5840 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 26
Valgeirsson et al.
3-Me t h y l-2-[3-(3-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (2b) was prepared according to general proce-
dure A. The crude product was dissolved in 0.5 M NaOH and
precipitated by addition of 4 M HCl. Yield: 83%. Mp: 165-
4 -N i t r o -2 -[3 -(3 -t r i fl u o r o m e t h y l p h e n y l )u r e i d o ]-
ben zoic a cid (2j) was prepared according to general proce-
dure A. The product was recrystallized (EtOH-0.5 M HCl).
1
Yield: 56%. Mp: 206-207 °C. H NMR (DMSO-d6): δ 14.28
1
166 °C. H NMR (DMSO-d6): δ 13.06 (1H, br s), 9.73 (1H, s),
(1H, br s), 10.67 (1H, s), 10.41 (1H, s), 9.32 (1H, s), 8.19 (1H,
d, J ) 8.8 Hz), 8.01 (1H, s), 7.84 (1H, d, J ) 8.8 Hz), 7.73 (1H,
d, J ) 8.0 Hz), 7.54 (1H, t, J ) 8.0 Hz), 7.36 (1H, d, J ) 8.0
Hz). Anal. (C15H10F3N2O5) C, H, N.
8.76 (1H, s), 8.00 (1H, s), 7.67 (1H, d, J ) 7.4 Hz), 7.58 (1H, d,
J ) 7.8 Hz), 7.51 (1H, t, J ) 7.4 Hz), 7.44 (1H, d, J ) 7.8 Hz)
7.28 (1H, d, J ) 7.4 Hz), 7.19 (1H, t, J ) 7.8 Hz), 2.25 (3H, s).
Anal. (C16H13F3N2O3‚1/4H2O) C, H, N.
3-[3-(3-Tr iflu or om eth ylp h en yl)u r eid o]n a p h th a len e-2-
ca r boxylic a cid (3) was prepared according to general
procedure A. The crude product was dissolved in 0.5 M NaOH
and precipitated by addition of 4 M HCl. Yield: 73%. Mp:
197-198 °C. 1H NMR (DMSO-d6): δ 13.75 (1H, br s), 10.45
(1H, s), 10.20 (1H, s), 8.81 (1H, s), 8.68 (1H, s), 8.10 (1H, s),
8.00 (1H, d, J ) 8.2 Hz), 7.86 (1H, d, J ) 8.2 Hz), 7.72 (1H, d,
J ) 7.3 Hz), 7.59 (1H, t, J ) 7.3 Hz), 7.53 (1H, t, J ) 8.2 Hz),
7.44 (1H, t, J ) 8.2 Hz), 7.33 (1H, d, J ) 7.3 Hz). Anal.
(C19H13F3N2O3‚1/4H2O) C, H, N.
4-Me t h y l-2-[3-(3-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (2c) was prepared according to general proce-
dure A. The product was recrystallized (EtOAc-heptane).
1
Yield: 87%. Mp: 179-182 °C. H NMR (DMSO-d6): δ 13.32
(1H, br s), 10.52 (1H, s), 10.17 (1H, s), 8.25 (1H, s), 8.05 (1H,
s), 7.86 (1H, d, J ) 7.8 Hz), 7.69 (1H, d, J ) 8.3 Hz), 7.52 (1H,
t, J ) 7.8 Hz), 7.32 (1H, d, J ) 7.8 Hz), 6.89 (1H, d, J ) 8.3
Hz), 2.34 (3H, s). Anal. (C16H13F3N2O3) C, H, N.
5-Me t h y l-2-[3-(3-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (2d ) was prepared according to general proce-
dure A. The product was recrystallized (MeOH-H2O). Yield:
72%. Mp: 183-184 °C (dec). 1H NMR (DMSO-d6): δ 13.45 (1H,
br s), 10.37 (1H, s), 10.13 (1H, s), 8.27 (1H, d, J ) 8.6 Hz),
8.02 (1H, s), 7.77 (1H, s), 7.70 (1H, d, J ) 7.9 Hz), 7.51 (1H, t,
J ) 7.9 Hz), 7.37 (1H, d, J ) 8.6 Hz), 7.31 (1H, d, J ) 7.9 Hz),
2.28 (3H, s). Anal. (C16H13F3N2O3) C, H, N.
4-Ch lor o-2-(3-p h en ylu r eid o)ben zoic a cid (4) was pre-
pared according to general procedure A. The product was
recrystallized (acetone-0.5 M HCl). Yield: 78%. Mp: 186-
188 °C. 1H NMR (DMSO-d6): δ 13.67 (1H, s), 10.49 (1H, s),
9.94 (1H, s), 8.53 (1H, s), 7.95 (1H, d, J ) 8.5 Hz), 7.52 (2H, d,
J ) 8 Hz), 7.29 (2H, t, J ) 8 Hz), 7.09 (1H, d, J ) 8.5 Hz),
7.00 (1H, t, J ) 8 Hz). Anal. (C14H11ClN2O3) C, H, N.
4-Ch lor o-2-[3-(2-flu or op h en yl)u r eid o]ben zoic a cid (5a )
was prepared according to general procedure A. The product
was recrystallized (EtOH-0.5 M HCl). Yield: 46%. Mp: 195-
196 °C. 1H NMR (DMSO-d6): δ 13.63 (1H, s), 10.46 (1H, s),
9.77 (1H, s), 8.44 (1H, s), 7.94 (1H, d, J ) 8.5), 7.83 (1H, t, J
) 7.8 Hz), 7.2 (4H, m). Anal. (C14H10ClFN2O3) C, H, N.
4-Ch lor o-2-[3-(2-ch lor oph en yl)u r eido]ben zoic acid (5b)
was prepared according to general procedure A. The product
was recrystallized (EtOH-0.5 M HCl). Yield: 32%. Mp: 181-
183 °C. 1H NMR (DMSO-d6): δ 13.61 (1H, br s), 10.50 (1H, s),
9.53 (1H, s), 8.44 (1H, s), 7.93 (1H, d, J ) 8.1 Hz), 7.79 (1H, d,
J ) 8.5 Hz), 7.49 (1H, d, J ) 8.1 Hz), 7.33 (1H, t, J ) 8.1 Hz),
6-Me t h y l-2-[3-(3-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (2e) was prepared according to general proce-
dure A. The crude product was dissolved in 0.5 M NaOH and
precipitated by addition of 4 M HCl. Yield: 68%. Mp: 181-
1
182 °C. H NMR (DMSO-d6): δ 13.55 (1H, br s), 9.86 (1H, s),
8.64 (1H, s), 8.00 (1H, s), 7.72 (1H, d, J ) 8.3 Hz), 7.56 (1H, d,
J ) 7.6 Hz), 7.51 (1H, t, J ) 8.1 Hz), 7.30 (1H, t, J ) 7.6 Hz),
7.27 (1H, d, J ) 8.1 Hz), 6.7 (1H, d, J ) 7.6 Hz), 2.34 (3H, s).
Anal. (C16H13F3N2O3‚1/6H2O) C, H, N.
4-F lu o r o -2-[3-(3-t r i flu o r o m e t h y lp h e n y l)u r e i d o ]-
ben zoic a cid (2f) was prepared according to general proce-
dure A. The product was recrystallized (EtOH-0.5 M HCl).
1
7.19 (1H, t, J ) 8.1 Hz), 7.11 (1H, d, J ) 8.5 Hz). Anal. (C14H10
Cl2N2O3) C, H, N.
-
Yield: 53%. Mp: 176-179 °C. H NMR (DMSO-d6): δ 13.62
(1H, br s), 10.76 (1H, s), 10.33 (1H, s), 8.27 (1H, d, J ) 12 Hz),
8.05 (1H, dd, J ) 12 Hz, 8 Hz), 8.01 (1H, s), 7.72 (1H, d, J )
8.3 Hz), 7.53 (1H, t, J ) 8.3 Hz), 7.34 (1H, d, J ) 8.3 Hz), 6.9
(1H, t, J ) 8 Hz). Anal. (C15H10F4N2O3) C, H, N.
2-[3-(2-Br om op h en yl)u r eid o]-4-ch lor oben zoic a cid (5c)
was prepared according to general procedure A. The product
was recrystallized (acetone-H2O). Yield: 48%. Mp: 195-197
°C. 1H NMR (DMSO-d6): δ 13.63 (1H, br s), 10.52 (1H, s), 9.46
(1H, s), 8.48 (1H, s), 7.93 (1H, d, J ) 8.6 Hz), 7.66 (1H, d, J )
8 Hz), 7.60 (1H, d, J ) 8 Hz), 7.38 (1H, t, J ) 8 Hz), 7.14 (1H,
t, J ) 8 Hz), 7.09 (1H, d, J ) 8.6 Hz). Anal. (C14H10BrClN2O3)
C, H, N.
4-C h lo r o -2-[3-(3-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (2g) was prepared according to general proce-
dure A. The product was recrystallized (acetone-0.5 M HCl).
1
Yield: 63%. Mp: 167-168 °C. H NMR (DMSO-d6): δ 13.78
(1H, br s), 10.69 (1H, s), 10.32 (1H, s), 8.53 (1H, s), 8.01 (1H,
s), 7.98 (1H, d, J ) 8.0 Hz), 7.71 (1H, d, J ) 7.8 Hz), 7.53 (1H,
t, J ) 7.8 Hz), 7.35 (1H, d, J ) 7.8 Hz), 7.13 (1H, d, J ) 8.0
Hz). Anal. (C15H10ClF3N2O3) C, H, N.
4-Ch lor o-2-[3-(2-iod op h en yl)u r eid o]ben zoic a cid (5d )
was prepared according to general procedure B and the product
recrystallized (EtOAc-heptane). Yield: 36%. Mp: 198-201
1
°C. H NMR (DMSO-d6): δ 13.64 (1H, br s), 10.54 (1H, br s),
4-B r o m o -2-[3-(3-t r i flu o r o m e t h y lp h e n y l)u r e i d o ]-
ben zoic a cid (2h ) was prepared according to general proce-
dure A. The product was recrystallized (acetone-0.5 M HCl).
9.37 (1H, s), 8.53 (1H, s), 7.93 (1H, d, J ) 8.6 Hz), 7.89 (1H, d,
J ) 7.5 Hz), 7.44 (1H, d, J ) 7.5 Hz), 7.40 (1H, t, J ) 7.5 Hz),
1
7.09 (1H, d, J ) 8.6 Hz), 7.00 (1H, t, J ) 7.5 Hz). Anal. (C14H10
ClIN2O3) C, H, N.
-
Yield: 58%. Mp: 177-178 °C. H NMR (DMSO-d6): δ 13.79
(1H, br s), 10.61 (1H, s), 10.31 (1H, s), 8.68 (1H, s), 8.01 (1H,
s), 7.88 (1H, d, J ) 8.3 Hz), 7.70 (1H, d, J ) 8.1 Hz), 7.53 (1H,
t, J ) 8.1 Hz), 7.34 (1H, d, J ) 8.1 Hz), 7.26 (1H, d, J ) 8.3
Hz). Anal. (C15H10BrF3N2O3) C, H, N.
4-C h lo r o -2-[3-(2-t r iflu o r o m e t h y lp h e n y l)u r e id o ]-
ben zoic a cid (5e) was prepared according to general proce-
dure A. The product was recrystallized (EtOAc-heptane).
1
Yield: 62%. Mp: 192-194 °C. H NMR (DMSO-d6): δ 13.70
4-Tr iflu or om eth yl-2-[3-(3-tr iflu or om eth ylp h en yl)u r e-
id o]ben zoic Acid (2i). 2-Nitro-4-trifluoromethylbenzoic acid
(10) (0.96 g, 4.1 mmol) was dissolved in EtOH (40 mL, 96%)
and Pd/C (5%, 50 mg) was added. The mixture was hydroge-
nated by stirring at 1 atm for 1 h, filtered through Celite, and
evaporated to dryness under reduced pressure. The product
(12i) was suspended in toluene and 3-trifluoromethylphenyl
isocyanate (11b) (1.09 g, 5.8 mmol) was added. The mixture
was stirred at room temperature for 24 h, the reaction mixture
was cooled, and the product was filtered off and washed with
toluene and heptane to yield 2i as a colorless crystalline solid
(1.37 g, 87%). Mp: 178-179 °C. 1H NMR (DMSO-d6): δ 14.07
(1H, br s), 10.66 (1H, s), 10.37 (1H, s), 8.90 (1H, s), 8.16 (1H,
d, J ) 8.3 Hz), 8.01 (1H, s), 7.73 (1H, d, J ) 7.9 Hz), 7.54 (1H,
t, J ) 7.9 Hz), 7.4 (1H, d, J ) 8.3 Hz), 7.35 (1H, d, J ) 7.9
Hz). Anal. (C16H10F6N2O3) C, H, N.
(1H, s), 10.61 (1H, s), 10.29 (1H, s), 8.54 (1H, s), 8.01 (1H, s),
7.97 (1H, d, J ) 8.6 Hz), 7.71 (1H, d, J ) 8.3 Hz), 7.53 (1H,
dd, J ) 8.3, 7.8 Hz), 7.35 (1H, d, J ) 7.8 Hz), 7.13 (1H, d, J )
8.6 Hz). Anal. (C15H10ClF3N2O3) C, H, N.
2-(3-Biph en yl-2-ylu r eido)-4-ch lor oben zoic acid (5f) was
prepared according to general procedure A. The product was
recrystallized (EtOAc-heptane). Yield: 65%. Mp: 208-209
°C. 1H NMR (DMSO-d6): δ 13.66 (1H, br s), 10.58 (1H, s), 10.07
(1H, s), 8.54 (1H, s), 7.97 (1H, d, J ) 8.5 Hz), 7.64 (6H, m),
7.44 (2H, t, J ) 7.5 Hz), 7.31 (1H, t, J ) 7.5 Hz), 7.11 (1H, d,
J ) 8.5 Hz). Anal. (C20H15ClN2O3‚1/3H2O) C, H, N.
4-Ch lor o-2-[3-(2-m eth oxyp h en yl)u r eid o]ben zoic a cid
(5g) was prepared according to general procedure A. The
product was recrystallized (EtOH-0.5 M HCl). Yield: 67%.
Mp: 181-183 °C. 1H NMR (DMSO-d6): δ 13.61 (1H, br s),