foil (0.83 g) were amalgamated
in a solution of HgCl2 (3 g) in EtOH (50 mL) and added to the
above vigorously boiling solution over 30 min. After the
reaction was complete (TLC), the reaction mixture was filtered
and the solids collected were washed with a solution of KOH
in aqueous EtOH. The filtrate was then strongly acidified with
conc. HCl and treated with FeCl3 under reflux for 45 min.
The reaction mixture was concentrated under reduced pres-
sure and solid KOAc added to adjust the pH to 7. The mixture
was cooled overnight, and the resulting precipitate was col-
lected and recrystallized from Me2CO to give 7-ethylacridine-
4-carboxylic acid (2u ) (0.77 g, 82%): mp 210-211.5 °C; 1H
NMR [(CD3)2SO] δ 1.35 (t, J ) 7.5 Hz, 3 H, CH3), 2.91 (q, J )
7.5 Hz, 2 H, CH2), 7.83 (dd, J ) 8.3, 7.2 Hz, 1 H, H-2), 7.97
(dd, J ) 9.0, 1.9 Hz, 1 H, H-6), 8.09 (br s, 1 H, H-8), 8.26 (d,
J ) 9.0 Hz, 1 H, H-5), 8.54 (dd, J ) 8.4, 1.2 Hz, 1 H, H-1),
8.71 (br d, J ) 7.0 Hz, 1 H, H-3), 9.43 (s, 1 H, H-9), 17.09 (br
s, 1 H, COOH). Anal. (C16H13NO2) C, H, N.
5-Br om oa cr id in e-4-ca r boxylic a cid (2i) was prepared by
reduction of the known8 5-bromo-9-oxoacridan-4-carboxylic
1
acid (1i) in 70% yield: mp (MeOH/H2O) 327 °C dec; H NMR
[(CD3)2SO] δ 7.71 (dd, J ) 8.3, 7.4 Hz, 1 H, H-2), 7.94 (dd, J )
8.4, 7.1 Hz, 1 H, H-7), 8.40 (dd, J ) 8.7, 0.8 Hz, 1 H, ArH),
8.50 (dd, J ) 7.3, 1.0 Hz, 1 H, ArH), 8.64 (dd, J ) 8.5, 1.3 Hz,
1 H, ArH), 8.85 (dd, J ) 7.1, 1.3 Hz, 1 H, ArH), 9.66 (s, 1 H,
H-9), 16.77 (br s, 1 H, COOH). Anal. (C14H8BrNO2) C, H, N,
Br.
6-F lu or oa cr id in e-4-ca r boxylic Acid (2o). Reaction of
4-fluoroanthranilic acid and methyl 2-iodobenzoate by the
method recorded below for the preparation of 2a gave methyl
2-[N-(5-fluoro-2-carboxyphenyl)amino]benzoate (8o) (34%): mp
(MeOH/H2O) 174-175 °C; 1H NMR [(CD3)2SO] δ 3.86 (s, 3 H,
CO2CH3), 6.74 (td, J ) 8.4, 2.4 Hz, 1 H, ArH), 7.09-7.13 (m,
2 H, 2 ArH), 7.54-7.62 (m, 2 H, 2 ArH), 7.93 (dd, J ) 7.9, 1.5
Hz, 1 H, ArH), 8.00 (dd, J ) 8.9, 7.0 Hz, 1 H, ArH), 10.93 (s,
1 H, NH), 13.12 (br s, 1 H, COOH). Anal. (C16H12FNO4‚0.5H2O)
C, H, N, F. Ring closure of this with PPE at 100 °C gave
methyl 6-fluoro-9-oxoacridan-4-carboxylate (13o) (96%): mp
(MeOH) 193-194 °C; 1H NMR [(CD3)2SO] δ 4.00 (s, 3 H, CO2-
CH3), 7.20 (td, J ) 8.7, 2.5 Hz, 1 H, H-7), 7.40 (t, J ) 7.7 Hz,
1 H, H-2), 7.85 (dd, J ) 10.3, 2.4 Hz, 1 H, H-5), 8.29 (dd, J )
12.3, 6.5 Hz, 1 H, H-8), 8.44 (dd, J ) 7.6, 1.6 Hz, 1 H, H-1),
8.55 (dd, J ) 8.0, 1.7 Hz, 1 H, H-3), 11.65 (s, 1 H, NH). Anal.
(C15H10FNO3) C, H, N, Cl. Hydrolysis of 13o in 2 N ethanolic
KOH gave 6-fluoro-9-oxoacridan-4-carboxylic acid (1o) (83%):
mp (MeOH/H2O) 338-341 °C; 1H NMR [(CD3)2SO] δ 7.13 (td,
J ) 8.8, 2.5 Hz, 1 H, H-7), 7.31 (t, J ) 7.7 Hz, 1 H, H-2), 7.63
(dd, J ) 10.7, 2.4 Hz, 1 H, H-5), 8.29 (dd, J ) 9.0, 6.5 Hz, 1 H,
H-8), 8.38-8.41 (m, 2 H, H-1 and H-3), 13.76 (br s, 1 H,
COOH). Anal. (C14H8FNO3‚0.25H2O) C, H, N, F. Reduction
of 1o as above gave 6-fluoroacridine-4-carboxylic acid (2o)
5-Eth yla cr id in e-4-ca r boxylic a cid (2c) was prepared as
above from the known8 5-ethylacridone (1c) in 79% yield, and
had mp (Me2CO) 239-240.5 °C: 1H NMR [(CD3)2SO] δ 1.43
(t, J ) 7.5 Hz, 3 H, CH3), 3.27-3.38 (m, 2 H, CH2), 7.73 (br t,
J ) 7.2 Hz, 1 H, H-2), 7.87 (br t, J ) 7.8 Hz, 1 H, H-7), 7.93
(br d, J ) 6.6 Hz, 1 H, ArH), 8.19 (br d, J ) 8.4 Hz, 1 H, ArH),
8.57 (br d, J ) 8.2 Hz, 1 H, ArH), 8.76 (br d, J ) 6.9 Hz, 1 H,
H-3), 9.54 (s, 1 H, H-9), 7.44 (br s, 1 H, COOH). Anal. (C16H13
NO2) C, H, N.
-
5-Isop r op yla cr id in e-4-ca r b oxylic a cid (2d ) was pre-
pared by similar reaction of 2-iodoisophthalic acid and 2-iso-
propylaniline to give 2-[(2-isopropylphenyl)amino]isophthalic
acid (15d ) (38%): mp (EtOAc/petroleum ether) 217-219 °C;
1H NMR [(CD3)2SO] δ 1.25 (d, J ) 6.8 Hz, 6 H, 2 CH3), 3.22-
3.29 (m, 1 H, CH), 6.81 (dd, J ) 7.4, 1.8 Hz, 1 H, H-3′ or H-6′),
6.93 (t, J ) 7.7 Hz, 1 H, H-2), 6.92-7.02 (m, 2 H, H-4′,5′), 7.26
(dd, J ) 7.1, 2.2 Hz, 1 H, H-6′ or H-3′), 7.90 (d, J ) 7.7 Hz, 2
H, H-4,6), 9.69 (s, 1 H, NH), 12.93 (br s, 2 H, 2 COOH). Anal.
(C17H17NO4) C, H, N. Cyclization of 15d as above gave
5-isopropyl-9-oxoacridan-4-carboxylic acid (1d ) (91%): mp
1
(91%): mp (MeOH/H2O) 268-270 °C; H NMR [(CD3)2SO] δ
7.76 (td, J ) 8.9, 2.5 Hz, 1 H, H-7), 7.86 (dd, J ) 8.4, 7.2 Hz,
1 H, H-2), 8.21 (dd, J ) 10.6, 2.4 Hz, 1 H, H-5), 8.45 (dd, J )
9.3, 6.4 Hz, 1 H, H-8), 8.58 (dd, J ) 8.4, 1.3 Hz, 1 H, H-1),
8.77 (dd, J ) 7.1, 1.5 Hz, 1 H, H-3), 9.60 (s, 1 H, H-9), 16.67
(br s, 1 H, COOH). Anal. (C14H8FNO2) C, H, N, F.
1
(MeOH/H2O) 304 °C dec; H NMR [(CD3)2SO] δ 1.42 (d, J )
6.8 Hz, 6 H, 2 CH3), 3.29-3.41 (m, 1 H, CH), 7.31-7.40 (m, 2
H, H-2 and H-7), 7.74 (dd, J ) 7.4, 1.2 Hz, 1 H, H-6), 8.15 (dd,
J ) 8.1, 1.2 Hz, 1 H, H-8), 8.47 (dd, J ) 7.6, 1.6 Hz, 1 H, H-3),
8.53 (dd, J ) 8.0, 1.6 Hz, 1 H, H-1), 12.48 (s, 1 H, NH), 14.07
(br s, 1 H, COOH). Anal. (C17H15NO3‚0.5H2O) C, H, N.
Reduction of 1d as above gave 2d (70%): mp (Me2CO) 238 °C
7-Isop r op yla cr id in e-4-ca r boxylic a cid (2v) was pre-
pared by similar reaction of 2-iodoisophthalic acid and 4-iso-
propylaniline to give 2-[(4-isopropylphenyl)amino]isophthalic
acid (15v) (62%): mp (EtOAc/petroleum ether) 208 °C dec; 1H
NMR [(CD3)2SO] δ 1.16 (d, J ) 6.9 Hz, 6 H, 2 CH3), 2.78-2.82
(m, 1 H, CH), 6.83 (d, J ) 8.4 Hz, 2 H, H-2′,6′ or H-3′,5′), 6.97
(t, J ) 7.7 Hz, 1 H, H-5), 7.07 (d, J ) 8.5 Hz, 2 H, H-3′,5′ or
H-2′,6′), 7.92 (d, J ) 7.7 Hz, 2 H, H-4,6), 9.66 (br s, 1 H, NH),
12.89 (br s, 2 H, 2 COOH). Anal. (C17H17NO4) C, H, N.
Cyclization of 15v as above gave 7-isopropyl-9-oxoacridan-4-
1
dec; H NMR [(CD3)2SO] δ 1.45 (d, J ) 6.8 Hz, 6 H, 2 CH3),
3.94-4.05 (m, 1 H, CH), 7.75 (dd, J ) 8.4, 7.1 Hz, 1 H, H-2 or
H-7), 7.86 (dd, J ) 8.4, 7.1 Hz, 1 H, H-7 or H-2), 7.95 (br d, J
) 6.9 Hz, 1 H, H-6), 8.18 (dd, J ) 8.4, 1.0 Hz, 1 H, H-8), 8.55
(dd, J ) 8.4, 1.4 Hz, 1 H, H-1), 8.75 (dd, J ) 7.1, 1.4 Hz, 1 H,
H-3), 9.52 (s, 1 H, H-9), 17.39 (br s, 1 H, COOH). Anal.
(C17H15NO2) C, H, N.
1
carboxylic acid (1v) (95%): mp (MeOH/H2O) 289-291 °C; H
NMR [(CD3)2SO] δ 1.28 (d, J ) 6.9 Hz, 6 H, 2 CH3), 3.03-3.07
(m, 1 H, CH), 7.34 (t, J ) 7.7 Hz, 1 H, H-2), 7.70 (dd, J ) 8.6,
1.6 Hz, 1 H, H-6), 7.74 (d, J ) 8.5 Hz, 1 H, H-5), 8.07 (d, J )
1.6 Hz, 1 H, H-8), 8.43 (dd, J ) 7.5, 1.6 Hz, 1 H, H-3), 8.54
(dd, J ) 7.9, 1.6 Hz, 1 H, H-1), 11.93 (s, 1 H, NH), 13.80 (br s,
1 H, COOH). Anal. (C17H15NO3‚0.25H2O) C, H, N. Reduction
5-P h en yla cr id in e-4-ca r boxylic Acid (2e) was prepared
by cyclization of the known18 N-(2-carboxyphenyl)-3-pheny-
lanthranilic acid in PPA to give 5-phenyl-9-oxoacridan-4-
carboxylic acid (1e) (99%): mp (MeOH/AcOH) 327-328.5 °C;
1H NMR [(CD3)2SO] δ 7.35 (t, J ) 7.8 Hz, 1 H, ArH), 7.43 (dd,
J ) 8.1, 7.4 Hz, 1 H, ArH), 7.54-7.64 (m, 5 H, ArH), 7.72 (dd,
J ) 7.1, 1.6 Hz, 1 H, ArH), 8.30 (dd, J ) 8.1, 1.4 Hz, 1 H,
ArH), 8.38 (dd, J ) 7.5, 1.6 Hz, 1 H, ArH), 8.52 (dd, J ) 8.0,
1.5 Hz, 1 H, ArH), 12.35 (br s, 1 H, NH), and 13.90 (br s, 1 H,
COOH). Anal. (C20H13NO3‚0.25H2O) C, H, N. Reduction of
this as above gave 5-phenylacridine-4-carboxylic acid (2e)
(35%): mp (Me2CO) 190.2-192.0 °C; 1H NMR [(CD3)2SO] δ
7.54-7.61 (m, 3 H, H-3′,4′,5′), 7.68-7.70 (m, 2 H, H-2′,6′), 7.86
(ddd, J ) 8.5, 6.9, 1.5 Hz, 2 H, H-2 and H-7), 8.02 (dd, J )
7.0, 1.3 Hz, 1 H, H-6 or H-8), 8.37 (dd, J ) 8.5, 1.3 Hz, 1 H,
H-8 or H-6), 8.58 (dd, J ) 8.5, 1.4 Hz, 1 H, H-1), 8.72 (dd, J )
1
of 1v as above gave 2v (51%): mp (Me2CO) 186-187 °C; H
NMR [(CD3)2SO] δ 1.37 (d, J ) 6.9 Hz, 6 H, 2 CH3), 3.15-3.25
(m, 1 H, CH), 7.84 (dd, J ) 8.3, 7.2 Hz, 1 H, H-2), 8.03 (dd, J
) 9.0, 1.8 Hz, 1 H, H-6), 8.11 (br s, 1 H, H-8), 8.27 (d, J ) 9.0
Hz, 1 H, H-5), 8.54 (dd, J ) 8.5, 1.0 Hz, 1 H, H-1), 8.73 (dd, J
) 7.0, 1.2 Hz, 1 H, H-3), 9.45 (s, 1 H, H-9), 17.10 (br s, 1 H,
COOH). Anal. (C17H15NO2) C, H, N.
7-ter t-Bu tyla cr id in e-4-ca r boxylic a cid (2w ) was pre-
pared by similar reaction of 2-iodoisophthalic acid and 4-tert-
butylaniline to give 2-[(4-tert-butylphenyl)amino]isophthalic