Toremifene Chemical Properties

Melting point:

108-110°C

Boiling point:

535.1±50.0 °C(Predicted)

Density 

1.104±0.06 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

25℃: DMSO 120mg/mL ;Water <1mg/mL; Ethanol <1mg/mL

pka

8.69±0.28(Predicted)

form 

Powder

color 

White to light yellow

Stability:

Light sensitive

CAS DataBase Reference

89778-26-7(CAS DataBase Reference)

IARC

3 (Vol. 66) 1996

Safety Information

HazardClass 

9

Toremifene Usage And Synthesis

Description

Toremifene is an antiestrogenic anticancer agent effective in the treatment of advanced recurrent breast cancer in postmenopausal patients. It is claimed to be more effective than tamoxifen in several rat mammary tumor models. Side-effects are mild, including hot flushes and sweating.

Chemical Properties

White-to-Off-White Solid

Originator

Farmos (Finland)

Uses

antineoplastic;selective estrogen receptor modulator

Uses

An antiestrogen and antineoplastic. Nonsteroidal antiestrogen structurally similar to tamoxifen

Uses

A chlorinated tamoxifen analogue, that induces apoptosis in some cells

Definition

ChEBI: Toremifene is a tertiary amine, an organochlorine compound and an aromatic ether. It has a role as an antineoplastic agent, an estrogen antagonist, an estrogen receptor modulator and a bone density conservation agent. It derives from a hydride of a stilbene.

Manufacturing Process

The reaction is performed under dry conditions. 2.1 g of lithium aluminum hydride and 50 ml of dry tetrahydrofuran are placed in a flask. Then 13.2 g of cinnamaldehyde in 50 ml of dry tetrahydrofuran are added while stirring and keeping the temperature at 25°-35°C. The stirring is continued for another 30 min at room temperature. Then 26.9 g of 4-[2-(N,N-dimethylamino)- ethoxy]benzophenone in 70 ml of dry tetrahydrofuran are added while stirring. The temperature is kept at 35°-45°C during the addition. After stirring for 2 h at 40°C the reaction mixture is poured into 150 ml of 25% ammonium chloride solution, and aluminium hydroxide is precipitated and filtered off. The filtrate is transferred to a separating funnel and the organic layer is separated. The aqueous layer is once again extracted with 60 ml of ethyl acetate. The organic layers are combined and dried over sodium sulfate. The solvent is evaporated. The residue is recrystallized from toluene. The yield is 27.5 g (68%) of 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]- butane-1,4-diol.
The reaction is performed under dry conditions. 40.5 g 1,2-diphenyl-1-[4-[2- (N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol and 150 ml of acetic acid anhydride are placed in a flask. The temperature is raised to 90°C, where it is kept until the primary OH-group is completely acetylated. [4-Acetoxy-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butan-1-ol is obtained as intermediate; melting point of the (RR, SS)-isomer pair is 97°-99°C. While stirring the reaction mixture, 30 ml of acetyl chloride in 50 ml of acetic acid anhydride are added at 90°C. The stirring is continued at this temperature for 2 h. The solvent is evaporated. Then 1 M sodium carbonate solution is added in excess, after which the product is extracted in toluene. The solution is dried over sodium sulfate, and the solvent is evaporated. The yield of the pure isomer mixture (Z:E 2:1) of 4-acetoxy-1,2-diphenyl-1-[4-[2-(N,N_x0002_dimethylamino)ethoxy]-phenyl]-1-butene is quantitative. The4-acetoxy-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]-phenyl]-1- butene are dissolved in 94% ethanol, after which water and 20% sodium hydroxide solution are added. The mixture is refluxed for 1 h. The solution is neutralized with 2 M hydrochloric acid, after wich the ethanol is evaporated. Water is added into the residue. The product is extracted in ethyl acetate, the ethyl acetate solution is dried and the solvent is avaporated. The product is recrystallized from a mixture of water and methanol. The yield of the pure mixture of the isomers (Z:E 2:1) of 1,2-diphenyl-1-[4-[2-(N,Ndimethylamino)ethoxy]phenyl]-1-buten-4-ol, melting point 93°-100°C, is quantitative.
Isolation of the (Z)-isomer as a free base: the mixture of the isomers (Z:E 2:1) of 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol is recrystallized from toluene, and 15.9 g (41%) of the (Z)-isomer is obtained, melting point 110°-112°C.
The reaction is performed under dry conditions. 42.4 g of (Z)-1,2-diphenyl-1- [4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol are dissolved in 250 ml of chloroform. Then 23.8 g of thionyl chloride are added dropwise. The mixture is refluxed 3 h. The solvent is evaporated, after which the product is recrystallized from ethyl acetate. The yield of the hydrochloride salt of 4- chloro-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]-phenyl]-1-butene (Z) is 36.7 g (83%), melting point 194°-196°C.
The base can be liberated from the salt with 1 M sodium carbonate solution, after which the base is extracted in toluene. The toluene solution is dried and the solvent is evaporated. The free base, 4-chloro-1,2-diphenyl-1-[4-[2-(N,Ndimethylamino)ethoxy]-phenyl]-1-butene (Z), has melting point 108°-110°C (from acetone). In practice it is usually used as citrate salt (1:1).

brand name

Fareston

Therapeutic Function

Antiestrogen, Antineoplastic

Clinical Use

Hormone dependent metastatic breast cancer in post menopausal women

Drug interactions

Potentially hazardous interactions with other drugs
Anticoagulants: enhanced anticoagulant effect of coumarins.
Cytotoxics: possible increased risk of ventricular arrhythmias with vandetanib - avoid.

Metabolism

Toremifene is metabolised mainly by the cytochrome P450 isoenzyme CYP3A4. The main metabolite is N-demethyltoremifene and has similar anti-oestrogenic activity but weaker anti-tumour activity than toremifene. Toremifene is eliminated mainly as metabolites in the faeces.

Toremifene(89778-26-7)Related Product Information

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• Chlorodiphenylphosphine
• Diphenyldimethoxysilane
• Dichlorodiphenylsilane
• Dimethyl sulfoxide
• Dimethyl ether
• Dimethyl sulfide
• Clomifene
• N,N-Dimethylformamide
• ETHANE
• 1,5-Diphenylcarbazide
• Dimethyl phthalate
• Dimethyldimethoxysilane
• Dimethyl fumarate
• 3,4'-DIAMINODIPHENYLMETHANE
• TOREMIFENE CITRATE
• Difluorochloromethane
• 4-hydroxybenzophenone (intermediate of toremifene citrate)