DESC:
CROSS REFERENCE TO RELATED APPLICATION

This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201941024569, filed on June 20, 2019, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Bazedoxifene acetate and its intermediates, in high yield and purity. The present invention further relates to novel, commercially viable and consistently reproducible processes for the preparation of highly pure crystalline Form B of Bazedoxifene acetate.

BACKGROUND OF THE INVENTION
U.S. Patent No. US 5,998,402 (hereinafter referred to as the US‘402 patent) discloses 2-phenylindole derivatives, pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are estrogen agonists/antagonists useful for the treatment of diseases associated with estrogen deficiency. Among them, Bazedoxifene acetate, chemically named as 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxy-phenyl)-3-methyl-1H-indol-5-ol acetate, is a third generation estrogen receptor modulator used for the treatment of moderate to severe vasomotor symptoms associated with menopause and prevention of postmenopausal osteoporosis in combination with conjugated estrogens. Bazedoxifene acetate is represented by the following structural formula I:

Bazedoxifene acetate was developed by Pfizer and approved in the European Union under the brand name CONBRIZA and it is orally administered as tablets containing 20 mg of Bazedoxifene; and is approved in the United States in combination with conjugated estrogens under the brand name DUAVEE® and it is orally administered as tablets containing 0.45 mg/20 mg of conjugated estrogens/bazedoxifene.
Various processes for the preparation of Bazedoxifene acetate, its intermediates, and related compounds are described in U.S. Patent Nos. US 5,998,402; US 6,005,102; US 7,968,732; US 8,889,896; U.S. Patent Application Nos. US 2010/0087661A1; US 2012/0253038A1; PCT Publication Nos. WO 2011/022596A2; WO 2013/001511A1; WO 2014/186325A1; and Journal Articles: Drugs of the Future 2002, 27(2), 117-121; Journal of Medicinal Chemistry, 2001, 44, 1654-1657. According to the US’402 patent, Bazedoxifene acetate is prepared by a process as depicted in scheme-1:

A
S

As per the process exemplified in Example 7 of the US’402 patent, 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole is prepared by the following process steps: 2-bromo-1-(4-benzyloxyphenyl)-1-propanone is reacted with 4-benzyloxy aniline hydrochloride under nitrogen atmosphere in dimethylformamide to produce a reaction mass; triethylamine is added to the resulting mass and the reaction mass is heated to 120°C; after completion of reaction, the resulting mass is cooled and 4-benzyloxy aniline hydrochloride was added; the reaction mass is heated to 150°C for 2 hours and 4-benzyloxy aniline hydrochloride is added; the resulting mass is heated to 150°C for an additional 30 minutes, the reaction mixture is cooled to room temperature, followed by usual work up to produce 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole.
As per the process exemplified in Example 26 of the US’402 patent, {4-[5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-acetic acid ethyl ester is prepared by the following process steps: a pre-cooled solution of 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole in dimethylformamide is reacted with sodium hydride; the reaction mixture is stirred for 20 minutes and (4-chloromethyl-phenoxy)-acetic acid ethyl ester is added and stirred for 18 hours at room temperature; after completion of reaction, the resulting mass is subjected to usual work up procedure to produce {4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]phenoxy}-acetic acid ethyl ester.
As per the process exemplified in Example 38 of the US’402 patent, 2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol is prepared by the following process steps: a solution of Lithium aluminum hydride in tetrahydrofuran is added to a pre-cooled solution of {4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]phenoxy}-acetic acid ethyl ester in tetrahydrofuran at 0°C; and the resulting mass is maintained for 30 minutes at the same temperature followed by usual work up to produce 2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol.
As per the process exemplified in Example 50 of the US’402 patent, 5-Benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole is prepared by the following process steps: tetra-bromomethane and triphenyl phosphine are added to a solution of 2-{4-[5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-indol-1-ylmethyl]-phenoxy}-ethanol in tetrahydrofuran; the resulting mass is stirred for 3 hours and then concentrated and chromatographed on a silica gel using a gradient elution from ethyl acetate/hexane to produce 5-benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole.
As per the process exemplified in Example 64 of the US’402 patent, 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole is prepared, in an analogous manner to Example 63, by reacting 5-benzyloxy-2-(4-benzyloxy-phenyl)-1-[4-(2-bromo-ethoxy)-benzyl]-3-methyl-1H-indole in tetrahydrofuran with azepane, followed by heating the resulting mass to reflux; after 5 hours, the reaction mixture is subjected to usual work up to produce 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole.
As per the process exemplified in Example 99 of the US’402 patent, 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (Bazedoxifene free base) is prepared, in analogous manner to Example 97, by reducing 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-1H-indole under hydrogen pressure in the presence of 10% Palladium on Carbon in ethanol to produce the reaction mass, followed by stirring the resulting mixture for 48 hours. The catalyst was filtered through Celite and the reaction mixture was concentrated and chromatographed on silica gel using a gradient elution of methanol/dichloromethane to produce 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol.
As per the process exemplified in Example 98 of the US’402 patent, Bazedoxifene acetate is prepared by reacting 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol (Bazedoxifene free base) with acetic acid in acetone.
US Patent No. US 8,889,896 (hereinafter referred to as the US’896 patent) discloses a process for the preparation of Bazedoxifene acetate, which is depicted in the below Scheme-2:

US Patent No. US 6,005,102 (hereinafter referred to as US’102 patent) discloses a process for the preparation of 5-Benzyloxy-2-(4-benzyloxy-phenyl)-3-1-[4-(2-hexa methyleneimine-1-yl-ethoxy)-benzyl]-1H-indole (Bazedoxifene benzyl derivative), an intermediate of Bazedoxifene acetate, which is depicted in the below Scheme-3:

US Patent Application Publication No. US2012/0253038A1 (hereinafter referred to as the US’038 application) discloses a process for the preparation of Bazedoxifene acetate, which is depicted in the below Scheme 4:

Bazedoxifene acetate is known to exhibit polymorphism and various crystalline forms of Bazedoxifene acetate namely crystalline Form A, crystalline Form B, amorphous Form C, crystalline Form D, and anhydrous crystalline Form D have been reported in the literature.
US Patent No. US 7,683,051 B2 (hereinafter referred to as the US’051 patent) assigned to Wyeth, discloses crystalline Form A of Bazedoxifene acetate and a process for the preparation thereof. According to the US’051 patent, crystalline Form A of Bazedoxifene acetate is characterized by having characteristic XRPD peaks at about 12.7 and 18.5 ± 0.2 degrees 2-theta; Infrared spectrum in KBr comprising one or more characteristic IR bands at about 1511 cm-1, 1467 cm-1, and 1242 cm-1; and DSC thermogram showing an endotherm maximum at about 176°C. The US’051 patent further characterizes the crystalline Form A of Bazedoxifene acetate by additional XRPD 2-theta peaks at about 9.8, 15.2, 16.0, 17.1, 17.4, 18.8, 19.6, 20.4, 20.7, 22.3, 23.5, 24.9, 25.6, 26.1, 27.4, 28.0, 28.7, 29.6, 29.9 and 30.7 ± 0.2 degrees.
US Patent No. US 7,683,052 B2 (hereinafter referred to as the US’052 patent) assigned to Wyeth, discloses crystalline Form B of Bazedoxifene acetate and a process for the preparation thereof. According to the US’052 patent, crystalline Form B of Bazedoxifene acetate is characterized by having characteristic XRPD peaks at about 13.3 and about 20.8 ± 0.2 degrees 2-theta; Infrared spectrum in KBr comprising one or more characteristic IR bands at about 1513 cm-1, 1449 cm-1, 1406 cm-1 and 1242 cm-1; and a DSC thermogram showing an endotherm maximum at about 181°C. The US’052 patent further characterizes the crystalline Form B of Bazedoxifene acetate by XRPD 2-theta peaks at about 12.1, 13.4, 14.5, 15.6, 15.9, 16.9, 18.8, 19.4, 21.6, 22.7, 22.8, 24.2, 25.0, 26.0, 29.9, 30.5 and 34.2 ± 0.2 degrees.
US Patent No. US 8,063,041 B2 (hereinafter referred to as the US’041 patent) assigned to Wyeth, discloses crystalline Form D of Bazedoxifene acetate and a process for the preparation thereof. According to the US’041 patent, the crystalline Form D is characterized by XRPD 2-theta peaks at about 10.6°, 14.0°, 17.1°, 17.5° and 24.2°; glass transition temperature between about 166°C and 168°C and with a Raman spectrum comprising one or more characteristic peaks at about 1561 cm-1, about 1589 cm-1 and about 1613 cm-1. The US’041 patent further characterizes the crystalline Form D of Bazedoxifene Acetate by XRPD 2-theta peaks at about 9.838, 11.513, 11.950, 12.668, 15.506, 18.110, 18.859, 19.797, 20.147, 20.519, 20.897, 21.321, 22.15, 22.31, 23.135, 24.023, 24.143, 24.879, 25.478, 26.020, 26.215, 26.387, 26.503, 26.903, 27.427, 27.937, 28.084, 28.210, 28.881, 28.963, 29.614, 29.827, 30.054, 30.821, 30.904, 31.281, 31.785, 31.944, 32.027, 33.024, 33.156, 33.255, 34.462, 34.561, 35.029, 36.027, 36.655, 37.294, 37.410, 38.030, 38.755, 39.579 and 39.795 degrees.
US Patent No. US 9,212,172 B2 (assigned to Dr. Reddy’s), discloses anhydrous Bazedoxifene acetate Form D and a process for the preparation thereof. The anhydrous Bazedoxifene acetate crystalline Form D is characterized by having characteristic XRPD 2-theta peaks at about 5.9, 7.8, 11.7 and 17.7 ± 0.2 degrees; additional XRPD 2-theta peaks at about 9.9, 12.8, 13.4, 15.7, 17.1, 19.9, 20.5, 23.3, and 34.6 ± 0.2 degrees; and a DSC Endotherm in the range from about 159°C to about 166°C.
The processes for the preparation of Bazedoxifene acetate and its intermediates as described in the aforementioned prior art suffer from the following major disadvantages and shortcomings:
a) the processes involve the use of corrosive, pyrophoric and difficult to handle reagents such as LiAlH4 and;
b) the processes involve the use of highly flammable solvents like tetrahydrofuran;
d) the processes involve the use of corrosive and pyrophoric reagents like CBr4 and BF3 etherate; and
e) the processes involve the use of tedious and cumbersome procedures like use of extreme low temperatures, prolonged reactions times, column chromatographic purifications - which are not suitable for industrial scale operations.
A need still remains for improved, commercially viable and industrially advantageous processes for the preparation of Bazedoxifene acetate, polymorphic forms thereof, and its intermediates with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
One object of the present invention is to provide novel, improved, commercially viable and industrially advantageous processes for the preparation of Bazedoxifene acetate and its intermediates, in high yields and purity.
Another object of the present invention is to provide a novel, commercially viable and consistently reproducible processes for the preparation of highly pure crystalline Form B of Bazedoxifene acetate.
In one aspect, provided herein is a process for the preparation of highly pure crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms by recrystallizing crude Bazedoxifene acetate from a mixture of acetic acid and water.
The synthesis of Bazedoxifene acetate as disclosed in the present invention is depicted in the below Scheme-5:

In another aspect, provided herein is a novel process for the preparation of Bazedoxifene acetate, which comprises: (a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride in presence of a suitable base and a suitable solvent to produce 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole; (b) reacting the benzyloxy intermediate compound obtained in step-(a) with oxalic acid dihydrate to produce an oxalate salt of the benzyloxy compound; (c) reacting the resulting oxalate salt of the benzyloxy compound with aqueous sodium hydroxide to produce pure benzyloxy intermediate compound; and (d) deprotecting the pure benzyloxy intermediate compound using a suitable reducing agent in a suitable solvent, followed by treating with acetic acid to produce Bazedoxifene acetate.
In another aspect, provided herein is a novel process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane hydrochloride, which comprises: (a) reacting 4-hydroxybenzaldehyde with 1-bromo-2-chloroethane in presence of a suitable base and a suitable solvent to produce 4-(2-chloroethoxy)benzaldehyde, (b) reacting 4-(2-chloroethoxy)benzaldehyde with azepane in presence of a suitable base and a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzaldehyde, (c) reducing 4-[2-(azepan-1-yl)ethoxy]benzaldehyde with a suitable reducing agent to produce 4-[2-(Azepan-1-yl)ethoxy]benzyl alcohol; and (d) reacting 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol with a chlorinating agent to produce 1-[2-(4-chloromethyl-phenoxy)ethylazepane hydrochloride.
The synthesis of 1-[2-(4-chloromethyl-phenoxy)ethylazepane hydrochloride, as described in the present invention is depicted below in Scheme 6:

The synthesis of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide, as described in the present invention is depicted below in Scheme 7:

The processes for the preparation of Bazedoxifene acetate and its intermediates disclosed herein are more convenient to operate at laboratory scale and on a commercial scale, which avoid the tedious and cumbersome prior art processes, thereby resolving the problems associated with the processes described in the prior art.
The processes for the preparation of Bazedoxifene acetate and its intermediates described herein have the following advantages over the processes described in the prior art:
(i) the processes avoid the use of the pyrophoric, explosive and difficult to handle reagents such as Sodium hydride;
(ii) the processes avoid the use of a highly flammable and industrially hazardous reagent such as LiAlH4;
(iii) the processes avoid the use of corrosive and expensive reagent such as CBr4 at the bromination stage; and
(iv) the processes avoid the use of tedious and cumbersome procedures such as prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolations, additional and excess amounts of solvents.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of crystalline Form B of Bazedoxifene acetate of formula I:

which comprises:
a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole of formula V:

or a salt thereof, with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane of formula VI:

or a salt thereof, in presence of a suitable base in a suitable solvent to produce 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of formula IV:

b) purifying the compound of formula IV by treating with oxalic acid dihydrate in a suitable solvent to produce 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt of formula III:

c) treating the compound of formula III with a suitable base in a suitable solvent to produce highly pure benzyloxy compound of formula IV; and
d) deprotecting the compound of formula IV by catalytic hydrogenation under hydrogen pressure in the presence of a suitable hydrogenation catalyst in a suitable solvent to produce Bazedoxifene free base, which is then treated with acetic acid in a suitable solvent to produce highly pure crystalline Form B of Bazedoxifene acetate of formula I.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds and intermediates obtained by the processes described in the present invention is selected from the group consisting of water, acetic acid, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, acetic acid, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, acetonitrile, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.
Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine.
Unless otherwise specified, the term ‘salt’ as used herein may include acid addition salts. Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, nitric acid, oxalic acid, acetic acid, propionic acid, citric acid, maleic acid, malic acid, tartaric acid, phthalic acid, succinic acid, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, benzenesulfonic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, oxalate, acetate, propionate, succinate, maleate, benzenesulfonate, toluenesulfonate, and the like. A most specific acid addition salt is oxalate or acetate.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C. For example, “room temperature” can refer to a temperature of about 25°C to about 30°C.
In one embodiment, the base used in step-(a) is an inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydride.
Specifically, the base used in step-(a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride.
In one embodiment, the solvent used in step-(a) include, but are not limited to, a polar aprotic solvent, a hydrocarbon solvent, a halogenated solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is dimethylsulfoxide.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about -5°C to about 70°C; specifically at a temperature of about 0°C to about 60°C. The reaction time may vary from about 30 minutes to about 5 hours; specifically from about 45 minutes to about 2 hours.
The reaction mass containing the 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of formula IV obtained in step-(a) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula III, or the compound of formula IV may be isolated and/or recrystallized and then used in the next step.
In one embodiment, 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of formula IV obtained in step-(a) may be isolated, purified and/or re-crystallized using a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or by the formation of a salt or a combination thereof.
In another embodiment, the suitable solvent used for isolating, purifying and/or recrystallizing the compound of formula IV obtained in step-(a) is selected from the group consisting of water, an alcohol, a ketone, a polar aprotic solvent, an ester, a hydrocarbon, a halogenated hydrocarbon, a nitrile solvent, and mixtures thereof. Specifically, the solvent used for isolating, purifying and/or recrystallizing the compound of formula IV obtained by the processes described herein is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, ethyl acetate, acetone, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, acetonitrile, dimethylformamide, acetic acid, dimethylacetamide, and mixtures thereof.
In one embodiment, the solvent used in step-(b) include, but are not limited to, an alcohol, a ketone, an ester, a polar aprotic solvent, a hydrocarbon solvent, a halogenated solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is toluene.
The 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate of formula III obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof.
In one embodiment, 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt of formula III obtained in step-(b) may be isolated, purified and/or re-crystallized using a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the suitable solvent used for isolating, purifying and/or recrystallizing the compound of formula III obtained in step-(b) is selected from the group as described hereinabove.
In one embodiment, the base used in step-(c) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof. A most specific base is sodium hydroxide.
In one embodiment, the solvent used in step-(c) include, but are not limited to, a polar aprotic solvent, a hydrocarbon solvent, a halogenated solvent, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof. A most specific solvent is toluene.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about 20°C to about 70°C; specifically at a temperature of about 25°C to about 65°C. The reaction time may vary from about 45 minutes to about 8 hours; specifically from about 1 hour to about 3 hours.
The 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of formula IV obtained in step-(c) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, a decolorization, or a combination thereof.
In one embodiment, the highly pure benzyloxy compound of formula IV obtained in step-(c) may be isolated, purified and/or re-crystallized using a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the suitable solvent used for isolating, purifying and/or recrystallizing the highly pure benzyloxy compound of formula IV obtained in step-(c) is selected from the group as described hereinabove.
In one embodiment, the deprotection in step-(d) is carried out under hydrogen pressure in the presence of a hydrogenation catalyst.
In another embodiment, the hydrogenation is carried out under hydrogen pressure of about 2 kg/cm2 to about 20 kg/cm2, specifically under pressure of about 1 kg/cm2 to about 10 kg/cm2.
Exemplary hydrogenation catalysts used in step-(d) include, but are not limited to, Raney nickel, Palladium on Carbon, Platinum oxide, Platinum on Carbon, and the like. Specifically, the hydrogenation catalyst used in step-(d) is Palladium on Carbon.
In one embodiment, the solvent used for catalytic hydrogenation in step-(d) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. A most preferable solvent used in step-(d) is a mixture of ethyl acetate and isopropyl alcohol.
In another embodiment, the catalytic hydrogenation in step-(d) is carried out at a temperature of about 20°C to about 80°C; specifically at a temperature of about 25°C to about 65°C. The reaction time may vary between about 30 minutes to about 15 hours; specifically from about 45 minutes to about 8 hours.
The reaction mass containing the of Bazedoxifene acetate of formula I obtained in step-(d) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the Bazedoxifene acetate of formula I may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the crystalline Form B of Bazedoxifene acetate of formula I obtained in step-(d) is selected from the group as described hereinabove.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of crystalline Form B of Bazedoxifene acetate of formula I:

which comprises:
(a) purifying the compound of formula IV:

by treating with oxalic acid dihydrate in a suitable solvent to produce 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate of formula III:

b) treating the compound of formula III with a suitable base in a suitable solvent to produce highly pure benzyloxy compound of formula IV; and
c) deprotecting the compound of formula IV by catalytic hydrogenation under hydrogen pressure in the presence of a suitable hydrogenation catalyst in a suitable solvent to produce Bazedoxifene free base, which is then treated with acetic acid in a suitable solvent to produce highly pure crystalline Form B of Bazedoxifene acetate of formula I.
The preparation of highly pure crystalline Form B of Bazedoxifene acetate of formula I as described in the above process steps-(a), (b) and (c) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI:

or a salt thereof, which comprises:
a) reacting 4-hydroxybenzaldehyde compound of formula X:

with 2-chlorobromoethane of formula XI:


in the presence of a suitable base, optionally in the presence of a suitable solvent, to produce 4-(2-chloroethoxy)benzaldehyde of formula IX:

b) reacting the compound of formula IX with azepane in the presence of a suitable base in a suitable solvent, optionally in presence of a catalyst, to produce 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof;
c) reducing the compound of formula VIII with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
d) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.
In one embodiment, the base used in step-(a) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. A most specific base is potassium carbonate.
In one embodiment, the reaction in step-(a) is optionally carried out in a suitable solvent. Exemplary solvents used in step-(a) include, but are not limited to, a ketone, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethylsulfoxide, and mixtures thereof. A most specific solvent used in step-(a) is acetonitrile.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 20°C to about reflux temperature of the solvent used; more specifically at the reflux temperature of the solvent used. The reaction time may vary from about 2 hours to about 26 hours, more specifically from about 3 hours to about 25 hours.
The reaction mass containing the 4-(2-chloroethoxy)benzaldehyde of formula IX obtained in step-(a) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VIII, or the compound of formula IX may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 4-(2-chloroethoxy)benzaldehyde of formula IX obtained in step-(a) may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for isolating, purifying and/or recrystallizing the 4-(2-chloroethoxy)benzaldehyde of formula IX obtained in step-(a) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent used for isolating, purifying and/or recrystallizing the 4-(2-chloroethoxy)benzaldehyde of formula IX is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
In one embodiment, the base used in step-(b) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof. A most specific base is potassium carbonate.
In one embodiment, the solvent used in step-(b) is selected from the group consisting of a ketone, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, and mixtures thereof. A most specific solvent used in step-(b) is acetonitrile.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 20°C to about reflux temperature of the solvent used; and more specifically at the reflux temperature of the solvent used. The reaction time may vary from about 2 hours to about 30 hours, more specifically from about 3 hours to about 25 hours.
The reaction mass containing the 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula VII, or the compound of formula VIII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII obtained in step-(b) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII obtained in step-(b) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
In one embodiment, the reducing agent used in step-(c) is selected from the group consisting of LiAlH4, LiBH4, NaBH4, NaBH3CN, NaBH(OAc)3, Mg(BH4)2, Al(BH4)3, Ca(BH4)2, Zn(BH4)2, Ce(BH4)3. A most specific reducing agent is NaBH4.
Exemplary solvents used in step-(c) include, but are not limited to, alcohols, ketones, an ester, a nitrile, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof. A most specific solvent is methanol.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about -5°C to about 30°C; more specifically at a temperature of about 0°C to about 15°C. The reaction time may vary from about 30 minutes to about 6 hours, more specifically from about 1 hour to about 3 hours.
The reaction mass containing the 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII obtained in step-(c) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula VI, or the compound of formula VII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII obtained in step-(c) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII obtained in step-(c) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
In one embodiment, the chlorinating agent used in step-(d) is selected from the group consisting of thionyl chloride, Phosphorous trichloride, Phosphorous pentachloride, N-chlorosuccinimide. A most specific chlorinating agent is thionyl chloride.
Exemplary solvents used in step-(d) include, but are not limited to, a hydrocarbon, a halogenated hydrocarbon, a nitrile, and mixtures thereof.
Specifically, the solvent used in step-(d) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof. A most specific solvent is dichloromethane.
In one embodiment, the reaction in step-(d) is carried out at a temperature of about -5°C to about 60°C; more specifically at a temperature of about 0°C to about 40°C. The reaction time may vary from about 45 minutes to about 8 hours, more specifically from about 1 hour to about 4 hours.
The reaction mass containing the 1-[2-(4-Chloromethyl-phenoxy)ethyl]azepane of formula VI obtained in step-(d) may be subjected to usual work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof.
In one embodiment, the 1-[2-(4-chloromethyl-phenoxy)ethyl]azepane of formula VI or a salt thereof obtained in step-(d) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 1-[2-(4-chloromethyl-phenoxy)ethyl]azepane of formula VI obtained in step-(d) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
According to another aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of 1-[2-(4-chloromethyl-phenoxy) ethylazepane of formula VI:

or a salt thereof, which comprises:
(a) reacting 4-(2-chloroethoxy)benzaldehyde of formula IX:

with azepane in the presence of a suitable base in a suitable solvent, optionally in presence of a catalyst, to produce 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof;
(b) reducing the compound of formula VIII with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
c) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.
The preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI or a salt thereof as described in the above process steps-(a), (b) and (c) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI:

or a salt thereof, which comprises:
a) reducing 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof, with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
(b) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.
The preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI or a salt thereof as described in the above process steps-(a) and (b) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel, commercially viable and industrially advantageous process for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V:

which comprises:
a) reacting 4-benzyloxyaniline compound of formula XV:

or a salt thereof, with 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV:

in the presence of a suitable base in a suitable solvent to produce 1-(3-benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide salt of formula XIII:

and
b) reacting the compound of formula XIII with 4-benzyloxyaniline of formula XV using a suitable solvent to produce 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V.
Exemplary solvents used in step-(a) include, but are not limited to, an alcohol, a ketone, a hydrocarbon, an ether, and mixtures thereof. Specifically, the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isopropyl ketone, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran, and mixtures thereof. A most specific solvent is isopropyl alcohol.
In one embodiment, the reaction in step-(a) is carried out in the presence of an organic or inorganic base selected from the group as described hereinabove. Specifically, the reaction in step-(a) is carried out in presence of an organic base. The organic base used in step-(a) is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine. A most specific base is triethylamine.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 25°C to about 90°C; more specifically at a temperature of about 30°C to about 85°C. The reaction time may vary from about 10 minutes to about 6 hours, and more specifically from about 30 minutes to about 2 hours.
The reaction mass containing the 1-(3-benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide of formula XIII obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula V, or the compound of formula XIII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 1-(3-benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide of formula XIII may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 1-(3-benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide salt of formula XIII obtained in step-(a) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
Exemplary solvents used in step-(b) include, but are not limited to, an alcohol, a ketone, a hydrocarbon, an ether, and mixtures thereof. Specifically, the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isopropyl ketone, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran and mixtures thereof. A most specific solvent is xylene.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to about 160°C; and more specifically at a temperature about 30°C to about 150°C. The reaction time may vary from about 45 minutes to about 30 hours, more specifically from about 1 hour to about 24 hours.
The reaction mass containing the 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V obtained in step-(b) by the process described in the present invention is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
According to another aspect, there is provided a novel process for the preparation of 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV:

which comprises:
a) reacting 1-(4-hydroxyphenyl)-1-propanone of formula XVII:

with benzyl chloride in the presence of a suitable base in a suitable solvent to produce 1-(4-benzyloxyphenyl)-1-propanone compound of formula XVI:

and
b) brominating the compound of formula XVI with a suitable brominating agent in a suitable solvent to produce 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV.
In one embodiment, the base used in step-(a) is an inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydride. A most specific base is potassium carbonate.
Exemplary solvents used in step-(a) include, but are not limited to, a polar aprotic solvent, a hydrocarbon solvent, a ketone, an ester, a nitrile, and mixtures thereof. Specifically, the solvent used in step-(a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, acetone, methyl ethylketone, methyl isobutylketone, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof. A most specific solvent is N,N-dimethylformamide.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 25°C to about 90°C; more specifically at a temperature of about 30°C to about 85°C. The reaction time may vary from about 20 minutes to about 8 hours; and more specifically from about 45 minutes to about 5 hours.
The reaction mass containing the 1-(4-benzyloxyphenyl)-1-propanone compound of formula XVI obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XIV, or the compound of formula XVI may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 1-(4-benzyloxyphenyl)-1-propanone compound of formula XVI may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the 1-(4-benzyloxyphenyl)-1-propanone compound of formula XVI obtained in step-(a) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
Exemplary solvents used in step-(b) include, but are not limited to, an alcohol, a hydrocarbon, a halogenated hydrocarbon, a ketone, a nitrile, and mixtures thereof. Specifically the solvents used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropylalcohol, toluene, xylene, dichloromethane, dichloroethane, acetone, methyl ethyl ketone, acetonitrile, propionitrile and mixtures thereof. A specific solvent is dichloromethane, toluene and mixtures thereof.
In one embodiment, the reaction in step-(b) is carried out in presence of an organic base. Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine. A specific base is triethylamine.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to about 50°C; more specifically at a temperature of about 30°C to about 40°C. The reaction time may vary from about 15 minutes to about 6 hours; and more specifically from about 30 minutes to about 3 hours.
The reaction mass containing the 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV obtained in step-(b) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
According to another aspect, there is provided a novel process for the preparation of 4-benzyloxyaniline compound of formula XV:

or a salt thereof, which comprises:
a) reacting 4-hydroxynitrobenzene compound of formula XIX:

with benzyl chloride in the presence of a suitable base in a suitable solvent to produce 4-benzyloxynitrobenzene compound of formula XVIII:

and
b) reducing the compound of formula XVIII with a suitable reducing agent using a suitable solvent to produce 4-Benzyloxyaniline compound of formula XV or salt thereof.
In one embodiment, the base used in step-(a) is an inorganic base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydride. A most specific base is potassium carbonate.
Exemplary solvents used in step-(a) include, but are not limited to, a polar aprotic solvent, a hydrocarbon solvent, a ketone, an ester, a nitrile, and mixtures thereof. Specifically, the solvent is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, acetone, methyl ethylketone, methyl isobutylketone, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile. A most specific solvent is N,N-dimethylformamide.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 25°C to about 90°C; more specifically at a temperature of about 30°C to about 85°C. The reaction time may vary from about 30 minutes to about 15 hours; and more specifically from about 45 minutes to about 13 hours.
The reaction mass containing the 4-benzyloxynitrobenzene of formula XVIII obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XV, or the compound of formula XVIII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 4-benzyloxynitrobenzene compound of formula XVIII may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound, 4-benzyloxynitrobenzene compound of formula XVIII obtained in step-(a) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
Exemplary reducing agents used in step-(b) include, but are not limited to, palladium on carbon and ammonium formate, palladium on carbon and hydrazine hydrate, palladium on carbon and formic acid, FeCl3 and ammonium chloride, FeCl3 and hydrazine hydrate, iron powder and ammonium chloride, iron powder and acetic acid, iron powder and HCl, Zinc dust and acetic acid, tin(II) chloride, Zinc dust and HCl, Zinc dust and ammonium formate, Zinc dust and ammonium chloride, sodium dithionite, Na2S, LiAlH4, NiBH4, and the like. Specifically, the reducing agent used in step-(b) is selected from the group consisting of iron powder and ammonium chloride, and iron powder and acetic acid.
Exemplary solvents used for reduction with a suitable reducing agent in step-(b) include, but are not limited to, a nitrile solvent, an ester solvent, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used for reduction with a suitable reducing agent in step-(b) is selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to about 90°C; more specifically at a temperature of about 30°C to about 85°C. The reaction time may vary from about 30 minutes to about 18 hours; more specifically from about 45 minutes to about 15 hours.
The reaction mass containing the 4-benzyloxyaniline compound of formula XV or a salt thereof obtained in step-(b) may be subjected to usual work up methods as described hereinabove.
In one embodiment, the 4-benzyloxyaniline compound of formula XV or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for isolating, purifying and/or recrystallizing the compound 4-benzyloxyaniline compound of formula XV obtained in step-(b) is selected from the group consisting of an ester, a ketone solvent, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of ethyl acetate, isopropyl acetate, butyl acetate, acetone, dichloromethane, dichloroethane, and mixtures thereof.
According to another aspect, there is provided a process for the preparation of highly pure crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms, comprising:
a) providing a solution of bazedoxifene acetate in acetic acid;
b) cooling the solution obtained in step-(b) at a temperature below about 45°C;
c) adding water to the solution obtained in step-(a) or step-(b) to cause crystallization; and
d) collecting the highly pure crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms obtained in step-(c).
Step-(a) of providing a solution of Bazedoxifene acetate includes dissolving Bazedoxifene acetate in acetic acid at a temperature of about 45°C to about 70°C, and preferably at a temperature of about 50°C to about 60°C, or obtaining an existing solution from a previous processing step.
After complete dissolution of Bazedoxifene acetate, the resulting solution is stirred at a temperature of about 50°C to about 60°C for at least 10 minutes, and specifically for about 20 minutes to about 30 minutes.
In another embodiment, the suspension obtained after addition of water in step-(c) is stirred at a temperature of about 20°C to about 40°C for at least 30 minutes and more specifically at a temperature of about 25°C to about 30°C for about 1 hour to about 5 hours.
The recovering in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
The highly pure crystalline Form B of Bazedoxifene acetate obtained by the process described herein is found to be more stable.
In one embodiment, the crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms obtained by the process disclosed herein is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 13.34, 14.41, 20.81 and 21.73 ± 0.2 degrees substantially in accordance with Figure 1; an infrared (FT-IR) spectrum having main bands at about 3423, 2927, 1614, 1560 and 1513 cm-1 substantially in accordance with Figure 2; and a Differential Scanning Calorimetric (DSC) thermogram having onset temperature at about 178.87°C and a sharp endotherm peak at about 181.81°C substantially in accordance with Figure 3.
In one embodiment, the crystalline Form B of Bazedoxifene acetate obtained by the process disclosed herein is further characterized by an X-ray powder diffraction pattern having additional 2-theta angle positions at about 12.00, 15.60, 15.87, 16.86, 18.76, 19.41, 22.70, 22.95, 24.17, 25.01, 25.94, 29.92 and 30.52 ± 0.2 degrees substantially in accordance with Figure 1; an infra red (FT-IR) spectrum having main bands at about 1449, 1407, 1368, 1277, 1246, 1206, 1172, 1080, 1013, 918, 848, 787 and 747 cm-1 substantially in accordance with Figure 2.
The highly pure crystalline Form B of Bazedoxifene acetate obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (“ICH”) guidelines.
Preferably, the drying is carried out at atmospheric pressure at temperatures such as about 40°C to about 85°C and most preferably at about 45°C to about 80°C. In one embodiment, the drying is carried out for any desired time period that achieves the desired result, preferably for a period of about 1 hour to 25 hours, and more preferably about 5 hours to 20 hours. Drying can be suitably carried out in a tray dryer, a vacuum oven, an air oven, or using a fluidized bed drier, a spin flash dryer, a flash dryer and the like. Drying equipment selection is well within the ordinary skill in the art.
The stable and highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein is free from other crystalline forms, which has very good flow properties and is consistently reproducible, and is found to be more stable. The crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein exhibits properties making it suitable for formulating Bazedoxifene acetate.
Further encompassed herein is the use of the highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein for the manufacture of a pharmaceutical composition together with a pharmaceutically acceptable carrier.
A specific pharmaceutical composition of highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein is selected from a solid dosage form and an oral suspension.
In one embodiment, the highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein, for use in the pharmaceutical compositions, has a D90 particle size of less than or equal to about 200 microns, specifically about 1 microns to about 110 microns, and most specifically about 4 microns to about 90 microns.
In another embodiment, the particle sizes of the highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein are accomplished by a mechanical process of reducing the size of particles which includes any one or more of cutting, chipping, crushing, milling, grinding, micronizing, trituration or other particle size reduction methods known in the art, to bring the solid state form to the desired particle size range.
The term “micronization” used herein means a process or method by which the size of a population of particles is reduced.
As used herein, the term “micron” or “µm” both are equivalent and refer to “micrometer” which is 1x10–6 meter.
As used herein, “crystalline particles” means any combination of single crystals, aggregates and agglomerates.
According to another aspect, there are provided pharmaceutical compositions comprising highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein and one or more pharmaceutically acceptable excipients.
According to another aspect, there is provided a process for preparing a pharmaceutical formulation comprising combining highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein, with one or more pharmaceutically acceptable excipients.
Yet in another embodiment, pharmaceutical compositions comprise at least a therapeutically effective amount of highly pure crystalline Form B of Bazedoxifene acetate obtained by the processes disclosed herein. Such pharmaceutical compositions may be administered to a mammalian patient in a dosage form, e.g., solid, liquid, powder, syrups, injectable solution, etc. Dosage forms may be adapted for administration to the patient by oral, parenteral, or any other acceptable route of administration. Oral dosage forms include, but are not limited to, tablets, pills, capsules, syrup, suspensions, powders, and the like.
The pharmaceutical compositions further contain one or more pharmaceutically acceptable excipients. Suitable excipients and the amounts to use may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field, e.g., the buffering agents, sweetening agents, binders, diluents, fillers, lubricants, wetting agents and disintegrants described hereinbelow.
Other excipients include binders, such as acacia gum, pregelatinized starch, sodium alginate, glucose and other binders used in wet and dry granulation and direct compression tableting processes; disintegrants such as sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose and others; lubricants like magnesium and calcium stearate and sodium stearyl fumarate; flavorings; sweeteners; preservatives; pharmaceutically acceptable dyes and glidants such as silicon dioxide.

INSTRUMENTAL DETAILS:
X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 400 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 0.4 seconds. The sample was simply placed on the sample holder. The instrument is operated at a voltage 40 KV and current 35 mA.
Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the production of the KBr compacts approximately 2 mg of sample was powdered with 200 mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm-1 to 650 cm-1.
Differential Scanning Calorimetry (DSC):
Differential Scanning Calorimetry (DSC) measurements were performed with a Differential Scanning Calorimeter (DSC Q200, Q Series Version-2.7.0.380, TA Instruments-Waters LLC) equilibrated at 50°C and Ramp at a scan rate of 10°C per minute to 210°C.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 4-Benzyloxynitrobenzene
Potassium carbonate (496 g) was added to a solution of 4-hydroxynitrobenzene (500 g) in dimethylformamide (1000 ml) at 25-30ºC and the resulting mixture was stirred for 10 minutes at the same temperature. The resulting mass was heated to 50ºC, followed by the slow addition of benzyl chloride (500 g) at the same temperature. After complete addition of benzyl chloride, the temperature of the reaction mass was raised to 80ºC and stirred for 13 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30ºC, water (2 lit) was added and stirred for 30 minutes at the same temperature. The solid obtained was filtered, washed with water (500 ml x 3) and then dried at 40-50ºC to produce 790 g of 4-Benzyloxynitrobenzene [Yield: 96%, Purity by HPLC: 98%].

Example 2
Preparation of 4-Benzyloxyaniline
Iron powder (183 g) was added to a solution of 4-benzyloxynitrobenzene (250 g) in acetonitrile (1000 ml) and water (1000 ml) at 25-30ºC and then ammonium chloride (290 g) was added at the same temperature. The resulting mass was stirred for 10 minutes. The temperature of the reaction mixture was raised to 75-85ºC under stirring and maintained at 75-85°C for 15 hours. After completion of the reaction, the resulting mass was filtered through hyflow and washed with acetonitrile (100 ml) and water (50 ml). The layers were separated and the aqueous layer was extracted with acetonitrile (100 ml x 2). The organic layers were combined and washed with 10% sodium chloride solution (25 ml). The solvent was distilled under vacuum to produce 185 g of 4-benzyloxyaniline as a solid [Yield: 85%; Purity by HPLC: 98%].

Example 3
Preparation of 1-(4-Benzyloxyphenyl)-1-propanone
Potassium carbonate (93 g) was added to a solution of 1-(4-hydroxyphenyl)-1-propanone (100 g) in dimethylformamide (300 ml) at 25-30°C and the resulting mass was stirred for 10 minutes at the same temperature, followed by the slow addition of Benzyl chloride (93 g). The temperature of the reaction mass was raised to 80-85°C and maintained for 5 hours at the same temperature. After completion of reaction, the resulting mass was filtered and washed with dimethylformamide (50 ml). Water (300 ml) was added to the resulting filtrate at 25-30°C and stirred for 1 hour. The solid obtained was filtered, washed with water (50 ml) and then dried at 50°C to produce 163 g of 1-(4-benzyloxyphenyl)-1-propanone [Yield: 98%; Purity by HPLC: 98%].

Example 4
Preparation of 2-Bromo-1-(4-benzyloxyphenyl)-1-propanone
Method-(A):
Acetic acid (127 g) was added to a solution of 1-(4-benzyloxyphenyl)-1-propanone (400 g) in toluene (1200 ml) and dichloromethane (1200 ml) at 25-30°C and stirred for 10 minutes at the same temperature. To the resulting mass, triethylamine (210 g) was slowly added at 25-30°C and then stirred for 15 minutes at the same temperature. To the resulting mass a solution of bromine (421 g) was added slowly and stirred for 2 hours. After completion of reaction, water (200 ml) was added to the resulting mass and stirred for 15 minutes. The layers were separated and the organic layer was washed with water (400 ml). The organic layer was distilled under reduced pressure to obtain a solid. Isopropyl alcohol (100 ml) was added to the resulting solid and stirred for (30 minutes). The resulting solid was filtered, washed with isopropyl alcohol (50 ml), and the dried the material at 40-50°C to produce 392 g of 2-Bromo-1-(4-benzyloxyphenyl)-1-propanone [Yield: 74%; Purity by HPLC: 99%].
Method-(B):
Bromine (146 g) was slowly added to a solution of 1-(4-Benzyloxyphenyl)-1-propanone (200 g) in toluene (2000 ml) and sulfuric acid (12.2 g) at 25-30°C, followed by stirring for 1-2 hours at the same temperature. After completion of reaction, water (100 ml) was added to the resulting mass and then stirred for 15 minutes. The layers were separated and the organic layer was washed with water. The organic layer was distilled under reduced pressure to obtain a solid. Isopropyl alcohol (200 ml) was added to the resulting solid and stirred for 30 minutes. The resulting solid was filtered, washed with isopropyl alcohol (100 ml), and then dried the material at 40-50°C to produce 176 g of 2-bromo-1-(4-benzyloxyphenyl)-1-propanone [Yield: 66%; Purity by HPLC: 99%].

Example 5
Preparation of 1-(3-Benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide
Triethylamine (139.2 g) was added to a solution of 2-bromo-1-(4-benzyloxyphenyl)-1-propanone (220 g) in isopropyl alcohol (1320 ml) and 4-benzyloxyaniline (144 g) at 25-30°C and then stirred for 10-15 minutes at the same temperature. The resulting mass was heated to 80-85°C and stirred for 15 minutes at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30°C. Water (200 ml) was added to the reaction mass at 25-30°C and then stirred for 1 hour at the same temperature. The solid obtained was filtered, washed with water (50 ml) and then dried the material at 50°C to produce 375 g of 1-(3-Benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide [Purity by HPLC: 98%].

Example 6
Preparation of 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide
1-(3-Benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide (400 g), 4-benzyloxyaniline (20 g) and xylene (600 ml) were taken into a reaction flask at 25-30°C and stirred for 10 minutes at the same temperature. The resulting mass was heated to reflux temperature by means of Dean-Stark apparatus and maintained for 24 hours. After completion of reaction, the resulting mass was cooled to 25-30°C and stirred for 3 hours at the same temperature. Xylene (400 ml) was added to the resulting mass and stirred for 1 hour. The solid obtained was filtered, washed with xylene (50 ml) and then dried the material at 40°C to produce 310 g of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide [Yield: 80%; Purity by HPLC: 98%].

Example 7
Preparation of 4-(2-Chloroethoxy)benzaldehyde
Potassium carbonate (450 g) was added to the solution of 4-hydroxybenzaldehyde (200 g) in acetonitrile (1200 ml) at 25-30°C. The resulting mass was heated to 75-85°C and 1-bromo-2-chloroethane (936 g) was added slowly, and then stirred for 24 hours at the same temperature. After completion of reaction, the resulting mass was cooled to 25-30°C and filtered. The filtrate was washed with acetonitrile (200 ml) and distilled under vacuum at 70-75°C to produce 300 g of 4-(2-chloroethoxy)benzaldehyde as a residue [Yield: 99%; Purity by HPLC: 96%].

Example 8
Preparation of 4-(2-Bromoethoxy)benzaldehyde
Potassium carbonate (678 g) was added to a solution of 4-hydroxybenzaldehyde (200 g) in 1,2-dibromoethane (4360 g) at 25-30°C. The resulting mass was heated to 115-120°C and then stirred for 3 hours at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30°C. The resulting mass was filtered and the filtrate was washed with 1,2-dibromoethane (1308 g) and distilled under vacuum at 60-65°C to produce 345 g of 4-(2-bromoethoxy)benzaldehyde as a residue [Yield: 92%; Purity by HPLC: 78.7%].

Example 9
Preparation of 4-[2-(Azepan-1-yl)ethoxy]benzaldehyde
Potassium carbonate (64 g) was added to the solution of 4-(2-chloroethoxy)benzaldehyde (300 g) in acetonitrile (900 ml) at 25-30°C and then stirred for 15 minutes, followed by the addition of azepane (242.5 g) at the same temperature. The resulting mass was heated to 80°C under stirring and maintained for 24 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30°C and filtered. The resulting filtrate was washed with acetonitrile (100 ml) and distilled under vacuum at 70-75°C to obtain a residue. The crude residue was dissolved in water (150 ml) at 25-30°C and stirred for 15 minutes at the same temperature. Ethyl acetate (500 ml) was added to the resulting mass and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The organic layers were combined and then washed with 5% HCl (300 ml) and distilled under vacuum at 65-70°C to produce 370 g of 4-[2-(azepan-1-yl)ethoxy]benzaldehyde as a residue [Yield: 92%; Purity by HPLC: 95%].

Example 10
Preparation of 4-[2-(Azepan-1-yl)ethoxy]benzaldehyde
Potassium carbonate (84.4 g) was added to the solution of 4-(2-bromoethoxy)benzaldehyde (140 g) in acetonitrile (900 ml) at 25-30°C and stirred for 15 minutes, followed by the addition of azepane (242.5 g) at the same temperature. The resulting mass was heated to 80°C under stirring and maintained for 15 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to 25-30°C and filtered. The resulting filtrate was washed with acetonitrile (100 ml) and distilled under vacuum at 70-75°C to obtain a residue. The crude residue was dissolved in water (150 ml) at 25-30°C and then stirred for 15 minutes at the same temperature. Ethyl acetate (500 ml) was added to the resulting mass and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with 5% HCl (300 ml) and distilled under vacuum at 65-70°C to produce 143 g of 4-[2-(Azepan-1-yl)ethoxy]benzaldehyde as a residue [Yield: 95%; Purity by HPLC: 95%].

Example 11
Preparation of 4-[2-(Azepan-1-yl)ethoxy]benzyl alcohol
Sodium borohydride (26 g) was slowly added to a solution of 4-[2-(azepan-1-yl)
ethoxy]benzaldehyde (340 g) in methanol (1020 ml) at 0°C and then stirred for 3 hours at the same temperature. After completion of reaction, the solvent was distilled off completely to obtain a residue. Dichloromethane (1320 ml) and water (340 ml) were added to the resulting residue slowly under stirring to get the clear solution. The layers were separated and the organic layer was used for the next step.

Example 12
Preparation of 1-[2-(4-Chloromethyl-phenoxy)ethylazepane hydrochloride
Thionyl chloride (310 g) was slowly added to the solution of 4-[2-(azepan-1-yl)ethoxy] benzyl alcohol (325 g) in dichloromethane (1320 ml) at 0-5°C for 1 hour. The resulting mass was stirred for 3-4 hours at 0-5°C. After completion of reaction, the solvent was distilled off completely under reduced pressure at 40°C and then co-distilled with toluene (325 ml x 2) to produce 253 g of 1-[2-(4-Chloromethyl-phenoxy)ethylazepane hydrochloride as a residue [Yield: 72%; Purity by HPLC: 91%].

Example 13
Preparation of 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole
Sodium hydride (15.5 g, 60%) was added to dimethylformamide (75 ml) under nitrogen atmosphere at 0-5°C and stirred for 10 minutes at the same temperature. To the resulting mixture, a solution of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide (50 g) in dimethylformamide 100 ml) was added at 0-5°C then and maintained for 1 hour at the same temperature. To the resulting mass, a solution of 1-[2-(4-chloromethyl-phenoxy)ethylazepane hydrochloride (33 g) in dimethylformamide (200 ml) was added and then stirred for 6 hours. After completion of reaction, acetic acid (1 ml) was added to the resulting mass and stirred for 15 minutes. Ethyl acetate (500 ml) was added to the reaction mass and then stirred for 15 minutes, followed by the slow addition of 10% ammonium chloride (500 ml) solution at 0-10°C and then stirring for 15 minutes. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml). The combined organic layers were distilled off under reduced pressure at 60-65°C and co-distilled with ethyl acetate (200 ml x 2) to obtain a solid. Isopropyl alcohol (150 ml) was added to the resulting solid and then stirred for 30 minutes. The solid was filtered and then dried at 50°C to produce 45 g of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole [Yield: 70%; Purity by HPLC: 90%].

Example 14
Preparation of 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (300 g) was dissolved in toluene (180 ml) at 25-30°C. The resulting solution was heated to 55-60°C, followed by slow addition of oxalic acid dihydrate (55.2 g) in ethanol (300 ml) and then stirred for 3-4 hours at the same temperature. Solid formation was observed. The resulting mass was cooled to 25-30°C. The solid obtained was filtered and washed with ethanol (100 ml) to produce 298 g of 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt [Yield: 83%; Purity by HPLC: 99.4%].

Example 15
Preparation of 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole
1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt (290 g) was dissolved in toluene (2030 ml) at 25-30°C. The resulting solution was heated to 60-65°C, followed by the addition of sodium hydroxide solution (61 g of sodium hydroxide in 581 ml of water) and then stirred for 2 hours at the same temperature. The resulting mass was filtered and washed with toluene. The layers were separated and the aqueous layer was extracted with toluene (800 ml x 2). The organic layers were combined and washed with water (1000 ml x 2) and treated with charcoal. The resulting mass was filtered and the solvent was distilled off under reduced pressure at 75°C to obtain a solid. Isopropyl alcohol (600 ml) was added to the resulting solid, the slurry was stirred for 1 hour and then filtered to produce 240 g of pure 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole [Yield: 98%; Purity by HPLC: 99.7%].

Example 16
Preparation of Crystalline Form B of Bazedoxifene acetate
The pure 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (90 g) obtained in example 15 was dissolved in a mixture of ethyl acetate (450 ml) and isopropyl alcohol (450 ml) at 25-30°C. To the resulting mass, 5% Palladium on Carbon (9 g) was added under hydrogen pressure of 9-10 kg/cm2, the resulting mixture was heated to 50-60°C and then stirred for 6-7 hours at the same temperature. After completion of reaction, the resulting mass was filtered and washed with ethyl acetate and isopropyl alcohol (54 ml). The resulting solution was treated with charcoal (2 g) and then stirred for 10 minutes, filtered the material through hyflow and washed with ethyl acetate and isopropyl alcohol (54 ml). To the resulting mass, a solution of acetic acid (10.8 g) in ethyl acetate (5 ml) was slowly added at 25-30°C and stirred overnight at the same temperature. The solid obtained was filtered, washed with water (30 ml) and then dried the material at 40°C to produce 55 g of crude Bazedoxifene acetate crystalline Form B. [Yield: 75%; Purity by HPLC: 99.64%; Content of ethyl acetate: 5686.2 ppm].
Purification:
Crude Bazedoxifene acetate crystalline Form B (54 g) and acetic acid (34 ml) were taken into a reaction flask at 25-30°C. The resulting mixture was heated to 50-60°C to form a clear solution and then stirred for 1 hour at the same temperature. The resulting mass was cooled to 40°C and water (119 ml) was added. The temperature of the resulting mass was decreased to 30°C and stirred for 4-5 hours at the same temperature. The solid obtained was filtered, washed the solid with water (34 ml) and then dried the material at 50°C to produce 51.3 g of pure Bazedoxifene acetate crystalline Form B [Yield: 95%; Purity by HPLC: 99.69%; Content of ethyl acetate: 178.5 ppm; and Melting point: 178.87 to 181.81°C].
,CLAIMS:
1. A process for the preparation of crystalline Form B of Bazedoxifene acetate of formula I:

which comprises:
a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole of formula V:

or a salt thereof, with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane of formula VI:

or a salt thereof, in presence of a suitable base in a suitable solvent to produce 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl -1H-indole of formula IV:

b) purifying the compound of formula IV by treating with oxalic acid dihydrate in a suitable solvent to produce 1-[4-(2-azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate salt of formula III:

c)

treating the compound of formula III with a suitable base in a suitable solvent to produce highly pure benzyloxy compound of formula IV; and
d) deprotecting the compound of formula IV by catalytic hydrogenation under hydrogen pressure in the presence of a suitable hydrogenation catalyst in a suitable solvent to produce Bazedoxifene free base, which is then treated with acetic acid in a suitable solvent to produce highly pure crystalline Form B of Bazedoxifene acetate of formula I.

2. The process as claimed in claim 1, wherein the base used in step-(a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate and sodium hydride; wherein the solvent used in step-(a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(c) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof; wherein the solvent used in step-(c) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the deprotection in step-(d) is carried out under hydrogen pressure in the presence of a hydrogenation catalyst; wherein the hydrogenation catalysts used in step-(d) include, but are not limited to, Raney nickel, Palladium on Carbon, Platinum oxide, Platinum on Carbon, and the like; wherein the hydrogenation is carried out under hydrogen pressure of about 2 kg/cm2 to about 20 kg/cm2; and wherein the solvent used for catalytic hydrogenation in step-(d) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

3. The process as claimed in claim 2, wherein the base used in step-(a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide and sodium hydride; wherein the solvent used in step-(a) is dimethylsulfoxide; wherein the solvent used in step-(b) is toluene; wherein the base used in step-(c) is sodium hydroxide; wherein the solvent used in step-(c) is toluene; wherein the hydrogenation catalysts used in step-(d) is Palladium on Carbon; wherein the hydrogenation is carried out under hydrogen pressure of about 1 kg/cm2 to about 10 kg/cm2; and wherein the solvent used for catalytic hydrogenation in step-(d) is a mixture of ethyl acetate and isopropyl alcohol.

4. A process for the preparation of crystalline Form B of Bazedoxifene acetate of formula I:

which comprises:
a) purifying the compound of formula IV:

by treating with oxalic acid dihydrate in a suitable solvent to produce 1-[4-(2-Azepan-1-yl-ethoxy)-benzyl]-5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole oxalate of formula III:

b) treating the compound of formula III with a suitable base in a suitable solvent to produce highly pure benzyloxy compound of formula IV; and
c) deprotecting the compound of formula IV by catalytic hydrogenation under hydrogen pressure in the presence of a suitable hydrogenation catalyst in a suitable solvent to produce Bazedoxifene free base, which is then treated with acetic acid in a suitable solvent to produce highly pure crystalline Form B of Bazedoxifene acetate of formula I.

5. The process as claimed in claim 4, wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, acetone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the base used in step-(b) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; wherein the deprotection in step-(c) is carried out under hydrogen pressure in the presence of a hydrogenation catalyst; wherein the hydrogenation catalysts used in step-(c) is selected from the group consisting of Raney nickel, Palladium on Carbon, Platinum oxide and Platinum on Carbon; wherein the hydrogenation is carried out under hydrogen pressure of about 2 kg/cm2 to about 20 kg/cm2; and wherein the solvent used for catalytic hydrogenation in step-(c) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

6. The process as claimed in claim 5, wherein the solvent used in step-(a) is toluene; wherein the base used in step-(b) is sodium hydroxide; wherein the solvent used in step-(b) is toluene; wherein the hydrogenation catalysts used in step-(c) is Palladium on Carbon; wherein the hydrogenation is carried out under hydrogen pressure of about 1 kg/cm2 to about 10 kg/cm2; and wherein the solvent used for catalytic hydrogenation in step-(c) is a mixture of ethyl acetate and isopropyl alcohol.

7. A process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI:

or a salt thereof, which comprises:
a) reacting 4-hydroxybenzaldehyde compound of formula X:

with 2-chlorobromoethane of formula XI:

in the presence of a suitable base, optionally in the presence of a suitable solvent, to produce 4-(2-chloroethoxy)benzaldehyde of formula IX:

b) reacting the compound of formula IX with azepane in the presence of a suitable base in a suitable solvent, optionally in presence of a catalyst, to produce 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof;
c) reducing the compound of formula VIII with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
d) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.

8. The process as claimed in claim 7, wherein the solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethylsulfoxide, and mixtures thereof; wherein the base used in step-(a) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; wherein the base used in step-(b) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, and mixtures thereof; wherein the reducing agent used in step-(c) is selected from the group consisting of LiAlH4, LiBH4, NaBH4, NaBH3CN, NaBH(OAc)3, Mg(BH4)2, Al(BH4)3, Ca(BH4)2, Zn(BH4)2 and Ce(BH4)3; wherein the solvent used in step-(c) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the chlorinating agent used in step-(d) is selected from the group consisting of thionyl chloride, Phosphorous trichloride, Phosphorous pentachloride, N-chlorosuccinimide; and wherein the solvent used in step-(d) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof.

9. The process as claimed in claim 8, wherein the solvent used in step-(a) is acetonitrile; wherein the base used in step-(a) is potassium carbonate; wherein the reaction in step-(a) is carried out at the reflux temperature of the solvent used; wherein the base used in step-(b) is potassium carbonate; wherein the solvent used in step-(b) is acetonitrile; wherein the reducing agent used in step-(c) is NaBH4; wherein the solvent used in step-(c) is methanol; wherein the chlorinating agent used in step-(d) is thionyl chloride; and wherein the solvent used in step-(d) is dichloromethane.

10. A process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI:

or a salt thereof, which comprises:
a) reacting 4-(2-chloroethoxy)benzaldehyde of formula IX:

with azepane in the presence of a suitable base in a suitable solvent, optionally in presence of a catalyst, to produce 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof;
b) reducing the compound of formula VIII with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
b) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.

11. The process as claimed in claim 10, wherein the base used in step-(a) is selected from the group consisting of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, and mixtures thereof; wherein the solvent used in step-(a) is selected from the group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, N,N-dimethyl formamide, N,N-dimethyl acetamide, dimethyl sulfoxide, and mixtures thereof; wherein the reducing agent used in step-(b) is selected from the group consisting of LiAlH4, LiBH4, NaBH4, NaBH3CN, NaBH(OAc)3, Mg(BH4)2, Al(BH4)3, Ca(BH4)2, Zn(BH4)2 and Ce(BH4)3; wherein the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the chlorinating agent used in step-(c) is selected from the group consisting of thionyl chloride, Phosphorous trichloride, Phosphorous pentachloride, N-chlorosuccinimide; and wherein the solvent used in step-(c) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof.

12. The process as claimed in claim 11, wherein the base used in step-(a) is potassium carbonate; wherein the solvent used in step-(a) is acetonitrile; wherein the reducing agent used in step-(b) is NaBH4; wherein the solvent used in step-(b) is methanol; wherein the chlorinating agent used in step-(c) is thionyl chloride; and wherein the solvent used in step-(c) is dichloromethane.

13. A process for the preparation of 1-[2-(4-chloromethyl-phenoxy)ethylazepane of formula VI:

or a salt thereof, which comprises:
a) reducing 4-[2-(azepan-1-yl)ethoxy]benzaldehyde of formula VIII:

or a salt thereof, with a suitable reducing agent in a suitable solvent to produce 4-[2-(azepan-1-yl)ethoxy]benzyl alcohol of formula VII:

or a salt thereof; and
c) reacting the compound of formula VII or a salt thereof with a suitable chlorinating agent in a suitable solvent to produce the compound of formula VI or a salt thereof.

14. The process as claimed in claim 13, wherein the reducing agent used in step-(a) is selected from the group consisting of LiAlH4, LiBH4, NaBH4, NaBH3CN, NaBH(OAc)3, Mg(BH4)2, Al(BH4)3, Ca(BH4)2, Zn(BH4)2 and Ce(BH4)3; wherein the solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof; wherein the chlorinating agent used in step-(b) is selected from the group consisting of thionyl chloride, Phosphorous trichloride, Phosphorous pentachloride, N-chlorosuccinimide; and wherein the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof.

15. The process as claimed in claim 14, wherein the reducing agent used in step-(a) is NaBH4; wherein the solvent used in step-(a) is methanol; wherein the chlorinating agent used in step-(b) is thionyl chloride; and wherein the solvent used in step-(b) is dichloromethane.

16. A process for the preparation of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V:

which comprises:
a) reacting 4-benzyloxyaniline compound of formula XV:

or a salt thereof, with 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV:

in the presence of a suitable base in a suitable solvent to produce 1-(3-benzyloxyphenyl)-2-(4-benzyloxy-phenylamino)-1-propanone hydrobromide salt of formula XIII:

and
b) reacting the compound of formula XIII with 4-benzyloxyaniline of formula XV using a suitable solvent to produce 5-Benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole hydrobromide salt of formula V.

17. The process as claimed in claim 16, wherein solvent used in step-(a) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isopropyl ketone, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran, and mixtures thereof; wherein the organic base used in step-(a) is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine; and wherein the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, methyl isopropyl ketone, toluene, xylene, tetrahydrofuran, methyl tetrahydrofuran and mixtures thereof.

18. The process as claimed in claim 17, wherein the solvent used in step-(a) is isopropyl alcohol; wherein the organic base used in step-(a) is triethylamine; and wherein the solvent used in step-(b) is xylene.

19. A process for the preparation of 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV:

which comprises:
a) reacting 1-(4-hydroxyphenyl)-1-propanone of formula XVII:

with benzyl chloride in the presence of a suitable base in a suitable solvent to produce 1-(4-benzyloxyphenyl)-1-propanone compound of formula XVI:

and
b) brominating the compound of formula XVI with a suitable brominating agent in a suitable solvent to produce 2-bromo-1-(4-benzyloxyphenyl)-1-propanone compound of formula XIV.

20. The process as claimed in claim 19, wherein the inorganic base used in step-(a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydride; wherein the solvent used in step-(a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, acetone, methyl ethylketone, methyl isobutylketone, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of methanol, ethanol, n-propanol, isopropylalcohol, toluene, xylene, dichloromethane, dichloroethane, acetone, methyl ethyl ketone, acetonitrile, propionitrile and mixtures thereof; and wherein the organic base used in step-(b) is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine.

21. The process as claimed in claim 20, wherein the inorganic base used in step-(a) is potassium carbonate; wherein the solvent used in step-(a) is N,N-dimethylformamide; wherein the solvent used in step-(b) is dichloromethane, toluene and mixtures thereof; and wherein the organic base used in step-(b) is triethylamine.

22. A process for the preparation of 4-benzyloxyaniline compound of formula XV:

or a salt thereof, which comprises:
a) reacting 4-hydroxynitrobenzene compound of formula XIX:

with benzyl chloride in the presence of a suitable base in a suitable solvent to produce 4-benzyloxynitrobenzene compound of formula XVIII:

and
b) reducing the compound of formula XVIII with a suitable reducing agent using a suitable solvent to produce 4-Benzyloxyaniline compound of formula XV or salt thereof.

23. The process as claimed in claim 22, wherein the inorganic base used in step-(a) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, sodium hydride; wherein the solvent used in step-(a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, toluene, xylene, acetone, methyl ethylketone, methyl isobutylketone, ethyl acetate, n-propyl acetate, isopropyl acetate, acetonitrile, propionitrile; wherein the reducing agents used in step-(b) include, but are not limited to, palladium on carbon and ammonium formate, palladium on carbon and hydrazine hydrate, palladium on carbon and formic acid, FeCl3 and ammonium chloride, FeCl3 and hydrazine hydrate, iron powder and ammonium chloride, iron powder and acetic acid, iron powder and HCl, Zinc dust and acetic acid, tin(II) chloride, Zinc dust and HCl, Zinc dust and ammonium formate, Zinc dust and ammonium chloride, sodium dithionite, Na2S, LiAlH4, NiBH4, and the like; and wherein solvent used in step-(b) is selected from the group consisting of acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.

24. A process for the preparation of highly pure crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms, comprising:
a) providing a solution of bazedoxifene acetate in acetic acid;
b) cooling the solution obtained in step-(b) at a temperature below about 45°C;
c) adding water to the solution obtained in step-(a) or step-(b) to cause crystallization; and
d) collecting the highly pure crystalline Form B of Bazedoxifene acetate essentially free of other crystalline forms obtained in step-(c).

25. The process as claimed in claim 24, wherein the solution of Bazedoxifene acetate in step-(a) is prepared by dissolving Bazedoxifene acetate in acetic acid at a temperature of about 45°C to about 70°C; wherein the suspension obtained after addition of water in step-(c) is stirred at a temperature of about 20°C to about 40°C for at least 30 minutes; wherein the recovering in step-(d) is carried out by filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.

26. The process as claimed in claim 25, wherein the solution of Bazedoxifene acetate in step-(a) is prepared by dissolving Bazedoxifene acetate in acetic acid at a temperature of about 50°C to about 60°C; wherein the suspension obtained after addition of water in step-(c) is stirred at a temperature of about 25°C to about 30°C for about 1 hour to about 5 hours.