Haloperidol CAS 52-86-8
Introduction：Basic information about Haloperidol CAS 52-86-8, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.
Haloperidol Basic information
| Product Name: | Haloperidol |
| Synonyms: | Einalon;4-(4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl)-1-(4-fluorophenyl)-1-butanon;4-(4-(para-Chlorophenyl)-4-hydroxypiperidino)-4'-fluorobutyrophenone;4-(4-(p-chlorophenyl)-4-hydroxypiperidino)-4’-fluoro-butyrophenon;4-(4-(p-chlorophenyl)-4-hydroxypiperidino)-4’-fluorobutyrophenone;4-(4-(p-Chlorophenyl)-4-hydroxypiperidino)-4'-fluorobutyrophenone;4-(4-hydroxy-4’-chloro-4-phenylpiperidino)-4’-fluorbutyrophenone;4-(4-hydroxy-4’-chloro-4-phenylpiperidino)-4’-fluorobutyrophenone |
| CAS: | 52-86-8 |
| MF: | C21H23ClFNO2 |
| MW: | 375.86 |
| EINECS: | 200-155-6 |
| Product Categories: | API;HALDOL;Dopamine receptor;Dopamine;Organics;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals |
| Mol File: | 52-86-8.mol |
Haloperidol Chemical Properties
| Melting point | 152 °C |
| Boiling point | 529.0±50.0 °C(Predicted) |
| density | 1.1820 (estimate) |
| Fp | 9℃ |
| storage temp. | 2-8°C |
| solubility | 45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 0.39 mg/mL |
| form | powder |
| pka | 8.3(at 25℃) |
| color | white |
| Water Solubility | 2.058mg/L(22.5 ºC) |
| Merck | 14,4598 |
| BCS Class | 4/3 |
| Major Application | pharmaceutical (small molecule) |
| InChI | 1S/C21H23ClFNO2/c22-18-7-5-17(6-8-18)21(26)11-14-24(15-12-21)13-1-2-20(25)16-3-9-19(23)10-4-16/h3-10,26H,1-2,11-15H2 |
| InChIKey | LNEPOXFFQSENCJ-UHFFFAOYSA-N |
| SMILES | OC1(CCN(CCCC(=O)c2ccc(F)cc2)CC1)c3ccc(Cl)cc3 |
| CAS DataBase Reference | 52-86-8(CAS DataBase Reference) |
| NIST Chemistry Reference | Haloperidol(52-86-8) |
| EPA Substance Registry System | Haloperidol (52-86-8) |
Safety Information
| Hazard Codes | T,F |
| Risk Statements | 60-61-25-36/37/38-43-39/23/24/25-23/24/25-11 |
| Safety Statements | 53-26-36/37/39-45-36/37-16 |
| RIDADR | UN 2811 6.1/PG 3 |
| WGK Germany | 3 |
| RTECS | EU1575000 |
| HazardClass | 6.1(b) |
| PackingGroup | III |
| HS Code | 2933399090 |
| Storage Class | 6.1C - Combustible acute toxic Cat.3 toxic compounds or compounds which causing chronic effects |
| Hazard Classifications | Acute Tox. 3 Oral Eye Irrit. 2 Repr. 2 Skin Irrit. 2 Skin Sens. 1 STOT SE 3 |
| Hazardous Substances Data | 52-86-8(Hazardous Substances Data) |
| Toxicity | LD50 orally in rats: 165 mg/kg (Goldenthal); i.p. in mice: 60 mg/kg (Collins, Horlington) |
| Description | Haloperidol is a butyrophenone with a long duration of action. It has lile α-adrenoceptor blocking activity and minimal effect on the cardiovascularsystem. It is an effective antiemetic but has a high incidence ofextrapyramidal adverse effects. Haloperidol may be used in the short-termmanagement of the acutely agitated patient (when sinister causes ofconfusion such as hypoxaemia and sepsis have been excluded) and in themanagement of delirium in ICU. The duration of action ofhaloperidol is approximately 24–48h. |
| Chemical Properties | White Crystalline Powder |
| Originator | Haldol,Janssen-Le Brun,France,1960 |
| History | Haloperidol (brand name Haldol) was first approved by the FDA on April 12, 1967, for the treatment of schizophrenia. It is a typical antipsychotic drug. However, due to its severe neurotoxicity and significant harm to the human body, it has gradually been phased out of the market. Haldol is also approved by the FDA for Tourette syndrome and hyperactivity or severe behavioral problems in children who are unresponsive to treatment or other medications. However, this drug can only be obtained through a doctor's prescription. |
| Uses | Haloperidol is one of the most actively used modern neuroleptics. Its high antipsychoticactivity is combined with a moderate sedative effect. It effectively stops various types ofpsychomotor excitement. It is used for schizophrenic psychoses, manic, paranoid, anddelirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origin. |
| Uses | Haloperidol has been used:
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| Uses | Antidyskinetic; antipsychotic |
| Definition | ChEBI: A compound composed of a central piperidine structure with hydroxy and p-chlorophenyl substituents at position 4 and an N-linked p-fluorobutyrophenone moiety. |
| Manufacturing Process | A stirred slurry of 120.0 parts 4-(4-chlorophenyl)-piperidin-4-ol hydrochlorideand 40.0 parts of potassium iodide in 500 parts of water is warmed to atemperature of about 35°C under a nitrogen atmosphere. Then, 70.0 parts ofpotassium hydroxide is added. After further heating to about 55°C. 138.0parts of 1,1 dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added. Thetemperature is then raised to about 102°C and heating continued for 3.5hours. After cooling to about 75°C. 785 parts of toluene is added to thereaction mixture and stirred for about 5 minutes. An additional 320 parts oftoluene is added and the water and organic layers separated. 102 parts ofmethanol is used to rinse the flask and added to the organic layer to provide asolution of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4,4-dimethoxybutyl]-piperidin-4-ol. Then, 59 parts of concentrated hydrochloric acid is added to astirred solution of the organic layer to precipitate a solid. The solid is filtered,rinsed twice with 550 parts by volume portions of a 10:9:1 acetone-toluenemethanol mixture, twice with 400 parts by volume portions of a 10:l acetonemethanol mixture, and air-dried. The dried solid is then dissolved in 1,950parts of methanol with gentle heating on a steam bath. The resulting solutionis filtered and 300 parts by volume of concentrated ammonium hydroxide isadded. Heating is continued to reflux and maintained thereat for about 1 hour.Then, 2,520 parts of water is added and the slurry stirred at about 75°C for1.5 hours. After cooling to about 25°C. the solid is filtered, washed twice with600 parts by volume portions of a 3:1 mixture of water-methanol, and airdried. The resulting product, 4-[4-chlorophenyl)-4-hydroxypiperidino]-4'-fluorobutyrophenone, is obtained in 32.5% yield. This product melts at about148.5°C to 150.5°C. |
| Brand name | Haldol (OrthoMcNeil). |
| Therapeutic Function | Antidyskinetic, Antipsychotic |
| General Description | Haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4-fluorobutyrophenone (Haldol), is anodorless white to yellow crystalline powder. Haloperidol iswell and rapidly absorbed and has a high bioavailability. It ismore than 90% bound to plasma proteins. Haloperidol is excretedslowly in the urine and feces. About 30% of a dose isexcreted in urine and about 20% of a dose in feces via biliaryelimination,and only 1% of a dose is excreted as unchangeddrug in the urine.Haloperidol is a minor substrate of CYP1A2 and a major substrate of CYP2D6 and CYP3A4.CYP2D6 inhibitors may increase the levels/effects ofhaloperidol.Haloperidol may increase the levels/effects ofCYP2D6 substrates and it may decrease the bioactivationof CYP2D6 prodrugs substrates. Haloperidol also is a moderateinhibitor of CYP2D6 and CYP3A4. CYP3A4 inducersmay decrease the levels/effects of haloperidol, whereasCYP3A4 inhibitors may increase the levels/effects ofhaloperidol. Centrally acting acetylcholinesterase inhibitorsmay increase the risk of antipsychotic-related EPS. The precisemechanism of antipsychotic action is unclear but isconsidered to be associated with the potent DA D2receptor–blocking activity in the mesolimbic system and theresulting adaptive changes in the brain. Haloperidol is usedprimarily for the long-term treatment of psychosis and is especiallyuseful in patients who are noncompliant with theirdrug treatment. |
| General Description | Haloperidol, 4[4-(p-chlorophenyl)-4-hydroxypiperidone]-4' -n-fluorobutyrophenone (Haldol),the representative of several related classes of aromaticbutylpiperidine derivatives, is a potent antipsychotic usefulin schizophrenia and in psychoses associated with braindamage. It is frequently chosen as the agent to terminatemania and often used in therapy for Gilles de la Tourettesyndrome. Haloperidol-induced dyskinesias may involveneurotoxicological metabolite similar to dopaminergic toxicantMPP+. |
| Pharmaceutical Applications | Haloperidol is an analogue of the dopamine D2 receptor antagonist and is an older antipsychotic drug. The drug is used in the treatment of schizophrenia, a neuropsychiatric disorder. In general, antipsychotic drugs work by blocking the dopamine D2 receptors. Haloperidol is such an antipsychotic drug, which was developed in the 1950s and entered the clinic soon after that. Its use is limited by the high incidence of extrapyramidal symptoms (movement disorders caused by drugs affecting the extrapyramidal system, a neural network which is part of the motor system). Nevertheless, haloperidol may be used for the rapid control of hyperactive psychotic states and is popular for treating restlessness in the elderly. |
| Biological Activity | Dopamine antagonist with selectivity for D 2 -like receptors (K i values are 1.2, ~ 7, 2.3, ~ 80 and ~ 100 nM for D 2 , D 3 , D 4 , D 1 and D 5 receptors respectively). Subtype-selective NMDA antagonist. |
| Biochem/physiol Actions | Haloperidol is a butyrophenone antipsychotic. It is also classified as a neuroleptic (powerful tranquilizer). Haloperidol acts as a D2, D3, and D4 dopamine receptor antagonist and thus causes Parkinson′s disorder. It also has a negative effect on the central nervous system. |
| Clinical Use | Sedative in severe anxiety Intractable hiccup Motor tics Nausea and vomiting Schizophrenia and other psychoses |
| Synthesis | Haloperidol, 4-[4-(p-chlorophenyl)-4-hydroxypiperidino]-4??-fluorobutyrophenone (6.3.8), is synthesized by the alkylation of 4-(4-chlorophenyl)-4-hydroxypiperidine(6.3.7) using 4??-chloro-4-fluorobutyrophenone (6.3.4). 4-(4-Chlorophenyl) -4-hydroxypiperidine (6.3.7) is synthesized from 2-(4-chlorophenyl)propene, which on reaction with formaldehyde and ammonium chloride gives the intermediate 4-methyl-4-(4-chlorophenyl)-1,3-oxazine (6.3.5), evidently through stages postulated for the Prince reaction. Treatment of theresulting product with hydrochloric acid leads to the formation of 4-(4-chlorophenyl)-1,2,3,6-tetrahydropiperidine (6.3.6), probably through a stage of opening of the hydrogenated 1,3-oxazine ring, followed by dehydration, and subsequent recyclization. Addition of hydrogen bromide to the double bond of 4-(4-chlorophenyl)1,2,3,6-tetrahydropipidine (6.3.6) andthe subsequent alkaline hydrolysis of the 4-(4-chlorophenyl)-4-bromopiperidine formed during the reaction, gives 4-(4-chlorophenyl)-4-hydroxypiperidine (6.3.7), the reaction of whichwith 4??-chloro-4-fluorobutyrophenone (6.3.4) gives the desired haloperidol (6.3.6) [41¨C46]. |
| Drug interactions | Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effects. Analgesics: increased risk of convulsions withtramadol; enhanced hypotensive and sedativeeffects with opioids; possibly severe drowsinesswith indometacin or acemetacin; increased risk ofventricular arrhythmias with methadone. Anti-arrhythmics: increased risk of ventriculararrhythmias with anti-arrhythmics that prolongthe QT interval; increased risk of ventriculararrhythmias with amiodarone or disopyramide -avoid. Antibacterials: increased risk of ventriculararrhythmias with moxifloxacin and delamanid -avoid with moxifloxacin; concentration reduced byrifampicin. Antidepressants: increased risk of ventriculararrhythmias with citalopram, escitalopram andtricyclics - avoid; concentration increased byfluoxetine and venlafaxine and possibly fluvoxamine;possible increased risk of convulsions withvortioxetine; concentration of tricyclics increased. Antiepileptics: metabolism increased bycarbamazepine, phenobarbital and primidone;lowered seizure threshold; concentration reduced byfosphenytoin and phenytoin. Antifungals: concentration possibly increased byitraconazole. Antimalarials: avoid with artemether/lumefantrineand piperaquine with artenimol; possible increased risk of ventricular arrhythmias with mefloquine orquinine - avoid. Antipsychotics: avoid concomitant use of depotformulations with clozapine (cannot be withdrawnquickly if neutropenia occurs); increased riskof ventricular arrhythmias with sulpiride anddroperidol and possibly risperidone - avoid withdroperidol; concentration possibly increased bychlorpromazine. Antivirals: concentration possibly increased withritonavir; increased risk of ventricular arrhythmiaswith saquinavir - avoid. Anxiolytics and hypnotics: increased sedativeeffects; concentration increased by alprazolam andbuspirone. Atomoxetine: increased risk of ventriculararrhythmias. Beta-blockers: increased risk of ventriculararrhythmias with sotalol. Cytotoxics: increased risk of ventricular arrhythmiaswith bosutinib, ceritinib and vandetanib - avoid with vandetanib; increased risk of ventricular arrhythmiaswith arsenic trioxide. Lithium: increased risk of extrapyramidal side effectsand possibly neurotoxicity. |
| Metabolism | Haloperidol is metabolised in the liver and is excreted inthe urine and, via the bile in the faeces; there is evidenceof enterohepatic recycling. Routes of metabolism ofhaloperidol include oxidative N-dealkylation, particularlyvia the cytochrome P450 isoenzymes CYP3A4 andCYP2D6, glucuronidation, and reduction of the ketonegroup to form an alcohol known as reduced haloperidol.Metabolites are ultimately conjugated with glycineand excreted in the urine. There is debate over thepharmacological activity of the metabolites. |
| Dosage forms | Dosage for haloperidol is as follows: ? Sedation: 2–10 mg i.v. or i.m. (max. 18 mg per 24 h). ? Antiemesis: 1.25 mg i.v. for prevention of postoperativenausea and vomiting (PONV). |
| references | [1] dr ananya mandal, md .haloperidol pharmacology. |
Haloperidol Preparation Products And Raw materials
| Raw materials | Thionyl chloride-->Gamma Butyrolactone-->Fluorobenzene-->Butyrophenone-->Ammonia-->4-(4-chlorophenyl)piperidin-4-ol hydrochloride-->Hydrochloric acid |
