67469-78-7

Basic information

• Product Name: Vanoxerine dihydrochloride
• Synonyms: GBR 12909;GBR 12909 DIHYDROCHLORIDE;1-(2-BIS-((4-FLUOROPHENYL)METHOXY)ETHYL)-4-(3-PHENYL-2-PROPYL)PIPERAZINE HCL;1-(2-BIS-[4-FLUOROPHENYL]-METHOXYETHYL)-4-(3-PHENYL-2-PROPYL)PIPERAZINE HYDROCHLORIDE;1-[2-[BIS(4-FLUOROPHENYL)METHOXY]ETHYL]-4-[3-PHENYLPROPYL]PIPERAZINE DIHYDROCHLORIDE;1-(2-[BIS(4-FLUOROPHENYL) METHOXY]ETHYL)-4-(3-PHENYLPROPYL) PIPERAZINE DIHYDROC;GBR-12909 DIHYDROCHLORIDE SELECTIVE DOPA MINE UP;Vanoxerine
• CAS NO: 67469-78-7
• Molecular Formula: C₂₈H₃₂F₂N₂O*2ClH
• Molecular Weight: 523.49
• Product Categories: Dopamine receptor
• Mol File: 67469-78-7.mol
• Article Data: 2

Chemical Properties

• Melting Point: 221 °C
• Boiling Point: 542.7 °C at 760 mmHg
• Flash Point: 282 °C
• Appearance: white/solid
• Vapor Pressure: 7.7E-12mmHg at 25°C
• Storage Temp.: Desiccate at RT
• Solubility: DMSO: >5 mg/mL Solutions freshly prepared daily
• Water Solubility: Soluble in DMSO to 50mM. Soluble to 5mM in water with warming.
• Stability: Stable for 2 years from date of purchase as supplied. Solutions in DMSO or distilled water may be stored at -20° for up to 1 month.
• CAS DataBase Reference: Vanoxerine dihydrochloride(CAS DataBase Reference)
• NIST Chemistry Reference: Vanoxerine dihydrochloride(67469-78-7)
• EPA Substance Registry System: Vanoxerine dihydrochloride(67469-78-7)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 67469-78-7(Hazardous Substances Data)

Usage

Description

Vanoxerine dihydrochloride, also known as GBR 12909, is a potent inhibitor that primarily blocks dopamine uptake. It is characterized by its high specificity for dopamine, with more than 100-fold less effectiveness at blocking serotonin or noradrenaline uptake. Vanoxerine dihydrochloride has demonstrated the ability to stimulate dopamine receptors in vivo and exhibits additional interactions with histamine H1 receptors and sigma receptors in rat brain.

Uses

Used in Pharmaceutical Industry:
Vanoxerine dihydrochloride is used as an antidepressant for its ability to effectively inhibit dopamine uptake, leading to the stimulation of dopamine receptors and potentially providing relief from depressive symptoms.
Used in Neurotransmitter Research:
Vanoxerine dihydrochloride is used as a dopamine reuptake inhibitor in the study of dopamine-related neurological processes and disorders. Its high specificity for dopamine makes it a valuable tool for investigating the role of dopamine in various conditions.
Used in Drug Development:
Vanoxerine dihydrochloride is used as a lead compound in the development of new medications targeting dopamine-related conditions. Its potent inhibition of dopamine uptake and interactions with other receptors make it a promising candidate for further research and potential therapeutic applications.
Used in Receptor Binding Studies:
Vanoxerine dihydrochloride is used as a research tool to study the binding properties of various receptors, including histamine H1 receptors and sigma receptors. Its ability to inhibit ligand binding to these receptors can provide insights into receptor function and potential drug interactions.

Hazard

A poison.

Biological Activity

Potent, competitive inhibitor of dopamine uptake (K i = 1 nM for inhibition of striatal dopamine uptake). Has > 100-fold lower affinity for the noradrenalin and 5-HT uptake carriers. Also a potent sigma ligand (IC 50 = 48 nM). Centrally active following systemic administration.

Biochem/physiol Actions

Highly selective dopamine reuptake inhibitor with behavioral effects similar to cocaine.

References

1) Andersen?et al. (1989),?The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action; Eur. J. Pharmacol.,?166?493 2) Contreras?et al. (1990),?GBR-12909 and fluspirilene potently inhibited binding of [3H] (+)3-PPP to sigma receptors in rat brain; Life Sci.,?47?PL133 3) Yorgason?et al. (2011),?Low and high affinity dopamine transporter inhibitors block dopamine uptake within 5 sec of intravenous injection; Neuroscience,?182?125

InChI:InChI=1/C28H32F2N2O.2ClH/c29-26-12-8-24(9-13-26)28(25-10-14-27(30)15-11-25)33-22-21-32-19-17-31(18-20-32)16-4-7-23-5-2-1-3-6-23;;/h1-3,5-6,8-15,28H,4,7,16-22H2;2*1H

Synthetic route

1-Bromo-3-phenylpropane (637-59-2) + 1-[2-(bis(4-fluorophenyl)methoxy)ethyl]piperazine (61897-33-4) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
With hydrogenchloride; potassium carbonate In ethanol for 3h; Heating;	60%

1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine (67469-69-6) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
With hydrogenchloride In ethanol at 15 - 25℃; for 2h; Concentration; Large scale;	116.9 g

1-(3-phenylpropyl)-piperazine dihydrochloride + 2-[bis(4-fluorophenyl)methoxy]ethyl iodide (321365-84-8) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium carbonate / water; butanone / 24 h / 75 - 80 °C / Large scale 2: hydrogenchloride / ethanol / 2 h / 15 - 25 °C / Large scale View Scheme

1-Bromo-3-phenylpropane (637-59-2) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: acetonitrile / 8 h / 75 - 80 °C / Large scale 2: hydrogenchloride / ethanol / 2 h / 20 - 30 °C / Large scale 3: sodium carbonate / water; butanone / 24 h / 75 - 80 °C / Large scale 4: hydrogenchloride / ethanol / 2 h / 15 - 25 °C / Large scale View Scheme

1-(3-phenylpropyl)piperazine (55455-92-0) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol / 2 h / 20 - 30 °C / Large scale 2: sodium carbonate / water; butanone / 24 h / 75 - 80 °C / Large scale 3: hydrogenchloride / ethanol / 2 h / 15 - 25 °C / Large scale View Scheme

4,4'-difluorobenzhydryl alcohol (365-24-2) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / toluene / 3.75 h / 40 - 85 °C / Large scale 2: sodium iodide / butanone / 24 h / 80 °C / Large scale 3: sodium carbonate / water; butanone / 24 h / 75 - 80 °C / Large scale 4: hydrogenchloride / ethanol / 2 h / 15 - 25 °C / Large scale View Scheme

2-[bis(4-fluorophenyl)methoxy]ethyl chloride (50366-31-9) → 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (67469-78-7)

Conditions	Yield
Multi-step reaction with 3 steps 1: sodium iodide / butanone / 24 h / 80 °C / Large scale 2: sodium carbonate / water; butanone / 24 h / 75 - 80 °C / Large scale 3: hydrogenchloride / ethanol / 2 h / 15 - 25 °C / Large scale View Scheme

Upstream product

• 637-59-2 1-Bromo-3-phenylpropane 
• 61897-33-4 1-[2-(bis(4-fluorophenyl)methoxy)ethyl]piperazine 
• 50366-31-9 2-[bis(4-fluorophenyl)methoxy]ethyl chloride 
• 365-24-2 4,4'-difluorobenzhydryl alcohol 
• 55455-92-0 1-(3-phenylpropyl)piperazine 
• 321365-84-8 2-[bis(4-fluorophenyl)methoxy]ethyl iodide 
• 67469-69-6 1-(2-(di(4-fluorophenyl)-methoxy)-ethyl)-4-(3-phenylpropyl)piperazine 

Relevant articles and documents

Scale-up synthesis of the dopamine uptake inhibitor GBR-12909

1-[2-[Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR-12909) is a dopamine uptake inhibitor. The development of a robust process for the preparation of this compound in kilogram quantities is described. The primary aims of the development work were to eliminate chromatographic purifications, to minimize the use of environmentally unacceptable reagents, and to improve the overall yield of the three-step convergent process. These objectives were met, with significant improvements obtained in the key coupling reaction of N-(3-phenylpropyl)piperazine dihydrochloride salt with 1-[bis(4-fluorophenyl)methoxy]-2-chloroethane, which was previously low-yielding and lacking in reproducibility.