774 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 4
Brief Articles
a white solid: 1H NMR (200 MHz, CDCl3) δ 8.22-7.19 (m, 7H,
ArH), 4.47 (q, J ) 7.1 Hz, 2H, OCH2), 2.38 and 2.39 (s, 3H,
CH3), 1.44 (t, J ) 7.1 Hz, 3H, CH3); MS m/e 419 (M+), 373 (M+
- C2H6O), 346 (M+ - C3H5O2). Anal. (C19H15Cl2N3O4) C, H,
N.
N-(P ip er id in -1-yl)-5-(2-a m in op h en yl)-1-(2,4-d ich lor o-
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (11). Com-
pound 11 was synthesized from 9 according to the procedure
applied to 10 and obtained in 89% yield as a white solid: mp
1
256-258 °C; H NMR (200 MHz, CDCl3) δ 7.67 (s, 1H, NH),
7.42 (dd, J ) 0.7 and 1.6 Hz, 1H, ArH), 7.24-7.22 (m, 2H,
ArH), 7.05 (t, J ) 7.7 Hz, 1H, ArH), 6.63-6.58 (m, 1H, ArH),
1.77-1.68 (m, 4H, CH2), 1.44-1.41 (m, 2H, CH2); MS m/e 443
(M+), 344 (M+ - C5H11N2). Anal. (C22H23Cl2N5O) C, H, N.
N-(P ip er id in -1-yl)-1-(2,4-d ich lor op h en yl)-4-m et h yl-5-
p h en yl-1H-p yr a zole-3-ca r boxa m id e (7). To a magnetically
stirred solution of ester 5 (520 mg, 1.38 mmol) in methanol (7
mL) was added a solution of potassium hydroxide (155 mg,
2.76 mmol) in methanol (5 mL). The mixture was heated under
reflux for 3 h. The cooling reaction mixture was then poured
into water (10 mL) and acidified with 10% hydrochloric acid.
The precipitate was filtered, washed with water, and dried
under vacuum to yield the corresponding acid (430 mg, 90%
yield) as a solid.
A solution of the crude acid (430 mg) and thionyl chloride
(270 µL, 4.14 mmol) in toluene (10 mL) was refluxed for 3 h.
Solvent was evaporated under reduced pressure, and the
residue was then redissolved in toluene (20 mL) and evapo-
rated to yield the crude carboxylic chloride (450 mg, 100%
yield) as a solid. A solution of the above carboxylic chloride
(450 mg, 1.24 mmol) in dichloromethane (5 mL) was added
dropwise to a solution of 1-aminopiperidine (215 µL, 1.92
mmol) and triethylamine (270 µL, 1.92 mmol) in dichlo-
romethane (5 mL) at 0 °C. After stirring at room temperature
for 3 h, the reaction mixture was added with brine and
extracted with dichloromethane (3 × 15 mL). The combined
extracts were washed with brine, dried over anhydrous sodium
sulfate, filtered, and evaporated. Flash column chromatogra-
phy on silica gel with petroleum ether/ethyl acetate (2:1) gave
carboxamide 7 (540 mg, 98% yield) as a white solid: mp 186-
187 °C; 1H NMR (200 MHz, CDCl3) δ 7.64 (s, 1H, NH), 7.42-
7.27 (m, 6H, ArH), 7.14-7.11 (m, 2H, ArH), 2.87 (t, J ) 5.2
Hz, 4H, NCH2), 2.38 (s, 3H, CH3), 1.79-1.66 (m, 4H, CH2),
1.46-1.42 (m, 2H, CH2); MS m/e 428 (M+), 329 (M+ - C5H11N2).
Anal. (C22H22Cl2N4O) C, H, N.
N -(P ip e r id in -1-yl)-1-(2,4-d ich lor op h e n yl)-5-(4-iod o-
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (12). To
a magnetically stirred solution of 10 (44 mg, 0.1 mmol) in
concentrated hydrochloric acid (0.5 mL) and ice (1 g) was added
dropwise a 1.0 M solution of sodium nitrite (100 µL, 0.1 mmol)
at 0 °C until iodine-starch paper turned blue. After being
stirred at the same temperature for additional 10 min, this
cold solution was transferred into a solution of potassium
iodide (166 mg, 1.0 mmol) in water (0.5 mL) at room temper-
ature, and stirring was continued for 4 h. The reaction mixture
was extracted with dichloromethane (3 × 10 mL). The com-
bined dichloromethane solution was washed with brine, dried
over anhydrous sodium sulfate, filtered, and evaporated.
Purification by flash column chromatography on silica gel with
petroleum ether/ethyl acetate (2:1) gave the p-iodide 12 (22
mg, 39% yield) as a white solid: mp 195-196 °C; 1H NMR
(200 MHz, CDCl3) δ 7.58 (d, J ) 8.2 Hz, 1H, ArH), 7.56 (s,
1H, NH), 7.37 (s, 1H, ArH), 7.38-7.18 (m, 3H, ArH), 6.78 (d,
J ) 8.2 Hz, 2H, ArH), 2.79 (t, J ) 5.0 Hz, 4H, NCH2), 2.29 (s,
3H, CH3), 1.71-1.63 (m, 4H, CH2), 1.38-1.36 (m, 2H, CH2);
MS m/e 554 (M+), 455 (M+ - C6H11N2O); HRMS m/e calcd,
554.0137; found, 554.0121. Anal. (C22H21Cl2IN4O) C, H, N.
N -(P ip e r id in -1-yl)-1-(2,4-d ich lor op h e n yl)-5-(2-iod o-
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (13). Com-
pound 13 was obtained from 11 by the method described for
compound 12 and was isolated as a white solid in 29% yield:
1
mp 107-109 °C; H NMR (200 MHz, CDCl3) δ 7.61-7.55 (m,
N-(P ip er id in -1-yl)-1-(2,4-d ich lor op h en yl)-4-m et h yl-5-
n itr op h en yl-1H-p yr a zole-3-ca r boxa m id e (8 a n d 9). Com-
pounds 8 and 9 were synthesized from p- and o-nitrate esters
6 according to the procedure described for compound 7.
Purification of the crude product by flash column chromatog-
raphy on silica gel with petroleum ether/ethyl acetate (3:2 to
1:1) gave the p-nitro compound 8 and o-nitro compound 9 in a
total yield of 98%. Compound 8: mp 142-143 °C; 1H NMR (500
MHz, CDCl3) δ 8.19 (d, J ) 8.3 Hz, 2H, ArH), 7.66 (s, 1H, NH),
7.43-7.32 (m, 3H, ArH), 7.32 (d, J ) 8.2 Hz, 2H, ArH), 2.87
(t, J ) 5.0 Hz, 4H, NCH2), 2.41 (s, 3H, CH3), 1.77-1.72 (m,
2H, ArH and NH), 7.43 (s, 1H, ArH), 7.37-7.36 (m, 1H, ArH),
7.24-7.18 (m, 2H, ArH), 6.99-6.96 (m, 2H, ArH), 2.79 (t, J )
5.2 Hz, 4H, NCH2), 2.30 (s, 3H, CH3), 1.74-1.60 (m, 4H, CH2),
1.41-1.36 (m, 2H, CH2); MS m/e 554 (M+), 455 (M+
-
C6H11N2O); HRMS m/e calcd, 554.0137; found, 554.0147. Anal.
(C22H21Cl2IN4O) C, H, N.
N-(P iper idin -1-yl)-1-(2,4-dich lor oph en yl)-5-eth yl-4-m eth -
yl-1H-p yr a zole-3-ca r boxa m id e (16). Compound 16 was
obtained from ester 15 according to the procedure described
for 7 and was isolated as a white solid in 88% yield: mp 151-
1
153 °C; H NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 2H, ArH
4H, CH2), 1.44 (bs, 2H, CH2); MS m/e 473 (M+), 374 (M+
-
and NH), 7.41-7.40 (m, 1H, ArH), 7.32 (d, J ) 8.4 Hz, 1H,
ArH), 2.83 (t, J ) 4.6 Hz, 4H, NCH2), 2.46-2.45 (m, 2H, CH2),
2.35 (s, 3H, CH3), 1.74-1.72 (m, 4H, CH2), 1.41 (brs, 2H, CH2),
0.97 (t, J ) 7.4 Hz, 3H, CH3); GC-MS m/e 380 (M+), 365 (M+
- CH3), 281 (M+ - C5H11N2). Anal. (C18H22Cl2N4O) C, H, N.
C5H11N2). Anal. (C22H21Cl2N5O3) C, H, N. Compound 9: mp
139-140 °C; 1H NMR (500 MHz, CDCl3) δ 8.19 (d, J ) 7.7
Hz, 1H, ArH), 8.01 (s, 1H, ArH), 7.64 (s, 1H, NH), 7.54 (t, J )
7.8 Hz, 1H, ArH), 7.74 (d, J ) 7.4 Hz, 1H, ArH), 7.42-7.34
(m, 3H, ArH), 2.87 (t, J ) 5.1 Hz, 4H, NCH2), 2.41 (s, 3H, CH3),
1.79-1.74 (m, 4H, CH2), 1.44 (bs, 2H, CH2); MS m/e 473 (M+),
374 (M+ - C5H11N2). Anal. (C22H21Cl2N5O3) C, H, N.
N -(P ip e r id in -1-y l)-1-(4-c h lor o p h e n yl)-5-(4-c h lo r o -
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (19). Com-
pound 19 was obtained from ester 18 according to the
procedure described for 7 and was isolated as a white solid in
82% yield: mp 169-170 °C; 1H NMR (500 MHz, CDCl3) δ 7.69
(s, 1H, NH), 7.35 (d, J ) 8.0 Hz, 2H, ArH), 7.30 (d, J ) 8.3
Hz, 2H, ArH), 7.15 (d, J ) 8.2 Hz, 2H, ArH), 7.07 (d, J ) 8.1
Hz, 2H, ArH), 2.88 (t, J ) 5.1 Hz, 4H, NCH2), 2.34 (s, 3H,
CH3), 1.78-1.71 (m, 4H, CH2), 1.46 (brs, 2H, CH2); GC-MS
m/e 428 (M+), 329 (M+ - C5H11N2), 301 (M+ - C6H11N2O). Anal.
(C22H22Cl2N4O) C, H, N.
N-(P ip er id in -1-yl)-5-(4-a m in op h en yl)-1-(2,4-d ich lor o-
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (10). Hy-
drazine (61 µL, 1.9 mmol) was added to a solution of 8 (300
mg, 0.63 mmol) in ethanol (20 mL) at room temperature. The
mixture was warmed to 30-40 °C and Raney nickel (10 mg,
50% slurry in water) was added. After no more nitrogen was
generated, another portion of Raney nickel (5.0 mg) was added
and the reaction mixture was warmed to 70 °C and stirred for
3 h. The catalyst was removed by filtration, and the crude
product was purified by flash column chromatography on silica
gel with petroleum ether/ethyl acetate (1:1) to afford p-amine
N-(P yr r olid in -1-yl)-5-(4-br om op h en yl)-1-(2,4-d ich lor o-
p h en yl)-4-m eth yl-1H-p yr a zole-3-ca r boxa m id e (22). Com-
pound 22 was obtained from 5-(4-bromophenyl)-1-(2,4-dichloro-
phenyl)-4-methyl-1H-pyrazole-3-carboxylic chloride (44 mg, 0.1
mmol), 1-aminopyrrolidine hydrochloride (25 mg, 0.2 mmol),
and triethylamine (55 µL, 0.4 mmol) according to the procedure
described for 7 and was isolated as a white solid in 90% yield:
mp 197-198 °C; 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 1H, NH),
7.45 (d, J ) 8.1 Hz, 2H, ArH), 7.43 (s, 1H, ArH), 7.31-7.27
(m, 2H, ArH), 6.99 (d, J ) 8.2 Hz, 2H, ArH), 3.02 (brs, 4H,
1
10 (263 mg, 94% yield) as a white solid: mp 211-212 °C; H
NMR (200 MHz, CDCl3) δ 7.65 (s, 1H, NH), 7.42 (dd, J ) 0.9
and 1.7 Hz, 1H, ArH), 7.27-7.26 (m, 2H, ArH), 6.88 (dd, J )
2.0 and 6.5 Hz, 2H, ArH), 6.59 (dd, J ) 2.0 and 6.6 Hz, 2H,
ArH), 3.74 (brs, 2H, NH2), 2.86 (t, J ) 5.2 Hz, 4H, NCH2), 2.35
(s, 3H, CH3), 1.76-1.69 (m, 4H, CH2), 1.45-1.41 (m, 2H, CH2);
MS m/e 443 (M+), 344 (M+ - C5H11N2). Anal. (C22H23Cl2N5O)
C, H, N.