Clozapine

Base Information

• Chemical Name: Clozapine
• CAS No.: 5786-21-0
• Molecular Formula: C18H19ClN4
• Molecular Weight: 326.829
• Hs Code.: 29339900
• Mol file: 5786-21-0.mol

Synonyms:Clorazil;Fazaclo;Iprox;Clozapina [INN-Spanish];8-Chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo(b,e)(1,4)diazepine;5H-Dibenzo(b,e)(1,4)diazepine, 8-chloro-11-(4-methyl-1-piperazinyl)-;Leponex;Asaleptin;Clozaril (TN);Clozapine [USAN:BAN:INN];8-chloro-11（4-methy-1-piperaziong）-5-H-dibenzo[b,e][1.4]diazepine;

Chemical Property of Clozapine

Chemical Property:

• Appearance/Colour: Yellow Crystalline Solid
• Vapor Pressure: 0mmHg at 25°C
• Melting Point: 182-185 °C
• Refractive Index: 1.681
• Boiling Point: 489.159 °C at 760 mmHg
• PKA: 3.70, 7.60(at 25℃)
• Flash Point: 249.635 °C
• PSA: 30.87000
• Density: 1.319 g/cm³
• LogP: 3.17210
• Storage Temp.: Store at RT
• Solubility.: ethanol: 1 mg/mL

Purity/Quality:

98%, ^*data from raw suppliers

Clozapine ^*data from reagent suppliers

Safty Information:

• Pictogram(s): Xn, Xi
• Hazard Codes: Xn,Xi,T,F
• Statements: 22-36/37/38-68-63-39/23/24/25-23/24/25-11
• Safety Statements: 26-36/37-45-16-7

MSDS Files:

SDS file from LookChem

Useful:

• Uses: 1. It is used for treating acute, chronic mania. It can be used to stabilize the emotion of human. It has good efficacy on treating symptoms like, vagrancy, sleep disorder, sadness, panic, tiredness, easy to be ill, sudden violence, and anger. 2. It can be used for treating crazy disease due to a variety of reasons such as losing temper, aggressive, emotional instability, anxiety, tension, and manic, etc. 3. It can be used for treating mental retardation-caused behavioral disorders such as linguistic disorder, poor presentation ability, poor thought and mental ability, lack of abstraction, generalization ability, low perception, narrow perception range, being difficult to distinguish small differences in body shape, size and color, lack of concentration, narrow attention range, poor memory, slow memorizing and reproducing inaccurately, na?ve behavior, immaturity, emotional instability, lack of self-control and impulsiveness, frequently being timid, withdrawn, shy, asymmetrical shape, uncoordinated movements, poor flexibility, performance, or hyperactivity, destruction, aggression. 4. It can be used for treating drug or alcohol-dependence withdrawal syndrome such as acute tremors, agitation, being easy to get startled, and nausea, vomiting and sweating. Upon drinking, the symptoms disappeared immediately, otherwise last for several days. There is sometimes even a short delusions, hallucinations and visual distortion, lisp. Finally, the patient may have seizures or delirium tremens. 5. Can be used for treating insomnia. It is applicable to the various manifestations of insomnia, such as dreaminess and being easy to wake up, heart palpitations, forgetfulness, and tiredness. 1. The product has not only a strong anti-psychotic effect, but also a calming effect as a novel broad-spectrum psychiatric drug which is suitable for treating acute and chronic schizophrenia. It has a good efficacy on treating paranoid hallucinations, youth-based diseases. In the angle of alleviating the symptoms, it is quite effective in treating agitation, hallucinations, delusions, contacts, and apastia. 2. Used as antipsychotics Clozapine is a neuroleptic, which expresses antipsychotic and sedative action. It does not cause general depression and extrapyramidal disorders. It is used for severe and chronic forms of schizophrenia, maniacal conditions, manic-depressive psychosis, psychomotor excitement, and various other psychotic conditions. An antipsychotic depigmentor
• Description: Clozapine (5786-21-0) is a dopamine D4?and D2?receptor antagonist. High affinity for the cloned rat dopamine D4?receptor (Ki?< 20 nM).1?Atypical neuroleptic agent.2?Antagonist at 5HT2A, 5HT2C, 5HT3, 5HT6 and 5HT7 receptors.3,4
• Therapeutic Function: Tranquilizer
• Clinical Use: Although clozapine demonstrates a favorable pharmacologicalprofile compared with typical antipsychotics, its useis restricted by a relatively high incidence of agranulocytosis.The exact mechanism for the cause of agranulocytosishas not been confirmed, but a highly reactive nitrenium ionthat is formed by the action of hepatic enzymes appears tobe involved.The mean elimination half-life of clozapine following a single 75-mg dose is 8 hours. Because of severaladverse effects, clozapine is only used in refractory casesof schizophrenia. Individuals with a history of seizures orpredisposed to seizures should be cautioned when takingclozapine. Similar to other atypical antipsychotic agents,clozapine causes an increased risk of mortality in elderly individualswith dementia-related psychoses.
• Drug interactions: Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; increased risk of ventricular arrhythmias with methadone. Anti-arrhythmics: increased risk of ventricular arrhythmias with anti-arrhythmics that prolong the QT interval; increased risk of arrhythmias with flecainide. Antibacterials: concentration possibly increased by erythromycin (possible increased risk of convulsions); concentration increased by ciprofloxacin; concentration possibly reduced by rifampicin; avoid with chloramphenicol and sulphonamides (increased risk agranulocytosis). Antidepressants: concentration possibly increased by citalopram, fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine (increased risk of toxicity); possibly increased CNS effects of MAOIs; possibly increased antimuscarinic effects with tricyclics; increased concentration of tricyclics. Antiepileptics: antagonises anticonvulsant effect; metabolism accelerated by carbamazepine, phenytoin and possibly phenobarbital; avoid with drugs known to cause agranulocytosis; concentration possibly increased or decreased by valproate. Antimalarials: avoid with artemether/lumefantrine. Antipsychotics: avoid with depot formulations (cannot be withdrawn quickly if neutropenia occurs); possible increased risk of ventricular arrhythmias with risperidone - avoid. Antivirals: concentration increased by ritonavir - avoid; increased risk of ventricular arrhythmias with saquinavir - avoid. Anxiolytics and hypnotics: increased sedative effects; adverse reports with clozapine and benzodiazepines.Atomoxetine: increased risk of ventricular arrhythmias. Cytotoxics: increased risk of agranulocytosis - avoid; increased risk of ventricular arrhythmias with arsenic trioxide. Lithium: increased risk of extrapyramidal side effects and possibly neurotoxicity. Penicillamine: increased risk of agranulocytosis - avoid. Ulcer-healing drugs: effects possibly enhanced by cimetidine; concentration possibly reduced by omeprazole.

Technology Process of Clozapine

There total 23 articles about Clozapine which guide to synthetic route it. The literature collected by LookChem mainly comes from the sharing of users and the free literature resources found by Internet computing technology. We keep the original model of the professional version of literature to make it easier and faster for users to retrieve and use. At the same time, we analyze and calculate the most feasible synthesis route with the highest yield for your reference as below:

synthetic route:

Reference yield: 97.0%

clozapine N-oxide → clozaril (5786-21-0)

Guidance literature:

With hydrogenchloride; titanium(III) chloride; In water; acetonitrile; at 20 ℃; for 1h;

DOI:10.1021/acs.oprd.5b00312

Reference yield: 88.0%

1-methyl-piperazine (109-01-3) + 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one (50892-62-1) → clozaril (5786-21-0)

Guidance literature:

With titanium tetrachloride; In 1,4-dioxane; toluene; for 2h; Heating;

DOI:10.1071/CH07197

Reference yield: 80.0%

N-(4-chloro-2-nitrophenyl)-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine (65514-72-9) → clozaril (5786-21-0)

Guidance literature:

With tributylphosphine; at 150 ℃; for 48h; Temperature; Reagent/catalyst;

DOI:10.1021/acs.joc.8b02682

upstream raw materials:

1-methyl-piperazine

8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one

N-(2-Amino-4-chlorophenyl)anthranilic acid

2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4''-methyl)piperazide

Downstream raw materials:

N-desmethylclozapine

Refernces

• 1、 Laha, Joydev K.,Manral, Neelam,Hunjan, Mandeep Kaur. "Palladium-catalysed regioselective: N -arylation of anthranilamides: A tandem route for dibenzodiazepinone synthesis". . p. 7339 - 7343. Retrieved 2019/05/24.
• 2、 Tryniszewski, Micha?,Bujok, Robert,Cmoch, Piotr,Gańczarczyk, Roman,Kulszewicz-Bajer, Irena,Wróbel, Zbigniew. "Direct Reductive Cyclocondensation of the Nitro Group with the Amido Group: Key Role of the Iminophosphorane Intermediate in the Synthesis of 1,4-Dibenzodiazepine Derivatives". . p. 2277 - 2286. Retrieved 2019/05/16.