The following specification particularly describes the nature of the invention and the manner in which it is to be performed.

Introduction

Aspects of the present disclosure include processes for preparing bazedoxifene and its salts.
The drug compound having the adopted name “bazedoxifene acetate” has a chemical name 1-[4-(2-azepan-1-yl-ethoxy)benzyl]-2-(4-hydroxyphenyl)-3-methyl-1H-indol-5-ol acetic acid  and has the chemical structure shown below as Formula I.

Bazedoxifene acetate belongs to the class of drugs typically referred to as selective estrogen receptor modulators (SERMs). Consistent with its classification  bazedoxifene demonstrates affinity for estrogen receptors (ER)  but shows tissue selective estrogenic effects. For example  bazedoxifene is estrogenic on bone and cardiovascular lipid parameters and antiestrogenic on uterine and mammary tissue and thus has the potential for treatment and prevention of bone tissue loss  replacement of estrogen and prevention of heart and vein diseases in post-menopausal women.
The preparation of bazedoxifene and its salts is described in U.S. Patent Nos. 5 998 402  6 479 535  and 6 005 102. An article by C. P. Miller et al.  “Design  Synthesis  and Preclinical Characterization of Novel  Highly Selective Indole Estrogens ” Journal of Medicinal Chemistry  Vol. 44  pages 1654-1657  2001  also reports the synthetic preparation of bazedoxifene acetate.
Three crystalline polymorphic forms of bazedoxifene acetate are disclosed in U.S. Patent Nos. 7 683 051 and 7 683 052  and in International Application Publication No. WO 2009/012734 A3. An amorphous form is described in International Application Publication No. WO 2009/102778 A1.
International Application Publication Nos. WO 2009/102771 A1 and WO 2009/102773 A1 relate to processes for preparation of polymorphic Form A of bazedoxifene acetate.
International Application Publication Nos. WO 2008/098527 A1 and WO 2009/012734 A2 pertain to bazedoxifene acetate. The first application discloses a crystalline intermediate compound  i.e.  N-(4-benzyloxyphenyl)--amino-4-benzyloxypropiophenone  a method for its preparation  and its use for preparation of bazedoxifene. The latter application is directed to salts of bazedoxifene with polycarboxylic acids  methods of preparation  a method of purification of bazedoxifene by preparation of a salt of bazedoxifene with a polycarboxylic acid  and a polymorphic form of bazedoxifene acetate designated as Form C.
European Patent Application No. 0802183 describes a synthesis of bazedoxifene  wherein 5-benzyloxy-2(4-benzyloxyphenyl)-1-[4-(2-bromoethoxy)benzyl]-3-methyl-indole is reacted with azepan  under suitable reaction conditions  followed by deprotection to yield bazedoxifene  which on subsequent treatment with acetone and acetic acid gives bazedoxifene acetate.
U.S. Patent No. 6 005 102 discloses the synthesis of an intermediate compound  4-(chloromethylphenoxy)-ethylhexamethyleneimine-1-yl hydrochloride  starting from p-hydroxybenzaldehyde  and its use for preparation of benzyl-protected bazedoxifene. According to the patent  synthesis of 4-(chloromethylphenoxy)-ethylhexamethyleneimine-1-yl hydrochloride from p-hydroxybenzaldehyde involves four steps with an overall yield of ~65%. The process involves the use of hazardous and pyrophoric reagents such as sodium hydride  sodium borohydride and thionyl chloride. Furthermore  the process involves sequential treatment of 4-(2-azepan-1-yl-ethoxy)-phenyl]-methanol in THF with HCl and thionyl chloride to conduct the chlorination and salt formation to afford 4-chloromethylphenoxy)-ethylhexamethyleneimine-1-yl hydrochloride  an intermediate of bazedoxifene.
U.S. Patent No. 7 375 251 B1 discloses a process for preparation of [4-(2-azepan-1-yl-ethoxy)phenyl]methanol by reacting a corresponding -haloacetamide with a p-hydroxybenzaldehyde or ester  in the presence of a base and optionally in the presence of a phase transfer catalyst  to afford the phenoxyacetamide  followed by its reduction to give the desired compound. The process involves use of an acid chloride  which is difficult to handle on an industrial scale.
In view of the disadvantages associated with the existing processes  simpler routes for preparing intermediates and bazedoxifene without the use of expensive reagents  complicated and costly equipment  and without complicated operations  and thus which are economical and industrially viable  are desirable.

SUMMARY
Aspects of the present disclosure provide processes for the preparation of bazedoxifene and its pharmaceutically acceptable salts. In embodiments  the compounds are substantially free from process-related impurities and intermediates.
A representative general preparation of bazedoxifene and its salts according to specific embodiments of the present disclosure proceeds as shown in Scheme 1 below  where Bn is a benzyl group and HX is an acid.
Scheme 1
In an aspect  the present disclosure provides processes for preparing bazedoxifene and its pharmaceutically acceptable salts  embodiments comprising at least one of the steps:
(a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (Formula II  where Bn is a benzyl group) with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (Formula III) or a salt thereof  such as the hydrochloride  in the presence of a suitable base  in a reaction inert solvent  to afford 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of Formula IV;

(b) deprotecting the compound of Formula IV under suitable deprotection conditions in a suitable solvent to yield an acid addition salt of bazedoxifene (Formula V)  either by performing the debenzylation under the conditions resulting directly in the salt of bazedoxifene  or optionally converting the bazedoxifene free base from the reaction mixture to its acid addition salt by treatment with a suitable acid HX; and

(c) optionally  purifying the acid addition salt of bazedoxifene obtained in step b) by a suitable purification technique and  if desired  generating the free base by treatment with a suitable base or preparing the acetate salt of bazedoxifene of enhanced purity by treatment of either the free base so generated or a salt with a source of acetate ion in a suitable solvent.
An aspect of the present disclosure provides processes for preparing bazedoxifene acid addition salt of enhanced purity  involving synthesis starting from 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (Formula II) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane or its hydrochloride salt (Formula III)  without isolation of intermediates.
In an aspect  the present disclosure provides processes for preparing bazedoxifene acetate  embodiments comprising at least one of the steps:
(a) treating bazedoxifene free base with a suitable acid HX to prepare an acid addition salt of bazedoxifene and  optionally  purifying the acid addition salt of bazedoxifene using a suitable purification technique;
(b) treating an acid addition salt of bazedoxifene  in a reaction inert solvent  with a suitable base  and
(c) treating bazedoxifene free base obtained in step b) with a source of acetate ion in a suitable solvent.
An aspect of the present disclosure provides processes for preparing an acid addition salt of bazedoxifene of enhanced purity  embodiments comprising at least one of the steps:
(a) treating bazedoxifene free base with an acid; and
(b) optionally  purifying the acid addition salt of bazedoxifene obtained in step a) using a suitable purification technique.
Purification techniques employed in step b) can include generation of bazedoxifene free base in a reaction inert solvent by employing a suitable base  followed by its reaction with a suitable acid in a reaction inert solvent or by conventional crystallization process.
The bazedoxifene free base employed in step a) of the above aspect can be obtained either by providing the isolated bazedoxifene free base in a suitable solvent or by debenzylating the dibenzylated bazedoxifene and using the reaction mixture comprising bazedoxifene free base for treatment with a suitable acid.
An aspect of the present disclosure includes crystalline bazedoxifene hydrochloride.
An aspect of the present disclosure provides processes for preparing an amorphous form of bazedoxifene free base  embodiments comprising at least one of the steps:
a) deprotecting benzylated bazedoxifene with a suitable reagent in a solvent for a time and under conditions suitable for forming a reaction mixture comprising bazedoxifene free base; and
b) removing solvent from the reaction mixture by a suitable technique to afford bazedoxifene free base.
An aspect of the present disclosure provides processes for preparing 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane and its salts  such as the hydrochloride salt  which is an intermediate for preparation of bazedoxifene  comprising:
a) reacting 4-hydroxybenzyl alcohol (Formula VI) with an alkylating agent  such as 1-(2-chloroethyl)azepane hydrochloride (Formula VII)  in the presence of a suitable base and phase transfer catalyst in a suitable reaction solvent  to afford [4-(2-azepan-1-yl-ethoxy)-phenyl]-methanol (Formula VIII); and

b) chlorinating the compound of Formula VIII with a suitable chlorinating agent in a reaction inert solvent  to yield 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride (Formula IIIA).

BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a powder X-ray diffraction (PXRD) pattern of bazedoxifene hydrochloride  obtained in accordance with Example 9.
Fig. 2 is a differential scanning calorimetry (DSC) curve of bazedoxifene hydrochloride  obtained in accordance with Example 9.
Fig. 3 is a thermogravimetric analysis (TGA) curve of bazedoxifene hydrochloride  obtained in accordance with Example 9.
Fig. 4 is a PXRD pattern of bazedoxifene acetate crystalline Form B  obtained in accordance with Example 14.

DETAILED DESCRIPTION
All percentages and ratios used herein are by weight of the total composition  unless the context indicates otherwise. All temperatures are in degrees Celsius unless specified otherwise. The present disclosure can comprise the components discussed in the present disclosure as well as other ingredients or elements described herein.
As used herein  "comprising" means the elements recited  or their equivalents in structure or function  plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise.
All ranges recited herein include the endpoints  including those that recite a range "between" two values.
Terms such as "about " "generally " "substantially " and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify  as those terms are understood by those of skill in the art. This includes  at very least  the degree of expected experimental error  technique error and instrument error for a given technique used to measure a value.
When a molecule or other material is identified herein as "pure"  it generally means  unless specified otherwise  that the material has 99% purity or more  as determined by methods conventional in the art such as high performance liquid chromatography (HPLC) and spectroscopic methods. In general  this refers to purity with regard to unwanted residual solvents  reaction by-products  impurities  and unreacted starting materials. "Substantially pure” refers to the same as "pure” except that the lower limit is about 98% purity and  likewise  "essentially pure” means the same as "pure" except that the lower limit is about 95% purity.
Powder X-ray diffraction pattern information herein has been generated using copper Kα radiation.
Bazedoxifene or a salt thereof is “substantially free from impurities” when it is substantially pure. This implies that the total impurity content will not exceed about 2% and  in general  the material will be considered as substantially free from an individual impurity if the amount of that impurity is less than about 1%.
Aspects of the present disclosure provide processes for the preparation of bazedoxifene and its pharmaceutically acceptable salts  substantially free of process-related impurities.
In an aspect  the present disclosure relates to processes for preparing bazedoxifene and its pharmaceutically acceptable derivatives  embodiments comprising at least one of the steps:
(a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (Formula II  where Bn is a benzyl group) with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (Formula III) or its salt  such as the hydrochloride  in the presence of a suitable base  in a reaction inert solvent  to afford 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of Formula IV;

(b) deprotecting the compound of Formula IV under suitable deprotection conditions in a suitable solvent  to yield an acid addition salt of bazedoxifene (Formula V)  by conducting the debenzylation under conditions resulting directly in a salt of bazedoxifene  or by converting bazedoxifene free base from the reaction mixture to an acid addition salt of bazedoxifene by treatment with a suitable acid HX in the form of a liquid or gas; and

(c) optionally  purifying the acid addition salt of bazedoxifene obtained in step b) using a suitable purification technique and  if desired  generating the free base by treatment with a suitable base  or preparing the acetate salt of bazedoxifene with enhanced purity by treatment of the free base so generated or a salt with a source of acetate ion in a suitable solvent.
Step a) involves reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (Formula II) with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (Formula III)  or its salt such as the hydrochloride  in the presence of a suitable base in a reaction inert solvent  to afford dibenzylated bazedoxifene free base or its salt.
Suitable bases for use in step a) include  but are not limited to: inorganic bases such as alkali metal hydrides  hydroxides  alkoxides and carbonates; and organic bases such as pyridine  lutidine  triethylamine  4-dimethylaminopyridine (DMAP)  dicyclohexylamine  diisopropylethylamine  and the like. A specific example of a useful base is sodium hydride.
Suitable solvents employed in step a) include  but are not limited to: aromatic hydrocarbons  such as  for example  benzene  toluene  and xylene; polar aprotic solvents  such as  for example  N N-dimethylformamide (DMF) and acetonitrile; ethers  such as  for example  1 4-dioxane  tetrahydrofuran (THF)  and methyl THF; and any mixtures thereof in various proportions.
Some suitable temperatures for conducting this step are about 0-10°C.
Step b) involves deprotecting the compound of Formula IV under suitable deprotection conditions in a suitable solvent  to yield an acid addition salt of bazedoxifene (Formula V) either by conducting the debenzylation under conditions resulting directly in a salt of bazedoxifene or optionally converting the bazedoxifene free base from the reaction mixture to an acid addition salt of bazedoxifene by treatment with a suitable acid.
The deprotection or debenzylation reaction of step b) may be carried out using hydrogen gas or a hydrogen source  e.g.  ammonium formate  ammonium acetate  hydrazine  cyclohexadiene  or any other hydrogen source  and a catalyst  such as  for example  Raney nickel  platinum oxide  platinum on activated carbon  palladium hydroxide  palladium on barium sulfate  palladium on activated carbon  and palladium carbonate. The amount of catalyst employed may be about 1–100%  or about 5–50%  or about 5–25%  of the weight of the compound of Formula IV.
The reaction may be carried out in a solvent that is inert to the reaction conditions including  but not limited to: alcohols  such as  for example  methanol  ethanol  and isopropanol; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  and t-butyl acetate; halogenated hydrocarbons  such as  for example  dichloromethane  dichloroethane  chloroform  and the like; hydrocarbons  such as  for example  toluene  xylene  cyclohexane  and the like; acetic acid; and any mixtures thereof in various proportions.
Hydrogen gas pressures for conducting the reaction may vary from about 1–100 Kg/cm2  or about 1–25 Kg/cm2  or about 1–10 Kg/cm2. The reaction times may vary depending on the activity of the catalyst and the amounts thereof used.
Suitable temperatures for conducting deprotection step (b) are about 10–75°C  or from about 20–40°C.
The compound obtained after deprotection in step (b) may optionally be isolated and/or further reacted with a pharmaceutically acceptable acid to afford a pharmaceutically acceptable acid addition salt of bazedoxifene. Alternatively  debenzylation can be done under the conditions that directly lead to preparation of an acid addition salt of bazedoxifene. For example debenzylation can be conducted using palladium on charcoal and hydrogen gas  in the presence of hydrochloric acid or benzyl chloride  or use of a catalytic amount of palladium on charcoal in the presence of an excess of ammonium formate or formic acid.
Step c) involves purification of the acid addition salt of bazedoxifene obtained in step b)  using a suitable purification technique
An acid addition salt may be purified in step c) using conventional crystallization techniques or by a basification-acidification process. The suitable crystallization techniques include  but are not limited to precipitation or slurrying in a solvent  concentrating  cooling  stirring  or shaking a solution containing the compound  combining a solution containing a compound with an anti-solvent  seeding and partial removal of the solvent  or combinations thereof  evaporation  flash evaporation  and the like. An anti-solvent as used herein refers to a liquid in which a compound of Formula V is poorly soluble. Compounds of Formula V can be subjected to any of the purification techniques more than one time until the desired purity for a compound of Formula V or Formula I is attained.
Evaporation as used herein refers to distilling of solvent almost completely  at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent using a technique such as  but not limited to  tray drying  spray drying  fluidized bed drying  and thin film drying  under reduced pressure or at atmospheric pressure.
Basifying-acidifying techniques involve generation of bazedoxifene free base of enhanced purity by treatment of a compound of Formula V with a suitable base  followed by reacting with a suitable acid in a reaction inert solvent to afford an acid addition salt of bazedoxifene that can be isolated by using conventional techniques.
Solvents that can be employed for crystallization  recrystallization  or slurrying include  but are not limited to: alcohols  such as  for example  C1–C4 alcohols; C2–C6 ketones  such as  for example  acetone  ethyl methyl ketone  and diethyl ketone; halogenated hydrocarbons  such as  for example  C1–C6 straight chain branched or aromatic chlorinated hydrocarbons  e.g.  dichloromethane  ethylene dichloride  chloroform  carbon tetrachloride  chlorobenzene  dichlorobenzene  and the like; hydrocarbons  such as  for example  toluene  xylene  cyclohexane  and the like; esters  such as  for example  ethyl acetate  isopropyl acetate  t-butyl acetate  and the like; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; nitriles  such as  for example  acetonitrile  propionitrile  and the like; aprotic solvents  such as  for example  dimethylsulfoxide (DMSO)  N N-dimethylformamide (DMF)  N N-dimethylacetamide (DMAC)  N-methylpyrrolidone (NMP)  and the like; water; and any combinations thereof in various proportions.
The reaction of step c) may be conducted for any desired time periods to achieve the desired product yield and purity. For example  reaction times for step c) may vary from about 30 minutes to about 10 hours  or longer.
An aspect of the present disclosure provides processes for preparing bazedoxifene and its pharmaceutically acceptable salts of enhanced purity  involving synthesis starting from 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (Formula II) and 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane (Formula III)  without isolation of intermediates.
Bazedoxifene acetate prepared by a process of the present disclosure can be substantially free from process-related impurities.
The present disclosure includes bazedoxifene acetate of Formula I  substantially free from the impurity 3-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-methyl-3H-indole of Formula IX  having an RRT about 0.82 (bazedoxifene = 1) in a HPLC method described below.

The present disclosure includes bazedoxifene acetate of Formula I  substantially free from the impurity 3-(4-(2-(azepan-1-yl)ethoxy)benzyl)-2-(4-hydroxyphenyl)-3-methyl-3H-indol-5-ol of Formula X having an RRT of 0.29 in a HPLC method described below.

The purity of the product can be increased by any purification technique  such as by recrystallizing or slurrying bazedoxifene free base or its acetate salt  or any other salt of bazedoxifene  in suitable solvents by processes known in the art. Suitable crystallization techniques include  but are not limited to: concentrating  cooling  stirring  or shaking  a solution containing the compound or by adding anti-solvent  adding seed crystals  evaporation  flash evaporation and the like. An anti-solvent as used herein refers to a solvent in which salt of bazedoxifene is less soluble or poorly soluble. The solvents that can be employed for crystallization include  but are not limited to: lower alcohols  such as methanol  ethanol  isopropyl alcohol; esters such as ethyl acetate  n-propyl acetate  and isopropyl acetate; ethers such as 1 4-dioxane and tetrahydrofuran; nitriles such as acetonitrile; and any mixtures thereof.
The prepared bazedoxifene acetate may be substantially free from impurities.
In embodiments  the bazedoxifene salt has high purity  such as at least about 99%  or at least about 99.5%  or at least about 99.9%  by weight as determined using high performance liquid chromatography (HPLC). Correspondingly  the level of impurities may be less than about 1%  0.5%  or 0.1%  by weight  as determined using HPLC.
In an aspect  the present disclosure provides processes for preparing bazedoxifene acetate having enhanced purity  embodiments comprising at least one of the steps:
(a) treating bazedoxifene free base with an acid to prepare an acid addition salt of bazedoxifene and  optionally  purifying the acid addition salt of bazedoxifene using a suitable purification technique;
(b) treating an acid addition salt of bazedoxifene in a reaction inert solvent with a suitable base; and
(c) treating the bazedoxifene free base with a source of acetate ion  in a suitable solvent.
Step a) involves treatment of bazedoxifene free base with a suitable acid.
Suitable acids employed in step a) include  but are not limited to  inorganic acids such as hydrochloric acid  sulphuric acid  and phosphoric acid  and organic acids such as methanesulfonic acid  benzenesulfonic acid  propionic acid  etc.
The acid employed can be in the form of an aqueous solution or alcohol solution  or can be used in gaseous form wherever applicable  to afford the acid addition salt of bazedoxifene. For example  hydrogen chloride gas can be passed through a mixture comprising bazedoxifene free base  to afford the bazedoxifene hydrochloride salt with enhanced purity.
The salt formation may be carried out in a solvent inert to the reaction conditions including  but not limited to: alcohols  such as  for example  methanol  ethanol  and isopropanol; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  and t-butyl acetate; ketones such as acetone  methyl isobutyl ketone  halogenated hydrocarbons  such as  for example  dichloromethane  dichloroethane  chloroform  and the like; hydrocarbons  such as  for example  toluene  xylene  and cyclohexane; nitriles such as acetonitrile; water; and any mixtures thereof.
Step b) involves basifiying the acid addition salt obtained in step a) with a suitable base  such as an organic base  in a suitable solvent.
Suitable bases for use in step b) include  but are not limited to  organic bases such as triethylamine  4-dimethylaminopyridine (DMAP)  dicyclohexylamine  diisopropylethylamine  morpholine  ammonium hydroxide  pyridine  lutidine  and the like.
Suitable solvents for the said reaction include  but are not limited to: alcohols  such as  for example  methanol  ethanol  and isopropanol; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  and t-butyl acetate; ketones  such as acetone and methyl isobutyl ketone; halogenated hydrocarbons  such as  for example  dichloromethane  dichloroethane  chloroform  and the like; hydrocarbons  such as  for example  toluene  xylene  and cyclohexane; nitriles  such as acetonitrile; water; and any mixtures thereof.
Optionally  in step b) bazedoxifene free base can be isolated from the mixture using any conventional technique.
Step c) involves treatment of bazedoxifene free base with a source of acetate ion in a reaction inert solvent  under conditions and times suitable for formation of bazedoxifene acetate.
Sources of acetate ion in step c) include  but are not limited to  acetic acid.
Suitable solvents for the said reaction include  but are not limited to: alcohols  such as  for example  methanol; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  ethyl acetate  isopropyl acetate  and t-butyl acetate; ketones such as acetone and methyl isobutyl ketone; halogenated hydrocarbons  such as  for example  dichloromethane  dichloroethane  chloroform  and the like; hydrocarbons  such as  for example  toluene  xylene  and cyclohexane; nitriles such as acetonitrile; and any mixtures thereof.
An aspect of the present disclosure provides processes for preparing an acid addition salt of bazedoxifene having enhanced purity  embodiments comprising at least one of the steps:
(a) treating bazedoxifene free base with an acid; and
(b) optionally  purifying the acid addition salt of bazedoxifene obtained in step a) by a suitable purification technique  such as by generating bazedoxifene free base in a reaction inert solvent by employing a suitable base  followed by its reaction with a suitable acid in a reaction inert solvent.
Solvents and acids employed in step a) and purification techniques employed in step b) are similar to those described in above-mentioned aspects.
The bazedoxifene free base can be obtained by providing the isolated bazedoxifene free base in a suitable solvent  or by debenzylating a dibenzylated bazedoxifene and using the reaction mixture comprising bazedoxifene free base for treatment with a suitable acid.
An aspect of the present disclosure provides crystalline bazedoxifene hydrochloride that can be characterized by any of PXRD  DSC  TGA  and Fourier-transform infrared (FT-IR) spectrophotometry techniques.
An aspect of the present disclosure provides processes for preparing an amorphous form of bazedoxifene free base  embodiments comprising at least one of the steps:
a) deprotecting a benzylated bazedoxifene with a suitable reagent in a solvent  for a time and under conditions suitable for forming a reaction mixture comprising bazedoxifene free base; and
b) removing solvent from the reaction mixture by a suitable technique  to afford bazedoxifene free base.
Deprotection conditions and solvents employed in step a) are same as those described above for other aspects.
Step b) involves removal of solvent from the reaction mixture. This can be achieved by complete distillation of solvent at atmospheric pressure or under reduced pressure. Flash evaporation can also be used  with techniques including  but not limited to  tray drying  spray drying  fluidized bed drying  and thin film drying  under reduced pressure or at atmospheric pressure.
In an aspect  the present disclosure provides processes for preparing 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane and its salts  such as the hydrochloride salt  embodiments comprising:
a) reacting 4-hydroxybenzyl alcohol (Formula VI) with an alkylating agent  such as 1-(2-chloroethyl)azepane hydrochloride (Formula VII)  in the presence of a suitable base and phase transfer catalyst in a suitable solvent  to afford [4-(2-azepan-1-yl-ethoxy)-phenyl]-methanol (Formula VIII); and

b) chlorinating the compound of Formula VIII with a suitable chlorinating agent in a reaction inert solvent to yield 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride (Formula IIIA).

Step a) involves alkylation of 4-hydroxybenzylalcohol with a reagent such as 1-(2-chloroethyl)-azepane or its hydrochloride  in the presence of a suitable base  phase transfer catalyst  and reaction inert solvent.
1-(2-Chloroethyl)azepane used in step a) may be either in the form of a free base or an acid addition salt. For example  step a) may employ 1-(2-chloroethyl)azepane hydrochloride.
Suitable bases employed in step a) include  but are not limited to: inorganic bases such as alkali metal hydroxides  alkoxides  and carbonates; and organic bases such as pyridine  lutidine  triethylamine  4-dimethylaminopyridine (DMAP)  dicyclohexylamine  diisopropylethylamine  and the like. A specific example of a useful base is sodium hydroxide.
Phase transfer catalysts are well known to one skilled in the art of organic synthesis. Phase transfer catalysts are of particular utility when at least the first and second compounds to be reacted with each other have such different solubility characteristics that there is no practical common solvent for them and  accordingly  combining a solvent for one of them with a solvent for the other of them results in a two-phase system. The phase transfer catalysts useful in the practice of the present disclosure are of the same type and used in the same manner and amounts as the phase transfer catalysts well known in the art. Examples of phase transfer catalysts useful in the practice of the present disclosure include tetrabutylammonium bromide (TBAB)  triethylbenzylammonium chloride  and tricetylmethylammonium chloride.
Suitable solvents that can be used in this step include  but are not limited to: halogenated hydrocarbons  such as  for example  C1–C6 straight chain branched or aromatic chlorinated hydrocarbons  e.g.  dichloromethane  ethylene dichloride  chloroform  carbon tetrachloride  chlorobenzene  dichlorobenzene  and the like; aliphatic  cyclic  or aromatic hydrocarbons  such as  for example  cyclohexane  toluene  and the like; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  methyl acetate  ethyl acetate  isopropyl acetate  t-butyl acetate  and the like; nitriles  such as  for example  acetonitrile  propionitrile  and the like; aprotic solvents  such as  for example  dimethylsulphoxide (DMSO)  N N-dimethylformamide (DMF)  N N-dimethylacetamide (DMAC)  N-methylpyrrolidone (NMP)  and the like; any mixtures thereof; and their combinations with water in various proportions.
Reaction temperatures may range from about room temperature to the reflux temperature of the solvent used.
Step b) involves chlorination of the compound of Formula VIII with a suitable chlorinating agent in a reaction inert solvent  to yield 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride (Formula IIIA).
Chlorinating agents employed in step b) can be any reagents that are a source of chlorine or chloride ion  such as dry hydrogen chloride gas  thionyl chloride  etc.  and mixtures thereof. Chlorination can be done either by using a single chlorinating agent or by sequential or simultaneous addition of two chlorinating agents.
Suitable solvents that can be used in this step include  but are not limited to: halogenated hydrocarbons  such as C1–C6 straight chain branched or aromatic chlorinated hydrocarbons  e.g.  dichloromethane  ethylene dichloride  chloroform  carbon tetrachloride  chlorobenzene  dichlorobenzene  and the like; aliphatic  cyclic  or aromatic hydrocarbons  such as  for example  cyclohexane  toluene  and the like; ethers  such as  for example  1 4-dioxane  THF  and methyl THF; esters  such as  for example  methyl acetate  ethyl acetate  isopropyl acetate  t-butyl acetate  and the like; nitriles  such as  for example  acetonitrile  propionitrile  and the like; aprotic solvents  such as  for example  dimethylsulphoxide (DMSO)  N N-dimethylformamide (DMF)  N N-dimethylacetamide (DMAC)  N-methylpyrrolidone (NMP)  and the like; and any mixtures thereof.
Step b) may be conducted at temperatures about 0°C up to the reflux temperature of the solvent  or about 0-50°C  or about 25-35°C.
Optionally  steps a) and b) can be carried out in a single vessel  starting from 4-hydroxybenzyl alcohol and 1-(2-chloroethyl)-azepane or its hydrochloride salt  without isolation of a compound of Formula VIII.
The intermediate compounds at any stage of the processes of the present disclosure  or an acid addition salt of bazedoxifene  can be recovered by using conventional techniques such as filtration  decantation  centrifugation  and the like  in the presence or absence of an inert atmosphere  such as  for example  nitrogen and the like.
The compounds at any stage of the processes of the present disclosure may be recovered from a suspension or solution  using any of techniques such as decantation  filtration by gravity or by suction  centrifugation  slow evaporation  and the like  or any other suitable techniques. The solids that are isolated may carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired  the solids may be washed with a solvent to wash out the mother liquor and/or impurities  and the resulting wet solids may optionally be dried. Evaporation  as used herein  refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique including  but not limited to  tray drying  spray drying  fluidized bed drying  and thin film drying  under reduced pressure or at atmospheric pressure.
The recovered solid may be optionally dried. Drying may be carried out using a tray dryer  vacuum oven  air oven  fluidized bed dryer  spin flash dryer  flash dryer  and the like  at atmospheric pressure or under reduced pressure. The drying may be carried out at temperatures less than about 200°C  or about 20°C to about 80°C  or about 30°C to about 60°C  or any other suitable temperatures  at atmospheric pressure or under reduced pressure. The drying may be carried out for any desired times until the desired quality of product is achieved  such as about 30 minutes to about 5 hours  or about 1 to about 4 hours. Shorter or longer times also are useful.
Bazedoxifene  its salts such as the acetate  and drug-related impurities may be analyzed using HPLC  for example by a method using a Symmetry shield Rp 18  (150×4.6 mm  3.5 m) column with the following parameters:
Flow rate 1.0 mL/minute.
Detector 220 nm.
Column oven temp. 25°C.
Injection volume 10 L.
Run time 70 minutes.
Elution Gradient.
Buffer 0.01M K2HPO4 in water  pH adjusted to 8 with H3PO4.
Mobile phase A Buffer and acetonitrile (600:400 by volume).
Mobile phase B Water and acetonitrile (100:900 by volume)
Diluent Acetonitrile and water (9:1 by volume)
Sample preparation Dissolve 5 mg of sample in diluent and make up the volume to 10 mL with diluent.
Aspects of the present disclosure include bazedoxifene  or a salt thereof such as the acetate  formulated as: solid oral dosage forms  such as  for example  powders  granules  pellets  tablets  capsules; liquid oral dosage forms  such as  for example  syrups  suspensions  dispersions  emulsions; injectable preparations  such as  for example  solutions  dispersions  freeze dried compositions Immediate release compositions may be conventional  dispersible  chewable  mouth dissolving  or flash melt preparations. Modified release compositions may comprise hydrophilic and/or hydrophobic release rate controlling substances to form matrix and/or reservoir systems. The compositions may be prepared by techniques such as direct blending  dry granulation  wet granulation  extrusion and spheronization  etc. Compositions may be uncoated  film coated  sugar coated  powder coated  enteric coated  or modified release coated.
Pharmaceutical compositions of bazedoxifene or a salt thereof comprise one or more pharmaceutically acceptable excipients. Useful pharmaceutically acceptable excipients include  but are not limited to: diluents  such as  for example starches  pregelatinized starches  lactose  powdered celluloses  microcrystalline celluloses  dicalcium phosphate  tricalcium phosphate  mannitol  sorbitol  sugar  and the like; binders  such as  for example acacia  guar gum  tragacanth  gelatin  polyvinylpyrrolidones  hydroxypropyl celluloses  hydroxypropyl methylcelluloses  pregelatinized starches  and the like; disintegrants  such as  for example starches  sodium starch glycolate  pregelatinized starches  crospovidones  croscarmellose sodiums  colloidal silicon dioxides  and the like; lubricants  such as  for example stearic acid  magnesium stearate  zinc stearate  and the like; glidants  such as  for example colloidal silicon dioxides  and the like; solubility or wetting enhancers  such as  for example anionic  cationic  and neutral surfactants; complex forming agents  such as  for example various grades of cyclodextrins; release rate controlling agents  such as  for example hydroxypropyl celluloses  hydroxymethyl celluloses  hydroxypropyl methylcelluloses  ethyl celluloses  methyl celluloses  various grades of methyl methacrylates  waxes  and the like. Other pharmaceutically acceptable excipients include  but are not limited to  film formers  plasticizers  colorants  flavoring agents  sweeteners  viscosity enhancers  preservatives  antioxidants  and the like.
Certain specific aspects and embodiments of the present disclosure will be explained in more detail with reference to the following examples  which are provided solely for purposes of illustration and are not to be construed as limiting the scope of the disclosure in any manner.

EXAMPLE 1: PREPARATION OF 5-BENZYLOXY-2-(4-BENZYLOXY-PHENYL)-3-METHYL-1H-INDOLE.
4’-Benzyloxy-2-bromophenylpropiophenone (50 g)  4-benzyloxyaniline hydrochloride (40.5 g)  triethylamine (50 mL) and N N-dimethylformamide (300 mL) are mixed and heated to about 100°C  and maintained at that temperature for 3-3.5 hours until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-55°C and additional 4-benzyloxyaniline hydrochloride (40.5 g) is added and stirred. The temperature is raised to 120-125°C and maintained for 5-5.5 hours  with completion of the reaction verified using TLC. After completion of the reaction  the mixture is allowed to cool to room temperature  then the mixture is added to a solution of 5% acetic acid (1000 mL) in water  followed by mixing with ethyl acetate (2000 mL). The organic layer is separated and washed with 5% sodium bicarbonate solution (1000 mL) and brine solution (1000 mL). The organic layer is distilled completely under vacuum and the residue is cooled to 45°C  then methanol (400 mL) is added and the mixture is stirred for 1-1.5 hours. The formed solid is filtered and washed with methanol (300 mL)  then dried under vacuum at 65°C for 4 hours to afford the title compound in 65.14% yield.

EXAMPLE 2: PREPARATION OF 5-BENZYLOXY-2-(4-BENZYLOXY-PHENYL)-3-METHYL-1H-INDOLE.
4’-Benzyloxy-2-bromophenylpropiophenone (10 Kg)  4-benzyloxyaniline hydrochloride (8.10 Kg)  triethylamine (10 L)  and N N-dimethylformamide (60 L) are mixed and heated to about 100-105°C  and maintained at that temperature until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-55°C and additional 4-benzyloxyaniline hydrochloride (8.10 Kg) is added and stirred. The temperature is raised to 120-125°C and the mixture is maintained at the same temperature for 5-5.5 hours  with completion of the reaction as verified using TLC. After completion of the reaction  the mixture is allowed to cool to 25-35°C  then the mixture is added to 5% aqueous acetic acid solution (10 L acetic acid in 190 L of water)  followed by mixing with ethyl acetate (400 L). The organic layer is separated and washed with 5% sodium bicarbonate solution (10 Kg in 200 L) and brine solution (70 Kg of NaCl in 490 L of water).The ethyl acetate is distilled under vacuum below 70°C (up to ~10 L reaction mass remains) and the residue is cooled to 40-50°C  then methanol (80 L) is added and the mixture is cooled to 25-35°C and stirred at same temperature for 1.5-2 hours. The formed solid is filtered and washed with methanol (60 L)  then dried under vacuum to afford the title compound in 65.14% yield.

EXAMPLE 3: PREPARATION OF 1-[2-(4-CHLOROMETHYL-PHENOXY)-ETHYL]-AZEPANE HYDROCHLORIDE.
4-Hydroxybenzyl alcohol (10 g) is added to a solution of sodium hydroxide (7.73 g) in water (150 mL). The mixture is stirred to obtain a clear solution  and then toluene (100 mL)  2-chloroethylazepan hydrochloride (20.74 g)  and tetrabutylammonium bromide (0.519 g) are added. The mixture is refluxed for completion of the reaction (1-1.5 hours)  as verified using TLC. The mixture is cooled to 25-35°C and the organic layer is separated and washed with 10% NaCl solution (100 mL) at 50°C. The organic layer is distilled completely under vacuum  and then dichloromethane (200 mL) is added to the residue. The mixture is stirred for dissolution under a nitrogen atmosphere. Dry HCl gas is passed through the solution for 30-60 minutes at 25-35°C and the mixture is stirred for 1-1.5 hours at the same temperature. About 85-90% of the solvent is distilled from the mixture  then acetone (60 mL) is added  and 85-90% of the solvent is distilled. This addition and distillation step is repeated twice with acetone (60 mL). To the residue  acetone (60 mL) is added and mixture is cooled to 0-5°C and further stirred at same temperature for 4-4.5 hours. The solid obtained is filtered under a nitrogen atmosphere  washed with chilled acetone (40 mL) under a nitrogen atmosphere  and dried under vacuum at 50-55°C for 4-5 hours to afford the title compound in 61.2% yield.

EXAMPLE 4: PREPARATION OF 1-[2-(4-CHLOROMETHYLPHENOXY)ETHYL]-AZEPANE HYDROCHLORIDE.
4-Hydroxybenzyl alcohol (1 Kg) is added to a solution of sodium hydroxide (0.77 Kg) in water (15 L). The mixture is stirred to obtain a clear solution  and then toluene (10 L)  2-chloroethylazepan hydrochloride (2.07 Kg)  and tetrabutylammonium bromide (0.05 Kg) are added. The mixture is refluxed at 85-90°C for completion of the reaction (1-1.5 hours)  as verified using TLC. The mixture is cooled to 25-35°C and the organic layer is separated and washed with 10% NaCl solution (1 Kg NaCl in 10 L of water) at 55-60°C. The organic layer is distilled completely under vacuum below 65°C  and residue is cooled to 25-35°C under a N2 atmosphere. Dichloromethane (20 L) is added to the residue and the mixture is stirred for dissolution under a nitrogen atmosphere. Dry HCl gas (6 Kg) is purged through the solution at 25-35°C until a turbid mass appears  followed by clear solution being observed. Purging of dry HCl gas is continued until reaction completion  as verified using TLC. About 85-90% of the solvent is distilled from the mixture under vacuum and acetone (5 L) is added  and 85-90% of the solvent is again distilled. This addition and distillation step is repeated once with acetone (5 L). The mass is cooled to 25-35°C followed by addition of acetone (3 L) and the mixture is stirred at 2.5-7.5°C for 4-4.5 hours. The solid obtained is filtered under a nitrogen atmosphere  washed with chilled acetone (2 L) under a nitrogen atmosphere  and dried under vacuum at 50-55°C for 10-12 hours to afford the title compound.

EXAMPLE 5: PREPARATION OF 1-[2-(4-CHLOROMETHYL-PHENOXY)-ETHYL]-AZEPANE HYDROCHLORIDE.
A mixture of [4-(2-Azepan-1-yl-ethoxy)phenyl]methanol (10 g) and toluene (100 mL) is stirred for 10 minutes at room temperature. The mass is cooled to 0-5°C  and dry HCl gas is passed through the mixture at 0-5°C until a thick mass is obtained (pH~2). The mass is stirred for 30 minutes at the same temperature  followed by addition of thionyl chloride (5.2 g) at 0-5°C over 20-30 minutes. The temperature is raised to 55-60°C with stirring until completion of reaction  as verified using TLC. The mixture is distilled below 60°C under vacuum  to afford a residue. Acetone (60 mL) is added and the mixture is stirred for 2 hours at 0-5°C under a nitrogen atmosphere. The solid is filtered and washed with chilled acetone (30 mL) under a nitrogen atmosphere  then dried under vacuum at 50°C for 3 hours to afford the title compound.

EXAMPLE 6: PREPARATION OF 1-[2-(4-CHLOROMETHYL-PHENOXY)-ETHYL]-AZEPANE HYDROCHLORIDE.
[4-(2-Azepan-1-yl-ethoxy)phenyl]methanol (10 g) and tetrahydrofuran (100 mL) are mixed. Dry hydrogen chloride gas is passed through the mixture until a thick mass is formed  followed by cooling to 0-5°C and addition of thionyl chloride (3.2 mL) at the same temperature. The mixture is heated to 50°C until it becomes clear and is stirred for 3-4 hours at 50°C until completion of the reaction  as verified using TLC. The mixture is distilled below 50°C under vacuum. Hexane (50 mL) and THF (120 mL) are added and the mixture is stirred for 30-45 minutes. The solid is filtered  washed with tetrahydrofuran (20 mL)  and dried to afford the title compound (~61% yield).

EXAMPLE 7: PREPARATION OF 5-BENZYLOXY-2-(4-BENZYLOXYPHENYL)-3-1-[4-(2-HEXAMETHYLENEIMINE-1-YL-ETHOXY)-BENZYL]-1H-INDOLE.
To a chilled mixture of sodium hydride (2.28 g) in N N-dimethylformamide (10 mL) and toluene (10 mL)  a solution of 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole (10 g) in N N-dimethylformamide (20 mL) is added at -5 to -1°C. The mixture is stirred for 30-45 minutes at the same temperature and then a solution of 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane hydrochloride (7.97 g) in N N-dimethylformamide (50 mL) is added over 30 minutes  below 5°C. The mixture is stirred at or below 5°C for ~2-3 hours and reaction progress is monitored using TLC. Acetic acid (0.8 mL) is added  followed by addition of ethyl acetate (100 mL) and water (100 mL). The mixture is filtered and the aqueous layer is extracted with ethyl acetate (100 mL  then 50 mL). The combined organic layer is washed with 10% brine solution (2×100 mL). The organic layer is separated and distilled under vacuum at 50°C to form a residue. Methanol (120 mL) is added to the residue and the mixture is stirred for 30 minutes at 25-30°C. The solid is filtered and washed with methanol (40 mL). Methanol (90 mL) is added and the mixture is stirred for 30 minutes at 25-30°C  the solid is filtered and washed with methanol (50 mL). The solid is dried under vacuum at 50°C for ~1.5 hours  to afford the title compound.

EXAMPLE 8: PREPARATION OF 5-BENZYLOXY-2-(4-BENZYLOXYPHENYL)-3-1-[4-(2-HEXAMETHYLENEIMINE-1-YL-ETHOXY)-BENZYL]-1H-INDOLE
To a chilled mixture of sodium hydride (2 Kg) in N N-dimethylformamide (8.6 L) and toluene (12.9 L)  a solution of 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole (8.6 Kg) in N N-dimethylformamide (18 L) is added at -5 to -1°C. Additional N N-dimethylformamide (8.6 L) is added. The mixture is stirred for 30-60 minutes at the same temperature. Separately  a solution of 1-[2-(4-chloromethylphenoxy)ethyl]azepane hydrochloride (6.79 Kg) in N N-dimethylformamide (43 L) is prepared at 55-60°C and slowly added to the above reaction mixture  below 5°C. The flask is charged with additional N N-dimethylformamide (8.6 L) and the mixture is stirred at or below 5°C for ~2-3 hours with reaction progress being monitored using TLC. Acetic acid (0.6 L) is added  followed by addition of ethyl acetate (86 L and 9 L) and water (86 L). The mixture is filtered and the aqueous layer is extracted with ethyl acetate (86 L  then 43 L). The combined organic layer is washed twice with 10% brine solution (8.6 Kg in 86 L water). The organic layer is separated and distilled under vacuum at 50°C to form a residue. Methanol (105 L) is added and the mixture is stirred for 1.5 to 2 hours at 25-35°C. The solid is filtered and washed with methanol (40 L and 90 L). The solid is dried under vacuum at below 50°C to afford the title compound.

EXAMPLE 9: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A flask is charged with 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (20 g)  acetone (240 mL) and methanol (80 mL)  10% palladium on carbon (4 g)  and water (8 mL). The mixture is stirred under 10 Kg/cm2 hydrogen pressure at 45-50°C until completion of the reaction (~2-2.5 hours)  as verified using TLC. The mixture is cooled to 25-35°C  filtered  and the solid is washed with methanol (60 mL). To the combined filtrate  aqueous hydrochloric acid (~11N  3.25 mL) is added and pH is adjusted below 1.5  then the mixture is stirred for 9-10 hours. The solid is filtered and washed with methanol (20 mL)  then suction dried. Acetone (120 mL) and water (24 mL) are charged to a flask containing the wet solid. Slowly  triethylamine (6 mL) is added to obtain a clear solution having pH ~9 and the mixture is stirred for 10-15 minutes. The pH of the mixture is adjusted with aq. hydrochloric acid (4.4 mL) to below 1.5 and mixture is stirred for 5-6 hours. The solid obtained is filtered and washed with acetone (20 mL)  then dried at 70°C for 4-5 hours to afford the title compound in ~67% yield.

EXAMPLE 10: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (10 g) and ethyl acetate (100 mL) is heated to 40°C to produce a clear solution  then 10% palladium on carbon (3 g) is added and the mixture is stirred under 10 Kg/cm2 hydrogen pressure at 45-50°C until completion of the reaction  as verified using TLC. The mixture is filtered and washed with ethyl acetate (20 mL). The filtrate is distilled completely under vacuum to afford a residue  methanol (40 mL) is added  and the mixture is stirred to produce a clear solution. Aqueous hydrochloric acid (~11N  11 mL) is added and the mixture is stirred for 2-3 hours. The solid is filtered and washed with methanol (10 mL)  then dried at 50°C for 3-4 hours to afford the title compound in 91.14% yield.

EXAMPLE 11: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A flask is charged with a mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (10 g)  THF (50 mL) and methanol (100 mL)  10% palladium on carbon (2 g)  and water (4 mL)  and the mixture is stirred under 10 Kg/cm2 hydrogen pressure at 40°C until completion of the reaction  as verified using TLC. The mixture is filtered and the solid washed with methanol (20 mL). To the filtrate  aqueous hydrochloric acid (~11N  2.5 mL) and L-ascorbic acid (0.01g) are added and the mixture is stirred overnight for salt formation. The solid obtained is filtered and washed with methanol (14 mL)  and dried at 50°C for 4-5 hours to afford the title compound in 51.6% yield.

EXAMPLE 12: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A flask is charged with a mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (10 g)  1 4-dioxane (50 mL)  and methanol (100 mL) at 40°C. To this mixture  10% palladium on carbon (2 g) and water (4 mL) are added and the mixture is stirred under 10 Kg/cm2 hydrogen pressure at 48-52°C until completion of the reaction  as verified using TLC. The mixture is cooled to 25-35°C  filtered  and the solid is washed with methanol (20 mL). To the filtrate  L-ascorbic acid (0.05 g) and aqueous hydrochloric acid (~11N  1.74 mL) are added and mixture is stirred for solid formation. The solid obtained is filtered and washed with methanol (20 mL)  and dried at 50°C for 4-5 hours to afford the title compound in 68.16% yield.

EXAMPLE 13: PREPARATION OF BAZEDOXIFENE ACETATE FROM BAZEDOXIFENE HYDROCHLORIDE  USING INORGANIC BASE.
A flask is charged with bazedoxifene hydrochloride (0.8 g  HPLC purity 99.5%)  ethyl acetate (30 mL)  and 5% aqueous sodium bicarbonate (5 g in 50 mL water). The mixture is heated to 50°C and stirred at the same temperature for 10-15 minutes. The aqueous layer is separated and extracted with ethyl acetate (20 mL). The organic layers are combined and distilled completely under vacuum. The residue is mixed with acetone (10 mL)  L-ascorbic acid (0.01 g) is added  and the mixture is heated to 40-45°C. To this mass  acetic acid is added (0.1 mL) and the mixture is cooled to 25-35°C  followed by stirring at the same temperature for 3-4 hours. The solid obtained is filtered and washed with acetone (2 mL)  then dried to afford the title compound in 72.87% yield (HPLC purity 99.38%).

EXAMPLE 14: PREPARATION OF BAZEDOXIFENE ACETATE FROM BAZEDOXIFENE HYDROCHLORIDE  USING ORGANIC BASE.
A flask is charged with bazedoxifene hydrochloride (70 g  HPLC purity 99.66%)  ethyl acetate (700 mL)  and water (700 mL). The mixture is stirred for 10 minutes  followed by addition of a mixture of triethylamine (42 mL) and ethyl acetate (70 mL) over 15 minutes. The clear solution is stirred and layers are separated. The aqueous layer is extracted with ethyl acetate (350 mL). The organic layers are combined and washed with 10% sodium chloride solution (2×350 mL)  followed by complete distillation under vacuum. The residue is mixed with acetone (700 mL) and solvent is distilled. This operation is repeated once with acetone (700 mL). To the residue  acetone (1050 mL) and L-ascorbic acid (0.48 g) are added at ~40°C  followed by addition of a solution of acetic acid (9.11 g) in acetone (70 mL) over ~20 minutes. The mixture is cooled to ~30°C and maintained at the same temperature for ~5 hours. The solid obtained is filtered and washed with acetone (140 mL)  then dried at 50°C to afford the title compound in 85.88% yield (HPLC purity 99.80%).

EXAMPLE 15: PREPARATION OF BAZEDOXIFENE MESYLATE.
To a mixture of bazedoxifene free base (5g)  acetone (25 mL)  and L-ascorbic acid (0.01 g)  methanesulfonic acid (0.75 mL) is added slowly and the mass is stirred for 2-3 hours. Methanol (5 mL) is added and the mixture is maintained for salt formation. The solid obtained is filtered and washed with acetone (15 mL)  then dried at 50°C for 4-5 hours to afford the title compound.

EXAMPLE 16: PREPARATION OF BAZEDOXIFENE PROPIONATE.
To a mixture of bazedoxifene free base (3 g) and acetone (24 mL)  propionic acid (0.52 g) is added and the mass is stirred for 3-4 hours for salt formation. The solid obtained is filtered and washed with acetone (6 mL)  then dried at 50°C for 4-5 hours to afford the title compound in 60.23% yield (HPLC purity 98.80%).

EXAMPLE 17: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
Bazedoxifene free base (3.5 g) and methanol (21 mL) are stirred to produce a clear solution. Dry HCl gas is passed through the solution until solid forms  and then the mixture is stirred for 1-2 hours. The solid obtained is filtered and washed with methanol (7 mL)  then dried at 50°C for 3-4 hours to afford the title compound in 87.79% yield.

EXAMPLE 18: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
Bazedoxifene free base (3.5 g) and methanol (21 mL) are stirred to produce a clear solution  followed by addition of aqueous hydrochloric acid (~11N  5.5 mL). The mixture is stirred for 1-2 hours. The solid is filtered and washed with methanol (7 mL)  then dried at 50°C for 3-4 hours to afford the title compound in 79.84% yield.

EXAMPLE 19: PURIFICATION OF BAZEDOXIFENE HYDROCHLORIDE.
Bazedoxifene hydrochloride (1 g) and methanol (40 mL) are mixed  followed by addition of water (20 mL) and mixing for dissolution. L-ascorbic acid (0.01 g) is added and the mixture is stirred for solid formation. The solid is filtered and washed with methanol (2 mL)  then dried at 50°C for 3-4 hours to afford the title compound in ~42% yield (HPLC purity 99.5%).

EXAMPLE 20: PURIFICATION OF BAZEDOXIFENE HYDROCHLORIDE.
Bazedoxifene hydrochloride (1 g) and acetone (30 mL) are mixed  followed by addition of water (20 mL) and mixing for dissolution. L-ascorbic acid (0.01 g) is added  the mixture is stirred for 12 hours  and 60% of the solvent is distilled under vacuum for solid formation. The solid is filtered and washed with acetone (20 mL)  then dried at 50°C for 3-4 hours to afford the title compound in ~40% yield (HPLC purity 99.4%).

EXAMPLE 21: PREPARATION OF BAZEDOXIFENE FREE BASE.
A mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (10 g)  acetone (150 mL) and methanol (100 mL)  10% palladium on carbon (2 g)  and water (4 mL) is stirred under 10 Kg/cm2 hydrogen pressure at 40°C until completion of the reaction  as verified using TLC. The mixture is cooled and filtered and the solid is washed with acetone (20 mL). The filtrate is distilled completely under vacuum  to afford bazedoxifene free base (7.1 g) in ~99.72% yield.

EXAMPLE 22: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A mixture of bazedoxifene free base (7.0 g) obtained in Example 22  methanol (100 mL)  acetone (150 mL)  and water (3 mL) is stirred to produce a clear solution. Aqueous hydrochloric acid (~11N  2.5 mL) and L-ascorbic acid (0.01 g) are added and the mixture is maintained for salt formation with stirring for 2-3 hours. The solid is filtered and washed with methanol (14 mL)  then dried at 50°C for 4-5 hours to afford the title compound in 79.57% yield.

EXAMPLE 23: PREPARATION OF BAZEDOXIFENE HYDROCHLORIDE.
A mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (30 g)  acetone (450 mL)  and methanol (150 mL) is stirred at 40°C. To this  10% palladium on carbon (6 g) and water (12 mL) are added  a hydrogen pressure of 10 Kg/cm2 is applied  and the mixture is heated to 50°C until completion of the reaction  as verified using TLC. The mixture is cooled to 25-35°C and filtered  and the solid is washed with methanol (60 mL). To the filtrate  L-ascorbic acid (0.15 g) and aq. hydrochloric acid (~11N  5.2 mL) are added and the mixture is maintained for salt formation. The solid is filtered and washed with methanol (60 mL)  then dried at 50°C for 4-5 hours to afford the title compound (~17 g) in ~75% yield (HPLC purity 98.99%).
The compound so obtained is divided into three parts  of 2 g each  and subjected to purification by the following methods.
A) To one portion of bazedoxifene hydrochloride (2 g)  acetone (40 mL) is added and the mixture is heated to 40-50°C. Water (30 mL) is slowly added and the mixture is cooled to 25-30°C  followed by stirring at the same temperature. About 10% of solvent is distilled under vacuum  causing solid formation  and the solid is filtered and washed with acetone (10 mL)  then suction dried to afford bazedoxifene hydrochloride (HPLC purity 99.46%).
B) To one portion of bazedoxifene hydrochloride (2g)  acetone (60 mL) is added and the mixture is heated to 40-50°C. Water (20 mL) is slowly added and the mixture is cooled to 25-30°C  followed by stirring at the same temperature. About 50% of the solvent is distilled under vacuum  causing solid formation  and the solid is filtered  washed with acetone (10 mL)  and suction dried to afford bazedoxifene hydrochloride (HPLC purity 99.47%).
C) To one portion of bazedoxifene hydrochloride (2g)  water (20 mL) is added and the mixture is heated to 40-50°C. THF (16 mL) is added and the mixture is cooled to 25-30°C  followed by stirring at the same temperature. About 50% of solvent is distilled under vacuum  causing solid formation  and the solid is filtered  and washed with THF (15 mL)  and suction dried to afford bazedoxifene hydrochloride.

EXAMPLE 24: PREPARATION OF BAZEDOXIFENE ACETATE FROM BAZEDOXIFENE HYDROCHLORIDE  USING ORGANIC BASE.
A mixture of bazedoxifene hydrochloride (5 g)  ethyl acetate (50 mL)  and water (50 mL) is stirred for 10 minutes  followed by addition of N-methylmorpholine (16 mL). The clear mixture is stirred and layers are separated. The aqueous layer is extracted with ethyl acetate (10 mL). The organic layers are combined and washed with 10% sodium chloride solution (2×25 mL) followed by complete distillation under vacuum. The residue is mixed with acetone (50 mL) and solvent is distilled. This operation is repeated once with acetone (50 mL). To the residue  acetone (5 mL) and L-ascorbic acid (0.48 g) are added and the mass is heated to ~40°C  followed by addition of acetic acid (0.65 mL) at the same temperature. The mixture is cooled to ~25-35°C and maintained at the same temperature for ~4-5 hours. The solid is filtered and washed with acetone (10 mL)  then dried at 50°C to afford the title compound in ~84% yield.

EXAMPLE 25: PREPARATION OF BAZEDOXIFENE FREE BASE.
Ethanol (80 mL)  10% palladium on carbon (7 g)  and a solution of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (15 g) in tetrahydrofuran (120 mL) are placed into an autoclave. The mixture is stirred under 4 Kg/cm2 hydrogen pressure at 25-30°C and completion of the reaction is determined using TLC. The mixture is filtered and washed with tetrahydrofuran (20 mL)  followed by distillation of the filtrate under vacuum to obtain a residue. Acetone (100 mL) is added to the residue followed by distillation to afford the title compound (10.1 g  93.5% yield).

EXAMPLE 26: PREPARATION OF BAZEDOXIFENE FREE BASE.
A mixture of 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (20 g)  methanol (200 mL)  10% palladium on carbon (8.0 g)  and ammonium formate (9.7 g) is heated to 50-55°C with constant stirring for about 1-2 hours and reaction progress is monitored using TLC. The mixture is filtered and solid is washed with methanol (40 mL). The solvent from the filtrate is distilled under vacuum to form a residue. Hexane (50 mL) is added to the residue  the mixture is stirred  and the solid is filtered  washed with hexane (10 mL)  and dried under vacuum to afford the title compound (2.6 g  72% yield).

EXAMPLE 27: PREPARATION OF BAZEDOXIFENE FREE BASE.
A mixture of 10% palladium on carbon (1.5 g)  ammonium formate (2.4 g)  acetone (50 mL)  and 1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (5 g) is heated to reflux and maintained until completion of the reaction (~1 hour). The mixture is cooled to 25-30°C and filtered  and the solid is washed with acetone (20 mL). The filtrate is completely distilled under vacuum to form the title compound in 99.7% yield.

EXAMPLE 28: PREPARATION OF BAZEDOXIFENE FREE BASE.
A mixture of 10% palladium on carbon (3 g)  ethyl acetate (100 mL)  1-(4-(2-(azepan-1-yl)ethoxy)benzyl)-5-(benzyloxy)-2-(4-benzyloxy)phenyl)-3-methyl-1H-indole (10 g)  and ammonium formate (4.8 g) is heated to 40-45°C and maintained until completion of the reaction (~3 hours). The mixture is cooled to 25-30°C and filtered  and the solid is washed with ethyl acetate (20 mL). The filtrate is completely distilled under vacuum to form the title compound in 98.2% yield.

EXAMPLE 29: PREPARATION OF BAZEDOXIFENE ACETATE.
Bazedoxifene free base (5.0 g) and ethyl acetate (30 mL) are mixed and heated to 50°C  then acetic acid (0.7 g) is slowly added. The mixture is stirred for about 1 hour at 50°C  then cooled to room temperature and stirred for ~2 hours. The mixture is then cooled to 0-5°C for gummy solid formation and the mass is completely distilled under vacuum to form a solid. Hexane is added to the solid and the mixture is stirred for about 1 hour. The solid is filtered and washed with hexane (20 mL)  then dried to afford the title compound (4.2 g  74.6% yield).

WE CLAIM:
1. A process for preparing bazedoxifene or a salt thereof  comprising:
(a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1H-indole of Formula II  where Bn is a benzyl group  with 1-[2-(4-chloromethyl-phenoxy)-ethyl]-azepane of Formula III  or a salt thereof  in the presence of a base  to yield 5-benzyloxy-2-(4-benzyloxy-phenyl)-3-methyl-1H-indole of Formula IV;

(b) debenzylating the compound of Formula IV and forming an acid addition salt of bazedoxifene of Formula V  where HX is an acid moiety;

(c) optionally  purifying the acid addition salt of bazedoxifene of Formula V; and 
(d) optionally  (i) generating bazedoxifene free base by reacting the acid addition salt of bazedoxifene with a suitable base and  optionally  preparing an acetate salt of bazedoxifene by reacting the free base with a source of acetate ion; or (ii) reacting the acid addition salt of bazedoxifene with a source of acetate ions to prepare an acetate salt of bazedoxifene.
2. The process according to claim 1  wherein (b) comprises either:
(i) directly forming the compound of Formula V; or
(ii) forming bazedoxifene free base and then reacting with an acid HX to yield the compound of Formula V.
3. The process according to claim 1  wherein a base in (a) is sodium hydride.
4. The process according to claim 1  wherein debenzylation is done by catalytic hydrogenation.
5. The process according to claim 1  wherein solvent in step (b) comprises water.
6. A process for preparing bazedoxifene acetate  comprising:
(a) reacting bazedoxifene free base with an acid to prepare an acid addition salt of bazedoxifene;
(b) optionally  purifying the acid addition salt of bazedoxifene from (a);
(c) reacting an acid addition salt of bazedoxifene from (a) or (b) with a suitable base to prepare bazedoxifene free base; and
(d) reacting bazedoxifene free base with a source of acetate ion.
7. The process according to claim 6  wherein an acid comprises hydrochloric acid  methanesulfonic acid  sulfuric acid  or phosphoric acid.
8. The process according to claim 6  wherein a base in (c) is an organic base.
9. The process according to claim 6  wherein a base in (c) comprises triethylamine  morpholine  or ammonium hydroxide.
10. A process for preparing an acid addition salt of bazedoxifene  comprising:
(a) reacting bazedoxifene free base with an acid;
(b) reacting the product of (a) with a base; and
(c) reacting the product of (b) with an acid; or
(d) optionally  instead of steps (b) and (c)  purifying the product of step (a) by crystallization.
11. The process of claim 11 where an acid in (a) is hydrochloric acid.