Preparation of Apraclonidine Hydrochloride
N-(2,6-Dichloro-4-nitrophenyl)formamide (2)
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To 132.0 mL (3.5 mol) of formic acid in a 1 L three-neck round bottom flask, was added
55.2 mL (0.58 mol) of acetic anhydride dropwise over 20 min with mechanical stirring
so as to keep the internal temperature at 55–60ꢀC. The reaction mixture was then cooled
to ambient temperature. 2,6-Dichloro-4-nitroaniline (1, 110.0 g, 0.53 mol) was added
within 20 min. and the mixture was heated at 55ꢀC for 6 h. After the completion of the
reaction as monitored by TLC (GF254, silica gel, n-hexane:ethyl acetate 4:1), the mixture
was evaporated under reduced pressure (about 80 mmHg) to give a yellow solid. Then,
500 mL water was added and stirring continued for 10 min (mechanical stirring). The
solid product was collected, washed with water and recrystallized from 95% EtOH to
give N-(2,6-dichloro-4-nitrophenyl)formamide 2 as a pale yellow solid (80.6 g, 65%),
mp. 158–160ꢀC. (lit.6 158.5–159.5ꢀC).
1H NMR(CDCl3): d 7.43 (s, 1H, NH), 8.32 (s, 2H, Ar-H), 8.61 (s, 1H, CHO). MS
(EI,70eV): m/z 234 [M]C,199,176,124,97.
(2,6-Dichloro-4-nitrophenyl)carbonimidic Dichloride (3). N-(2,6-dichloro-4-nitrophenyl)
formamide (50.5 g, 0.22 mol) was added to a mixture of SOCl2 (70.0 mL, 0.97 mol) and
SO2Cl2 (35.0 mL, 0.43 mol) over 15 min. The mixture was heated to 60ꢀC and stirred using
magnetic stir bar until N-(2,6-dichloro-4-nitrophenyl)formamide was consumed (at least 8 h,
monitored by TLC, GF254, silica gel, n-hexane:ethyl acetate 4:1). Evaporation under reduced
pressure (about 60 mmHg) afforded a red-brown oil that was used directly without further
purification in the next step.
N-(2,6-Dichloro-4-nitrophenyl)-4,5-dihydro-1H-imidazol-2-amine (4). Ethylenediamine
(13.2 g, 0.22 mol), triethylamine (44.5 g, 0.44 mol) and tetrahydrofuran (300 mL) were
added to a 1L three-neck round bottom flask and the mixture was stirred (mechanical stir-
ring) in an ice bath for 15 min. Then a solution of 3 in tetrahydrofuran (50 mL) was added
dropwise into this reaction mixture at 5–10ꢀC over about 0.5 h. The mixture was stirred for
6 h at room temperature until the starting material was consumed (monitored by TLC,
GF254, silica gel, n-hexane:ethyl acetate 3:1). The solvent was removed by distillation under
reduced pressure (about 60 mmHg). Water 400 mL was added and the mixture was stirred
for 10 min. The solid formed was collected, dried overnight and purified by recrystalliza-
tion from 95% EtOH to provide the product 4 as a yellow solid (36.7 g, 62%), mp. 287–
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289ꢀC (lit.6 283–285ꢀC). H NMR(DMSO-d6): d 3.41 (s, 4H, CH2), 6.74 (s, 2H, Ar-H),
8.16 (s, 2H, 2NH). 13C NMR(DMSO-d6): d 42.26, 123.94, 128.77, 139.62, 153.97, 157.63.
MS(EI,70eV): m/z 275 [M]C, 255, 213, 161, 107, 81.
2,6-Dichloro-N1-(4,5-dihydro-1H-imidazol-2-yl)-1,4-benzenediamine (5). To a suspen-
sion of compound 4 (27.4 g, 0.1 mol) and 5% Pd/C (0.3 g) in 95% ethanol (200 mL), was
added 85% hydrazine hydrate (11.8 g, 0.2 mol) dropwise (40 min.) at room temperature.
The mixture was heated at reflux for 8 h and then the hot solution was filtered immediately
using suction to remove the Pd/C. Upon cooling the filtrate to room temperature, the
precipitated solid was collected and recrystallized from 95% EtOH to afford 19.1 g (78%)
of apraclonidine (5) as a yellowish white solid, mp. 225–227ꢀC (lit.6 227–229ꢀC).
1H NMR (DMSO-d6): d 3.26 (s, 4H, CH2), 4.97 (s, 2H, 2NH), 5.91 (brs, 2H, NH2), 6.55
(s, 2H, Ar-H). 13C NMR (DMSO-d6): d 42.33, 114.19, 129.19, 135.38, 143.98, 158.37.
MS(EI,70eV): m/z 246, 244[M] C, 209, 186, 174, 139, 124, 99, 73.