52-86-8

Basic information

• Product Name: Haloperidol
• Synonyms: 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;4-(4-Hydroxy-4'-chloro-4-phenylpiperidino)-4'-fluorobutyrophenone
• CAS NO: 52-86-8
• Molecular Formula: C₂₁H₂₃ClFNO₂
• Molecular Weight: 375.86
• EINECS: 200-155-6
• Product Categories: Organics;Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Dopamine receptor;Dopamine;API;HALDOL
• Mol File: 52-86-8.mol
• Article Data: 20

Chemical Properties

• Melting Point: 152 °C
• Boiling Point: 529.034 °C at 760 mmHg
• Flash Point: 9℃
• Appearance: white/powder
• Density: 1.1820 (estimate)
• Vapor Pressure: 5.07E-12mmHg at 25°C
• Storage Temp.: Store at RT
• Solubility: 45% (w/v) aq 2-hydroxypropyl-β-cyclodextrin: 0.39 mg/m
• PKA: 8.3(at 25℃)
• Water Solubility: 2.058mg/L(22.5 oC)
• Merck: 14,4598
• CAS DataBase Reference: Haloperidol(CAS DataBase Reference)
• NIST Chemistry Reference: Haloperidol(52-86-8)
• EPA Substance Registry System: Haloperidol(52-86-8)

Safety Data

• Hazard Codes: T,F
• 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
• Hazardous Substances Data: 52-86-8(Hazardous Substances Data)

Usage

Description

Haloperidol is a butyrophenone with a long duration of action. It has lile α- adrenoceptor blocking activity and minimal effect on the cardiovascular system. It is an effective antiemetic but has a high incidence of extrapyramidal adverse effects. Haloperidol may be used in the short-term management of the acutely agitated patient (when sinister causes of confusion such as hypoxaemia and sepsis have been excluded) and in the management of delirium in ICU. The duration of action of haloperidol is approximately 24–48h.

Chemical Properties

White Crystalline Powder

Originator

Haldol,Janssen-Le Brun,France,1960

Uses

Different sources of media describe the Uses of 52-86-8 differently. You can refer to the following data:
1. Haloperidol is one of the most actively used modern neuroleptics. Its high antipsychotic activity is combined with a moderate sedative effect. It effectively stops various types of psychomotor excitement. It is used for schizophrenic psychoses, manic, paranoid, and delirious conditions, depression, psychomotor excitement of various origins, and for delirium and hallucinations of different origin.
2. Haloperidol has been used:in ethanol to serves as an inhibitor of Erg2pto address the mechanism of haloperidol in ferroptosis using hepatocellular carcinoma cells: Hep G2 and Huh-7 cell linesin receptor internalization assayas an antipsychotic drug in Dulbecco′s Modified Eagle medium

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 hydrochloride and 40.0 parts of potassium iodide in 500 parts of water is warmed to a temperature of about 35°C under a nitrogen atmosphere. Then, 70.0 parts of potassium hydroxide is added. After further heating to about 55°C. 138.0 parts of 1,1 dimethoxy-1-(4-fluorophenyl)-4-chlorobutane is added. The temperature is then raised to about 102°C and heating continued for 3.5 hours. After cooling to about 75°C. 785 parts of toluene is added to the reaction mixture and stirred for about 5 minutes. An additional 320 parts of toluene is added and the water and organic layers separated. 102 parts of methanol is used to rinse the flask and added to the organic layer to provide a solution of 4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4,4-dimethoxybutyl]- piperidin-4-ol. Then, 59 parts of concentrated hydrochloric acid is added to a stirred 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 1,950 parts of methanol with gentle heating on a steam bath. The resulting solution is filtered and 300 parts by volume of concentrated ammonium hydroxide is added. 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 for 1.5 hours. After cooling to about 25°C. the solid is filtered, washed twice with 600 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 about 148.5°C to 150.5°C.

Brand name

Haldol (OrthoMcNeil).

Therapeutic Function

Antidyskinetic, Antipsychotic

General Description

Different sources of media describe the General Description of 52-86-8 differently. You can refer to the following data:
1. 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.
2. 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 the resulting 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) and the 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 which with 4′-chloro-4-fluorobutyrophenone (6.3.4) gives the desired haloperidol (6.3.6) [41–46].

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effects. Analgesics: increased risk of convulsions with tramadol; enhanced hypotensive and sedative effects with opioids; possibly severe drowsiness with indometacin or acemetacin; 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 ventricular arrhythmias with amiodarone or disopyramide - avoid. Antibacterials: increased risk of ventricular arrhythmias with moxifloxacin and delamanid - avoid with moxifloxacin; concentration reduced by rifampicin. Antidepressants: increased risk of ventricular arrhythmias with citalopram, escitalopram and tricyclics - avoid; concentration increased by fluoxetine and venlafaxine and possibly fluvoxamine; possible increased risk of convulsions with vortioxetine; concentration of tricyclics increased. Antiepileptics: metabolism increased by carbamazepine, phenobarbital and primidone; lowered seizure threshold; concentration reduced by fosphenytoin and phenytoin. Antifungals: concentration possibly increased by itraconazole. Antimalarials: avoid with artemether/lumefantrine and piperaquine with artenimol; possible increased risk of ventricular arrhythmias with mefloquine or quinine - avoid. Antipsychotics: avoid concomitant use of depot formulations with clozapine (cannot be withdrawn quickly if neutropenia occurs); increased risk of ventricular arrhythmias with sulpiride and droperidol and possibly risperidone - avoid with droperidol; concentration possibly increased by chlorpromazine. Antivirals: concentration possibly increased with ritonavir; increased risk of ventricular arrhythmias with saquinavir - avoid. Anxiolytics and hypnotics: increased sedative effects; concentration increased by alprazolam and buspirone. Atomoxetine: increased risk of ventricular arrhythmias. Beta-blockers: increased risk of ventricular arrhythmias with sotalol. Cytotoxics: increased risk of ventricular arrhythmias with bosutinib, ceritinib and vandetanib - avoid with vandetanib; increased risk of ventricular arrhythmias with arsenic trioxide. Lithium: increased risk of extrapyramidal side effects and possibly neurotoxicity.

Metabolism

Haloperidol is metabolised in the liver and is excreted in the urine and, via the bile in the faeces; there is evidence of enterohepatic recycling. Routes of metabolism of haloperidol include oxidative N-dealkylation, particularly via the cytochrome P450 isoenzymes CYP3A4 and CYP2D6, glucuronidation, and reduction of the ketone group to form an alcohol known as reduced haloperidol. Metabolites are ultimately conjugated with glycine and excreted in the urine. There is debate over the pharmacological 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 postoperative nausea and vomiting (PONV).

InChI:InChI=1/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/p+1

Synthetic route

4-(4-chlorophenyl)-1-<4-(4-nitrophenyl)-4-oxobutyl>-4-piperidinol (150717-69-4) → haloperidol (52-86-8)

Conditions	Yield
With tetrabutyl ammonium fluoride In dimethyl sulfoxide at 160℃; for 0.166667h; Inert atmosphere; Microwave irradiation; Anhydrous conditions;	99%
With hydrogen fluoride; potassium oxalate; potassium carbonate; [2.2.2]cryptande	65%
With hydrogen fluoride; potassium oxalate; potassium carbonate; [2.2.2]cryptande In dimethyl sulfoxide at 160℃; for 0.333333h;	60%

4-(4-chlorophenyl)-4-hydroxypiperidine (39512-49-7) + 4-(4-fluorophenyl)-4-oxo-n-butyl chloride (3874-54-2) → haloperidol (52-86-8)

Conditions	Yield
With potassium carbonate; potassium iodide In acetonitrile at 75℃; for 24h; Temperature;	88%
With potassium iodide In toluene for 45h; Reflux;	85%
With potassium iodide In toluene at 130℃; for 45h; Sealed tube;	79%

4-<4-(4-chlorophenyl)-4-hydroxypiperidino>-1,1-ethylenedioxy-1-(4-fluorophenyl)butane (56660-99-2) → haloperidol (52-86-8)

Conditions	Yield
With hydrogenchloride In methanol for 6h; Heating;	65%
With hydrogenchloride In methanol for 2h; Heating;	65%

4-fluorophenyl trifluoromethanesulfonate (132993-23-8) + 4-(4-chlorophenyl)-1-(4-hydroxybutyl)piperidin-4-ol → haloperidol (52-86-8)

Conditions	Yield
With 2,2,6,6-tetramethyl-piperidine; bis(1,5-cyclooctadiene)nickel (0); acetone; [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine] In toluene at 130℃; for 20h; Inert atmosphere;	37%

Chlorohaloperidol (59995-68-5) → haloperidol (52-86-8)

Conditions	Yield
With hydrogen fluoride; tetra(n-butyl)ammonium hydroxide

4-(4-chlorophenyl)-4-hydroxypiperidine (39512-49-7) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / acetic acid; NaCNBH3 / methanol / 30 h / 20 °C 2: 65 percent / conc. HCl / methanol / 2 h / Heating View Scheme
Multi-step reaction with 2 steps 1: K2CO3, KI / dimethylformamide / 17.5 h / 100 °C 2: 65 percent / conc. HCl / methanol / 6 h / Heating View Scheme
Multi-step reaction with 2 steps 1: potassium iodide / toluene / 48 h / Reflux; Inert atmosphere 2: bis(1,5-cyclooctadiene)nickel (0); [2-((diphenylphospino)methyl)-2-methyl-1,3-propanediyl]bis[diphenylphosphine]; acetone; 2,2,6,6-tetramethyl-piperidine / toluene / 20 h / 130 °C / Inert atmosphere View Scheme

methyl 3-(4-fluorobenzoyl)-propionate (39560-31-1) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 83 percent / p-TsOH / benzene / 20 h / Heating 2: 93 percent / DIBAL-H / CH2Cl2; tetrahydrofuran / 1 h / -78 °C 3: 78 percent / acetic acid; NaCNBH3 / methanol / 30 h / 20 °C 4: 65 percent / conc. HCl / methanol / 2 h / Heating View Scheme

3-[2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]propionaldehyde (847025-06-3) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 78 percent / acetic acid; NaCNBH3 / methanol / 30 h / 20 °C 2: 65 percent / conc. HCl / methanol / 2 h / Heating View Scheme

3-[2-(4-fluorophenyl)-[1,3]dioxolan-2-yl]propionic acid methyl ester (847025-05-2) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 93 percent / DIBAL-H / CH2Cl2; tetrahydrofuran / 1 h / -78 °C 2: 78 percent / acetic acid; NaCNBH3 / methanol / 30 h / 20 °C 3: 65 percent / conc. HCl / methanol / 2 h / Heating View Scheme

(4-aminophenyl)(cyclopropyl)methanone (57189-90-9) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1) HBF4, NaNO2, 2) Cu, NaNO2 / 1) H2O, 30 min, 2) H2O, 1 h 2: 75 percent / conc. HCl / methanol / 0.5 h / 120 °C 3: 31 percent / KI / toluene / 100 - 110 °C 4: 60 percent / HF, potassium carbonate, potassium oxalate, kryptofix 222 / dimethylsulfoxide / 0.33 h / 160 °C View Scheme

1-(4-acetylaminophenyl)-4-chloro-1-butanone (56924-11-9) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 5 steps 1: 90 percent / 4 M NaOH / ethanol / 2 h / Heating 2: 1) HBF4, NaNO2, 2) Cu, NaNO2 / 1) H2O, 30 min, 2) H2O, 1 h 3: 75 percent / conc. HCl / methanol / 0.5 h / 120 °C 4: 31 percent / KI / toluene / 100 - 110 °C 5: 60 percent / HF, potassium carbonate, potassium oxalate, kryptofix 222 / dimethylsulfoxide / 0.33 h / 160 °C View Scheme

Acetanilid (103-84-4) → haloperidol (52-86-8)

Conditions

Yield

Multi-step reaction with 6 steps 1: 20 percent / AlCl3 / CS2 / room temperature, 30 min; 60 deg C, 2 h 2: 90 percent / 4 M NaOH / ethanol / 2 h / Heating 3: 1) HBF4, NaNO2, 2) Cu, NaNO2 / 1) H2O, 30 min, 2) H2O, 1 h 4: 75 percent / conc. HCl / methanol / 0.5 h / 120 °C 5: 31 percent / KI / toluene / 100 - 110 °C 6: 60 percent / HF, potassium carbonate, potassium oxalate, kryptofix 222 / dimethylsulfoxide / 0.33 h / 160 °C View Scheme

cyclopropyl(4-nitrophenyl)methanone (93639-12-4) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 75 percent / conc. HCl / methanol / 0.5 h / 120 °C 2: 31 percent / KI / toluene / 100 - 110 °C 3: 60 percent / HF, potassium carbonate, potassium oxalate, kryptofix 222 / dimethylsulfoxide / 0.33 h / 160 °C View Scheme

4-chloro-4'-nitrobutyrophenone (93639-13-5) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 31 percent / KI / toluene / 100 - 110 °C 2: 60 percent / HF, potassium carbonate, potassium oxalate, kryptofix 222 / dimethylsulfoxide / 0.33 h / 160 °C View Scheme

4-(4-fluorophenyl)-4-oxo-n-butyl chloride (3874-54-2) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: p-toluenesulfonic acid / benzene / 12 h / Heating 2: K2CO3, KI / dimethylformamide / 17.5 h / 100 °C 3: 65 percent / conc. HCl / methanol / 6 h / Heating View Scheme

4-chloro-1-(4-fluorophenyl)-1,1-(ethylenedioxy)butane (3308-94-9) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: K2CO3, KI / dimethylformamide / 17.5 h / 100 °C 2: 65 percent / conc. HCl / methanol / 6 h / Heating View Scheme

fluorobenzene (462-06-6) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: AlCl3 2: toluene View Scheme

4-Brom-4-(4-chlor-phenyl)-piperidin (91335-13-6) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: NaOH-solution; water 2: toluene View Scheme

reduced haloperidol (34104-67-1) → haloperidol (52-86-8)

Conditions	Yield
With manganese dioxide In chloroform

1-(4-chlorobut-1-yn-1-yl)-4-fluorobenzene (1183278-95-6) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: iron(III) chloride; water; silver(I) triflimide / 1,4-dioxane / 18 h 2: potassium iodide / toluene / 25 h / 125 °C View Scheme
Multi-step reaction with 2 steps 1: bis(trifluoromethanesulfonyl)amide; water / 1,4-dioxane / 100 °C 2: potassium iodide; sodium hydrogencarbonate / toluene / 100 °C View Scheme

bromochlorobenzene (106-39-8) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: iodine; magnesium / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 1.2: 6 h / 30 °C / Inert atmosphere 1.3: 3 h / 60 °C / Inert atmosphere 2.1: hydrogen; palladium on activated charcoal / water / 24 h / 25 °C / 750.08 Torr 3.1: potassium carbonate; potassium iodide / acetonitrile / 24 h / 75 °C View Scheme

N-benzyl-2-piperidinone (4783-65-7) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: iodine; magnesium / tetrahydrofuran / 4 h / 60 - 70 °C / Inert atmosphere 1.2: 6 h / 30 °C / Inert atmosphere 1.3: 3 h / 60 °C / Inert atmosphere 2.1: hydrogen; palladium on activated charcoal / water / 24 h / 25 °C / 750.08 Torr 3.1: potassium carbonate; potassium iodide / acetonitrile / 24 h / 75 °C View Scheme

N-benzyl-4-(4-chlorophenyl)-4-hydroxypiperidin (56108-25-9) → haloperidol (52-86-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: hydrogen; palladium on activated charcoal / water / 24 h / 25 °C / 750.08 Torr 2: potassium carbonate; potassium iodide / acetonitrile / 24 h / 75 °C View Scheme

haloperidol (52-86-8) → C21H21(2)H2ClFNO2

Conditions	Yield
With tris(pentafluorophenyl)borate; water-d2 In toluene at 100℃; for 12h; Inert atmosphere; regioselective reaction;	97%
With [(N,N′-bis(2,6-diisopropylphenyl)-2,3-butanediimine)Ni(μ−H)]2; deuterium at -196 - 80℃; under 760.051 Torr; for 24h; Reagent/catalyst; Sealed tube;	32 mg

haloperidol (52-86-8) + benzoyl chloride (98-88-4) → benzoic acid haloperidol ester

Conditions	Yield
With N-ethyl-N,N-diisopropylamine In dichloromethane for 24h; Inert atmosphere;	96.7%

haloperidol (52-86-8) → Haloperidol N-oxide

Conditions	Yield
With perfluoro-cis-2-n-butyl-3-n-propyloxaziridine; HCFC-225ca,cb In dichloromethane at -60℃; for 0.333333h;	96%
In CaH2; dichloromethane	71%

haloperidol (52-86-8) → 4-[4-(4-deuteriophenyl)-4-hydroxypiperidino]-4′-fluorobutyrophenone

Conditions	Yield
With bis(η3-allyl-μ-chloropalladium(II)); 1-deuteriodiphenylmethanol; 3-(2,6-dibenzhydryl-4-methylphenyl)-4,5-dimethyl-1-(2,4,6-trimethylbenzyl)imidazolium chloride; caesium carbonate In toluene at 90℃; for 16h; Inert atmosphere;	94%

haloperidol (52-86-8) + 7,7',8,8'-tetracyanoquinodimethane (1518-16-7) → C21H23ClFNO2*C12H4N4 (1421948-04-0)

Conditions	Yield
In methanol; chloroform at 20℃; for 0.75h;	93%

haloperidol (52-86-8) + cyclohexylamine (108-91-8) → 4-<4-(4-Chlorophenyl)-4-hydroxypiperidino>-4'-(cyclohexylamino)butyrophenone

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 5h; Heating;	92%

haloperidol (52-86-8) + N,N-dimethylethylenediamine (108-00-9) → 4-<4-(4-Chlorophenyl)-4-hydroxypiperidino>-4'-<<2-(dimethylamino)ethyl>amino>butyrophenone

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 5h; Heating;	92%

2-(2-methylphenyl)pyridine (10273-89-9) + haloperidol (52-86-8) → C33H33FN2O2

Conditions	Yield
With C17H24N5Ru(1+)*F6P(1-); potassium acetate; potassium carbonate In 1-methyl-pyrrolidin-2-one at 35℃; for 48h; Inert atmosphere;	92%

haloperidol (52-86-8) + 3-trifluoromethylaniline (98-16-8) → 1-(4-fluorophenyl)-4-(4-hydroxy-4-(4-((3-(trifluoromethyl)phenyl)amino)phenyl)piperidin-1-yl)butan-1-one (1612891-27-6)

Conditions	Yield
With Pd-PEPPSI-(2,6-(3-pentyl)pentylphenyl-2H-imidazol-2-ylidene)Cl-o-picoline; caesium carbonate In 1,2-dimethoxyethane at 45℃; for 24h; Buchwald-Hartwig Coupling; Inert atmosphere; Glovebox;	91%

haloperidol (52-86-8) → reduced haloperidol (34104-67-1)

Conditions	Yield
With sodium tetrahydroborate In methanol at 20℃; for 1.33333h;	90%
With sodium tetrahydroborate In ethanol at 0 - 20℃;	90%
With human liver dihydrodiol dehydrogenase 1; NADPH In phosphate buffer at 25℃; pH=6.0; Enzyme kinetics; Further Variations:; Reagents;

1,2-propanediene (463-49-0) + haloperidol (52-86-8) → C24H29ClFNO2

Conditions	Yield
Stage #1: haloperidol With copper diacetate; 2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl In tetrahydrofuran for 0.0833333h; Inert atmosphere; Stage #2: 1,2-propanediene With (dimethoxy)methylsilane In tetrahydrofuran at 20℃; for 12h; Inert atmosphere;	90%

piperidine (110-89-4) + haloperidol (52-86-8) → 4-<4-(4-Chlorophenyl)-4-hydroxypiperidino>-4'-piperidinobutyrophenone

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h; Ambient temperature;	89%

haloperidol (52-86-8) + 2,4,6-Trinitrophenol (88-89-1) → C21H23ClFNO2*C6H3N3O7 (1216665-74-5)

Conditions	Yield
In methanol; chloroform at 20℃; for 0.75h;	89%

haloperidol (52-86-8) → C21H19(2)H4ClFNO2

Conditions	Yield
With [(N,N’-bis(1R,2R,3R,5S)-(−)-isopinocampheyl-1,2-ethanediimine-radical)NiI(μ2-H)]2; deuterium at -196 - 80℃; under 760.051 Torr; for 24h; Reagent/catalyst; Sealed tube;	89%

1.3-propanedithiol (109-80-8) + haloperidol (52-86-8) → (1,3-propanethioacetal)-4-[4-(p-chlorophenyl)-4-hydroxypiperidinyl]-4'-fluorobutyrophenone

Conditions	Yield
With trifluoroborane diethyl ether In methanol; hexane; dichloromethane; ethyl acetate	88%

haloperidol (52-86-8) + 1-ethylpropylzinc bromide → 1-(4-fluorophenyl)-4-(4-hydroxy-4-(4-(pentan-3-yl)phenyl)piperidin-1-yl)butan-1-one

Conditions	Yield
Stage #1: haloperidol With C40H55Cl5N3Pd In toluene at 0℃; for 0.0833333h; Negishi Coupling; Inert atmosphere; Cooling with ice; Stage #2: 1-ethylpropylzinc bromide In tetrahydrofuran; toluene at 23℃; for 16h; Inert atmosphere;	88%

haloperidol (52-86-8) + propargyl bromide (106-96-7) → C24H26ClFNO2(1+)*Br(1-)

Conditions	Yield
In tetrahydrofuran for 2h; Solvent; Temperature; Inert atmosphere; Reflux;	88%

haloperidol (52-86-8) → (+)-Dihydrohaloperidol

Conditions	Yield
With C37H40MnN2O2P2(1+)*Br(1-); sodium t-butanolate In isopropyl alcohol; toluene at 50℃; for 6h; Inert atmosphere; Schlenk technique; enantioselective reaction;	85%

haloperidol (52-86-8) → C42H47F2N3O4 + 4-<4-hydroxy-4-(4-aminophenyl)piperidinyl>-1-(4-fluorophenyl)butanone (114361-10-3)

Conditions	Yield
With C46H71Cl3N2Pd; ammonia; sodium t-butanolate In 1,4-dioxane at 80℃; for 2h; Inert atmosphere; Schlenk technique;	A n/a B 84%

haloperidol (52-86-8) → 4-(4-chlorophenyl)-1-<4-(4-fluorophenyl)-4-oxobutyl>-1,2,3,6-tetrahydopyridine (52669-92-8)

Conditions	Yield
With hydrogenchloride; acetic acid for 24h; Reflux; Inert atmosphere;	84%

N-tert-butyldimethylsilyl-S-fluoromethyl-S-(2-pyridyl)sulfoximine + haloperidol (52-86-8) → (E)-4-(4-chlorophenyl)-1-(5-fluoro-4-(4-fluorophenyl)pent-4-enyl)piperidin-4-ol

Conditions	Yield
Stage #1: N-tert-butyldimethylsilyl-S-fluoromethyl-S-(2-pyridyl)sulfoximine With potassium hexamethylsilazane In tetrahydrofuran at -78℃; for 0.5h; Inert atmosphere; Stage #2: haloperidol In tetrahydrofuran at -78℃; for 3h; Inert atmosphere; stereoselective reaction;	82%

haloperidol (52-86-8) + 1-amino-3-(dimethylamino)propane (109-55-7) → 4-<4-(4-Chlorophenyl)-4-hydroxypiperidino>-4'-<<3-(dimethylamino)propyl>amino>butyrophenone

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide for 3h; Heating;	80%

haloperidol (52-86-8) + 2-(aminooxy)-N,N-diethylethanamine dihydrochloride (21894-85-9, 87272-47-7, 113437-87-9) → 4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one O-(2-diethylamino-ethyl)-oxime

Conditions	Yield
With pyridine In ethanol for 32h; Heating;	76.9%

haloperidol (52-86-8) + butan-1-ol (71-36-3) → 1-(n-Butoxyphenyl)-4-<4-(4-chlorophenyl)-4-hydroxypiperidino>-n-butyl alcohol

Conditions	Yield
With sodium amide for 1h; Heating;	75%

haloperidol (52-86-8) → 4-(4'-chlorophenyl)-1-(4'-(4-fluorophenyl)butyl)piperidin-4-ol (164668-08-0)

Conditions	Yield
With [(C6H6)(PCy3)(CO)RuH]+*BF4−; hydrogen; phenol In 1,4-dioxane; isopropyl alcohol under 1520.1 Torr; for 12h; Inert atmosphere; Glovebox; Schlenk technique; chemoselective reaction;	68%

haloperidol (52-86-8) + O-(2-Pyrrolidin-1-yl-ethyl)-hydroxylamine; hydrochloride → 4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one O-(2-pyrrolidin-1-yl-ethyl)-oxime

Conditions	Yield
With pyridine In ethanol for 32h; Heating;	67.7%

3-(tert-butyloxycarbonylamino)propionic acid (3303-84-2) + haloperidol (52-86-8) → C29H36ClFN2O5 (853994-07-7)

Conditions	Yield
Stage #1: 3-(tert-butyloxycarbonylamino)propionic acid; haloperidol With dmap In dichloromethane for 0.5h; Cooling with ice; Stage #2: With dicyclohexyl-carbodiimide In dichloromethane at 20℃; for 25h; Cooling with ice;	64.6%

Upstream product

• 39512-49-7 4-(4-chlorophenyl)-4-hydroxypiperidine 
• 3874-54-2 4-(4-fluorophenyl)-4-oxo-n-butyl chloride 
• 56108-25-9 N-benzyl-4-(4-chlorophenyl)-4-hydroxypiperidin 
• 4783-65-7 N-benzyl-2-piperidinone 
• 106-39-8 bromochlorobenzene 
• 1183278-95-6 1-(4-chlorobut-1-yn-1-yl)-4-fluorobenzene 
• 91335-13-6 4-Brom-4-(4-chlor-phenyl)-piperidin 
• 462-06-6 fluorobenzene 
• 3308-94-9 4-chloro-1-(4-fluorophenyl)-1,1-(ethylenedioxy)butane 
• 93639-13-5 4-chloro-4'-nitrobutyrophenone 
• 93639-12-4 cyclopropyl(4-nitrophenyl)methanone 
• 103-84-4 Acetanilid 
• 56924-11-9 1-(4-acetylaminophenyl)-4-chloro-1-butanone 
• 57189-90-9 (4-aminophenyl)(cyclopropyl)methanone 

Downstream Products

• 459-57-4 4-fluorobenzaldehyde 
• 403-42-9 1-(4-fluorophenyl)ethanone 
• 61668-02-8 1-(4-fluorophenyl)but-3-en-1-one 
• 108-90-7 chlorobenzene 
• 107-02-8 acrolein 
• 51308-82-8 4-[4-(p-chlorophenyl)-4-hydroxypiperidinyl]-4'-fluorobutyrophenone hydrazone 
• 1622913-84-1 bis{4-(4-chlorophenyl)-1-[4(4-fluorophenyl)-4-oxobutyl]piperidin-4-yl} sebacate 
• 1622913-85-2 bis{4-(4-chlorophenyl)-1-[4-(4-fluorophenyl)-4-oxobutyl]piperidine-4-yl} dodecanedioate 

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