198481-33-3

Basic information

• Product Name: BAZEDOXIFENE ACETATE
• Synonyms: BAZEDOXIFENE ACETATE;1-(p-(2-(Hexahydro-1H-azepin-1-yl)ethoxy)benzyl)-2-(p-hydroxyphenyl)-3-methylindol-5-ol monoacetate (salt);1H-Indol-5-ol, 1-((4-(2-(hexahydro-1H-azepin-1-yl)ethoxy)phenyl)methyl)-2-(4-hydroxyphenyl)-3-methyl-, monoacetate (salt);Bazedoxifene acetate [usan];Unii-J70472ud3d;Viviant;Way-140424;1-((4-(2-(Hexahydro-1H-azepin-1-yl)ethoxy)phenyl)methyl)-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol monoacetate
• CAS NO: 198481-33-3
• Molecular Formula: C30H34N2O3.C2H4O2
• Molecular Weight: 530.661
• EINECS: 1592732-453-0
• Product Categories: Bazedoxifene Acetate;Inhibitors
• Mol File: 198481-33-3.mol
• Article Data: 24

Chemical Properties

• Melting Point: 174-178°
• Boiling Point: 694.4oC at 760 mmHg
• Flash Point: 373.8oC
• Appearance: white to beige/
• Vapor Pressure: 6.33E-20mmHg at 25°C
• Storage Temp.: ?20°C
• Solubility: DMSO: soluble15mg/mL, clear
• CAS DataBase Reference: BAZEDOXIFENE ACETATE(CAS DataBase Reference)
• NIST Chemistry Reference: BAZEDOXIFENE ACETATE(198481-33-3)
• EPA Substance Registry System: BAZEDOXIFENE ACETATE(198481-33-3)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 198481-33-3(Hazardous Substances Data)

Usage

Chemical Properties

Pale Beige Solid

Uses

Different sources of media describe the Uses of 198481-33-3 differently. You can refer to the following data:
1. Bazedoxifene Acetate is a nonsteroidal selective estrogen receptor modulator (SERM). Bazedoxifene Acetate is used as an antiosteoporotic.
2. Bazedoxifene acetate has been used to study its efficacy in inhibiting the interleukin-6 (IL-6)/IL-6R/glycoprotein 130 pathway and its effects on medulloblastoma cells.

Biological Activity

bazedoxifene, a novel selective estrogen receptor modulator (serm), has been developed to have favorable effects on bone and the lipid profile while minimizing stimulation of uterine or breast tissues. two large phase iii

Biochem/physiol Actions

Bazedoxifene is a third generation nonsteroidal selective estrogen receptor modulator (SERM), used clinically to treat postmenopausal osteoporosis. Bazedoxifene binds to estrogen receptor-α with IC50 = 26 nM, similar to that of raloxifene, but lower affinity than 17-β estradiol. Bazedoxifene did not stimulate proliferation of MCF-7 cells, instead inhibited 17β -estradiol-induced proliferation with IC50 = 0.19 nM, exhibiting a desirable profile of agonist/antagonist activity.

Clinical Use

The selective estrogen receptor modulator bazedoxifene acetate was approved in Spain for the treatment of osteoporosis in postmenopausal women. The drug was discovered by Wyeth (now Pfizer) and licensed to Almirall. Clinical trials with bazedoxifene along with conjugated estrogens demonstrated significant improvement in bone mineral density and prevented bone loss in postmenopausal women without osteoporosis. It also reduces fracture risks among women with postmenopausal osteroporosis.

Synthesis

Among many syntheses reported for this drug, the most recent process scale synthesis (multi-kg scale) is highlighted and involves the union of azepane ether 9 and indole 12. 4-Hydroxybenzyl alcohol (6) was converted in two steps to chloride 9 (the Scheme). The reaction of 6 with 2-chloroethyl azepane hydrochloride (7) in a biphasic mixture of sodium hydroxide and toluene in the presence of tetrabutylammonium bromide (TBAB) gave the desired intermediate alcohol 8 in 61% yield. Treatment of 8 with thionyl chloride (SOCl2) gave the requisite chloride 9 in 61% yield. The reaction of 2-bromopropiophenone (10) with an excess of 4-benzyloxy aniline hydrochloride (11) in the presence of triethylamine (TEA) in N,N-dimethylformamide (DMF) at elevated temperatures resulted in indole 12 in 65% yield. Alkylation of 12 with benzylchloride 9 in the presence of sodium hydride (NaH) afforded N-alkylated compound 13. The benzyl ether functionalities from compound 13 were removed via hydrogenolysis and subsequently subjected to acidic conditions, providing diol 14 as the hydrochloride salt in 91% yield. The hydrochloride was then exchanged for the acetate via free base preparation with 5% sodium bicarbonate or triethylamine, followed by treatment with acetic acid giving bazedoxifene acetate (II) in 73–85% yield.

InChI:InChI=1/C30H34N2O3.C2H4O2/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;1-2(3)4/h6-15,20,33-34H,2-5,16-19,21H2,1H3;1H3,(H,3,4)

Upstream product

• 64-19-7 acetic acid 
• 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 
• 51388-20-6 4-benzyloxyaniline hydrochloride 
• 198479-63-9 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole 
• 223251-16-9 [4-(2-hexamethyleneimino-1-yl-ethoxy)-phenyl]-methanol 
• 5349-60-0 1-(4-methoxyphenyl)-1-propanol 
• 123-08-0 4-hydroxy-benzaldehyde 
• 52227-33-5 2,3,4,5,6,7-hexahydro-1-(2-chloro-ethanoyl]-1H-azepine 
• 767630-86-4 4-(2-oxo-2-hexamethyleneimino-ethoxy)-benzaldehyde 
• 70-70-2 4-hydroxypropiophenone 
• 4495-66-3 4-benzyloxypropiophenone 
• 35081-45-9 1-<4-(benzyloxy)phenyl>-2-bromo-1-propanone 
• 22042-73-5 4-(2-hydroxy-ethoxy)-benzaldehyde 

Downstream Products

• 1354966-34-9 bazedoxifene L-lactate 

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.

PROCESS FOR THE PREPARATION OF BAZEDOXIFENE

The invention relates to a process for preparation of the compound 3-methyl-5-benzyloxy-2-(4-benzyloxyphenyl)-1H-indole 5, an intermediate for the synthesis of bazedoxifene and bazedoxifene acetate.

Industrial production method for bazedoxifene acetate

The invention discloses an industrial production method for bazedoxifene acetate. The production method comprises the following steps: taking p-hydroxy benzaldehyde as a starting material, substituting with chloracetyl-hexamethyleneimine, reducing with borohydride and chlorinating with a chlorinating agent to obtain a compound 4; reacting the compound 4 with 5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-1H-indole to obtain a compound 5; and carrying out debenzylation to obtain a compound 6, and salifying with acetic acid to obtain a target compound which is the bazedoxifene acetate. The defective workmanship of preparation in the prior art is solved, the used reagent is low in cost and easy to obtain, environmental pollution is small, safety is high, an operation process is simple, and thus, the bazedoxifene acetate is suitable for being produced industrially.