Process for the preparation of Bazedoxifene acetate polymorphic form
A
INTRODUCTION
The present application provides a process for the preparation of Bazedoxifene acetate polymorphic form A. 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 055,998,402, 056,380,166, US6,005,102 and WO 2011022596A2.
The Polymorphic forms of Bazedoxifene acetate are disclosed in the various literature. 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. US8063041 disclose Polymorphic form D of Bazedoxifene acetate and its methods of preparation. Amorphous Bazedoxifene acetate and preparation thereof is disclosed in US 20100310870.
Methods of preparing polymorphic form A of Bazedoxifene acetate are also described in prior art IN1317/MUM/2011, US8618284 and US7683051 as well as a method of enhancing the stability of form A. Although many processes have been described for the preparation of polymorphic form A but none of these reported literature is yielding consistently pure polymorphic A.
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 another aspect, the present invention provides Polymorphic form A of Bazedoxifene acetate, having a DSC pattern, which is in accordance with FIG. 2;
In a further aspect, the present invention provides a process for the preparation of Bazedoxifene acetate polymorphic form A 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 a hydrogenation catalyst;
c) optionally isolating the free base of Bazedoxifene;
d) treating said solution with acetic acid to crystallize polymorphic form A of Bazedoxifene acetate;

e) Isolating the polymorphic form A of Bazedoxifene acetate.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. V. X-ray powder diffraction (XRPD) pattern of Bazedoxifene acetate polymorphic form A.
FIG. 2: DSC 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
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Bazedoxifene) in the presence of hydrogen source and hydrogenation catalyst;
c) optionally isolating the free base of Bazedoxifene;
d) treating said solution with acetic acid to crystallize polymorphic form A of Bazedoxifene acetate;
e) Isolating the polymorphic form A of 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 2-methyltetrahydrofuran, 1,4-Dioxane 1,3-dioxalane 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, ammoniumacetate, hydrazine, cyclohexadiene, or any other hydrogen source, and a catalyst.such as, for example, Raney nickel, platinum oxide, platinum on activated carbon,palladium hydroxide, palladium on barium sulfate, palladium on activated carbon,and palladium carbonate.
In certain embodiments, in step (c) the Bazedoxifene free base may be isolated.
In certain embodiments, in step (d) 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 20 range of 4-40degree with step size of 0.03degree.
DSC Measurement is performed with seal pan at a scan rate of 10°C/min from 50°C to 200°C under nitrogen purge by using SHIMADZU DSC-60 (SHIMADZU CORPORATION).
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.

EXAMPLES
Example 1
1H-lndol-5-ol. 1-ff4-r2-fhexahvdro-1H-a2epin-1-vhethoxvlphenvllmethvl1-2-(4-hvdroxvphenvl)-3-methvl-, acetate fBazedoxifene acetate)
Charged 70.0g of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1H-indole (Benzylated Bazedoxifene) and 2-methyl tetrahydrofuran (490mL) into a autoclave reactor at 25-30°C. Added 7.0g of 10%Pd/C in to the reactor. Stirred the reaction mass for 6-10hrs at 25-30°C under hydrogen atmosphere. After completion of the reaction, mass is filtered over celite and washed with 2-methyl tetrahydrofuran(140ml_). Cool the filtrate to 10-12°C and then added 8.4g of Acetic acid dissolved in 70mL of 2-methyl tetrahydrofuran. Stirred the reaction for 5-10hrs at 10-12°C. Filtered the reaction mass to obtain Polymorphic form A of Bazedoxifene acetate.
Weight: 42.Og; HPLC purity: 99.84%
Example 2
1H-lndol-5-ol. 1-ff4-[2-(hexahvdro-1H-azepin-1-yl)ethoxvlphenvl1methvll-2-(4-hvdroxyphenvl)-3-methvl-. acetate fBazedoxifene acetate)

Charged 50.Og of 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-benzyloxyphenyl)-5-benzyloxy-3-methyl-1 H-indole (Benzylated Bazedoxifene) and 1,4-Dioxane (350mL) into a autoclave reactor at 25-30°C. Added 5.0g of 10%Pd/C in to the reactor. Stirred the reaction mass for 6-10hrs at 25-30°C under hydrogen atmosphere. After completion of the reaction, mass is filtered over celite and washed with 1,4-Dioxane (80mL). Cool the filtrate to 10-12°C and then added 6.0g of Acetic acid dissolved in 50ml_ of 1,4-Dioxane. Stirred the reaction for 5-10hrs at 10-12°C. Filtered the reaction mass to obtain Polymorphic form A of Bazedoxifene acetate.
Weight: 32.0g; HPLC purity: 99.80%

What we claim are:
1. 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 optionally in.the presence of a hydrogenation catalyst
c) optionally isolating the free base of Bazedoxifene;
d) treating said solution with acetic acid to crystallize polymorphic Form A of Bazedoxifene acetate;
e) Isolating the polymorphic form A of Bazedoxifene acetate.

2. The method according to claim 1, wherein step a) the solvent is selected from 2-methyltetrahydrofuran,1,4-dioxane ,1,3-dioxalane and their mixtures thereof.
3. The method according to claim 1, wherein said hydrogenating reagent isH2.
4. The method according to claim 1, wherein said hydrogenating catalyst is Pd/C.
5. The method according to claim 1, wherein isolating polymorphic form A of
Bazedoxifene acetate by filteration washing and drying.