Synthesis of Rimonabant Hydrochloride
167
5 h, the reaction mixture was cooled to 5◦C and the precipitated solid was collected.
The solid obtained was washed with 200 mL of cold THF to afford the title compound
as a light yellow-green solid (141.2 g), mp. 163–163.5◦C. The combined filtrate and
wash liquid was concentrated to about 800 mL to afford an additional 36.5 g of product,
mp. 162.5–163.5◦C. The overall weight of the combined products was 177.7 g (80%)
1
from 1. ESI-MS: m/z = 223.0[M+H]+. H NMR(CDCl3):δ 2.14 (s, 3H), 7.57 (d, J =
6.9 Hz, 2H), 7.87 (d, J = 6.9 Hz, 2H).
Anal. Calcd for C11H7ClO3: C, 59.35; H, 3.17. Found: C, 59.63; H, 3.01.
5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylic Acid (6)
Triethylamine (51 g, 0.5 mol) was added dropwise to a solution of 11 (111.3 g, 0.5 mol)
and 2,4- chlorophenylhydrazine hydrochloride (106.8 g, 0.5 mol) in toluene (2 L). The
reaction mixture was stirred at 20◦C for 12 h followed by filtration of Et3N.HCl and
concentration in vacuo. The residue was dissolved in toluene (1 L), to which was added
p-toluenesulfonic acid (8.6 g, 0.05 mol) and the mixture was refluxed for 12 h. After
cooling to room temperature, an NaOH solution (5%, 1 L) was added and the mixture was
stirred vigorously for 0.5 h. After separation of the layers, the pH of the aqueous phase was
adjusted to 2 by the addition of conc. HCl. The resulting precipitate was collected, dried
and recrystallized from 80% aqueous acetic acid to give 145.5 g (76%) of a white solid,
mp. 215.8–217.0◦C (lit.3 mp. 210◦C).
1H NMR(DMSO-d6):δ 2.23(s, 3H), 7.23(d, J = 8.4 Hz, 2H), 7.45(d, J = 8.4 Hz, 2H),
7.57(dd, J1 = 8.5 Hz, J2 = 2.2 Hz, 1H), 7.70(d, J = 8.5 Hz, 1H), 7.77(d, J = 2.2 Hz, 1H),
12.91(br, 1H).
Anal. Calcd for C17H11Cl3N2O2: C, 53.50; H, 2.91; N, 7.34. Found: C, 53.61; H, 2.79;
N, 7.32.
Rimonabant Hydrochloride (8)
To a suspension of 6 (38.2 g, 0.1 mol) in dichloromethane (250 mL) containing DMF (1 mL)
in an ice bath was added a solution of oxalyl chloride (10 mL, 0.11 mol) in dichloromethane
(20 mL). After the addition, the reaction mixture was stirred for 2 h at room temperature
before being added to a solution of N-aminopiperidine (12.0 g, 0.12 mol) and triethylamine
(17 mL, 0.12 mol) in dichloromethane (200 mL); the addition was carried out slowly so as
to keep temperature at 10–15◦C; then the reaction mixture was stirred at room temperature
for another 1 h and then washed with water (200 mL × 2), and dried over anhydrous sodium
sulfate. After filtration, the pH of the solution was adjusted to 1 by passing HCl gas. The
white solid obtained was recrystallized from a mixture of methanol and ether (1:3) to give
the pure product (33.0 g, 66%) as a white solid, mp. 229–235◦C (dec.). [lit.3 mp. 224◦C
(dec.)].
ESI-MS: m/z = 463.1[M-Cl]+; 1H NMR(DMSO-d6):δ 1.46∼1.59 (m, 2H), 1.80∼1.82
(m, 4H), 2.33 (s, 3H), 3.34∼3.39 (m, 4H), 7.24 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz,
2H), 7.58∼7.79 (m, 3H), 8.59 (br, 1H); 11.09 (s, 1H).
Anal. Calcd for C22H22Cl4N4O: C, 52.82; H, 4.43; N, 11.20. Found: C, 52.73; H, 4.44;
N, 11.12.