Process for the preparation of Bazedoxifene acetate
INTRODUCTION
The present invention is related to methods of preparing polymorphic Form A of Bazedoxifene acetate; The present application also provides an industrially viable process for the preparation of Bazedoxifene acetate polymorphic form A.
Bazedoxifene acetate, 1H-lndol-5-ol, 1-[[4-[2-(hexahydro-1H-azepin-1-yl)ethoxy]phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-acetate, is a third generation selective estrogen receptor modulator (SERM). Bazedoxifene acetate exhibits estrogen-agonistic tissue-selective activity on the skeletal system and lipid metabolism also acts as an estrogen antagonist on breast and uterine tissue. It is marketed under the brand name Conbriza. The chemical structure of Bazedoxifene acetate is as follows:
As per EMEA/CHMP/660889/2008 Bazedoxifene acetate polymorphic form A is showing better bioavailability over the Polymorphic form B of Bazedoxifene acetate.

Conventional processes for preparing Bazedoxifene acetate are disclosed in US5.998.402, US6,380,166, US6,005,102 and WO 2011022596A2.
The Polymorphic forms of Bazedoxifene acetate are disclosed in the various literatures. For example, polymorphic form A of Bazedoxifene acetate and its methods of preparation are disclosed in US7,683,051. US7.683.052 discloses the polymorphic form B of Bazedoxifene acetate and process of preparing the same.
US8618284 discloses the process for the preparation of Bazedoxifene acetate polymorphic form A which involves the debenzylation of the Benzylated bazedoxifene in the presence of unreduced Pd catalyst on carbon.
Bazedoxifene acetate polymorphic form A has higher solubility in both aqueous and organic solvent systems. This is particularly advantageous in formulations where the solubility of the composition is of concern.
As the polymorphic form A of Bazedoxifene acetate provides better bioavailability in formulations and conventional procedures are not resulting into polymorphic form A. There is a need for a new and improved method that can produce pure polymorphic form A of Bazedoxifene acetate with reproducibility's. The methods of preparing polymorphic form A of Bazedoxifene acetate described herein help meet these and other needs.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.

SUMMARY OF THE INVENTION
The present invention relates to the process for the preparation of Bazedoxifene acetate polymorphic form A.
In one aspect, the present invention provides Polymorphic form A of Bazedoxifene acetate, having an X-ray powder diffraction (XRPD) pattern, which is in accordance with FIG. 1. XRPD data consistent with form A is provided in Table 1.

In a further aspect, the present invention provides a process for the preparation of Form A of Bazedoxifene acetate comprising the following steps:
a) dissolving 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1 H-indole (Benzylated Bazedoxifene) in a solvent or solvent mixture;
b) catalytic reduction of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1 H-indole (Benzylated Bazedoxifene) in the presence of hydrogen source and hydrogenation catalyst;
c) filtering the reaction mass and treating the reaction mixture with an anti-oxidant;
d) optionally isolating the free base of Bazedoxifene;
e) treating said solution with acetic acid to obtain Bazedoxifene acetate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1: X-ray powder diffraction (XRPD) pattern of Bazedoxifene acetate polymorphic form A.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of polymorphic form A of Bazedoxifene acetate and a process for the preparation thereof.
In one embodiment, the present disclosure provides a method of preparing polymorphic form A of Bazedoxifene acetate, the method comprising:
a) dissolving 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-<4-. benzyloxyphenyl)-5-benzyloxy-3-methyl-1 H-indole (Benzylated Bazedoxifene) in a solvent or solvent mixture;
b) catalytic reduction of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1 H-indole (Benzylated Bazedoxifene) in the presence of hydrogen source and a hydrogenation catalyst;
c) filtering the reaction mass and treating the reaction mixture with an anti-oxidant;
d) optionally isolating the free base of Bazedoxifene;
e) treating said solution with acetic acid to obtain Bazedoxifene acetate,

In certain embodiments, in step (a) The benzylated bazedoxifene is in dissolved with a solvent or a solvent mixture, wherein solvent is selected from ethyl acetate, acetone, cyclohexane and ethanol and their mixtures thereof.
The solution may be heated to dissolve Benzylated Bazedoxifene .The temperature suitable for dissolving Benzylated Bazedoxifene depends on the solvent or solvents used and the amount of Benzylated Bazedoxifene in the solution. Typically, the temperature is at least about 20° C. to about reflux. Preferably, the temperature is about 20° C. to about 80° C. and more preferably at about 20° C. to about 40° C.
In certain embodiments, in step (b) of the method described herein, the hydrogenation source is hydrogen gas or a hydrogen source, e.g., ammonium formate, ammonium acetate, hydrazine, cyclohexadiene, or any other hydrogen source.
In certain embodiments, in step (b) of the method described herein, the catalyst is a Pd/C catalyst. In one embodiment, the Pd/C catalyst used is the reduced Pd/c or a mixture of reduced and unreduced Pd/C catalyst.
In certain embodiments, in step (c) the reaction mass is filtered and then anti-oxidant is added to the reaction mixture.
In certain embodiments, in step (c) of the method described herein, said antioxidant is selected from ascorbic acid, sodium ascorbate, ascorbyl palmitate, citric acid, and the like. In another embodiment, said antioxidant is ascorbic acid.
In certain embodiments, in step (d) Bazedoxifene freebase may be
isolated.

In certain embodiments, in step (e) the optionally isolated Bazedoxifene can be converted to Bazedoxifene acetate using acetic acid.
In certain embodiments, in step (e) of the above process the solid is isolated, whereas any conventional method such as filtration, centrifugation or evaporation of the solvent may be applied.
In certain embodiments, the polymorphic pure form A of Bazedoxifene acetate prepared according to the present invention comprises essentially pure polymorph A containing at least about 95%, preferably at least 97%, more preferably at least 99%, and most preferably at least 99.9% of Bazedoxifene polymorph A, when measured by XRD or DSC.
Accordingly, the present invention further relates to polymorphic pure form A of Bazedoxifene acetate with a polymorphic purity of at least about 95%, preferably at least 97%, more preferably at least 99%, and most preferably at least 99.9% of Bazedoxifene acetate polymorph A.
Powder XRD of sample was recorded on a PANalytical EMPYREAN (PANalytical, The Netherlands) diffractometer using Cu-Ka radiation at 45kV and 40mA.Diffraction pattern was collected over 29 range of 4-40degree with step size of 0.03degree.
HPLC:
Related substances test is performed by using the HPLC instrument with UV-Visible detector (Make Waters, Model: e2695).
Sample analysis has been carried out by injecting 5uL of 0.5mg/mL sample solution through HPLC gradient elution with a flow rate 1.0 mL/min, using X-Bridge phenyl (150x4.6)mm, 3.5pm at a wavelength 220nm

Buffer: 0.01 M K2HP04 in Water, pH=8.0, Mobile Phase A: Buffer: Acetonitrile (70:30, v/v),
Mobile Phase-B: Acetonitrile: Methanol (80:20, v/v)
The following examples are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the feature and advantages.

Charged 70.Og of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-<4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1H-indole (Benzylated Bazedoxifene) in to a mixture of ethanol(525ml) and ethyl acetate (175ml) into a autoclave reactor at 25-30°C. Added 7.0g of 10%Pd/C in to the reaction mixture. Stirred the reaction mass for 3 hrs at 30-35°C under hydrogen atmosphere. After completion of the reaction, reaction mass is filtered. Added L-Ascorbic acid (0.7gms) to the filtrate. 7.7gms of Acetic acid is added to the reaction mass at 30-35°C. Maintained the reaction for 30 Min. Cooled the reaction mass to 0-5°C for 60-90 min. Filtered the reaction mass to obtain Polymorphic form A of Bazedoxifene acetate.
Weight: 44.5g; HPLC purity: 99.77%
For, Eisai Pharmaceuticals India Pvt. limited,