Apraclonidine hydrochloride

Chemical properties

Crystalline Solid

Originator

Alfadrops,Cipla Limited,India

The Uses of Apraclonidine hydrochloride

Apraclonidine hydrochloride can be used as α-Adrenergic agonist; structural analog of clonidine and be used for treatment of post-surgical elevated intraocular pressure.

The Uses of Apraclonidine hydrochloride

a-Adrenergic agonist; structural analog of clonidine. Used for treatment of post-surgical elevated intraocular pressure

Definition

ChEBI: The hydrochloride salt of apraclonidine.

Manufacturing Process

The preparation of p-aminoclonidine (apraclonidine) consists of 6 steps.
In the first step 2,6-dichloro-4-nitroaniline was converted to 2,6-dicloro-4- nitrophenylisothiocyanate by addition of thiophosgene in toluene according to the method described in Great Britain Patent No.: 1,131,780 (Beck et al.).
The second step involved the conversation of 2,6-dichloro-4-nitrophenylisothiocyanate to 1-(2-aminoethyl)-3-(2,6-dichloro-4-nitrophenyl)-thiourea ethylenediamine solvate. The solution of 2,6-dicloro-4-nitrophenylisothiocyanate (432 g, 1.73 mol) in 2 L of toluene was added dropwise to the cooled (0°C) solution ethylenediamine (244 ml, 3.66 mol, 2.1 eq.) in toluene (4 L) under a nitrogen atmosphere. 2-Propanol (1 L) was added and after 5 minutes, the solid was collected by filtration, washed with 20% 2- propanol/toluene, and dried to a constant weight of 602 g (94%). This product is hygroscopic, mp 120°C (dec.).
The third step was the conversation of 1-(2-aminoethyl)-3-(2,6-dichloro-4- nitrophenyl)-thiourea ethylenediamine solvate to 2-[(2,6-dicloro-4- nitrophenyl)imino]imidazoline ethylenediamine solvate. (500 g, 1.35 mol) of above prepared thiourea solvate was suspended with toluene (4 L) and was heated at reflux for 15 hours. The mixture was cooled to 23°C and 1 M aqueous hydrochloric acid (4 L) was added. After stirring for 10 min the biphasic mixture was filtered to remove a sticky insoluble material. The aqueous phase was neutralized to pH=7.0 using 50% NaOH. After stirring for 1 hour the yellow solid was collected by filtration, washed with water (4 L) and t-butyl methyl ether (2 L) and dried in air to constant weight of 195 g (52%), m.p. 289-292°C.
The fourth step was the conversation of 2-[2,6-dichloro-4-nitrophenyl) imino]imidazoline (150 g, 0.55 mol) in methanol (1,5 L) to 2-[(2,6-dichloro-4- aminophenyl)imino]imidazoline by hydrogen with 30 g Raney nickel catalyst at 23°C for 22 hours. After removing the catalyst hydrogen chloride gas was bubbled into solution until pH of the reaction mixture was 1.0. The solvent was rotary removed in vacuum and the residual solid was slurried with 2- propanol (1 L). The solvent was again removed by rotary evaporation, the cream solid was triturated with 2-propanol (600 ml). After aging for 1 hour, the solid was collected by filtration, washed with 2-propanol and t-butyl methyl ether, and dried for 15 hours at 6°C and t-butyl methyl ether, and dried for 15 hours at 60°C and 20 mm Hg. Yield of dihydrochloride 167 g (96%), mp 260°C (dec.).
The dihydrochloride was converted to the monochloride (step 5) by adding 5 M aqueous sodium hydroxide dropwise to pH=6.5 at 5°C for 2 hours. Yield of hydrochloride 87%.
The last step was recrystallization of product from water. The recrystallized material had m.p. 300°C. Calculated for: C9H10Cl2N4HCl: C, 38.39; H, 3.94; N, 19.90; Cl, 37.78. Found: C, 38.36; H, 3.91; N, 19.83; Cl, 37.77.

brand name

Iopidine (Alcon).

Therapeutic Function

Antiglaucoma