89778-26-7

Basic information

• Product Name: Toremifene
• Synonyms: (2-[4-((Z)-4-CHLORO-1,2-DIPHENYL-BUT-1-ENYL)-PHENOXY]-ETHYL)-DIMETHYL-AMINE;2-[4-(4-chloro-1,2-diphenyl-but-1-enyl)phenoxy]-n,n-dimethyl-ethanamine;TOREMIFENE;(z)-2-(4-(4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-n,n-dimethylethanamine;2-(para-((z)-4-chloro-1,2-diphenyl-1-butenyl)phenoxy)-n,n-dimethylethylamine;2-diphenyl-1-butenyl)phenoxy)-n,n-dimethyl-2-(4-(4-chloro-(z)-ethanamin;(Z)-2-[4-(4-Chloro-1，2-diphenyl-1-butenyl)phenoxyl]-N，N-dimethylethylamine;C08166
• CAS NO: 89778-26-7
• Molecular Formula: C₂₆H₂₈ClNO
• Molecular Weight: 405.96
• Product Categories: Inhibitors;Intermediates & Fine Chemicals;Pharmaceuticals;Anti-cancer & immunity
• Mol File: 89778-26-7.mol
• Article Data: 3

Chemical Properties

• Melting Point: 108-110°C
• Boiling Point: 535.1 °C at 760 mmHg
• Flash Point: 277.4 °C
• Appearance: /
• Density: 1.104 g/cm³
• Vapor Pressure: 1.58E-11mmHg at 25°C
• PKA: 8.69±0.28(Predicted)
• CAS DataBase Reference: Toremifene(CAS DataBase Reference)
• NIST Chemistry Reference: Toremifene(89778-26-7)
• EPA Substance Registry System: Toremifene(89778-26-7)

Safety Data

• HazardClass: 9
• Hazardous Substances Data: 89778-26-7(Hazardous Substances Data)

Usage

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.

Originator

Farmos (Finland)

Uses

Different sources of media describe the Uses of 89778-26-7 differently. You can refer to the following data:
1. An antiestrogen and antineoplastic. Nonsteroidal antiestrogen structurally similar to tamoxifen
2. antineoplastic;selective estrogen receptor modulator
3. A chlorinated tamoxifen analogue, that induces apoptosis in some cells

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

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.

InChI:InChI=1/C26H28ClNO.C6H8O7/c1-28(2)19-20-29-24-15-13-23(14-16-24)26(22-11-7-4-8-12-22)25(17-18-27)21-9-5-3-6-10-21;7-3(8)1-6(13,5(11)12)2-4(9)10/h3-16H,17-20H2,1-2H3;13H,1-2H2,(H,7,8)(H,9,10)(H,11,12)/b26-25-;

Upstream product

• 89778-37-0 4-(4-hydroxyphenyl)-3,4-diphenyl-but-3-en-1-ol 
• 97151-03-6 (Z)-1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]-1-buten-4-ol 
• 5650-41-9 3-hydroxy-1-phenylpropan-1-one 
• 1137-42-4 4-Hydroxybenzophenone 
• 1262682-37-0 4-hydroxy-1,2-diphenyl-1-[4-[2-N,N-dimethylamino]ethoxy]-phenyl-1-butene 
• 141854-25-3 1,2-diphenyl-1-[4-[2-(N,N-dimethylamino)ethoxy]phenyl]butane-1,4-diol 

Downstream Products

• 89778-27-8 toremifene citrate 

Relevant articles and documents

Toremifene synthesis method

The invention provides a synthesis method of toremifene. The synthesis method comprises the following steps: S1. performing McMurry reaction to a compound B as shown in a structural formula II and a compound C as shown in a structural formula III, to obtain a compound D as shown in a structural formula IV; S2. performing selective alkylation reaction of phenolic hydroxyl to the compound D and a compound E as shown in a structural formula V or hydrochloride of the compound E, to obtain a compound F as shown in a structural formula VI; and S3. reacting the compound F with thionyl chloride, to obtain the toremifene, wherein the structural formula II, the structural formula III, the structural formula IV, the structural formula V and the structural formula VI are respectively shown in the specification. The obtained compound D has higher stereoselectivity, therefore, the reaction yield of the toremifene with a Z configuration can be increased when the compound D serves as an intermediate to synthesize the toremifene, and the purity of the toremifene with the Z configuration can be improved; and the synthesis method is stable in technology, mild in reaction conditions, the intermediate is easily separated, and the synthesis method can be used for mass production.

TOREMIFENE CRYSTALLIZATION METHOD

The invention relates to a method for isolating toremifene from a mixture of toremifene and its corresponding E isomer. The method comprises contacting the isomer mixture with a first solvent comprising methanol, allowing toremifene to crystallize in said first solvent, allowing the crystallized product of the previous step to crystallize from a second solvent comprising acetone, methyl ethyl ketone or ethyl acetate, and optionally converting toremifene crystallized from the previous step to a pharmaceutically acceptable salt thereof.