2944 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 16
Macielag et al.
7.83 (d, J ) 2.3 Hz, 1H), 7.60 (d, J ) 8.6 Hz, 2H), 7.42 (d, J )
8.6 Hz, 2H), 1.29 (s, 9H). Anal. (C17H17Cl2NO2) C, H, N.
N-P h en yl-3,5-d ich lor o-2-h yd r oxyben za m id e (22): yield
45%; mp 135-136 °C (lit.19 mp 124-125 °C); 1H NMR (DMSO-
d6) δ 12.81 (br s, 1H), 10.65 (br s, 1H), 8.14 (d, J ) 2.0 Hz,
1H), 7.83 (d, J ) 2.0 Hz, 1H), 7.69 (d, J ) 7.9 Hz, 2H), 7.41
(m, 2H), 7.20 (t, J ) 7.2 Hz, 1H). Anal. (C13H9Cl2NO2) C, H,
N.
11.57 (s, 1H), 8.28 (s, 1H), 7.81 (d, J ) 8.3 Hz, 1H), 7.53-
7.38 (m, 6H), 7.21 (d, J ) 8.3 Hz, 1H), 6.04 (s, 1H), 2.36 (s,
3H); IR 3329-2930, 1649, 1619, 1586 cm-1
. Anal. (C23H15-
Cl2F3N2O2) C, H, N.
N-{5-Ch lor o-4-[(4-ch lor op h en yl)cya n om eth yl]-2-m eth -
ylp h en yl}-2,3-d ih yd r oxyben za m id e (8): yield 10%; mp
172-174 °C; 1H NMR (DMSO-d6) δ 11.29 (br s, 1H), 10.58 (s,
1H), 9.79 (br s, 1H), 8.21 (s, 1H), 7.52-7.38 (m, 6H), 7.01 (d,
J ) 7.6 Hz, 1H), 6.81 (t, J ) 7.6 Hz, 1H), 6.03 (s, 1H). Anal.
(C22H16Cl2N2O3‚0.1H2O) C, H, N.
N-(3,4-Dich lor op h en yl)-2-h yd r oxy-5-(tr iflu or om eth yl)-
ben za m id e (15): yield 46%; mp 184-185 °C; 1H NMR (DMSO-
d6) δ 12.07 (br s, 1H), 10.67 (s, 1H), 8.12 (d, J ) 2.1 Hz, 2H),
7.74 (d, J ) 8.6 Hz, 1H), 7.70-7.63 (m, 2H), 7.18 (d, J ) 8.6
Hz, 1H); IR 3113, 1636, 1618, 1586 cm-1; MS (CI) m/z 350 (M
+ H). Anal. (C14H8Cl2F3NO2) C, H, N.
N-(4-Nit r op h en yl)-3,5-d ich lor o-2-h yd r oxyb en za m id e
(23): yield 30%; mp >250 °C (lit.19 mp >330 °C); 1H NMR
(DMSO-d6) δ 12.62 (br s, 1H), 10.74 (br s, 1H), 8.24 (d, J ) 9.3
Hz, 2H), 8.15 (d, J ) 2.2 Hz, 1H), 8.01 (d, J ) 9.3 Hz, 2H),
7.56 (d, J ) 2.2 Hz, 1H). Anal. (C13H8Cl2N2O4) C, H, N.
N -(4-Me t h oxyp h e n yl)-3,5-d ich lor o-2-h yd r oxyb e n z-
a m id e (24): yield 25%; mp 173-174 °C (lit.19 mp 173-174
1
°C); H NMR (DMSO-d6) δ 13.09 (br s, 1H), 10.57 (br s, 1H),
N-(3,4-Dich lor op h en yl)-2,3-d ih yd r oxyben za m id e (16):
yield 20%; mp 204-206 °C; 1H NMR (CDCl3) δ 11.72 (br s,
1H), 9.64 (br s, 1H), 7.97 (d, J ) 2.2 Hz, 1H), 7.61 (dd, J ) 8.7
Hz, 2.1 Hz, 1H), 7.43-7.40 (m, 2H), 7.11 (br s, 1H), 7.08 (d, J
) 7.5 Hz, 1H), 6.81 (t, J ) 7.5 Hz, 1H); MS (CI) m/z 299 (M +
H).
8.15 (d, J ) 2.4 Hz, 1H), 7.82 (d, J ) 2.4 Hz, 1H), 7.58 (d, J )
8.6 Hz, 2H), 6.98 (d, J ) 8.6 Hz, 2H). Anal. (C14H11Cl2NO3)
C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Sa licyla n ilid es
3 a n d 11. N-{5-Ch lor o-4-[(4-ch lor op h en yl)cya n om eth yl]-
2-m eth ylph en yl}-2-h ydr oxy-3,5-bis(tr iflu or om eth yl)ben z-
a m id e (3). To a suspension of 2-methoxy-3,5-bis(trifluoro-
methyl)benzoic acid (120 mg, 0.42 mmol) in THF (10 mL) were
added oxalyl chloride (63 mg, 0.50 mmol) and catalytic DMF
(0.2 mL) with stirring. The mixture was stirred at room
temperature for 1 h. Pyridine (0.1 mL) and 4-chlorophenyl-
(2-chloro-4-amino-5-methylphenyl)cyanomethane (150 mg, 0.52
mmol) were added, and the mixture was stirred at room
temperature for an additional 2 h. The reaction mixture was
quenched with 1 N HCl (10 mL) and extracted with ethyl
acetate (20 mL). The organic extract was sequentially washed
with concentrated HCl (10 mL), brine (10 mL), saturated
sodium bicarbonate (10 mL), and brine (10 mL) and dried over
MgSO4. After evaporation of the solvent, {5-chloro-4-[(4-
chlorophenyl)cyanomethyl]-2-methylphenyl}-2-methoxy-3,5-
bis(trifluoromethyl)benzamide was obtained (185 mg, 79%) as
a yellow solid: mp 185-187 °C; 1H NMR (CDCl3) δ 8.58 (s,
1H), 8.53 (s, 1H), 8.07 (s, 1H), 7.37 (d, J ) 9 Hz, 2H), 7.35 (s,
1H), 7.32 (d, J ) 9 Hz, 2H), 5.61 (s, 1H), 4.03 (s, 3H), 2.37 (s,
3H); IR 3240, 1687, 1658 cm-1; MS (CI) m/z 561 (M + H).
To a solution of {5-chloro-4-[(4-chlorophenyl)cyanomethyl]-
2-methylphenyl}-2-methoxy-3,5-bis(trifluoromethyl)benz-
amide in CH2Cl2 was added BBr3 (1.0 M in CH2Cl2, 1 mL, 1
mmol) with stirring at room temperature. The reaction
mixture was stirred for 3 h at room temperature and then
evaporated to dryness. Water was added (20 mL) and the
mixture extracted with ethyl acetate (20 mL). The organic
extract was washed with brine (20 mL), dried over MgSO4,
and concentrated in vacuo. Flash chromatography on silica
gel (hexane/ethyl acetate/acetic acid, 8:2:0.1) gave 3 (95 mg,
73%) as a white solid: mp 172-173 °C; 1H NMR (CDCl3) δ
12.05 (br s, 1H), 8.57 (s, 1H), 7.98 (s, 1H), 7.96 (s, 1H), 7.54 (s,
1H), 7.51 (d, J ) 8 Hz, 2H), 7.41 (d, J ) 8 Hz, 2H), 6.04 (s,
1H), 2.32 (s, 3H); IR 3345, 1656 cm-1; MS (ES) m/z 547 (M +
H). Anal. (C24H14Cl2F6N2O2) C, H, N.
N -{4-[2-Am in o-1-(4-ch lor op h e n yl)e t h yl]-5-ch lor o-2-
m eth ylp h en yl}-3,5-d iiod o-2-h yd r oxyben za m id e h yd r o-
ch lor id e (17). 4-Chlorophenyl-(2-chloro-4-amino-5-meth-
ylphenyl)cyanomethane (874 mg, 3.0 mmol) was hydrogenated
at 50 psi for 21 h in a mixture containing Raney nickel (1.0
g), acetic acid (6 mL), and acetic anhydride (15 mL). After
filtration through Celite, the reaction mixture was neutralized
with saturated NaHCO3 and extracted with ethyl acetate (3
× 100 mL). The combined ethyl acetate extracts were washed
with brine (50 mL), dried over MgSO4, and concentrated in
vacuo to give a white solid. Recrystallization from ethyl
acetate/hexane gave N-[2-(4-chlorophenyl)-2-(2-chloro-4-acetyl-
amino-5-methylphenyl)]ethylacetamide (750 mg, 66%) as a
white solid: 1H NMR (DMSO-d6) δ 9.33 (br s, 1H), 7.97 (t, J
) 4.3 Hz, 1H), 7.54 (s, 1H), 7.35 (s, 1H), 7.33 (d, J ) 8.1 Hz,
2H), 7.23 (d, J ) 8.1 Hz, 2H), 4.53 (t, J ) 7.7 Hz, 1H), 3.76-
3.51 (m, 2H), 2.21 (s, 3H), 2.07 (s, 3H), 1.74 (s, 3H).
N-[2-(4-Chlorophenyl)-2-(2-chloro-4-acetylamino-5-methyl-
phenyl)]ethylacetamide (750 mg, 2.0 mmol) was dissolved in
a mixture of ethanol (5 mL) and concentrated HCl (5 mL), and
the mixture was heated to reflux temperature for 24 h. The
reaction mixture was adjusted to pH 5 with 2 N NaOH and
then extracted with ethyl acetate (3 × 100 mL). The combined
extracts were dried over MgSO4, and the solvent was removed
in vacuo. The residue was recrystallized from ethyl acetate
to give 2-(4-chlorophenyl)-2-(2-chloro-4-amino-5-methylphen-
yl)ethylamine hydrochloride (426 mg, 65%) as a white solid:
1H NMR (DMSO-d6) δ 8.03 (br s, 3H), 7.39 (d, J ) 8.3 Hz,
2H), 7.31 (d, J ) 8.3 Hz, 2H), 7.17 (s, 1H), 6.64 (s, 1H), 5.15
(br s, 2H), 4.56 (t, J ) 7.7 Hz, 1H), 3.49-3.34 (m, 2H), 2.05 (s,
3H).
2-(4-Chlorophenyl)-2-(2-chloro-4-amino-5-methylphenyl)-
ethylamine hydrochloride (264 mg, 0.80 mmol) was dissolved
in THF (5 mL) containing Et3N (122 µL, 0.90 mmol). The
mixture was cooled to 5 °C and treated with di-tert-butyl
dicarbonate (182 mg, 0.80 mmol). The reaction was stirred
for 16 h and concentrated in vacuo. Flash chromatography
on silica gel (hexane/ethyl acetate, 7:3) afforded N-tert-butoxy-
carbonyl-2-(4-chlorophenyl)-2-(2-chloro-4-amino-5-methylphen-
yl)ethylamine (300 mg, 95%): 1H NMR (CDCl3) δ 7.25 (d, J )
8.6 Hz, 2H), 7.17 (d, J ) 8.6 Hz, 2H), 6.89 (s, 1H), 6.68 (s,
1H), 4.55-4.42 (m, 2H), 3.81-3.52 (m, 3H), 2.12 (s, 3H), 1.41
(s, 9H).
N-{4-[2-(N′-tert-Butoxycarbonylamino)-1-(4-chlorophenyl)-
ethyl]-5-chloro-2-methylphenyl}-3,5-diiodo-2-hydroxybenz-
amide was prepared from N-tert-butoxycarbonyl-2-(4-chlo-
rophenyl)-2-(2-chloro-4-amino-5-methylphenyl)ethylamine (300
mg, 0.76 mmol) and 3,5-diiodosalicylic acid (296 mg, 0.76
mmol) as described for 6 above.
N-(3,4-Dich lor op h en yl)-2-h yd r oxy-3,5-b is(t r iflu or o-
m eth yl)ben za m id e (11): yield 97%; mp 148-150 °C; 1H NMR
(DMSO-d6) δ 11.55 (s, 1H), 8.63 (s, 1H), 8.05 (m, 2H), 7.62 (m,
2H); IR 3442, 1661, 1607 cm-1; MS (ES) m/z 416 (M+ - 1).
Anal. (C15H7Cl2F6NO2) C, H, N.
Gen er a l P r oced u r e for P r ep a r a tion of Sa licyla n ilid es
7, 8, 15, a n d 16. N-{5-Ch lor o-4-[(4-ch lor op h en yl)cya n o-
m eth yl]-2-m eth ylp h en yl}-2-h yd r oxy-5-(tr iflu or om eth yl)-
ben za m id e (7). N-{5-chloro-4-[(4-chlorophenyl)cyanomethyl-
2-methylphenyl}-2-methoxy-5-(trifluoromethyl)benzamide (pre-
pared as described for 3 above) (816 mg, 1.65 mmol) and
pyridine hydrochloride (16.2 g, 0.14 mol) were heated at 190
°C with stirring for 2 h under a nitrogen atmosphere. The
melt was cooled and the solidified mass triturated with 3 N
HCl. The precipitated solid was filtered, washed with 3 N
HCl and water, and dried. Flash chromatography on silica
gel (ethyl acetate/methylene chloride, 1:1) gave 7 (348 mg,
44%) as a white solid: mp 120 °C; 1H NMR (DMSO-d6) δ
The crude product was dissolved in CH2Cl2 (20 mL) and
treated with trifluoroacetic acid (5 mL) containing a few drops
of anisole. After 30 min the reaction mixture was neutralized