5786-21-0

Basic information

• Product Name: Clozapine
• Synonyms: 5H-Dibenzo[b,e][1,4]diazepine, 8-chloro-11-(4-methyl-1-piperazinyl)-;Asaleptin;clorazil;Clozapin;e)(1,4)diazepine,8-chloro-11-(4-methyl-1-piperazinyl)-5h-dibenzo(;Iprox;Lepotex;W-801
• CAS NO: 5786-21-0
• Molecular Formula: C₁₈H₁₉ClN₄
• Molecular Weight: 326.82
• EINECS: 227-313-7
• Product Categories: Active Pharmaceutical Ingredients;Intermediates & Fine Chemicals;Pharmaceuticals;Dopamine receptor;Miscellaneous;API;Isotope;BENOQUIN;Other APIs
• Mol File: 5786-21-0.mol
• Article Data: 16

Chemical Properties

• Melting Point: 182-185°C
• Boiling Point: 482.71°C (rough estimate)
• Flash Point: 9℃
• Appearance: pale yellow/
• Density: 1.1327 (rough estimate)
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.6110 (estimate)
• Storage Temp.: Store at RT
• Solubility: ethanol: 1 mg/mL
• PKA: 3.70, 7.60(at 25℃)
• Stability: Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.
• Merck: 14,2423
• CAS DataBase Reference: Clozapine(CAS DataBase Reference)
• NIST Chemistry Reference: Clozapine(5786-21-0)
• EPA Substance Registry System: Clozapine(5786-21-0)

Safety Data

• 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
• RIDADR: UN 2811 6.1/PG 3
• WGK Germany: 3
• RTECS: HP1750000
• HazardClass: 6.1(b)
• PackingGroup: III
• Hazardous Substances Data: 5786-21-0(Hazardous Substances Data)

Usage

Description

Clozapine, also known as Clozaril, is a second-generation antipsychotic medication used in the treatment of psychiatric disorders such as schizophrenia. It is a yellow crystalline powder that is slightly soluble in water and has a molecular weight of 326.83 with a melting point of 183-184 °C. Clozapine is an atypical neuroleptic agent that acts as an antagonist at dopamine D4 and D2 receptors, as well as at 5HT2A, 5HT2C, 5HT3, 5HT6, and 5HT7 receptors. It is known for its strong antipsychotic effects, low incidence of extrapyramidal symptoms (EPS), and potent sedative and hypnotic properties.

Uses

Used in Psychiatry:
Clozapine is used as an antipsychotic for treating acute and chronic schizophrenia. It is effective in managing both positive and negative symptoms of the disorder, including agitation, hallucinations, delusions, and emotional instability. Clozapine is particularly useful for patients who have not responded well to standard neuroleptics.
Used in Treatment of Mania and Sleep Disorders:
Clozapine is used as a mood stabilizer and sedative for treating acute and chronic mania, as well as severe sleep disorders. It helps in stabilizing emotions and alleviating symptoms such as vagrancy, sleep disorder, sadness, panic, tiredness, sudden violence, and anger.
Used in Treatment of Mental Retardation-Caused Behavioral Disorders:
Clozapine is used as a behavioral intervention for treating mental retardation-caused behavioral disorders. It helps in managing symptoms such as linguistic disorder, poor presentation ability, poor thought and mental ability, lack of abstraction, low perception, narrow attention range, poor memory, naive behavior, emotional instability, lack of self-control, and impulsiveness.
Used in Treatment of Drug or Alcohol-Dependence Withdrawal Syndrome:
Clozapine is used as a therapeutic agent for treating drug or alcohol-dependence withdrawal syndrome. It helps in managing symptoms such as acute tremors, agitation, being easy to get startled, nausea, vomiting, and sweating. It can also alleviate short delusions, hallucinations, and visual distortion associated with withdrawal.
Used as a Depigmentor:
Clozapine is used as a depigmenting agent in certain applications, although this use is not directly mentioned in the provided materials.

Pharmacological effects

1. Antipsychotic effects: Clozapine has good efficacy on treating various types of acute and chronic psychiatric disease. It can alleviate symptoms like excitement, agitation, hallucinations, delusion, thought disorder, depersonalization, and strange movements. The mechanism may be associated with its blocking effect on the dopamine receptor of mesolimbic system, but does not affect the dopamine receptors in the striatum, so this product rarely produces extrapyramidal reactions. 2. Sedative and hypnotic effects: This product can inhibit the spontaneous activity when applied in low-dose. High dose can increase automatic activity. Clozapine can directly inhibit the brain ascending reticular activating system. 3. Anti-cholinergic, anti-histamine and anti-adrenergic effects: The product has a strong anti-acetylcholine effect, and also has suppressing effect on histamine, norepinephrine and epinephrine.

Pharmacodynamics

This product is a kind of major tranquilizer which has well therapeutic effect on treating acute and chronic schizophrenia. Its mechanism of action is probably playing a pharmacological effect on central dopamine nerve. It can selectively block dopamine receptors in the limbic system with small effect on nigrostriatal dopamine receptor, so it has a strong anti-psychotic effect. The extrapyramidal side effects are rare. Its function also has no dependence on the activity of adenylate cyclase.

Pharmacokinetics

Its absorption through oral administration happens quickly and completely. There is no food effect on the rate and extent of absorption. It is widely distributed to various organizations after rapid absorption and there are large individual differences in bioavailability with an average deviation of about 50% to 60%. It also has hepatic first-pass effect. The plasma concentration reaches peak 3.2 hours (1-4 hours) after taking drugs and has an elimination half-life (t1/2β) about 9 hours. The apparent volume of distribution (Vd) is 4.04~13.78L/kg. It has a high tissue binding rate. After being metabolized by the liver, 80% of it is in the form of metabolites presented in urine and feces. Its major metabolites include N-demethylated clozapine, and the N-oxidant of clozapine. Under the same dose and a constant body weight, serum drug concentrations of female patients are significantly higher than that of male patients. Smoking can accelerate the metabolism of this product. Drug metabolism and renal clearance are significantly lower in the elderly. This product can be secreted from the milk, and can penetrate through the blood-brain barrier. The above information is edited by the lookchem of Dai Xiongfeng.

Synthetic route

Use 2,5-dichloro-nitrobenzene (2) and anthranilic acid (3) to react in DMF to generate 2-(4-chloro-2-nitro) dimethylbenzene (4), dimethylbenzene undergoes hydrazine hydrate/ferric chloride catalytic reduction to produce 2-(2-amino-4-chlorophenyl) dimethylbenzene (5), dimethylbenzene goes through cyclization reaction with the catalysis of polyphosphoric acid to obtain 8-chloro-5,10-dihydro-11H-dibenzo [b, e] [1,4]-dinitrogen-11-one (6). Product in step 6 is condensed together with N-methylpiperazine in the effect of titanium tetrachloride to get the final product. Figure 1 the synthesis route of clozapine

Precautions

1. Induction of the decrease of neutropenia or its development into agranulocytosis is the most serious side effects of this product. So do not take drugs which causes leukopenia simultaneously while taking clozapine, especially avoid taking the traditional antipsychotic or antidepressant drugs or long-acting antipsychotics. Leukocyte count should be performed before treatment in order to understand the patient to return to normal polymorphonuclear leukocytes index. After the start of treatment, weekly leukocyte count should be performed for 18 consecutive weeks. Then the test should be done at least once a month. Do the same things during long-term medication. At each time of consultation, remind the patients to seek medical treatment immediately when infection or fever occurs. When there is an infection or WBC is less than 3.5 × 109/L or be much lower compared to the initial measured index, the white blood cell count should be reviewed immediately. If the absolute value of leukocyte reduced to 3 × 109/L or less and/or neutrophil polymorphonuclear leukocytes have an absolute value being less than 1.5 × 109/L, should be immediately discontinued. 2. For patients with a history of seizures or cardiovascular, renal, hepatic insufficiency, apply a lower initial dose and should increase the dose more gradually. 3. For patients with non-serious liver disease, clinical monitoring and regularly check of liver function is necessary. 4. Remind the patient that this product has the role of triggering drowsiness. So do not drive and operate machinery while taking the drug. 5. It has interaction with the central sedative and antipsychotic drugs, so be cautious when taking medicine. 6. Lactating women should not be breastfeeding upon medication. 7. Disable who are allergic to clozapine. 8. Patients with neutropenia, agranulocytosis or an apparent history of blood disease; Be cautious for patients of alcohol and drug-induced psychosis, poisoning and coma, severe heart, liver, kidney diseases, angle-closure glaucoma, and prostatic hypertrophy-caused urinary tract disease.

Side effects

Common adverse reactions include salivation (significantly during sleeping), nausea, vomiting, and abdominal distension. Occasionally fever, neutropenia, and a long-term drug addiction occur.

Side effects

A serious drawback to the use of clozapine, however, is the potentially fatal agranulocytosis that is reported to occur in 1 to 2% of unmonitored patients, necessitating weekly white blood cell counts for at least the first 6 months of pharmacotherapy.

Contraindications

Children under 16 years of age, patients of angle-closure glaucoma, prostatic hyperplasia, spastic disorders or with a history of epilepsy and severe cardiovascular disease should take with caution. Disable it for patients with significantly inhibited central nervous system and with a history of myelosuppression or abnormal blood cells.

Production methods

2-amino-4-chloro-diphenylamine-2'-carboxylic acid (4''-methyl) piperazine reacts with phosphorus oxychloride to get clozapine.

Originator

Leponex,Wander,W. Germany,1974

Manufacturing Process

7.4 g of 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4"-methyl) piperazide and 35 ml of phosphoroxychloride are heated for 3 hours under reflux in the presence of 1.4 ml of N,N-dimethylaniline. Upon concentration of the reaction mixture in vacuo as far as possible, the residue is distributed between benzene and ammonia/ice water. The benzene solution is extracted with dilute acetic acid. The acid extract is clarified with charcoal and treated with concentrated ammonia water to precipitate the alkaline substance, which is dissolved in ether. The ethereal solution is washed with water and dried over sodium sulfate. The residue obtained yields, after recrystallization from ether/petroleum ether 2.9 g (41% of the theoretical yield) of 8-chloro-11-(4- methyl-1-piperazinyl)-5H-dibenzo[b,e][1,4]diazepine in the form of yellow grains of melting point 182° to 184°C (from acetone/petroleum ether).

Therapeutic Function

Tranquilizer

World Health Organization (WHO)

Clozapine, a tricyclic neuroleptic, was introduced in 1972 for the treatment of psychosis. In 1975 its use was associated with cases of agranulocytosis, particularly in Finland. These cases, which included several fatalities, resulted in the withdrawal of the drug in some countries. However, clozapine remains available in at least 30 countries, in some cases only on special request, for the treatment of severe psychotic disorders unresponsive to other neuroleptics provided that close monitoring of the blood count is feasible. In 1989, it was introduced in the United States for the treatment of severe schizophrenia. Lately, the use of clozapine in the United Kingdom has been associated with convulsions. (Reference: (WHODIB) WHO Drug Information Bulletin, 2: 10, , 1977)

Biological Activity

Atypical antipsychotic drug, with a much lower tendency to cause extrapyramidal side effects than conventional neuroleptics. Displays a broad range of pharmacological actions; the antipsychotic effects are thought to be mediated principally by 5-HT 2A/2C and dopamine receptor blockade (K i values are 21, 170, 170, 230 and 330 nM for D 4 , D 3 , D 1 , D 2 and D 5 receptors respectively).

Biochem/physiol Actions

Atypical antipsychotic compound. Selective antagonist for D4-dopamine receptor. Antagonist at 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 serotonin receptors.

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.

Synthesis

Clozapine, 8-chloro-11-(4-methyl-1-piperazinyl)-5H-dibenzo[b,e] [1,4]diazepine (6.5.7) is synthesized by two methods. According to the first, 4-chloro-2-nitroaniline in the presence of copper filings is acylated by the o-chlorobenzoic acid methyl ester, forming the corresponding diphenylamine (6.5.4). By reacting this with N-methyl piperazine, the ester group in the resulting polyfunctional diphenylamine is transformed into the amide (6.5.5). The nitro group in the resulting 4-chloro-2- nitro-2′-carb-(N′-methyl piperazino)amide (6.5.5) is further reduced into an amine group by hydrogen in the presence of Raney nickel. Reacting the resulting product (6.5.6) with phosphorous oxychloride yields in heterocyclization into the desired dibenzodiazepine, clozapine (6.5.7). The other way of synthesis of clozapine is from 8-chloro-10,11-dihydro-5H-dibenzo[b,e]1, 4-diazepin-11-thione, which is alkylated at the sulfur atom of the dibenzodiazepine ring by 4-nitrobenzylchloride in the presence of potassium tert-butoxide, giving N-methyl derivative (6.5.8). Reaction of this with N-methylpiperazine gives the desired clozapine (6.5.7).

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.

Metabolism

Clozapine is orally active and metabolized mainly by CYP3A4 to inactive desmethyl, hydroxyl, and N-oxide derivatives, with a half-life of approximately 12 hours. Clozapine has relatively low affinity for brain dopamine D1 and D2 receptors (moderate affinity for D4) in comparison to its affinity at adrenergic α1 and α2, histamine H1, muscarinic M1 and serotonin 5-HT2A receptors.

References

1) Seeman and Van Tol (1994),?Dopamine receptor pharmacology;? Trends Pharmacol. Sci.,?15?264 2) Ellenbroek?et al. (1991),?The involvement of dopamine D1 and D2 receptors in the effects of the classical neuroleptic haloperidol and the atypical neuroleptic clozapine;? Eur. J. Pharmacol.,?196?103 3) Canton?et al.?(1990),?Binding of the typical and atypical antipsychotics to 5-HT1C and 5-HT2 sites: clozapine potently interacts with 5-HT1C sites;? Eur. J. Pharmacol.,?191?93 4) Kuoppamaki?et al.?(1993),?Clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists;? Eur. J. Pharmacol., 245?179

InChI:InChI=1/C18H19ClN4/c1-22-8-10-23(11-9-22)18-14-4-2-3-5-15(14)20-16-7-6-13(19)12-17(16)21-18/h2-7,12,20H,8-11H2,1H3

Synthetic route

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

Conditions	Yield
With hydrogenchloride; titanium(III) chloride In water; acetonitrile at 20℃; for 1h;	97%

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)

Conditions	Yield
With titanium tetrachloride In 1,4-dioxane; toluene for 2h; Heating;	88%
With titanium tetrachloride	53%
With hydrogenchloride; titanium tetrachloride In water; methoxybenzene; isopropyl alcohol; toluene
With titanium tetrachloride

clozapine N-oxide + (2E)-3-phenyl-2-propen-1-ol (4407-36-7) → 1-phenyl-propane-1,2,3-triol (63157-81-3) + clozaril (5786-21-0)

Conditions	Yield
With osmium(VIII) oxide In water; tert-butyl alcohol at 20℃; for 19h; Inert atmosphere;	A 73% B 84%

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

Conditions	Yield
With tributylphosphine at 150℃; for 48h; Temperature; Reagent/catalyst;	80%
Multi-step reaction with 2 steps 1: 3 h / 150 °C 2: triphenylphosphine / 230 °C View Scheme

N-{4-chloro-2-[(triphenylphosphoranylidene)amino]phenyl}-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine → clozaril (5786-21-0)

Conditions	Yield
With triphenylphosphine at 230℃;	65%

styrene (292638-84-7) + clozapine N-oxide → phenylethane 1,2-diol (93-56-1) + clozaril (5786-21-0)

Conditions	Yield
With osmium(VIII) oxide In water; tert-butyl alcohol at 20℃; for 19h; Inert atmosphere;	A 8% B 53%

4-Chloro-2-nitroaniline (89-63-4) → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: o-xylene / Dean-Stark 1.2: Reflux 2.1: iron; calcium chloride / water / 90 - 100 °C 3.1: triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 2.33 h / 20 °C 4.1: titanium tetrachloride / o-xylene / 10 - 15 °C / Reflux 5.1: titanium tetrachloride / 10 °C / Reflux View Scheme
Multi-step reaction with 6 steps 1.2: 12 h / 20 °C / Reflux 2.1: iodine / 3 h / 50 - 55 °C 3.1: sodium dithionate / methanol / 2 h / 50 - 55 °C 4.1: toluene / 0 - 5 °C 5.1: trichlorophosphate / 3 h / Reflux 6.1: potassium carbonate / ethanol / 3 h / Reflux View Scheme

bromobenzene (108-86-1) → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 6 steps 1.2: 12 h / 20 °C / Reflux 2.1: iodine / 3 h / 50 - 55 °C 3.1: sodium dithionate / methanol / 2 h / 50 - 55 °C 4.1: toluene / 0 - 5 °C 5.1: trichlorophosphate / 3 h / Reflux 6.1: potassium carbonate / ethanol / 3 h / Reflux View Scheme

N-(4-chloro-2-nitrophenyl)benzenamine (16611-15-7) → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 5 steps 1: iodine / 3 h / 50 - 55 °C 2: sodium dithionate / methanol / 2 h / 50 - 55 °C 3: toluene / 0 - 5 °C 4: trichlorophosphate / 3 h / Reflux 5: potassium carbonate / ethanol / 3 h / Reflux View Scheme

ortho-chlorobenzoic acid (118-91-2) → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: o-xylene / Dean-Stark 1.2: Reflux 2.1: iron; calcium chloride / water / 90 - 100 °C 3.1: triethylamine / dichloromethane / 0.33 h / 20 °C 3.2: 2.33 h / 20 °C 4.1: titanium tetrachloride / o-xylene / 10 - 15 °C / Reflux 5.1: titanium tetrachloride / 10 °C / Reflux View Scheme

N-(4-chloro-2-nitrophenyl)-N-phenylacetamide → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: sodium dithionate / methanol / 2 h / 50 - 55 °C 2: toluene / 0 - 5 °C 3: trichlorophosphate / 3 h / Reflux 4: potassium carbonate / ethanol / 3 h / Reflux View Scheme

N-(4-chloro-2-aminophenyl)-N-phenylacetamide → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: toluene / 0 - 5 °C 2: trichlorophosphate / 3 h / Reflux 3: potassium carbonate / ethanol / 3 h / Reflux View Scheme

N-(2-(N-phenylacetamido)-5-chlorophenyl)-4-methylpiperazine-1-carboxamide → clozaril (5786-21-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: trichlorophosphate / 3 h / Reflux 2: potassium carbonate / ethanol / 3 h / Reflux View Scheme

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

Conditions	Yield
With potassium carbonate In ethanol for 3h; Reflux;	5 g

2-(2-methylphenyl)pyridine (10273-89-9) + clozaril (5786-21-0) → C30H29N5

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 48h; Inert atmosphere;	96%

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

Conditions	Yield
Stage #1: clozaril With 3-chloro-benzenecarboperoxoic acid In methanol at 23℃; for 0.166667h; Inert atmosphere; Stage #2: With triethylamine In methanol for 0.166667h; Inert atmosphere;	94%
With 3-chloro-benzenecarboperoxoic acid In dichloromethane at 20℃; for 0.166667h;

mesitylenesulfonylhydroxylamine (36016-40-7) + clozaril (5786-21-0) → 1-amino-4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1-methylhexahydropyrazin-1-ium 2,4,6-trimethyl-1-benzenesulfonate

Conditions	Yield
In dichloromethane at 0℃; for 0.333333h;	82%

ethyl 5-bromovalerate (14660-52-7) + clozaril (5786-21-0) → C25H31ClN4O2

Conditions	Yield
With potassium tert-butylate In N,N-dimethyl-formamide at 20℃;	80%

carbon dioxide (124-38-9) + clozaril (5786-21-0) → C19H19N5

Conditions	Yield
With nickel(II) acetylacetonate; potassium fluoride; phenylsilane; ammonia; zinc; bis(2-diphenylphosphinoethyl)phenylphosphine In 1-methyl-pyrrolidin-2-one at 90 - 140℃; under 760.051 Torr; for 20h; Sealed tube;	80%

N,N,6-trimethyl-2-(4-methylphenyl)imidazo[1,2-a]pyridine-3-acetamide (82626-48-0) + clozaril (5786-21-0) → C37H39N7O

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 144h; Reagent/catalyst; Inert atmosphere;	76%
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 144h; Inert atmosphere; Glovebox;	76%

clozaril (5786-21-0) → N-desmethylclozapine (6104-71-8)

Conditions	Yield
Stage #1: clozaril With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dicholoroethane at 0℃; for 22.5h; Inert atmosphere; Reflux; Stage #2: With methanol at 50℃; for 2h; Inert atmosphere;	69%
Stage #1: clozaril With carbonochloridic acid 1-chloro-ethyl ester In 1,2-dichloro-ethane for 24h; Reflux; Stage #2: With methanol at 50℃; for 2h;
With cytochrome P450 1A2; cytochrome P450 3A4

clozaril (5786-21-0) + bis(pinacol)diborane (73183-34-3) → 11-(4-methylpiperazin-1-yl)-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5H-dibenzo[b,e][1,4]diazepine

Conditions	Yield
With tris-(dibenzylideneacetone)dipalladium(0); potassium acetate; XPhos In 1,4-dioxane at 110℃; for 12h; Inert atmosphere; Sealed tube;	59%

clozaril (5786-21-0) + methyl iodide (74-88-4) → 4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)-1,1-dimethylpiperazin-1-ium iodide

Conditions	Yield
In acetone at 20℃;	55%

n-decanoyl chloride (112-13-0) + clozaril (5786-21-0) → 1-[8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-yl]decan-1-one (1357146-74-7)

Conditions	Yield
With pyridine; N-ethyl-N,N-diisopropylamine In dichloromethane at 20℃; for 2h; Inert atmosphere;	36%

clozaril (5786-21-0) → 7-Hydroxyclozapine (355004-92-1) + C18H19ClN4O (1239601-19-4)

Conditions	Yield
Stage #1: clozaril With ethylenediaminetetraacetic acid trisodium salt; oxygen; manganese (II) acetate tetrahydrate; ascorbic acid In water pH=4; Udenfriend reaction; Stage #2: With ferrous(II) sulfate heptahydrate; ethylenediaminetetraacetic acid trisodium salt; oxygen In water at 45℃; for 2h; Udenfriend reaction;	A 4.93% B 2.98%

GLUTATHIONE (70-18-8) + clozaril (5786-21-0) → C-6 glutathionyl clozapine + C-9 glutathionyl clozapine

Conditions	Yield
With horseradish peroxidase type VI; dihydrogen peroxide In phosphoric acid at 25℃; for 4h; pH=7.4; Oxidation; Enzymatic reaction;
With sodium hypochlorite In ethanol; water Oxidation;

clozaril (5786-21-0) → clozapine nitrenium ion

Conditions	Yield
With hypochloric acid In water at 25℃; pH=6; Kinetics; Oxidation;

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + N-acetylcystein (616-91-1) + clozaril (5786-21-0) + keyhole limpet hemocyanin → clozapine-N-acetylcystein-modified keyhole limpet hemocyanin

Conditions	Yield
Stage #1: N-acetylcystein; clozaril With sodium hypochlorite In ethanol for 0.166667h; pH=4.0; Stage #2: 1-hydroxy-pyrrolidine-2,5-dione With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide; acetonitrile Stage #3: keyhole limpet hemocyanin In phosphate buffer; acetonitrile at 20℃; for 1h; pH=8.0;

1-hydroxy-pyrrolidine-2,5-dione (6066-82-6) + N-acetylcystein (616-91-1) + clozaril (5786-21-0) + rabbit serum albumin → clozapine-N-acetylcystein-modified rabbit serum albumin

Conditions	Yield
Stage #1: N-acetylcystein; clozaril With sodium hypochlorite In ethanol for 0.166667h; pH=4.0; Stage #2: 1-hydroxy-pyrrolidine-2,5-dione With N-(3-dimethylaminopropyl)-N-ethylcarbodiimide In N,N-dimethyl-formamide; acetonitrile Stage #3: rabbit serum albumin In phosphate buffer; acetonitrile at 20℃; for 1h; pH=8.0;

clozaril (5786-21-0) → 8-chloro-11-(4-methylpiperazin-1-yl)-5-nitroso-5H-dibenzo[b,e][1,4]diazepine (156632-03-0)

Conditions	Yield
With isopentyl nitrite In dichloromethane
With isopentyl nitrite In dichloromethane at 20℃; for 3h;

clozaril (5786-21-0) → 8-chloro-11-(4-methyl-piperazin-1-yl)-5-nitro-5H-dibenzo[b,e][1,4]diazepine

Conditions	Yield
With isopentyl nitrite In dichloromethane at 20℃; for 3h;

clozaril (5786-21-0) → 8-chloro-11-(4-methylpiperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepin-5-amine (136772-01-5)

Conditions	Yield
Multi-step reaction with 2 steps 1: isoamyl nitrite / CH2Cl2 2: AcOH; Zn View Scheme
Multi-step reaction with 2 steps 1: isoamyl nitrite / CH2Cl2 / 3 h / 20 °C 2: 0.84 g / Zn; AcOH / 3 h View Scheme
Multi-step reaction with 2 steps 1: isopentyl nitrite / dichloromethane / 3 h / 20 °C 2: acetic acid; zinc / 4 h / 10 - 15 °C View Scheme
Stage #1: clozaril With isopentyl nitrite In dichloromethane at 27℃; for 3h; Stage #2: With acetic acid; zinc at 10 - 15℃; for 1h;

clozaril (5786-21-0) → N-[8-chloro-11-(4-methyl-piperazin-1-yl)-dibenzo[b,e][1,4]diazepin-5-yl]-nicotinamide

Conditions	Yield
Multi-step reaction with 3 steps 1.1: isoamyl nitrite / CH2Cl2 / 3 h / 20 °C 2.1: 0.84 g / Zn; AcOH / 3 h 3.1: Argopore-CHO resin; NaBH3CN; AcOH 3.2: Et3N 3.3: TFA View Scheme

Upstream product

• 109-01-3 1-methyl-piperazine 
• 50892-62-1 8-chloro-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one 
• 67990-66-3 N-(2-Amino-4-chlorophenyl)anthranilic acid 
• 65514-71-8 2-amino-4-chlorodiphenylamine-2'-carboxylic acid (4''-methyl)piperazide 
• 50373-22-3 8,11-dichloro-5H-dibenzo[b,e][1,4]-diazepine 
• 118-91-2 ortho-chlorobenzoic acid 
• 16611-15-7 N-(4-chloro-2-nitrophenyl)benzenamine 
• 108-86-1 bromobenzene 
• 89-63-4 4-Chloro-2-nitroaniline 
• 69414-55-7 C₁₃H₈Cl₂N₂O₃ 
• 60091-87-4 2-(4-Chlor-2-nitrophenyl)aminobenzencarbonsaeure 
• 65514-72-9 N-(4-chloro-2-nitrophenyl)-N-{2-[(4-methylpiperazin-1-yl)carbonyl]phenyl}amine 
• 4407-36-7 (2E)-3-phenyl-2-propen-1-ol 
• 100-42-5 styrene 

Downstream Products

• 6104-71-8 N-desmethylclozapine 

Relevant articles and documents

Aminimides as potential CNS acting agents. I. Design, synthesis, and receptor binding of 4′-aryl aminimide analogues of clozapine as prospective novel antipsychotics

A series of substituted 1-[4-(8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-yl)- 1-methylhexahydropyrazin-1-ium]-1-aminimide derivatives were designed on the basis of the physicochemical properties of the aminimide functional group and synthesized as potential antipsychotic agents for the treatment of schizophrenia. The target compounds were readily prepared in two steps from clozapine (8-chloro-11-(4-methylpiperazino)-5H-dibenzo[b,e][1,4]diazepine) and involved N-acylation of a common hydrazinium salt intermediate by an acyl chloride or activated ester in the presence of a strong base. The aminimides were tested for in vitro activity at the dopamine D4 and serotonin 5-HT2A receptors and were found to possess modest affinity for both receptor systems. CSIRO 2007.

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

A class of dialkylamino-substituted dibenzodiazepines and their hetero analogues was synthesized by the intramolecular aza-Wittig condensation of the amido group with iminophosphoranes. The one-pot, two-step procedure includes reductive synthesis of the intermediate iminophosphoranes from the corresponding nitroamides and tributylphosphine.

Applications of TiCl3 as a Diagnostic Reagent for the Detection of Nitro- and N-Oxide-Containing Compounds as Potentially Mutagenic Impurities Using Ultrahigh-Performance Liquid Chromatography Coupled with High-Resolution Mass Spectrometry

The ICH has strict guidelines for limiting the presence of potentially mutagenic impurities (PMIs) in marketed drugs. Therefore, it is important to fully characterize and quantitate all possible PMIs that could arise during the process of synthesizing and developing a drug. Two important and prevalent examples of PMIs are compounds containing N-oxide and nitro functional groups. TiCl3 derivatization is an established method for determining the presence or absence of N-oxide metabolites by reduction to the corresponding amine. In this study, we demonstrate a novel application of TiCl3 reduction combined with high-resolution UHPLC/HRMS to analyze PMIs. The results indicate that a variety of N-oxide- and nitro-containing compounds can be readily characterized by this facile platform method. In addition, we show that this chemical derivatization method can be utilized to enhance the ionization of nitro-containing compounds for LC/MS analysis.