89778-26-7 Usage
Description
Toremifene is a nonsteroidal antiestrogenic anticancer agent, structurally similar to tamoxifen, and is effective in the treatment of advanced recurrent breast cancer in postmenopausal patients. It is considered more effective than tamoxifen in several rat mammary tumor models and has mild side-effects, such as hot flushes and sweating.
Uses
Used in Oncology:
Toremifene is used as an antineoplastic agent for inducing apoptosis in some cancer cells, particularly in the treatment of advanced recurrent breast cancer in postmenopausal patients.
Used in Hormone Therapy:
Toremifene is used as a selective estrogen receptor modulator, acting as an antiestrogen to help regulate hormone levels and counteract the effects of estrogen in hormone-dependent cancers.
Used in Pharmaceutical Industry:
As a chlorinated tamoxifen analogue, Toremifene is utilized in the development of pharmaceutical drugs for cancer treatment, specifically targeting hormone-dependent tumors and providing an alternative to tamoxifen with potentially better efficacy and fewer side effects.
Originator
Farmos (Finland)
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).
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.
Check Digit Verification of cas no
The CAS Registry Mumber 89778-26-7 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 8,9,7,7 and 8 respectively; the second part has 2 digits, 2 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 89778-26:
(7*8)+(6*9)+(5*7)+(4*7)+(3*8)+(2*2)+(1*6)=207
207 % 10 = 7
So 89778-26-7 is a valid CAS Registry Number.
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-;
89778-26-7Relevant articles and documents
Toremifene synthesis method
-
, (2017/04/12)
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
-
Page 5-6, (2008/06/13)
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.