66711-21-5

Basic information

• Product Name: Apraclonidine
• Synonyms: 4-aminoclonidine;APRACLONIDINE;Apraclondine Hcl;Apraclonldine;2-((4-Amino-2,6-dichlorophenyl)imino)imidazolidine;2,6-Dichloro-N-(4,5-dihydro-1H-imidazol-2-yl)benzene-1,4-diamine;2,6-Dichloro-N-[(4,5-dihydro-1H-imidazol)-2-yl]-1,4-benzenediamine;Aplonidine
• CAS NO: 66711-21-5
• Molecular Formula: C₉H₁₀Cl₂N₄
• Molecular Weight: 245.11
• Mol File: 66711-21-5.mol
• Article Data: 6

Chemical Properties

• Melting Point: >230°
• Boiling Point: 395.5 °C at 760 mmHg
• Flash Point: 193 °C
• Appearance: white/solid
• Density: 1.63 g/cm³
• Vapor Pressure: 1.83E-06mmHg at 25°C
• Storage Temp.: 2-8°C
• Solubility: 45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 1.4 mg/mL
• CAS DataBase Reference: Apraclonidine(CAS DataBase Reference)
• NIST Chemistry Reference: Apraclonidine(66711-21-5)
• EPA Substance Registry System: Apraclonidine(66711-21-5)

Safety Data

• Hazard Codes: T
• Statements: 23/24/25
• Safety Statements: 22-36/37/39-45
• RIDADR: UN 2811 6.1/PG 1
• WGK Germany: 3
• Hazardous Substances Data: 66711-21-5(Hazardous Substances Data)

Usage

Originator

Alfadrops,Cipla Limited,India

Definition

ChEBI: An imidazoline compound having a 4-amino-2,6-dichloroanilino group at the 2-position.

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.

General Description

In addition to its therapeutic use as an antihypertensiveagent, clonidine has been found to provide beneficialeffects in several other situations, including glaucoma,spasticity, migraine prophylaxis, opiate withdrawal syndrome,and anesthesia. This has prompted the developmentof analogs of clonidine for specific use in some of the mentionedareas. Two of such examples are apraclonidine andbrimonidine. Apraclonidine does not cross the BBB.However, brimonidine can cross the BBB and hence canproduce hypotension and sedation, although these CNSeffects are slight compared with those of clonidine. CNS effectsof these drugs are correlated well to their log P, pKa,and thus log D value. Both apraclonidine and brimonidineare selective α2-agonists with α1: α2 ratios of 30:1 and1,000:1, respectively. Brimonidine is a much more selectiveα2-agonist than clonidine or apraclonidine and is a firstlineagent for treating glaucoma. Apraclonidines’s primarymechanism of action may be related to a reduction of aqueousformation, whereas brimonidine lowers intraocularpressure by reducing aqueous humor production and increasinguveoscleral outflow. Apraclonidine is used specificallyto control elevations in intraocular pressure that canoccur during laser surgery on the eye. Another example istizanidine (Zanaflex), which finds use in treating spasticityassociated with multiple sclerosis or spinal cord injury. Bystimulating 2-adrenergic receptors, it is believed to decreasethe release of excitatory amino acid NTs from spinalcord interneurons.

Veterinary Drugs and Treatments

Apraclonidine is an alpha2 adrenergic agonist used to reduce aqueous humor secretion. Apraclonidine is a relatively selective, alphaadrenergic agonist and does not have significant membrane stabilizing (local anesthetic) activity. The onset of action is within 3 – 5 hours of a single dose. It apparently is less effective than brimonidine in dogs and is very potent, causing vomiting and diarrhea in cats and dogs. Apraclonidine will reduce aqueous production but must be combined with other agents for adequate control. Neither the beta-blockers nor alpha-agonists are as effective as the carbonic anhydrase inhibitors in decreasing aqueous production.

InChI:InChI=1/C9H10Cl2N4.ClH/c10-6-3-5(12)4-7(11)8(6)15-9-13-1-2-14-9;/h3-4H,1-2,12H2,(H2,13,14,15);1H

Upstream product

• 65936-26-7 2-(2',6'-dichloro-4'-nitroanilino)-2-imidazoline 
• 99-30-9 4-nitro-2,6-dichloroaniline 
• 70106-94-4 N-(2,6-dichloro-4-nitrophenyl)formamide 
• 73218-65-2 (2,6-dichloro-4-nitrophenyl)carbonimidic dichloride 
• 65936-26-7 p-Nitroclonidine 

Downstream Products

• 108294-56-0 2-({2,6-dichloro-4-[3,3-(1,4-butanediyl)triazeno]phenyl}imino)imidazolidine 
• 81913-29-3 isothiocyanato-4 clonidine 
• 73217-88-6 p-aminoclonidine hydrochloride 
• 73218-79-8 2-[(4-amino-2,6-dichlorophenyl)imino]imidazolidine monohydrochloride 

Relevant articles and documents

A α2 - Adrenergic receptor agonist hydrochloric acid an le decides and its preparation method

The invention relates to an alpha2-adrenergic receptor stimulant apraclonidine hydrochloride and a preparation method thereof. The structural formula is shown in the specification. The preparation comprises the following steps: 2, 6-dichloro-4-nitroaniline, formic acid and acetic anhydride are mixed, heated and stirred, react and recrystallize, N-(2, 6-dichloro-4-nitrophenyl) formamide is obtained and then stirred, flows back and reacts with sulfuryl chloride and thionyl chloride, N-(2, 6-dichloro-4-nitrophenyl) dichlorocarbamide is obtained and dropwise added to an ethyl acetate solution containing ethylenediamine and triethylamine, the mixture is stirred for reaction for 1-10 h under the condition of 5-8 DEG C, 2-(2',6'-dichloro-4'- nitroanilino)-2-imidazoline is prepared, then a reducing agent is added to the solvent for reduction, hydrochloric acid is finally added to a reaction liquid, and stirring and backflow are performed for 1.5 h for preparation. The preparation process is simple to operate, the yield is high, the cost is low, the reaction route is short, little three wastes are generated, and industrial production is facilitated.

Process for preparation of clonidine derivatives

A novel process for preparing clonidine derivatives has been discovered which is shorter, less expensive and safer than previously known methods. A new thiourea complex has also been discovered which can be directly cyclized to produce the corresponding heterocyclic product.

Radioiodinated p-iodoclonidine: a high-affinity probe for the alpha 2-adrenergic receptor.

The chemical synthesis of 2-[(2,6-dichloro-4-iodophenyl)imino]imidazolidine (PIC) and its radioiodinated analogue [125I]PIC is described. PIC was synthesized from 2,6-dichloroaniline in five synthetic steps. This agent displayed a high affinity for the alpha 2-adrenergic receptor (IC50 = 1.5 nM) in competitive binding assays conducted with purified human platelet plasma membrane fractions. For the synthesis of radioiodinated PIC the triazene intermediate 11 was synthesized from 2,6-dichloro-4-nitroaniline in five synthetic steps. Acid-catalyzed decomposition of 11 with no-carrier-added Na125I afforded high specific activity [125I]PIC. In view of its high affinity for the alpha 2-adrenergic receptor, [125I]PIC is a potentially useful probe for studies in adrenergic pharmacology.