68392-35-8

Basic information

• Product Name: Afimoxifene
• Synonyms: AFIMOXIFENE;4-[1-[4-[2-(Dimethylamino)ethoxy]phenyl]-2-phenyl-1-butenyl]phenol;4-Hydroxytamoxifen, (E)-isomer;4-Hydroxytamoxifen, (Z)-isomer;4-Monohydroxytamoxifen;4-Oht hydrotamoxifen;C016601;(E/Z)-4-Hydroxy Tamoxifen
• CAS NO: 68392-35-8
• Molecular Formula: C₂₆H₂₉NO₂
• Molecular Weight: 387.51
• Product Categories: Amines;Aromatics;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 68392-35-8.mol

Chemical Properties

• Melting Point: 135-144°C
• Boiling Point: 514.4±50.0 °C(Predicted)
• Appearance: white to off-white/
• Density: 1.092
• Storage Temp.: Refrigerator
• Solubility: methanol: soluble10mg/mL
• PKA: 9.38±0.15(Predicted)
• CAS DataBase Reference: Afimoxifene(CAS DataBase Reference)
• NIST Chemistry Reference: Afimoxifene(68392-35-8)
• EPA Substance Registry System: Afimoxifene(68392-35-8)

Safety Data

• Hazard Codes: Xn
• Statements: 63-20/21/22
• Safety Statements: 22-23-36
• RIDADR: UN1170 - class 3 - PG 2 - Ethanol, solution
• WGK Germany: 3
• RTECS: SL1210000
• Hazardous Substances Data: 68392-35-8(Hazardous Substances Data)

Usage

Chemical Properties

Off-White Solid

Uses

Different sources of media describe the Uses of 68392-35-8 differently. You can refer to the following data:
1. A selective estrogen receptor modulator.
2. (E/Z)-4-Hydroxy Tamoxifen is selective estrogen receptor modulator.

Brand name

TamoGel (Ascend Therapeutics).

General Description

4-Hydroxytamoxifen is a first generation, selective estrogen receptor modulator (SERM) that functions as an antagonist in breast cancer cells but can display estrogen-like activities in the uterus and bone.

Biological Activity

4-hydroxytamoxifen is an estrogen receptor modulator.estrogen receptor can be selectively stimulated or inhibited, providing promising therapeutic opportunities for auto-immune diseases, prostate and breast cancer, as well as depression.

Biochem/physiol Actions

Metabolite of the chemotherapeutic drug tamoxifen, exhibiting more potent estrogen agonist/antagonist activity than the parent drug. Also active as intra-membranous inhibitor of lipid peroxidation.

in vitro

previous study was conducted to evaluate the effects of tamoxifen and its active metabolite 4-hydroxytamoxifen on isolated rat cardiac myocyte mechanical function and calcium handling. results showed that myocytes treated with 4-hydroxytamoxifen had similarly to tamoxifen-treated cells to both calcium handling and contractility [1].

in vivo

previous animal study compared the extent of dna adduct formation in sd rats treated with seven tamoxifen or 4-hydroxytamoxifen. results showed that the liver weights and microsomal rates were not changed by tamoxifen or 4-hydroxytamoxifen treatment. moreover, the uterine weights were significantly decreased and uterine peroxidase activity was marginally decreased in tamoxifen or 4-hydroxytamoxifen treated rats. in addition, hepatic dna adduct levels in rats treated with 4-hydroxytamoxifen did not differ from control rats. similaryly, the adduct levels in uterus dna from rats treated with tamoxifen or 4-hydroxytamoxifen were not different from those in control rats [2].

IC 50

27 and 18 μm for mcf-7 and mda-mb-231 cell proliferation

references

[1] asp ml,martindale jj,metzger jm. direct, differential effects of tamoxifen, 4-hydroxytamoxifen, and raloxifene on cardiac myocyte contractility and calcium handling. plos one.2013 oct 24;8(10):e78768. [2] beland fa,mcdaniel lp,marques mm. comparison of the dna adducts formed by tamoxifen and 4-hydroxytamoxifen in vivo. carcinogenesis.1999 mar;20(3):471-7.[3] lee o et al. a randomized phase ii presurgical trial of transdermal 4-hydroxytamoxifen gel versus oral tamoxifen in women with ductal carcinoma in situ of the breast. clin cancer res.2014 jul 15;20(14):3672-82.

InChI:InChI=1/C26H29NO2/c1-4-25(20-8-6-5-7-9-20)26(21-10-14-23(28)15-11-21)22-12-16-24(17-13-22)29-19-18-27(2)3/h5-17,28H,4,18-19H2,1-3H3/b26-25-

Synthetic route

C37H34BrNO7 → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
With water In methanol for 0.0333333h; Quantum yield; Photolysis;	73%

(2-chloroethyl)dimethylamine hydrochloride (4584-46-7) + 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene (91221-46-4) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Stage #1: 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene With caesium carbonate In N,N-dimethyl-formamide for 0.5h; Reflux; Stage #2: (2-chloroethyl)dimethylamine hydrochloride In N,N-dimethyl-formamide at 120℃; for 7h;	67%
Stage #1: 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene With caesium carbonate In N,N-dimethyl-formamide at 70 - 80℃; for 0.166667h; Stage #2: (2-chloroethyl)dimethylamine hydrochloride In N,N-dimethyl-formamide for 1.75h;	30%
Stage #1: 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 0.166667h; Stage #2: (2-chloroethyl)dimethylamine hydrochloride In N,N-dimethyl-formamide at 80℃; for 5.5h;	13.6%
Stage #1: 1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene With caesium carbonate In N,N-dimethyl-formamide at 80℃; for 0.166667h; Stage #2: (2-chloroethyl)dimethylamine hydrochloride In N,N-dimethyl-formamide at 80℃; for 5.5h;	13.6%

dimethyl amine (124-40-3) + E/Z-1-[4-(2-bromoethoxy)phenyl]-1-(4-hydroxyphenyl)-2-phenylbutene (147323-02-2) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
In tetrahydrofuran at 60℃; for 43h;	31%

1,1-bis(4-hydroxyphenyl)-2-phenyl-1-butene (91221-46-4) + 2-(dimethylamino)ethyl chloride (107-99-3) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
With caesium carbonate In N,N-dimethyl-formamide Inert atmosphere;	24%

Propylbenzene (103-65-1) → 4-hydroxytamoxifen (68392-35-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium tert-butoxide; n-butyllithium; tetramethylethylenediamine / hexane; tetrahydrofuran / 0.5 h / 20 °C 1.2: 97 percent / hexane; tetrahydrofuran / 4.5 h / -78 - 20 °C 2.1: 93 percent / aq. hydrochloric acid / ethanol; CH2Cl2 / Heating 3.1: 90 percent / aq. sodium hydroxide; tetrabutylammonium hydrogen sulfate / 18 h / 20 °C 4.1: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 5.1: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

4-hydroxy-4'-methoxybenzophenone (61002-54-8) → 4-hydroxytamoxifen (68392-35-8)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: sodium hydride / dimethylformamide / 1 h / 0 °C 1.2: 95 percent / dimethylformamide / 2 h / 20 °C 2.1: potassium tert-butoxide; n-butyllithium; tetramethylethylenediamine / hexane; tetrahydrofuran / 0.5 h / 20 °C 2.2: 97 percent / hexane; tetrahydrofuran / 4.5 h / -78 - 20 °C 3.1: 93 percent / aq. hydrochloric acid / ethanol; CH2Cl2 / Heating 4.1: 90 percent / aq. sodium hydroxide; tetrabutylammonium hydrogen sulfate / 18 h / 20 °C 5.1: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 6.1: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

4-(methoxymethoxy)-4'-methoxybenzophenone (115499-97-3) → 4-hydroxytamoxifen (68392-35-8)

Conditions

Yield

Multi-step reaction with 5 steps 1.1: potassium tert-butoxide; n-butyllithium; tetramethylethylenediamine / hexane; tetrahydrofuran / 0.5 h / 20 °C 1.2: 97 percent / hexane; tetrahydrofuran / 4.5 h / -78 - 20 °C 2.1: 93 percent / aq. hydrochloric acid / ethanol; CH2Cl2 / Heating 3.1: 90 percent / aq. sodium hydroxide; tetrabutylammonium hydrogen sulfate / 18 h / 20 °C 4.1: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 5.1: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

E/Z-1-(4-hydroxyphenyl)-1-(4-methoxyphenyl)-2-phenylbutene (850256-19-8) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 90 percent / aq. sodium hydroxide; tetrabutylammonium hydrogen sulfate / 18 h / 20 °C 2: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 3: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

1-(4-methoxymethoxyphenyl)-1-(4-methoxyphenyl)-2-phenylbutan-1-ol (671791-56-3) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Multi-step reaction with 4 steps 1: 93 percent / aq. hydrochloric acid / ethanol; CH2Cl2 / Heating 2: 90 percent / aq. sodium hydroxide; tetrabutylammonium hydrogen sulfate / 18 h / 20 °C 3: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 4: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

E/Z-1-[4-(2-bromoethoxy)phenyl]-1-(4-methoxyphenyl)-2-phenylbut-1-ene (850256-21-2) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: 57 percent / boron tribromide / CH2Cl2 / 4.5 h 2: 31 percent / tetrahydrofuran / 43 h / 60 °C View Scheme

uridine 3'-(4-hydroxytamoxifen phosphate) (1361392-98-4) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
With sodium chloride pH=6; Mes-NaOH buffer; Enzymatic reaction;

4,4'-Dihydroxybenzophenone (611-99-4) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: titanium tetrachloride; zinc / tetrahydrofuran / 2 h / 0 °C / Inert atmosphere; Reflux; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 70 - 80 °C 2.2: 1.75 h View Scheme
Multi-step reaction with 2 steps 1.1: zinc; titanium tetrachloride / tetrahydrofuran / 12 h / -20 °C / Inert atmosphere; Reflux; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / Reflux 2.2: 7 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1.1: titanium tetrachloride; zinc / tetrahydrofuran / 2 h / -10 - 95 °C / Inert atmosphere 1.2: 2 h / 0 - 95 °C / Inert atmosphere; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 80 °C 2.2: 5.5 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1.1: zinc; titanium tetrachloride / tetrahydrofuran / 2 h / Inert atmosphere; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 80 °C 2.2: 5.5 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: titanium tetrachloride; zinc / tetrahydrofuran / Inert atmosphere 2: caesium carbonate / N,N-dimethyl-formamide / Inert atmosphere View Scheme

tamoxifen (10540-29-1) → N-desmethyltamoxifen + 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
With Vitamin C; Agrocybe aegerita peroxygenase; dihydrogen peroxide at 20℃; for 0.05h; pH=7; aq. phosphate buffer; Enzymatic reaction; regioselective reaction;

1-phenyl-propan-1-one (93-55-0) → 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: zinc; titanium tetrachloride / tetrahydrofuran / 12 h / -20 °C / Inert atmosphere; Reflux; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.5 h / Reflux 2.2: 7 h / 120 °C View Scheme
Multi-step reaction with 2 steps 1.1: zinc; titanium tetrachloride / tetrahydrofuran / 2 h / Inert atmosphere; Darkness 2.1: caesium carbonate / N,N-dimethyl-formamide / 0.17 h / 80 °C 2.2: 5.5 h / 80 °C View Scheme
Multi-step reaction with 2 steps 1: titanium tetrachloride; zinc / tetrahydrofuran / Inert atmosphere 2: caesium carbonate / N,N-dimethyl-formamide / Inert atmosphere View Scheme

C46H54N4O7 → C31H39N3O3 + 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
for 0.166667h; Quantum yield; Kinetics; Photolysis;

C36H34BrNO5 → C36H34BrNO5 + 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Claisen Rearrangement; Photolysis;

C36H34BrNO5 → 4-hydroxytamoxifen (68392-35-8) + 6-bnromo-7-hydroxy-4-(hydroxymethyl)-2H-chromen-2-one (223420-41-5)

Conditions	Yield
With water In methanol Quantum yield; Photolysis;

C40H44N2O4 → C40H44N2O4 + 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
Quantum yield; Claisen Rearrangement; Photolysis;

C42H44BrN3O8 → C31H39N3O3 + 4-hydroxytamoxifen (68392-35-8)

Conditions	Yield
With water In methanol for 0.0833333h; Quantum yield; Kinetics; Photolysis;

4-hydroxytamoxifen (68392-35-8) + 2-methacryloyloxyethyl hydrogen succinate (20882-04-6) → C36H41NO7

Conditions	Yield
Stage #1: 2-methacryloyloxyethyl hydrogen succinate With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: 4-hydroxytamoxifen In dichloromethane for 16h;	96.02%
Stage #1: 2-methacryloyloxyethyl hydrogen succinate With dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In dichloromethane at 0 - 20℃; for 0.5h; Stage #2: 4-hydroxytamoxifen In dichloromethane for 16h;	96.02%

trifluoromethylsulfonic anhydride (358-23-6) + 4-hydroxytamoxifen (68392-35-8) → (E,Z)-4-(1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenyl trifluoromethanesulfonate (1370699-80-1)

Conditions	Yield
With pyridine In dichloromethane at 0 - 20℃; for 1h;	95%

2-(dimethylamino)ethyl chloride (107-99-3) + 4-hydroxytamoxifen (68392-35-8) → [2-(4-{1-[4-(2-Dimethylamino-ethoxy)-phenyl]-2-phenyl-but-1-enyl}-phenoxy)-ethyl]-dimethyl-amine

Conditions	Yield
With sodium methylate In N,N-dimethyl-formamide; toluene for 5h; Heating;	83%

N1-methyl-N1-(2-phenylcyclopropyl)ethane-1,2-diamine + 4-Nitrophenyl chloroformate (7693-46-1) + 4-hydroxytamoxifen (68392-35-8) → 4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenyl (2-(methyl(2-phenylcyclopropyl)amino)ethyl)carbamate

Conditions	Yield
Stage #1: 4-Nitrophenyl chloroformate; 4-hydroxytamoxifen With pyridine In dichloromethane at 20℃; for 24h; Cooling with ice; Stage #2: N1-methyl-N1-(2-phenylcyclopropyl)ethane-1,2-diamine With triethylamine In dichloromethane at 20℃; for 22h; Cooling with ice;	68.4%

pivaloyl chloride (3282-30-2) + 4-hydroxytamoxifen (68392-35-8) → 2,2-Dimethyl-propionic acid 4-{(Z)-1-[4-(2-dimethylamino-ethoxy)-phenyl]-2-phenyl-but-1-enyl}-phenyl ester + (E)-4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenyl pivalate

Conditions	Yield
With sodium hydroxide In chloroform for 3h; Ambient temperature; Title compound not separated from byproducts;

acetyl chloride (75-36-5) + 4-hydroxytamoxifen (68392-35-8) → (E)-4-{1-[4-(2-dimethylaminoethoxy)phenyl]-2-phenylbut-1-enyl}phenyl acetate (76117-70-9) + C28H31NO3

Conditions	Yield
With pyridine for 1h; Friedel Crafts Acylation; Heating / reflux;

5'-O-(4,4'-dimethoxytrityl)-2'-O-(tert-butyldimethylsilyl)uridine-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]phosphoramidite (144490-31-3, 118362-03-1, 131349-31-0, 131349-37-6) + 4-hydroxytamoxifen (68392-35-8) → C65H75N4O12PSi (1361390-71-7)

Conditions	Yield
Stage #1: 5'-O-(4,4'-dimethoxytrityl)-2'-O-(tert-butyldimethylsilyl)uridine-3'-[(2-cyanoethyl)-(N,N-diisopropyl)]phosphoramidite; 4-hydroxytamoxifen With N-methylbenzimidazolium triflate In acetonitrile for 2.5h; Molecular sieve; Stage #2: With pyridine; water; iodine In tetrahydrofuran for 1h;

4-hydroxytamoxifen (68392-35-8) → N,N-dimethyl-2-(4-(2-phenyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)but-1-en-1-yl)phenoxy)ethanamine (1370699-81-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: pyridine / dichloromethane / 1 h / 0 - 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 80 °C / Inert atmosphere View Scheme

4-hydroxytamoxifen (68392-35-8) → potassium [4-(1-{4-[2-(dimethylamino)ethoxy]phenyl}-2-phenylbut-1-en-1-yl)phenyl]trifluoroboranuide (1371574-63-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dichloromethane / 1 h / 0 - 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 80 °C / Inert atmosphere 3: potassium hydrogen difluoride / methanol; water / 0.25 h / 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → (4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenyl)boronic acid (1370699-82-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: pyridine / dichloromethane / 1 h / 0 - 20 °C 2: (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride; potassium acetate / 1,4-dioxane / 80 °C / Inert atmosphere 3: potassium hydrogen difluoride / methanol; water / 0.25 h / 20 °C 4: chloro-trimethyl-silane / water; acetonitrile / 1 h / 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → (E/Z)-4-hydroxy-N-desmethyltamoxifen hydrochloride (1197194-41-4)

Conditions	Yield
Stage #1: 4-hydroxytamoxifen With carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene In dichloromethane at 0℃; for 12.5h; Reflux; Stage #2: With hydrogenchloride In methanol; water for 3h; Reflux;

4-hydroxytamoxifen (68392-35-8) → C43H44N4O4 (1426676-56-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 12.5 h / 0 °C / Reflux 1.2: 3 h / Reflux 2.1: dichloromethane / 8 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 3.2: 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → C47H52N4O6 (1426676-59-6)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 12.5 h / 0 °C / Reflux 1.2: 3 h / Reflux 2.1: dichloromethane / 8 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 20 °C 3.2: 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → C45H53ClN7O4Pt(2+)*2NO3(1-)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 12.5 h / 0 °C / Reflux 1.2: 3 h / Reflux 2.1: dichloromethane / 8 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 3 h / 20 °C 3.2: 20 °C 4.1: silver nitrate / N,N-dimethyl-formamide 4.2: 120 h / -10 - 4 °C 4.3: 0.5 h / 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → C49H61ClN7O6Pt(2+)*2NO3(1-)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 12.5 h / 0 °C / Reflux 1.2: 3 h / Reflux 2.1: dichloromethane / 8 h / 20 °C 3.1: trifluoroacetic acid / dichloromethane / 20 °C 3.2: 20 °C 4.1: silver nitrate / N,N-dimethyl-formamide 4.2: -10 - 4 °C 4.3: 20 °C View Scheme

4-hydroxytamoxifen (68392-35-8) → C48H52N4O6

Conditions	Yield
Multi-step reaction with 2 steps 1.1: carbonochloridic acid 1-chloro-ethyl ester; N,N,N',N'-tetramethyl-1,8-diaminonaphthalene / dichloromethane / 12.5 h / 0 °C / Reflux 1.2: 3 h / Reflux 2.1: dichloromethane / 8 h / 20 °C View Scheme