FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10, rule 13)

1. Title of the invention
"Process for preparation of Bazedoxifene, salts and intermediate thereof

2. Applicant(s)

Name Nationality Address

USV LIMITED Indian company incorporated Arvind Vitthal Gandhi Chowk, B.S.D. Marg, Station Road,
under Companies Act, 1956' Govandi. Mumbai- 400088. Maharashtra, India
3. Preamble to the description
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the invention :
The present invention relates to a process for preparation of Bazedoxifene or pharmaceutically acceptable salt thereof, in particular Bazedoxifene acetate (1). The present invention further relates to a novel polymorphic form of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, a key intermediate used in the preparation of Bazedoxifene and process for preparation thereof.

(1) Background of the invention:
Bazedoxifene, chemically known as l-[[4-[2-(Hexahydro-lH-azepin-l-yl)ethoxy]
phenyl]methyl]-2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol or 2-(4-Hydroxy
phenyl)-3-methyl-1 -[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-1 H-indol-5-ol or
l-[4-(2-azepan-l-ylethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol is a
third-generation selective estrogen receptor modulator (SERM). Bazedoxifene acetate
is commercially marketed by Wyeth and Almirall in Europe under the brand name of
CONBRIZA for the treatment of postmenopausal osteoporosis in women at increased
risk of fracture. Bazedoxifene is available as film coated tablet containing
Bazedoxifene acetate equivalent to 20mg bazedoxifene for oral administration. The
recommended dose of CONBRIZA is one tablet once daily at any time of day with or
without food. CONBRIZA should be taken with an adequate amount of calcium and
vitamin D.
Bazedoxifene acts as both an estrogen-receptor agonist and/or antagonist, depending upon the cell and tissue type and target genes. Bazedoxifene decreases bone resorption and reduces biochemical markers of bone turnover to the premenopausal

range. These effects on bone remodeling lead to an increase in bone mineral density (BMD), which in turn contributes to a reduction in the risk of fractures. Bazedoxifene functions primarily as an estrogen-receptor antagonist in uterine and breast tissues.
US5998402 discloses novel 2-phenyl-l-[4-(2-aminoethoxy)-benzyl] indole compounds useful as estrogenic agents, synthetic preparation, pharmaceutical compositions and methods of treatment utilizing these compounds.
US6005102 discloses a process for preparation of Bazedoxifene in two parts,
i. Synthesis of N-side chain compound, (4-chloromethyl-phenoxy)-ethyl-
hexamethyleneimine-1-yl hydrochloride (5); and ii. Formation of Bazedoxifene acetate (1) from (4-chloromethyl-phenoxy)-ethyl-
hexamethyleneimine-1-yl hydrochloride (5) and 5-benzyloxy-2-(4-benzyloxy
phenyl)-3-methyl-1H-indole (6).
i) Synthesis of (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-1 -yl hydrochloride (5) involves the condensation of 2-(hexamethyleneimino)ethyl chloride with p-hydroxy benzaldehyde to form 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzaldehyde (3). Compound (3) is reduced using sodium borohydride in methanol to give 4-(2-hexamethyleneimine-1 -yl-ethoxy)-benzyl alcohol (4) followed by conversion of compound (4) into its hydrochloride salt (4a). Compound (4a) is then subjected to chlorination to form compound (5). Alternatively compound (4) can be prepared in one step from 4-hydroxy benzyl alcohol as represented in Scheme I. 4-hydroxy benzyl alcohol is treated with 2-(hexamethyleneimino)ethyl chloride to yield 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4). Compound (4) is further converted to its hydrochloride salt (4a) followed by chlorination of compound (4a) to form compound (5).


Scheme I
ii) Synthesis of Bazedoxifene acetate (1) is accomplished in three steps as represented in Scheme II,
a) condensation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (6) with (4-chIoromethyIphenoxy)-ethyl-hexamethyleneimine-1 -yl hydrochloride (5) to form 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-1 H-indole(7);
b) deprotection of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole (7) using Pd/C to yield Bazedoxifene base (8), which is not isolated;
a) treating Bazedoxifene base (8) in situ with acetic acid in presence of antioxidant to form the acetate salt.


Scheme II
US7375251 and US20080207898 discloses processes and intermediates for the preparation of aminoethoxybenzyl alcohols that can be used in the preparation of pharmaceuticals.
WO2011022596 discloses the processes for preparing Bazedoxifene and its pharmaceutically acceptable salts by reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole with l-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane or a salt thereof, such as the hydrochloride in the presence of a suitable base to obtain 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole which is then subjected to deprotection reaction to obtain acid addition salt of Bazedoxifene either by performing the debenzylation under the conditions resulting directly in the salt of bazedoxifene or optionally converting free base of Bazedoxifene from the reaction mixture to its acid addition salt by treatment with suitable acid HX; and optionally purifying the acid addition salt of bazedoxifene and if desired, generating bazedoxifene free base by reacting the acid addition salt of bazedoxifene with a suitable base or preparing an acetate salt of bazedoxifene by reacting either the free base or salt with a source of acetate ion.

The disadvantages of the processes disclosed in prior art are as follows :
1. Debenzylation reaction as discussed in US6005102 requires extremely long time nearly 48 hours for completion.
2. Purification of final product is achieved using column chromatography which is not viable on a commercial scale.
In view of the above mentioned disadvantages, there exists a need to develop a simple and commercially viable process for the preparation of Bazedoxifene or its pharmaceutically acceptable salt. The present invention provides an industrially viable process for preparation of Bazedoxifene or pharmaceutically acceptable salt thereof in high yield and purity by overcoming the difficulties of the prior art. Pharmaceutically acceptable salt is selected from acetate, propionate, mesylate, esylate, fumarate, HC1, HBr or the like, preferably acetate.
Polymorphism is the ability of a compound to exhibit more than one orientation or conformation of molecules within the crystal lattice. Many organic compounds, including active pharmaceutical ingredients (API) exhibit polymorphism. Drug substances may exist in various polymorphic forms, which may differ from each other in terms of stability, solubility, compressibility, flowability and spectroscopic properties thus affecting dissolution, bioavailability and handling characteristics of the substance.
WO2005100316 and WO2005100314 discloses crystalline polymorphic forms A and B of Bazedoxifene acetate.
WO2009102773 discloses the process for preparation of polymorphic form A of Bazedoxifene acetate. This document further discusses a method of enhancing the stability of polymorphic Form A of Bazedoxifene acetate.
US6005102 discloses the recovery of 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-l-[4-(2-hexamethyleneimine-1-yl-ethoxy)-benzyl]-lH-indole, compound (7), characterized by NMR. But polymorphism is not reported for 5-Benzyloxy-2-(4-

benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, the hydroxy protected intermediate (7) of Bazedoxifene.
The present invention provides a novel polymorph of the hydroxy protected intermediate (7) of Bazedoxifene and process for preparation thereof. Hydroxy protected intermediate (7) of Bazedoxifene obtained by the process of the present invention has purity of more than 95%. Use of pure hydroxy protected intermediate (7) reduces the time of debenzylation and provides Bazedoxifene acetate having purity more than about 99.5%.
Object of the invention:
An object of the present invention is to provide an improved process for the preparation of Bazedoxifene or its pharmaceutically acceptable salt.
Another object of present invention is to provide a process for purification of 5-Benzyloxy-2-(4-benzyloxy-phenyf)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, the hydroxy protected intermediate (7) of Bazedoxifene.
Yet another object of present invention provides a novel polymorph of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1 -[4-(2-hexamethyleneimine-1 -yl-ethoxy)-benzyl] -lH-indole, the hydroxy protected intermediate (7) of Bazedoxifene and process for preparation thereof.
Yet another object of present invention provides a process for preparation of Bazedoxifene or pharmaceutically acceptable salt thereof substantially free of compound selected from 2-(4-hydroxyphenyl-3-methyl-1H-indol-5-ol and 1-(4-hydroxy benzyl)-2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol.
Summary of the invention:
According to one aspect of the present invention, there is provided a process for preparation of Bazedoxifene or pharmaceutically acceptable salt thereof comprising the steps of,
a) alkylating 4-hydroxy benzyl alcohol with 2-chloroethyl hexamethyleneimine

or salt thereof in presence of a base and chlorinated hydrocarbon to obtain 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol or its salt;
b) treating 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol or its salt with a halogenating agent in an ester solvent optionally in presence of catalyst to obtain (4-halomethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof;
c) converting (4-haIomethyl-phenoxy)-ethyl-hexamethyleneirmne-1 -yl or salt thereof to Bazedoxifene or pharmaceutically acceptable salt thereof.
Preferably, chlorinated hydrocarbon used in step a) is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride or chloroform; said ester solvent is selected from ethyl acetate, methyl acetate, propyl acetate or butyl acetate; said base is selected from sodium hydroxide, potassium hydroxide, ammonia, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, cesium hydroxide or mixture thereof.
Preferably, alkylation is carried out at a temperature of 20 to 40°C, preferably at 25 to 30°C in presence of phase transfer catalyst selected from tetrabutyl ammonium bromide, benzyltrimethyl ammonium chloride, benzyltriethylammonium chloride or methyltrioctylammonium chloride; and said treatment with halogenating agent is carried out optionally in presence of catalytic amount of dimethyl amino pyridine or dimethyl formamide.
Preferably, halogenating agent is a chlorinating agent selected from thionyl chloride or phosphorus pentachloride and said (4-halomethyl-phenoxy)-ethyl-hexamethylene imine-1-yl is (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl.
Another aspect of the present invention provides the conversion of (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl to Bazedoxifene or its pharmaceutically acceptable salt by a process comprising the steps of,
a) condensing (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof with 5-Benzyloxy-2-(4-benzyloxy phenyl)-3 -methyl-1 H-indole in

presence of base selected from sodium hydride, potassium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or mixture thereof at a temperature of -10 to 10°C to obtain a reaction mixture containing 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yI-ethoxy)-benzyl]-lH-indole, hydroxy protected intermediate;
b) isolating said hydroxy protected intermediate; and
c) debenzylating said hydroxy protected intermediate to obtain Bazedoxifene or its pharmaceutically acceptable salt.
Preferably hydroxy protected intermediate is isolated from the reaction mixture by treating the reaction mixture with about 10 to 30 volumes of methanol and wherein isolated 5-BenzyIoxy-2-(4-benzy]oxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine -l-yl-ethoxy)-benzyl]-lH-indole, hydroxy protected intermediate is characterized by X-ray diffraction pattern having peaks at 2-theta values of about 5.3, 10.5, 13.1, 15.6 and 21.4 degrees.
Another aspect of the present invention provides a process for purification of hydroxy protected intermediate comprising the steps of,
a) treating hydroxy protected intermediate with first solvent selected from ethyl acetate, methyl acetate, propyl acetate, butyl acetate or water at reflux temperature to obtain a reaction mixture;
b) optionally treating said reaction mixture with activated charcoal;
c) adding second solvent selected from hexane, pentane or heptane in a dropwise manner to the mixture obtained in step a) or b) to isolate pure 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, hydroxy protected intermediate having purity of more than 97%.
Preferably, 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-hexamethylene imine-1 -yl-ethoxy)-benzyl]-1H-indole, hydroxy protected intermediate is characterized by X-ray diffraction pattern having peaks at 2-theta values of about 5.3,

10.5, 13.1, 15.6 and 21.4 degrees.
Preferably, the pharmaceutically acceptable salt is Bazedoxifene acetate.
Another aspect of the present invention provides a process for debenzylation of hydroxy protected intermediate comprising the steps of,
a) subjecting hydroxy protected intermediate to hydrogenation reaction in presence of 10% w/w Pd/C, solvent selected from ethanol, methanol, n-propanol, isopropanol, ethyl acetate, methyl acetate or mixture thereof at 20 to 40°C and 50 psi pressure for about 4 hours to obtain a reaction mixture;
b) filtering the reaction mixture followed by treating the obtained filtrate with L-ascorbic acid and 0.9 - 1.1 moles of glacial acetic acid to obtain a mixture;
c) seeding the mixture obtained in step b) with Bazedoxifene acetate Form A followed by strring the obtanined mixture under nitrogen atmosphere to obtain Bazedoxifene acetate Form A.
Another aspect of the present invention provides Bazedoxifene or pharmaceutically acceptable salt thereof substantially free of compound selected from 2-(4-hydroxyphenyl-3-methyl-lH-indol-5-ol and l-(4-hydroxybenzyl)-2-(4-hydroxy phenyl)-3-methyl-lH-indol-5-ol.
Brief Description of the Drawings:
Fig. 1: XRPD of hydroxy protected intermediate (7) of Bazedoxifene obtained
according to US6005102.
Fig. 2: XRPD of hydroxy protected intermediate (7) of Bazedoxifene obtained by the
process of the present invention.
Fig. 3: XRPD of Bazedoxifene acetate obtained by the process of the present
invention.
Detailed description of the invention:
The present invention relates to a simple, commercially viable and improved process for the preparation of Bazedoxifene or pharmaceutically acceptable salts thereof.

According to one embodiment of the present invention, there is provided a process for preparation of Bazedoxifene or pharmaceutically acceptable salt thereof comprising the steps of,
a) alkylating 4-hydroxy benzyl alcohol with 2-chloroethyl hexamethyleneimine or salt thereof in presence of a base and chlorinated hydrocarbon to obtain 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) or its salt;
b) treating compound (4) or its salt with a halogenating agent in an ester solvent optionally in presence of catalyst to obtain (4-haIomethyl-phenoxy)-ethyl-hexamethyleneimine-1-yl or salt thereof; and
c) converting (4-halomethyl-phenoxy)-ethyl-hexamethyleneimine-1 -yl or salt thereof to Bazedoxifene or pharmaceutically acceptable salt thereof.
Alkylation step is carried out in the presence of a phase transfer catalyst selected from quaternary ammonium salt such as tetrabutyl ammonium bromide, benzyltrimethylammonium chloride, benzyltriethylammonium chloride or methyltrioctylammonium chloride preferably tetrabutyl ammonium bromide. Other phase transfer catalyst which can be used is selected from tetrabutyl ammonium chloride, benzyl tributyl ammonium chloride, benzyl triethyl ammonium bromide, tetraethyl ammonium bromide, tetraethyl ammonium chloride or acetyl trimethyl ammonium bromide. The base used is selected from sodium hydroxide, potassium hydroxide, ammonia, sodium hydride, potassium hydride, potassium tertiary butoxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, cesium hydroxide or mixture thereof. Chlorinated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride, chloroform or the like, preferably methylene dichloride.
According to a preferred embodiment of the present invention, 4-hydroxy benzyl alcohol is alkylated with 2-chloroethyl hexamethyleneimine hydrochloride in the presence of sodium hydroxide, benzyl triethylammonium chloride or tetrabutyl ammonium bromide and methylene dichloride. This mixture is stirred at 20 to 40°C, preferably at 25 to 30°C for 24 hours. After the completion of the reaction, the layers

are separated. The organic layer is washed with about 2-10% aqueous solution of a base, preferably 4% solution to remove unreacted 4-hydroxy benzyl alcohol, followed by washing with water and brine. The organic layer is dried over anhydrous sodium sulphate and concentrated to obtain 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) as a yellowish brown oil. The obtained yellowish brown oil can be used for the next step without further purification.
The base used for washing the organic layer is selected from sodium hydroxide, potassium hydroxide or calcium hydroxide preferably sodium hydroxide,
Prior art discloses the use of toluene as organic solvent in the alkylation step. It is found that use of toluene results in emulsion formation during the work-up. It takes longer time for separation of the layers. In the present invention, methylene dichloride (MDC) is used which facilitates the reaction at room temperature. Further the use of methylene dichloride (MDC) enables easy separation. The obtained oil can be used for the farther reaction without any further purification.
4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) thus obtained is treated with a salt forming agent to convert compound (4) to the corresponding salt. Salt forming agent is selected from HC1, HBr, ammonium chloride, thionyl chloride or the like, preferably HCI. Preferably, 4-(2-hexamethyleneimine-1 -yl-ethoxy)-benzyl alcohol (4) is dissolved in a suitable solvent selected from ether, water or mixture thereof to obtain a solution. Ether is selected from tetrahydrofuran (THF), 1,4-dioxane, diethyl ether, methyl-t-butyl ether or diisopropyl ether preferably tetrahydrofuran (THF). Gaseous HCI is bubbled through the solution at 20 to 40°C, preferably at 25 to 30°C till pH 2 to 3 is achieved. A white precipitate is formed which is filtered, washed and dried. The obtained compound (4a) is further dried, if required, in hot air oven at 60-70°C for about 6 to 9 hours, preferably for 7 to 8 hours. The obtained compound (4a) can be used as such in the next step without further purification.
4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) or salt thereof is converted

to 4-(halomethyl-phenoxy)-ethyl-hexamethyleneimine-l-yI or salt thereof by treating 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) or its salt with a halogenating agent in an ester solvent optionally in presence of catalyst. Halogenating agent is selected from chlorinating agent or brominating agent preferably chlorinating agent. Chlorinating agent used is selected from phosphorus pentachloride or thionyl chloride, preferably thionyl chloride. 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol (4) or salt thereof, in particular its hydrochloride salt (4a) is suspended in an ester solvent to obtain a suspension. This suspension is optionally treated with catalytic amount of dimethylamino pyridine or dimethyl formamide, preferably dimethylamino pyridine at temperature of 10 to 25°C, preferably at 15 to 20°C followed by addition of thionyl chloride in a drop wise manner to obtain a suspension. The temperature of the suspension increases to about 30-50°C, preferably 35-40°C. After complete addition, the temperature is increased gradually and mixture is stirred for 0.5 to 2 hours at a temperature of about 40 to 70°C, preferably at 50-65°C until a clear solution is obtained. The mixture is filtered through hyflo-bed. The filtrate is concentrated to remove excess thionyl chloride followed by stripping of the oily residue with an organic solvent selected from ester or ether, preferably ester to remove traces of thionyl chloride. The residue is cooled to room temperature followed by the addition of a suitable solvent selected from ester or ether to obtain a solid which is filtered, washed and dried to get (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-1-yl hydrochloride (5) as a free flowing solid.
(4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-1-yl hydrochloride (5) thus obtained is converted to Bazedoxifene or pharmaceutically acceptable salt thereof.
Ester is selected from ethyl acetate, methyl acetate, propyl acetate or butyl acetate preferably ethyl acetate. Ether is selected from tetrahydrofuran (THF), diethyl ether, diisopropyl ether, methyl t-butyl ether or 1,4-dioxane preferably tetrahydrofuran (THF). The addition of dimethyl amino pyridine or dimethyl formamide in catalytic amount increases the rate of reaction and the reaction tends to complete within 3 to 4 hours.

Use of ester solvent enables precipitation of compound (5) in high yield. Besides, traces of thionyl chloride are removed by stripping using ester solvent and the product obtained is substantially free of thionyl chloride. Compound (5) is practically insoluble in ester solvent and hence can be separated easily thereby making the process industrially viable.
Another embodiment of the present invention provides conversion of (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-1-yl to Bazedoxifene or pharmaceutically acceptable salt thereof by a process comprising the steps of,
a) condensing (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof with 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (6) in presence of base to obtain a reaction mixture containing 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, hydroxy protected intermediate (7);
b) isolating the hydroxy protected intermediate (7); and
c) debenzylating the hydroxy protected intermediate to obtain Bazedoxifene or pharmaceutically acceptable salt thereof.
The base used is selected from sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixture thereof. Suitable solvent used is selected from polar aprotic solvent, hydrocarbon, water or mixture thereof. Polar aprotic solvent is selected from dimethyl formamide, dimethyl acetamide, dichloromethane, tetrahydrofuran or dimethyl sulfoxide, preferably dimethyl formamide. Hydrocarbon is selected from aliphatic or aromatic hydrocarbon such as hexane, pentane, heptane, toluene or xylene.
In a preferred embodiment, (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or its salt, in particular hydrochloride salt (5) is condensed with 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole (6) in the presence of sodium hydride and dimethyl formamide to get the hydroxy protected intermediate, 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1 -[4-(2-hexamethyleneimine-1 -yl-ethoxy)-benzyl]- 1H-

indole (7). To a solution of 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole (6) in dimethyl formamide is added sodium hydride in a lot-wise manner at temperature of-10 to 10°C, preferably 0 to 5°C. After the completion of addition, the mixture is stirred for 30 to 90 min, preferably 45 to 60 min. (4-chloromethyl-phenoxy)-ethyI-hexamethyleneimine-1-yl or its hydrochloride (5) is added to the reaction mixture in portions by maintaining the temperature between 0 to 10°C. After the addition is complete, the temperature of the resulting mixture is allowed to reach 25-30°C and stirred at the same temperature for about 2 hours till the completion of reaction. The reaction mixture is then diluted with 1-3 volumes of alcohol, preferably 2 volumes of alcohol for the decomposition of sodium hydride maintaining the temperature at 0 to 10°C followed by stirring at the same temperature for 20 to 60 minutes, preferably for 45 minutes to obtain a reaction mixture. The reaction mixture is further diluted with 15 to 20 volumes, preferably 18 volumes of alcohol and stirred at 20 to 40°C, preferably at 25 to 30°C for 10 to 15 hours, preferably for 12 hours to precipitate the product. The product thus obtained is filtered, washed with 0.5 to 1.5 volumes of methanol, preferably 1 volume of methanol followed by slurry wash with water and hydrocarbon solvent.
Suitable solvent used for work up procedure such as extraction or washing is selected from alcohol, hydrocarbon, water or mixture thereof. Alcohol used is selected from C1-C4 alcohol such as methanol, ethanol, n-propanol or isopropyl alcohol, preferably, methanol. Hydrocarbon is selected from aliphatic or aromatic hydrocarbon such as hexane, pentane, heptane, toluene or xylene.
Prior art discloses the use of ethyl acetate for the extraction of hydroxy protected intermediate. The disadvantage with the prior art process is that the hydroxy protected intermediate obtained is only about 85 % pure which further affects the purity of the final product. The present invention involves the use of alcohol for the isolation of the hydroxy protected intermediate by precipitation. The process of the present invention provides hydroxy protected intermediate having purity of more than 95%.
Preferably hydroxy protected intermediate (7) is purified by a process comprising the

steps of,
a) treating hydroxy protected intermediate (7) with a suitable solvent to get a solution; and
b) isolating pure hydroxy protected intermediate (7). ,
According to a more preferred embodiment, the present invention provides the purification of hydroxy protected intermediate, 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-hexamethyleneimine-1 -yl-ethoxy)-benzyl]-1 H-indole (7) by a process comprising the steps of, treating compound (7) with a first solvent at reflux temperature, preferably at 70-75°C. Optionally, activated charcoal (about 2-5% w/w) is added to the mixture and stirred for about 10-25 min, preferably for 15-20 min. The resulting hot mixture is filtered through hyflo bed. The filtrate is cooled to room temperature. A second solvent is added to the filtrate in a dropwise manner and the mixture is stirred for 1-4 hours, preferably for 2-3 hours to precipitate the solid. The obtained solid is filtered, washed with solvent and dried. The hydroxy protected intermediate compound (7) obtained according to present invention is substantially pure having purity of more than 97%. Purification improves the appearance of the hydroxy protected intermediate (7).
The first solvent used is selected from ester, water or mixture thereof. Ester is selected from ethyl acetate, methyl acetate or butyl acetate. Second solvent is selected from hydrocarbon such as hexane, pentane or heptane preferably hexane.
Another embodiment of the present invention provides a novel polymorph of hydroxy protected intermediate, 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1 -[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole (7). The hydroxy protected intermediate (7) obtained according to present invention is characterized by a X-ray diffraction pattern as represented in Fig. 2. It is further characterized by X-ray diffraction pattern having characteristic peaks expressed as 2-theta values of about 5.3, 10.5, 13.1, 15.6 and 21.4 deg. The relative intensities of the peaks can vary, depending upon the sample preparation technique, the sample mounting procedure and particular instrument employed.

5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH indole (7) obtained by following Example 12 of US6005102 is characterized by X-ray powder diffraction pattern as shown in Fig 1.
The inventors of the present invention have surprisingly found that use of hydroxy protected intermediate (7) having purity more than about 95% reduces the debenzylation reaction time. Debenzylation reaction as described in the prior art requires about 48 hours. In the process of the present invention, debenzylation is carried out at a temperature of 20 to 40°C, preferably 25 to 30°C in about 4 to 5 hours.
The debenzylation of hydroxy protected intermediate (7) is carried out by catalytic hydrogenation followed by treatment with an antioxidant and acetic acid to obtain Bazedoxifene acetate. Optionally seeding can be carried out using crystals of Bazedoxifene acetate Form A or Form B, preferably Form A. It has been found that immediate seeding of the reaction mixture with Bazedoxifene acetate Form A crystals help in controlling the contamination due to Form B. Debenzylation of hydroxy protected intermediate is carried out by a process comprising the steps of,
a) subjecting hydroxy protected intermediate to hydrogenation reaction in presence of 10% w/w Pd/C, solvent selected from ethanol, methanol, n-propanol, isopropanol, ethyl acetate, methyl acetate or mixture thereof at 20 to 40°C and 50 psi pressure for about 4 hours to obtain a reaction mixture;
b) filtering the reaction mixture followed by treating the obtained filtrate with L-ascorbic acid and 0.9 to 1.1 moles of glacial acetic acid to obtain a mixture; and
c) seeding the mixture obtained in step b) with Bazedoxifene acetate Form A to obtain Bazedoxifene acetate Form A.
Hydroxy protected intermediate (7), alcohol and suitable catalyst are charged into a hydrogenation vessel. Catalyst is used in an amount of about 10 to 30% w/w, preferably 10% w/w with respect to the hydroxy protected intermediate (7). The hydrogenation is carried out at a temperature of about 20 to 40°C, preferably 25-35°C at 45 to 55 psi, preferably 50 psi pressure for 3 to 5 hrs, preferably for 4 to 4.5 hrs.

The progress of reaction is monitored by TLC. The debenzylation reaction is completed in about 4 hours. After the completion of the reaction, the mixture is filtered through hyflo-bed and subsequently rinsed with alcohol, preferably ethanol (denatured with 5% v/v ethyl acetate). The filtrate containing Bazedoxifene base is treated with antioxidant and transferred to another flask under nitrogen to prevent air-oxidation of the filtrate containing the debenzylated compound. Glacial acetic acid is added dropwise at 20 to 40°C, preferably at 25-30°C to the filtrate. The filtrate is stirred for 10 to 30 minutes, preferably for 20 minutes followed by seeding with Bazedoxifene acetate Form A immediately to obtain a mixture. The resulting mixture is stirred overnight under nitrogen atmosphere at the same temperature. The mixture is cooled to a temperature of-10 to 10°C, preferably 0-5°C and maintained at the same temperature to obtain a solid. The resulting solid is isolated, washed with cold alcohol or mixture of alcohol with an ester and dried at 60 to 75°C, preferably at 65 to 70°C till LOD of less than 1% is achieved. Preferably a chilled mixture of ethanol (95%) and ethyl acetate (5%) is used.
Suitable catalyst used for the debenzylation of the hydroxy protected intermediate is selected from palladium/carbon (Pd/C), platinum/carbon or oxides thereof supported on various supports such as carbon, alumina and the like. Suitable antioxidant is selected from L-ascorbic acid, sodium ascorbate, ascorbyl palmitate, citric acid, propyl gallate, alpha tocopherol (vitamin E), vitamin E acetate, butylated hydroxytoluene, butylated hydroxyanisole or mixture thereof.
About 0.9-1.1, preferably 0.95-1.05 moles of Glacial acetic acid with respect to hydroxy protected intermediate is used for salt formation.
Prior art reports that Form A can easily convert to Form B upon contact with ethanol. During the process for preparation of Bazedoxifene acetate Form A, it is possible that Form A may get contaminated with Form B or Form A can partially transform into Form B in the presence of solvent. In order to avoid this contamination or transformation, immediate seeding is performed on the reaction mixture after treatment with ascorbic acid and glacial acetic acid. It has been surprisingly found by

the inventors of the present invention that immediate seeding produce stable Bazedoxifene acetate Form A. Bazedoxifene acetate Form A obtained by the process of the present invention is substantially free of Form B and is highly stable.
Another embodiment of the present invention provides a process for purification of Bazedoxifene acetate comprising the steps of,
a) treating Bazedoxifene acetate with an alcohol in presence of antioxidant to obtain a reaction mixture;
b) optionally filtering the reaction mixture obtained in step a);
c) treating the mixture obtained in step b) with an ester solvent followed by subjecting the obtained mixture to immediate seeding with Bazedoxifene acetate Form A; and
d) isolating pure Bazedoxifene acetate Form A.
Alcohol is selected from ethanol, methanol, n-propanol, isopropanol. Antioxidant is selected from L-ascorbic acid, sodium ascorbate, ascorbyl palmitate, citric acid, propyl gallate, alpha tocopherol (vitamin E), Vitamin E acetate, butylated hydroxytoluene or butylated hydroxyanisole. Ester solvent is selected from ethyl acetate, methyl acetate, propyl acetate, butyl acetate or the like.
In a preferred embodiment, a mixture of Bazedoxifene acetate, 8 to 12 volumes of ethanol, preferably 10 volumes of ethanol (denatured with 5% v/v of ethyl acetate) with respect to Bazedoxifene acetate and L-ascorbic acid is refluxed to obtain a clear solution. The solution is stirred for 10 to 30 min, preferably 15-20 min and filtered through hyflo-bed to obtain a filtrate. The filtrate is washed with 0.5 to 2.5 volumes of hot ethanol, preferably 1-2 volumes of hot ethanol and is further treated with ethyl acetate at temperature of about 40 to 60°C, preferably 50°C followed by addition of seeds of Bazedoxifene acetate Form A. This mixture is stirred at 25 to 30°C for 1 to 4 hours, preferably for 2-3 hours. This mixture is cooled to 0-5°C and maintained at the same temperature for 10 to 30 minutes, preferably for 15 to 20 min to obtain a solid. The obtained solid is filtered, washed with a mixture of ethanol (95%) and ethyl acetate (5%) and dried till LOD less than 1% is achieved to obtain pure Bazedoxifene

acetate. Preferably about 0.5 to 1% w/w of L-ascorbic acid is used.
Preferably Bazedoxifene acetate obtained by following the process of the present invention is polymorph Form A. Pure Bazedoxifene acetate obtained according to present invention is substantially free of other forms and has chemical purity of more than 99% with all known impurities below 0.15% and unknown impurities below 0.1%.
Prior art discloses the purification of Bazedoxifene by column chromatography which is not viable on a commercial scale as it is time consuming and expensive. The present process provides purification using alcohol to obtain Bazedoxifene acetate in high yield and purity.
Bazedoxifene acetate Form A obtained according to the present invention is characterized by X-ray powder diffraction pattern as shown in Fig. 3. Bazedoxifene acetate Form A is further characterized by peaks expressed as 2-theta at about 12.7, 15.2, 16.0, 17.1, 18.5, 18.8, 20.3, 20.7, 22.3 and 23.6 degrees. Form A is identified by one or more solid state analytical methods.

Scheme III
The process for preparation of Bazedoxifene acetate according to the present invention is illustrated in Scheme III below,

5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-lH-indole(6) used in the condensation reaction is prepared by the Bischler method or by any known method. The preparation process comprises refluxing 2-bromo-4'-benzyloxypropiophenone and 4-benzyloxyaniline hydrochloride in N,N-dimethylformamide to get compound (6).
Another embodiment of the present invention provides Bazedoxifene or pharmaceutially acceptable salt thereof substantially free of compound selected from 2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol (9) and l-(4-hydroxy benzyl)-2- (4-hydroxyphenyl)-3-methyl-lH -indol-5-ol (10).

2-(4-hydroxyphenyl)-3-methyl-1 H-indol-5-ol and 1 -(4-hydroxybenzyl)-2-(4-hydroxy phenyl)-3-methyl-lH-indol-5-ol are the impurities produced during the synthesis or debenzylation step. The process of the present invention produces pure hydroxy protected intermediate which helps in reducing the time required for debenzylation reaction. In the process of the present invention, the debenzylation reaction is carried out at a temperature of about 25 to 30°C in about 5 hours. The process of the present invention provides substantially pure Bazedoxifene or pharmaceutically acceptable salt thereof wherein these impurities are controlled well below 0.15% thus complying with the ICH guidelines.
Another embodiment of the present invention provides pharmaceutical composition comprising Bazedoxifene acetate, prepared by the process of the present invention. Bazedoxifene acetate obtained by the process of the present invention can be combined with a pharmaceutically acceptable carrier to form suitable pharmaceutical compositions, used for treatment of postmenopausal osteoporosis in women at increased risk of fracture.

Another embodiment of the present invention provides Bazedoxifene acetate such that 90% of the particles have particle size less than or equal to 500 microns, preferably less than or equal to 300 microns, more preferably less than or equal to 100 microns. Bazedoxifene acetate particles can be further micronized by conventional methods to obtain reduced particles having particle size such that 90% of the particles have particle size less than or equal to 20 microns, preferably less than or equal to 10 microns.
Unless otherwise indicated, the following definitions are set forth to illustrate and
define the meaning and scope of the various terms used to describe the invention
herein,
The term "substantially pure or substantially free" means Bazedoxifene acetate
having less than about 1 %, preferably less than about 0.5%, more preferably Jess than
about 0.3%, most preferably less than about 0.15% of undesired impurities or other
polymorphic forms.
The term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
The term "debenzylation" means removal of benzyl group from a compound having functional groups protected by benzyl protecting groups.
The term "room temperature" means the temperature from about 10°C to 45°C, preferably 25°C to 35°C.
The term "micronization" means a process or method by which the size of particles are reduced.
The term "pharmaceutically acceptable" means that which is useful in preparing a pharmaceutical composition that is generally non-oxic and is not biologically undesirable and includes that which is acceptable for human pharmaceutical use. X-ray powder diffraction pattern are obtained on Xpert'PRO, PANalytical, diffractometer equipped with accelerator detector using Copper Ka (n - 1.5406 Ao)

radiation with scanning range between 2-theta 4-50° at a scanning speed of 27min.
The following examples are for illustrative purposes only and are not intended to limit the scope of the invention in any way.
Examples:
Example 1: 4-(2-hexamethyleneimine-l-yI-ethoxy)-benzyl alcohol (4):
500 gm of 4-hydroxy benzyl alcohol (4 mol) was dissolved in 5N sodium hydroxide solution (9.3 L) to obtain a solution. 5 L of methylene dichloride (MDC) was added to the solution followed by addition of 2-chloroethyl hexamethyleneimine hydrochloride (795gm, 4 mol) and tetrabutyl ammonium bromide (22.5 g). The obtained mixture was stirred at temperature of 25 to 30°C for 24 hrs. After completion of reaction, the layers were separated. Aqueous layer was extracted with MDC (2 x 2.5L). The combined MDC layers were washed with 4% of sodium hydroxide solution (2.0 L) followed by washing with water (3.0 L), brine (3.0 L) and dried over anhydrous sodium sulphate. The obtained solution was evaporated on rotary evaporator to get the title compound as yellowish brown oil. Yield: 715g, 71%
Benzyl triethylammonium chloride can be used in place of tetrabutyl ammonium bromide.
Example 2
4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol hydrochloride (4a)
The obtained oil (715gm) from example 1 was dissolved in 3.6L of THF to get a solution. Gaseous HC1 was bubbled through the solution at 25-30°C for 3-4 hrs till pH of 2-3 was achieved. The white solid which precipitated out was filtered, washed with THF and suck dried. The product was further dried in hot air oven at 60-70°C for 7- 8 hours to yield the titled compound. Yield: 872 gm, 95%
Example 3a
(4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l- yl hydrochloride (5)
100gm of 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol hydrochloride (0.35 mol) was suspended in 300ml of ethyl acetate and stirred at 15-20°C. Thionyl chloride

(38.4ml; 0.52 mol) was added in a dropwise manner at the same temperature to the obtained suspension. The temperature was allowed to increase upto 35 to 40°C. After complete addition, the temperature was gradually increased. The reaction mixture was stirred at 60-65°C for 0.5 to 2 hrs till clear solution was obtained. The mixture was filtered through a hyflo-bed. The obtained clear solution was concentrated to remove excess thionyl chloride followed by stripping with ethyl acetate twice to remove traces of thionyl chloride. The residue was cooled to room temperature followed by addition of ethyl acetate. The mixture was stirred at room temperature. The resulting solid was filtered and washed with ethyl acetate. The wet solid was suck dried, air dried and further dried at 60- 65 °C for 3-4 hours to get the titled compound. Yield: 90gm, 85%.
Example 3b
(4-chloromethyl-phenoxy)-ethyl-hexamethyIeneimine-l- yl hydrochloride (5)
100gm of 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol hydrochloride (0.35 mol) was suspended in 300ml of ethyl acetate and stirred at 15-20°C. Catalytic amount of dimethyl amino pyridine (1 gm) was added to the obtained suspension followed by addition of thionyl chloride (38.4ml; 0.52 mol) in a dropwise manner at the same temperature to the obtained suspension. The temperature was allowed to increase upto 35 to 40°C. After complete addition, the temperature was gradually increased. The reaction mixture was stirred at 50-55°C for 0.5 to 2 hrs till clear solution was obtained. The mixture was filtered through a hyflo-bed. The obtained clear solution was concentrated to remove excess thionyl chloride followed by stripping with ethyl acetate twice to remove traces of thionyl chloride. The residue was cooled to room temperature followed by addition of ethyl acetate. The mixture was stirred at room temperature. The resulting solid was filtered and washed with ethyl acetate. The wet solid was suck dried, air dried and further dried at 60- 65 °C for 3-4 hours to get the titled compound. Yield: 90gm, 85%.
Example 4: 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-l-[4-(2-hexamethylene imine-l-yl-ethoxy)-benzyl]-lH-indole(7)
A solution of 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyI-lH-indole (200 gm, 0.47

mol) (6) in DMF (800ml) was prepared and stirred. 100gm of sodium hydride (60% suspension in mineral oil) was added in a lot wise manner at 0 to 5 °C to the above solution. After complete addition, the mixture was stirred for 45 min to 60 min. (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl hydrochloride (196 gm, 0.64 mol) was added to the reaction mixture in portions and the temperature was maintained between 0 to 10°C. After complete addition, the temperature of the reaction mixture was allowed to reach 25-30°C and the mixture was stirred at the same temperature for 2 hours till completion of reaction. The obtained mixture was diluted with 2 volumes of methanol for decomposition of sodium hydride, maintaining the temperature at 0-10°C and stirred at the same temperature for 45 minutes. The reaction mixture was further diluted with 18 volumes of methanol and stirred at 25-30°C for 10-12 hours to precipitate the solid. The obtained solid was filtered, washed with 1 volume of methanol. The wet cake was slurry washed with 4L of water followed by 2L of hexane. The obtained solid was suck dried, air dried and then dried in oven at 60-70°C for 8 to 10 hours to get the titled product. Yield: 205gm, 66%; Purity: more than 95%.
Example 5
Purification of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexa
methyleneimine-l-yl-ethoxy)-benzyl]-lH-indole
A solution of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethylene imine-l-yl-ethoxy)-benzyl]-1H-indole (205gm) was prepared in ethyl acetate (800ml) under heating at 70-75°C and charcoalized. The reaction mixture was stirred for 15-20 minutes. The reaction mixture was filtered through hyflo bed. The obtained filtrate was transferred to a flask and cooled to room temperature. 1.6L of hexane was added to the obtained filtrate in dropwise manner followed by stirring the mixture for 2-3 hours to precipitate out the solid. The obtained solid was filtered, washed with hexane and air dried. The product was dried at 60-65°C for 4-6 hrs. Yield: 180gm, 90%; Purity: more than 97%.

Example 6: 2-(4-Hydroxyphenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl)-1H-indol-5-ol acetate [Bazedoxifene acetate] (1)
5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole (125 gm, 0.19mol) is subjected to debenzylation in presence of ethanol (denatured with 5% v/v of ethyl acetate) (1.4L) and 10 % palladium on carbon (12.5 gm) at 25-35 °C at 50 psi pressure for 4 - 4.5 hr in a 2 L hydrogenation vessel. After the completion of reaction, the mixture was filtered through hyflo-bed, which was subsequently rinsed with 125ml of ethanol (denatured with 5% v/v ethyl acetate). The filtrate was treated with 0.52 gm of L-ascorbic acid (0.003 mol) and transferred to another round bottom flask under nitrogen. 10.5 ml of Glacial acetic acid (0.184 M) was added to the resulting mixture in a dropwise manner at temperature of 25-30°C. The mixture was stirred for 20 minutes followed by seeding with bazedoxifene acetate Form A and stirred overnight under nitrogen atmosphere at same temperature. The mixture was cooled to 0 to 5°C and maintained at the same temperature for 2 hours to get a solid. The resulting solid was isolated and washed with 125 ml of chilled ethanol (denatured with 5% v/v ethyl acetate) and suck air dried. The product was then vacuum dried at 65 to 70°C till LOD less than 1% was achieved. Yield: 82gm, 91%; Purity: more than 99%.
Example 7: Purification of Bazedoxifene acetate
Crude bazedoxifene acetate (82gm) was stirred in 820 ml ethanol. 0.5% w/w L-ascorbic acid was added to the mixture and refluxed to get a clear solution. The solution was stirred for 15-20 minutes and then filtered through hyflo bed. The hyflo bed was washed with 1-2 vol (82 ml) of hot ethanol. The filtrate was transferred to another reactor followed by addition of 45 ml of ethyl acetate and the temperature was allowed to reach 50°C. The reaction mixture was seeded with Bazedoxifene acetate Form A and stirred at 25-30°C for 2-3 hrs. The mixture was cooled to 0-5°C and maintained at the same temperature for 15 to 20 minutes. The obtained solid was then filtered, washed with 82 ml of chilled ethanol (denatured with 5% v/v ethyl acetate) and dried. The product was dried at 65-70 °C under vacuum till LOD less than 1% was achieved. Yield: 65gm, 80%; Purity:more than 99.5%

We claim,
1. A process for preparation of Bazedoxifene or pharmaceutically acceptable salt
thereof comprising the steps of,
a) alkylating 4-hydroxy benzyl alcohol with 2-chloroethyl hexamethylene imine or salt thereof in the presence of a base and chlorinated hydrocarbon to obtain 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol or its salt;
b) treating 4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl alcohol or its salt with a halogenating agent in an ester solvent optionally in presence of catalyst to obtain (4-halomethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof;
c) converting (4-halomethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof to Bazedoxifene or pharmaceutically acceptable salt thereof.

2. The process as claimed in claim 1, wherein said chlorinated hydrocarbon is selected from methylene dichloride, ethylene dichloride, carbon tetrachloride or chloroform; said ester solvent is selected from ethyl acetate, methyl acetate, propyl acetate or butyl acetate; said base is selected from sodium hydroxide, potassium hydroxide, ammonia, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, cesium hydroxide or mixture thereof.
3. The process as claimed in claim 1, wherein said alkylation is carried out at a temperature of 25 to 30°C in presence of phase transfer catalyst selected from tetrabutyl ammonium bromide, benzyltrimethyl ammonium chloride, benzyltriethylammonium chloride or methyl trioctylammonium chloride; and said treatment with halogenating agent is carried out optionally in presence of catalytic amount of dimethyl amino pyridine or dimethyl formamide.
4. The process as claimed in claim 1, wherein said halogenating agent is a chlorinating agent selected from thionyl chloride or phosphorus pentachloride

and said (4-halomethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl is (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-1 -yl.
5. The process as claimed in claim 4, wherein said conversion of (4-
chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl to Bazedoxifene or its
pharmaceutically acceptable salt is carried out by a process comprising the
steps of,
a) condensing (4-chloromethyl-phenoxy)-ethyl-hexamethyleneimine-l-yl or salt thereof with 5-Benzyloxy-2-(4-benzyloxy phenyl)-3-methyl-lH-indole in presence of base selected from sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide or mixture thereof at a temperature of -10 to 10°C to obtain a reaction mixture containing 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1 -[4-(2-hexamethylene imine-l-yl-ethoxy)-benzyl]-1H-indole, hydroxy protected intermediate;
b) isolating said hydroxy protected intermediate; and
c) debenzylating said hydroxy protected intermediate to obtain Bazedoxifene or its pharmaceutically acceptable salt.

6. The process as claimed in claim 5, wherein said isolation of hydroxy protected intermediate from the reaction mixture is carried out by treating the reaction mixture with 10 to 30 volumes of methanol and wherein isolated 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole, hydroxy protected intermediate is characterized by X-ray diffraction pattern having peaks at 2-theta values of about 5.3, 10.5, 13.1, 15.6 and 21.4 degrees.
7. The process as claimed in claim 6, wherein said hydroxy protected intermediate is further purified by a process comprising the steps of,
a) treating hydroxy protected intermediate with first solvent selected from

ethyl acetate, methyl acetate, propyl acetate, butyl acetate or water at reflux temperature to obtain a reaction mixture;
b) optionally treating said reaction mixture with activated charcoal;
c) adding second solvent selected from hexane, pentane or heptane in a dropwise manner to mixture from step a) or b) to isolate pure 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-l-[4-(2-hexamethylene imine-1-yl-ethoxy)-benzyl]-1 H-indole, hydroxy protected intermediate having purity of more than 97%.

8. 5-Benzyloxy-2-(4-benzyIoxy-phenyl)-3-methyl-1 -[4-(2-hexamethyleneimine-l-yl-ethoxy)-benzyl]-lH-indole(hydroxy protected intermediate) characterized by X-ray diffraction pattern having peaks at 2-theta values of about 5.3, 10.5, 13.1, 15.6 and 21.4 degrees.
9. The process as claimed in claim 5, wherein said pharmaceutically acceptable salt is Bazedoxifene acetate and said debenzylation of hydroxy protected intermediate is carried out by a process comprising the steps of,

a) subjecting hydroxy protected intermediate to hydrogenation reaction in presence of 10% w/w Pd/C, solvent selected from ethanol, methanol, n-propanol, isopropanol, ethyl acetate, methyl acetate or mixture thereof at 20 to 40°C and 50 psi pressure for about 4-5 hours to obtain a reaction mixture;
b) filtering said reaction mixture followed by treating the obtained filtrate with L-ascorbic acid and 0.9-1.1 moles of glacial acetic acid to obtain a mixture;
c) seeding the mixture obtained in step b) with Bazedoxifene acetate Form A followed by stirring the obtained mixture under nitrogen atmosphere to obtain Bazedoxifene acetate Form A.

10. Bazedoxifene or pharmaceutically acceptable salt thereof substantially free of compound selected from 2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol and 1-(4-hydroxybenzyl)-2-(4-hydroxyphenyl)-3-methyl-lH-indol-5-ol.