7358 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 23
Murineddu et al.
ether/EtOAc 4:6); mp 134 °C; IR 1653, 3206; API-ES calcd for
455.38, found 455.1. Anal. (C24H24Cl2N4O) C, H, Cl, N.
7.52 (d, 1H, J ) 8.0 Hz). Anal. (C19H14Cl2N2O2) C, H, Cl, N.
General Procedure III: Synthesis of Tricyclic Esters
(7a-f). A stirred mixture of diketoester 6 (1.0 equiv, 4 mmol)
and 2,4-dichlorophenylhydrazine hydrochloride (1.15 equiv) in
EtOH (28 mL) was heated under reflux for 3 h. The mixture
was allowed to cool to room temperature, and the solvent was
removed under reduced pressure to give a red-orange solid,
which was purified by flash chromatography to afford the
analytically pure product.
1-(2′,4′-Dichlorophenyl)-N-piperidin-1-yl-1,4,5,6-tetra-
hydrobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxa-
mide (4o).18 General procedure I was used to convert 8f and
N-aminopiperidine. The mixture was purified by flash chro-
matography (petroleum ether/EtOAc, 6:4) to afford 4o (0.40
g, 73%) as a white solid. Rf ) 0.63 (petroleum ether/EtOAc
6:4); mp 165-168 °C (167-169 °C);18 IR 1650, 3165; API-ES
calcd for 455.38, found 455.1. Anal. (C24H24Cl2N4O) C, H, Cl,
N.
General Procedure II: Synthesis of Carboxylic Acids
(8a-f). To a mixture of ester 7 (1.0 equiv, 5 mmol) in methanol
(25 mL) was added a solution of potassium hydroxide (2.0
equiv) in methanol (18 mL). The resulting mixture was heated
under reflux overnight. The mixture was allowed to cool to
room temperature and then poured into water and acidified
with 1 N HCl. The precipitate was filtered, washed with water,
and air-dried to yield the analytically pure acid.
8-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-
benzo[6,7]cyclohepta[1,2c]pyrazole-3-carboxylic Acid
(8a).1 General procedure II was used to convert 7a into the
title product 8a (1.91 g, 94.0%) as a white solid. Rf ) 0.41
(CHCl3/MeOH 9:1); mp 270 °C (270 °C);1 IR 1690, 3410; 1H
NMR (CDCl3) δ 2.25-2.30 (m, 2H), 2.68 (t, 2H, J ) 6.4 Hz),
3.10-3.23 (m, 2H), 4.50 (br s, 1H, OH exchange with D2O),
6.61 (d, 1H, J ) 8.4 Hz), 7.03 (dd, 1H, Jo ) 8.2 Hz, Jm ) 2.2
Hz), 7.32 (d, 1H, J ) 2.0 Hz), 7.39-7.44 (m, 2H), 7.52 (d, 1H,
J ) 8.0 Hz). Anal. (C19H13Cl3N2O2) C, H, Cl, N.
Ethyl 8-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate
(7a).1 General procedure III was used to convert 6a and 2,4-
dichlorophenylhydrazine hydrochloride into the title product.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 8.5:1.5) to afford 7a (1.18 g, 68%) as a yellow
solid. Rf ) 0.39 (petroleum ether/EtOAc, 8.5:1.5); mp 158-
160 °C (triturated with petroleum ether) (160-161 °C)1; IR
1
1724; H NMR (CDCl3) δ 1.43 (t, 3H, J ) 7.2 Hz), 2.20-2.36
(m, 2H), 2.66 (t, 2H, J ) 6.4 Hz), 3.10-3.30 (m, 2H), 4.45 (q,
2H, J ) 7.2 Hz), 6.60 (d, 1H, J ) 8.4 Hz), 7.02 (dd, 1H, Jo )
8.4 Hz, Jm ) 2.2 Hz), 7.31 (d, 1H, J ) 1.8 Hz), 7.37-7.42 (m,
2H), 7-54 (d, 1H, J ) 9.2 Hz). Anal. (C21H17Cl3N2O2) C, H,
Cl, N.
Ethyl 8-Bromo-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate
(7b). General procedure III was used to convert 7b and 2,4-
dichlorophenylhydrazine hydrochloride into the title product.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 8.5:1.5) to afford 7b (1.49 g, 78%) as a white solid.
Rf ) 0.66 (petroleum ether/EtOAc, 8.5:1.5); mp 90 °C (tritu-
rated with petroleum ether); IR 1724; 1H NMR (CDCl3) δ 1.43
(t, 3H, J ) 7.0 Hz), 2.20-2.40 (m, 2H), 2.66 (t, 2H, J ) 6.4
Hz), 3.10-3.30 (m, 2H), 4.46 (q, 2H, J ) 7.0 Hz), 6.54 (d, 1H,
J ) 8.2 Hz), 7.17 (dd, 1H, Jo ) 8.2 Hz, Jm ) 2.0 Hz), 7.35-
7.42 (m, 2H), 7.46 (d, 1H, J ) 2.0 Hz), 7.54 (d, 1H, J ) 9.4
Hz). Anal. (C21H17BrCl2N2O2) C, H, Cl, N.
Ethyl 8-Methyl-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate (7c).
General procedure III was used to convert 7c and 2,4-
dichlorophenylhydrazine hydrochloride into the title product.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 8.5:1.5) to afford 7c (1.05 g, 63%) as a white solid.
Rf ) 0.65 (petroleum ether/EtOAc, 8.5:1.5); mp 75 °C (tritu-
rated with petroleum ether); IR 1715; 1H NMR (CDCl3) δ 1.43
(t, 3H, J ) 7.0 Hz), 2.20-2.32 (m, 5H), 2.65 (t, 2H, J ) 6.2
Hz), 3.00-3.25 (m, 2H), 4.45 (q, 2H, J ) 7.2 Hz), 6.56 (d, 1H,
J ) 7.8 Hz), 6.84 (d, 1H, J ) 7.2 Hz), 7.12 (s, 1H), 7.34-7.38-
7.41 (m, 2H), 7.53 (d, 1H, J ) 7.8 Hz). Anal. (C22H20Cl2N2O2)
C, H, Cl, N.
Ethyl 7-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate
(7d). General procedure III was used to convert 6d and 2,4-
dichlorophenylhydrazine hydrochloride into the title product.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 8.5:1.5) to afford 7d (0.94 g, 54%) as a white solid.
Rf ) 0.29 (petroleum ether/EtOAc, 8.5:1.5); mp 93 °C (tritu-
rated with petroleum ether); IR 1715; 1H NMR (CDCl3) δ 1.44
(t, 3H, J ) 7.0 Hz), 2.20-2.40 (m, 2H), 2.60-2.83 (m, 2H),
2.90-3.24 (m, 2H), 4.46 (q, 2H, J ) 7.2 Hz), 6.58 (d, 1H, J )
7.8 Hz), 6.98 (t, 1H, J ) 7.8 Hz), 7.26-7.42 (m, 3H), 7-55 (d,
1H, J ) 8.8 Hz). Anal. (C21H17Cl3N2O2) C, H, Cl, N.
8-Bromo-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-
benzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic Acid
(8b). General procedure II was used to convert 7b into the
title product 8b (2.21 g, 98.0%) as a white solid. Rf ) 0.76
1
(CHCl3/MeOH 9:1); mp 144-146 °C; IR 1692, 3470; H NMR
(CDCl3) δ 2.18-2.38 (m, 2H), 2.64-2.70 (m, 2H), 3.10-3.30
(m, 2H), 4.70 (br s, 1H, OH exchange with D2O), 6.55 (d, 1H,
J ) 8.2 Hz), 7.18 (dd, 1H, Jo ) 8.2 Hz, Jm ) 1.8 Hz), 7.39-
7.56 (m, 4H). Anal. (C19H13BrCl2N2O2) C, H, Cl, N.
8-Methyl-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-
benzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic Acid
(8c). General procedure II was used to convert 7c into the title
product 8c (1.82 g, 94.0%) as a white solid. Rf ) 0.52 (CHCl3/
MeOH 9:1); mp 145 °C; IR 1682, 3377; 1H NMR (CDCl3) δ
2.18-2.35 (m, 5H), 2.66 (t, 2H, J ) 6.0 Hz), 2.90-3.20 (m, 2H),
4.30 (br s, 1H, OH exchange with D2O), 6.57 (d, 1H, J ) 7.8
Hz), 6.85 (d, 1H, J ) 8.0 Hz), 7.13 (s, 1H), 7.35-7.42 (m, 2H),
7.52 (d, 1H, J ) 8.0 Hz). Anal. (C20H16Cl2N2O2) C, H, Cl, N.
7-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-
benzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic Acid
(8d). General procedure II was used to convert 7d into the
title product 8d (1.97 g, 97.0%) as a white solid. Rf ) 0.48
1
(CHCl3/MeOH 9:1); mp 125-128 °C; IR 1720, 3419; H NMR
(CDCl3) δ 2.26-2.40 (m, 2H), 2.50-3.40 (m, 4H), 4.78 (br s,
1H, OH exchange with D2O), 6.59 (d, 1H, J ) 7.6 Hz), 6.99 (t,
1H, J ) 8.0 Hz), 7.30-7.45 (m, 3H), 7.54 (d, 1H, J ) 8.0 Hz).
Anal. (C19H13Cl3N2O2) C, H, Cl, N.
9-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-
benzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylic Acid
(8e). General procedure II was used to convert 7e into the title
product 8e (1.99 g, 98.0%) as a white solid. Rf ) 0.60 (CHCl3/
MeOH 9:1); mp 250 °C; IR 1716, 3419; 1H NMR (CDCl3) δ
2.25-2.27 (m, 2H), 2.67 (t, 2H, J ) 6.4 Hz), 3.07-3.32 (m, 2H),
4.78 (br s, 1H, OH exchange with D2O), 6.65 (d, 1H, J ) 1.8
Hz), 7.20-7.32 (m, 2H), 7.40-7.50 (m, 2H), 7.57 (d, 1H, J )
9.0 Hz). Anal. (C19H13Cl3N2O2) C, H, Cl, N.
1-(2′,4′-Dichlorophenyl)-1,4,5,6-tetrahydrobenzo[6,7]-
cyclohepta[1,2-c]pyrazole-3-carboxylic Acid (8f).18 Gen-
eral procedure II was used to convert 7f into the title product
8f (1.71 g, 92.0%) as a yellow solid. Rf ) 0.48 (CHCl3/MeOH
9:1); mp 262-264 °C (262-264 °C);18 IR 1695, 3420; 1H NMR
(CDCl3) δ 2.25-2.31 (m, 2H), 2.71 (t, 2H, J ) 6.2 Hz), 2.75-
3.20 (m, 2H), 3.70 (br s, 1H, OH exchange with D2O), 6.69 (d,
1H, J ) 7.6 Hz), 7.05 (t, 1H, J ) 7.0 Hz), 7.18-7.48 (m, 4H),
Ethyl 9-Chloro-1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahy-
drobenzo[6,7]cyclohepta[1,2-c]pyrazole-3-carboxylate (7e).
General procedure III was used to convert 6e and 2,4-
dichlorophenylhydrazine hydrochloride into the title product.
The residue was purified by flash chromatography (petroleum
ether/EtOAc, 9:1) to afford 7e (1.18 g, 68%) as a white solid.
Rf ) 0.43 (petroleum ether/EtOAc, 9:1); mp 176-177 °C
1
(triturated with petroleum ether); IR 1709; H NMR (CDCl3)
δ 1.43 (t, 3H, J ) 7.0 Hz), 2.10-2.35 (m, 2H), 2.66 (t, 2H, J )
6.8 Hz), 3.10-3.40 (m, 2H), 4.46 (q, 2H, J ) 7.2 Hz), 6.65 (s,
1H), 7.15-7.30 (m, 2H), 7.35-7.50 (m, 2H), 7-57 (d, 1H, J )
9.0 Hz). Anal. (C21H17Cl3N2O2) C, H, Cl, N.