198481-32-2

Basic information

• Product Name: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol
• Synonyms: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol;1-((4-(2-Hexahydro-1H-azepin-1-yl)ethoxy)phenyl)methyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol;1H-Indol-5-ol, 1-((4-(2-(hexahydro-1H-azepin-1-yl)ethoxy)phenyl)methyl)-2-(4-hydroxyphenyl)-3-methyl-;Bazedoxifene;Bazedoxifene [inn];Bazedoxifeno;Bazedoxifeno [inn-spanish];Tse-424
• CAS NO: 198481-32-2
• Molecular Formula: C₃₀H₃₄N₂O₃
• Molecular Weight: 470.60
• EINECS: 1592732-453-0
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 198481-32-2.mol
• Article Data: 34

Chemical Properties

• Melting Point: 98-102°
• Boiling Point: 694.4 °C at 760 mmHg
• Flash Point: 373.8 °C
• Appearance: /
• Density: 1.19
• Vapor Pressure: 6.33E-20mmHg at 25°C
• Refractive Index: 1.622
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: Chloroform (Slightly), DMSO (Slightly), Methanol (Slightly)
• PKA: 10.12±0.15(Predicted)
• CAS DataBase Reference: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol(CAS DataBase Reference)
• NIST Chemistry Reference: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol(198481-32-2)
• EPA Substance Registry System: 1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol(198481-32-2)

Safety Data

• Hazardous Substances Data: 198481-32-2(Hazardous Substances Data)

Usage

Description

1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol, also known as Bazedoxifene, is a nonsteroidal selective estrogen receptor modulator (SERM). It is a compound with a complex chemical structure that has been developed for the treatment of postmenopausal osteoporosis. Bazedoxifene selectively targets estrogen receptors, modulating their activity in a tissue-specific manner, which makes it a promising candidate for various therapeutic applications.

Uses

Used in Pharmaceutical Industry:
1-[[4-[2-(azepan-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-indol-5-ol is used as an antiosteoporotic agent for the prevention and treatment of postmenopausal osteoporosis. Bazedoxifene works by selectively modulating the activity of estrogen receptors in bone tissue, reducing bone resorption and promoting bone formation, thus helping to maintain bone density and strength.
Additionally, Bazedoxifene has been studied for its potential applications in other areas, such as the treatment of breast cancer and endometriosis. However, its primary use remains in the pharmaceutical industry for the management of postmenopausal osteoporosis.

Clinical Use

Bazedoxifene is an indole-based SERM that is under investigation for the treatment and prevention of postmenopausal osteoporosis. It also is being evaluated in combination with Premarin (conjugated estrogens). Bazedoxifene displaces 17β-estradiol from estrogen receptors and has excellent binding affinity for the receptor itself. Unlike raloxifene, this agent does not cause hot flashes at the doses required to have a beneficial effect on bone. In addition, it does not cause uterine or mammary gland stimulation.

Enzyme inhibitor

This potent and selective estrogen receptor modulator, or SERM (FW = 530.65 g/mol; CAS 198481-33-3; Solubility: 00 mM in DMSO), also named 1-[[4-[2- (hexahydro-1H-azepin-1-yl) ethoxy]phenyl]methyl]-2- (4- hydroxyphenyl) -3-methyl-1H-indol-5-ol, selectivity targets the extrogen receptor ERα (IC50 = 26 nM), with weaker action against ERβ (IC50 = 99 nM), inhibiting 17β-estradiol-induced proliferation of MCF-7 cells. Bazedoxifene represents a promising new treatment for osteoporosis, one with a potential for less uterine and vasomotor effects than selective estrogen receptor modulators now used clinically.

InChI:InChI=1/C30H34N2O3/c1-22-28-20-26(34)12-15-29(28)32(30(22)24-8-10-25(33)11-9-24)21-23-6-13-27(14-7-23)35-19-18-31-16-4-2-3-5-17-31/h6-15,20,33-34H,2-5,16-19,21H2,1H3

Synthetic route

5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole (198480-21-6) → bazedoxifene (198481-32-2)

Conditions	Yield
With palladium on activated charcoal; hydrogen; sodium hydroxide In ethanol; ethyl acetate Solvent; Reagent/catalyst;	100%
With hydrogen; 2.34% Pd/C In tetrahydrofuran; ethanol for 5h;	99%
With hydrogen; palladium 10% on activated carbon In methanol; water; acetone at 40℃; under 7355.72 Torr; Product distribution / selectivity;	99.72%

1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-methoxy-2-(4-methoxy-phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With trimethylsilyl iodide In chloroform at 20℃; for 5h;	95%
With hydrogen iodide	36.3 g

1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride (223251-25-0) + 4-(5-acetoxy-3-methyl-1H-indol-2-yl)phenyl acetate (91444-55-2) → bazedoxifene (198481-32-2)

Conditions	Yield
Stage #1: 4-(5-acetoxy-3-methyl-1H-indol-2-yl)phenyl acetate With sodium hydride In N,N-dimethyl-formamide at 0 - 5℃; for 2h; Inert atmosphere; Stage #2: 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride In N,N-dimethyl-formamide at 0 - 25℃; for 15h; Stage #3: With sodium hydroxide In N,N-dimethyl-formamide at 25℃; for 15h; Solvent; Temperature; Reagent/catalyst;	89%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(tert-butoxy)-2-(4-(tert-butoxy)phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With hydrogen bromide; acetic acid at 20℃; for 0.5h;	87%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-(benzoyloxy)phenyl)-3-methyl-1H-indol-5-yl benzoate → bazedoxifene (198481-32-2)

Conditions	Yield
With triethylamine In methanol; water for 5h; Reflux;	86%

1-[4-(2-azepan-1-yl-ethoxy)benzyl]-5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With ammonium formate; 10 wt% Pd(OH)2 on carbon In acetone	85%

4-(5-acetoxy-1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-3-methyl-1H-indol-2-yl)phenyl acetate → bazedoxifene (198481-32-2)

Conditions	Yield
With ammonia In methanol; water at 20℃; for 3h;	85%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-3-methyl-2-(4-(pivaloyloxy)phenyl)-1Hindol-5-yl pivalate → bazedoxifene (198481-32-2)

Conditions	Yield
With methanol; potassium carbonate at 45℃; for 3h;	83%

1-(2-{4-[5-Hydroxy-2-(4-hydroxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethyl)-azepane-2,7-dione (1251936-45-4) → bazedoxifene (198481-32-2)

Conditions	Yield
With sodium tetrahydroborate; boron trifluoride diethyl etherate In tetrahydrofuran at 5 - 10℃; for 4h;	80.7%

hexamethylene imine (111-49-9) + 2-(4-((5-hydroxy-2-(4-hydroxyphenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethyl 4-methylbenzenesulfonate (1343413-19-3) → bazedoxifene (198481-32-2)

Conditions	Yield
In toluene at 70 - 75℃; for 12h;	80%

ethyl 2-((1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-(2-ethoxy-2-oxoethoxy)phenyl)-3-methyl-1H-indol-5-yl)oxy)acetate → bazedoxifene (198481-32-2)

Conditions	Yield
With sodium hydroxide In methanol; water at 20℃; for 3h;	79%

1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride → bazedoxifene (198481-32-2)

Conditions	Yield
With triethylamine In dichloromethane; water pH=9.5 - 10.5; Product distribution / selectivity;	73.27%

1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride (223251-25-0) + 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (91444-54-1) → bazedoxifene (198481-32-2)

Conditions	Yield
Stage #1: 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride; 2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol With sodium hydride In N,N-dimethyl-formamide at 0℃; for 1h; Stage #2: 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride In N,N-dimethyl-formamide at 0 - 5℃; for 3.91h;	70.18%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(2-ethoxyethoxy)-2-(4-(2-ethoxyethoxy)phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With boron tribromide In methanol for 5h; Reflux;	69%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(cyclopentyloxy)-2-(4-(cyclopentyloxy)phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With hydrogen bromide; acetic acid In methanol at 50℃; for 2h;	61%

hexanedial (1072-21-5) + 1-[4-(2-Amino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol (1251936-44-3) → bazedoxifene (198481-32-2)

Conditions	Yield
10 wt% Pd(OH)2 on carbon at 45 - 50℃; under 3677.86 - 5884.58 Torr;	45%

1-(4-(2(azepan-1-yl)ethoxy)benzyl)-5-((2-methoxyethoxy)methoxy)-2-(4-((2-methoxyethoxy)methoxy)phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With acetyl chloride In methanol at 0 - 2℃; for 3h;	42%

1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-((4-methoxybenzyl)oxy)-2-(4-((4-methoxybenzyl)oxy)phenyl)-3-methyl-1H-indole → bazedoxifene (198481-32-2)

Conditions	Yield
With 2,3-dicyano-5,6-dichloro-p-benzoquinone In dichloromethane at 20℃; for 20h;	15%

(4-hydroxyphenyl)methanol (623-05-2) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: K2CO3 2.1: SOCl2 / tetrahydrofuran 3.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 3.2: 59 percent / dimethylformamide / 18 h / 20 °C 4.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 5.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 6.1: tetrahydrofuran 7.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 4 steps 1.1: sodium hydroxide / tetrabutylammomium bromide / toluene; water / Reflux 2.1: hydrogenchloride / dichloromethane / 25 - 35 °C / Inert atmosphere 3.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 3.2: 5 °C 4.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr View Scheme
Multi-step reaction with 7 steps 1.1: potassium carbonate / acetonitrile / 60 °C 2.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 0.75 h / 0 °C / Inert atmosphere 3.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 °C 3.2: 20 °C 4.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 5.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 6.1: tetrahydrofuran / Reflux 7.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

1-<4-(benzyloxy)phenyl>-2-bromo-1-propanone (35081-45-9) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 51 percent / Et3N / dimethylformamide / Heating 2.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 2.2: 59 percent / dimethylformamide / 18 h / 20 °C 3.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 4.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 5.1: tetrahydrofuran 6.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr View Scheme
Multi-step reaction with 6 steps 1.1: triethylamine / N,N-dimethyl-formamide / 4 h / 120 - 150 °C / Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 °C 2.2: 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 4.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 5.1: tetrahydrofuran / Reflux 6.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 4 h / 115 °C 2: sodium hydride / N,N-dimethyl-formamide / 10 h / 20 °C 3: boron trifluoride diethyl etherate / dichloromethane; ethanethiol / 4 h / 0 - 25 °C View Scheme

4-benzyloxyaniline hydrochloride (51388-20-6) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: 51 percent / Et3N / dimethylformamide / Heating 2.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 2.2: 59 percent / dimethylformamide / 18 h / 20 °C 3.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 4.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 5.1: tetrahydrofuran 6.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / N,N-dimethyl-formamide / 100 - 125 °C 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr View Scheme
Multi-step reaction with 3 steps 1: triethylamine / N,N-dimethyl-formamide / 4 h / 115 °C 2: sodium hydride / N,N-dimethyl-formamide / 10 h / 20 °C 3: boron trifluoride diethyl etherate / dichloromethane; ethanethiol / 4 h / 0 - 25 °C View Scheme

ethyl [p-(chloromethyl)phenoxy]acetate (80494-75-3) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 1.2: 59 percent / dimethylformamide / 18 h / 20 °C 2.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 3.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 4.1: tetrahydrofuran 5.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 4.1: tetrahydrofuran / Reflux 5.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

ethyl 2-(4-hydroxymethylphenoxy)acetate (103258-64-6) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: SOCl2 / tetrahydrofuran 2.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 2.2: 59 percent / dimethylformamide / 18 h / 20 °C 3.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 4.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 5.1: tetrahydrofuran 6.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 6 steps 1.1: thionyl chloride; N,N-dimethyl-formamide / dichloromethane / 0.75 h / 0 °C / Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 °C 2.2: 20 °C 3.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 4.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 5.1: tetrahydrofuran / Reflux 6.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (198479-63-9) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: sodium hydride / dimethylformamide / 0.33 h / 0 °C 1.2: 59 percent / dimethylformamide / 18 h / 20 °C 2.1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 3.1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 4.1: tetrahydrofuran 5.1: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 1.2: 5 °C 2.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr View Scheme
Multi-step reaction with 5 steps 1.1: sodium hydride / N,N-dimethyl-formamide / 0.33 h / 0 °C 1.2: 20 °C 2.1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 3.1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 4.1: tetrahydrofuran / Reflux 5.1: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol (198479-95-7) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 2: tetrahydrofuran 3: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 3 steps 1: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 2: tetrahydrofuran / Reflux 3: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

5-benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole (198480-07-8) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: tetrahydrofuran 2: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 2 steps 1: tetrahydrofuran / Reflux 2: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

{4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl ester (198479-82-2) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 78 percent / LiAlH4 / tetrahydrofuran / 0.5 h / 0 °C 2: 87 percent / CBr4; Ph3P / tetrahydrofuran / 3 h / 20 °C 3: tetrahydrofuran 4: H2 / Pd/C / ethanol; tetrahydrofuran / 20 °C View Scheme
Multi-step reaction with 4 steps 1: lithium aluminium tetrahydride / tetrahydrofuran / 0.5 h / 0 °C 2: carbon tetrabromide; triphenylphosphine / tetrahydrofuran / 20 °C 3: tetrahydrofuran / Reflux 4: palladium 10% on activated carbon; hydrogen / tetrahydrofuran; ethanol / 20 °C View Scheme

C30H36N2O9P2 (1049816-47-8) → bazedoxifene (198481-32-2)

Conditions	Yield
With water; alkaline phosphatase pH=7.4; Conversion of starting material; Tris buffer; Enzymatic reaction;

[4-(2-hexamethyleneimino-1-yl-ethoxy)-phenyl]-methanol (223251-16-9) → bazedoxifene (198481-32-2)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: hydrogenchloride / dichloromethane / 25 - 35 °C / Inert atmosphere 2.1: sodium hydride / N,N-dimethyl-formamide; toluene / -5 - -1 °C 2.2: 5 °C 3.1: hydrogen / palladium 10% on activated carbon / water; acetone; methanol / 40 °C / 7355.72 Torr View Scheme

acetic acid (64-19-7) + bazedoxifene (198481-32-2) → bazedoxifene acetate

Conditions	Yield
for 6h; Heating;	98.5%
In ethanol; ethyl acetate at 20 - 30℃;	95.5%
In acetone at 20 - 55℃;	95%

tert-butyldimethylsilyl chloride (18162-48-6) + bazedoxifene (198481-32-2) → C42H62N2O3Si2

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;	93.48%

chloro-trimethyl-silane (75-77-4) + bazedoxifene (198481-32-2) → C36H50N2O3Si2

Conditions	Yield
With triethylamine In dichloromethane at 0 - 20℃; for 4h; Inert atmosphere;	90.3%

bazedoxifene (198481-32-2) → 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol hydrochloride

Conditions	Yield
With hydrogenchloride In methanol Product distribution / selectivity;	87.79%
With hydrogenchloride In methanol; water

L-Lactic acid (79-33-4) + bazedoxifene (198481-32-2) → bazedoxifene L-lactate (1354966-34-9)

Conditions	Yield
Stage #1: L-Lactic acid In ethanol at 60℃; for 0.25h; Stage #2: bazedoxifene In ethanol at 60℃; for 0.333333h; Solvent;	66.4%

propionic acid (802294-64-0) + bazedoxifene (198481-32-2) → 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol propionate (1266685-12-4)

Conditions	Yield
In acetone	60.23%

formic acid (64-18-6) + bazedoxifene (198481-32-2) → 1-[4-(2-azepan-1-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol formic acid salt

Conditions	Yield
In ethyl acetate at 77℃;	50%

Upstream product

• 198480-21-6 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole 
• 623-05-2 (4-hydroxyphenyl)methanol 
• 35081-45-9 1-<4-(benzyloxy)phenyl>-2-bromo-1-propanone 
• 51388-20-6 4-benzyloxyaniline hydrochloride 
• 80494-75-3 ethyl [p-(chloromethyl)phenoxy]acetate 
• 103258-64-6 ethyl 2-(4-hydroxymethylphenoxy)acetate 
• 198479-63-9 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole 
• 198479-95-7 2-(4-((5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indol-1-yl)methyl)phenoxy)ethanol 
• 198480-07-8 5-benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole 
• 198479-82-2 {4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl ester 
• 1049816-47-8 C₃₀H₃₆N₂O₉P₂ 
• 223251-16-9 [4-(2-hexamethyleneimino-1-yl-ethoxy)-phenyl]-methanol 
• 223251-25-0 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride 
• 26487-67-2 1-(2-chloroethyl)azepane hydrochloride 

Downstream Products

• 866331-90-0 bazedoxifene ascorbate 
• 198481-33-3 bazedoxifene acetate 
• 1266685-11-3 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol mesylate 
• 1266685-12-4 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol propionate 
• 1354966-34-9 bazedoxifene L-lactate 
• 1049816-47-8 C₃₀H₃₆N₂O₉P₂ 
• 1049816-44-5 C₄₆H₆₈N₂O₉P₂ 
• 1174289-22-5 bazedoxifene N-oxide 

Relevant articles and documents

Preparation method of bazedoxifene acetate crystal form A

The invention discloses a preparation method of a bazedoxifene acetate crystal form A. The method comprises the following steps: taking 1-(4-(2-(azepine-1-yl) ethoxy) benzyl)-5-(benzyloxy)-2-(4-(benzyloxy) phenyl)-3-methyl-1H-indole as a raw material; preparing bazedoxifene acetate free alkali, preparing a bazedoxifene acetate crude product, preparing a bazedoxifene acetate crystal form B, preparing a bazedoxifene acetate crystal form C and preparing the bazedoxifene acetate crystal form A. A mixed solvent is adopted in the hydrogenation process of the method; the rate and the activity of thepalladium-carbon reduction reaction are improved; an antioxidant is added, so that the stability of the bazedoxifene free alkali is improved, the conversion from the crystal form B to the crystal formC is increased in the middle, key parameters for converting the crystal form C into the crystal form A are found, the purity of the crystal form A in the next step is greatly improved, and the production cost for producing the bazedoxifene acetate crystal form A is effectively reduced.

Preparation method and application of bazedoxifene acetate crystal form D

The invention belongs to the field of medicines, and in particular relates to a preparation method and application of a bazedoxifene acetate crystal form D. The method comprises the following steps: dissolving a compound A into a first good organic solvent; adding a catalyst and ammonium formate into the first good organic solvent, and performing a reaction; performing filtration to remove the catalyst, washing the filtrate by using an inorganic alkali aqueous solution, and separating an organic phase; performing concentration on the organic phase to obtain a bazedoxifene free alkali; dissolving the bazedoxifene free base into a second good organic solvent; adding glacial acetic acid into the second good organic solvent, and performing crystallization; and performing filtration to obtain the bazedoxifene acetate crystal form D, wherein the compound A has a structure represented by a formula I shown in the description. The technical solution provided by the invention does not require high-pressure hydrogenation, the solvent system is simple, the reaction equipment requirements are low, the industrialization is easy to realize, and the obtained bazedoxifene acetate crystal form D hashigh purity.

Acetic acid [...] and intermediate preparation method

The invention discloses a bazedoxifene acetate intermediate and a preparation method thereof. The invention also discloses a method for preparing bazedoxifene acetate from the bazedoxifene acetate intermediate. The invention provides a method for preparing a novel intermediate of bazedoxifene acetate key as shown in the formula (II), the intermediate employs C1-6 alkyl acyl as protective group, and the method for preparing bazedoxifene acetate using the intermediate has the following advantages: (1) high pressure hydrogenation reaction with high risk for deprotection according to the traditional method (using benzyl as a protective group for protecting phenolic group) is avoided, and thereby greatly reducing danger of the experiment; 2. the reaction time is reduced and the industrial energy consumption is reduced; 3. the reaction of the present invention does not need palladium 10% on carbon; the preparation method is environmental friendly, and is suitable for industrial production, and has the advantages of mild condition and operation convenience.