198481-33-3

Usage

Uses

Used in Pharmaceutical Industry:
Bazedoxifene Acetate is used as an antiosteoporotic agent for the treatment and prevention of osteoporosis in postmenopausal women. It helps to increase bone mineral density and reduce the risk of fractures by selectively modulating the effects of estrogen on bone tissue.
Used in Oncology Research:
Bazedoxifene Acetate is used as a research compound to study its efficacy in inhibiting the interleukin-6 (IL-6)/IL-6R/glycoprotein 130 pathway and its effects on medulloblastoma cells. This application aims to explore the potential of Bazedoxifene Acetate in cancer treatment, particularly in targeting specific signaling pathways involved in tumor growth and progression.

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 
• 198481-32-2 bazedoxifene 
• 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 
• 35081-45-9 1-<4-(benzyloxy)phenyl>-2-bromo-1-propanone 
• 223251-25-0 1-{2-[4-(chloromethyl)phenoxy]ethyl}hexahydro-1H-azepine hydrochloride 
• 26487-67-2 1-(2-chloroethyl)azepane hydrochloride 
• 1072-21-5 hexanedial 
• 1251936-44-3 1-[4-(2-Amino-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol 
• 66784-42-7 adipic acid anhydride 
• 123226-38-0 4-hydroxymethyl-phenoxy acetonitrile 

Downstream Products

• 1354966-34-9 bazedoxifene L-lactate 

Relevant academic research and scientific papers

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.

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.

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.

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.

Bazedoxifene Acetate polymorphism A preparation method

The present invention discloses a Bazedoxifene Acetate polymorphism A preparation method, wherein a raw material Bazedoxifene free alkali is dissolved in a single solvent methanol, and salt forming and crystallization are performed to directly obtain the

Preparation method of bazedoxifene acetate

The invention discloses a preparation method of bazedoxifene acetate. The method is characterized in that raney nickel is used as a catalyst, and a compound I and hydrogen react in a microreactor to obtain bazedoxifene under the conditions that the temperature is 20 to 40DEG C and the hydrogen pressure is controlled to be 0.1 to 0.5Mpa. According to the method, the raney nickel with lower price is used to replace expensive palladium carbon, so that the production cost is effectively reduced, the microreactor is used and the production is in streamline operation; an obtained product is high in yield and good in quality; the preparation method has the advantages of high reaction efficiency, mild reaction conditions, safe and controllable operation, short reaction time and low cost; the method is easier for industrial production (The formula is shown in the description).

Method for the preparation of high purity Bazedoxifene Acetate

The present invention relates to a method for producing bazedoxifene acetate using a reducing agent or a reducing agent and an antioxidant and, more specifically, to a method for producing bazedoxifene acetate with high purity by removing bazedoxifene N-oxide within less than 0.01%.COPYRIGHT KIPO 2017

A preparation method of A palestinian multi-past profuse crystal acetate

The invention belongs to the technical field of chemical pharmacy and relates to a preparation method of a bazedoxifene acetate crystal form A. The preparation method of the bazedoxifene acetate crystal form A comprises the following steps: step 1, in the presence of palladium/carbon serving as a catalyst, dissolving hexamethyleneimine benzyloxy benzpyrole and ammonium formate in a benign organic solvent to have reaction; step 2, after the reaction is finished completely, filtering the palladium on activated carbon, cooling the filtrate, adding acetic acid and a toxic inorganic solvent, stirring, crystallizing, filtering and drying to obtain a crude crystal form A product; step 3, under the protection and presence of inert gas, dissolving the crude crystal form A product in the benign organic solvent, heating and dissolving; step 4, thermally filtering the solution, cooling the filtrate, dropwise adding the toxic inorganic solvent and crystallizing; step 5, after the crystallization is ended, filtering the solution and drying the solid to obtain the bazedoxifene acetate crystal form A.

palestinian multi-past fragrance method for the preparation of acetic acid

The invention discloses a preparation method of bazedoxifene acetate. The method comprises the following steps: carrying out a condensation cyclization reaction on 1-(4-Pg1 oxygroup phenyl) propyl alcohol (II) and N-{4-(2-azacycloheptane-1-yl-ethyoxyl-ben