WO2011022596A2

WO2011022596A2 - Preparation of bazedoxifene and its salts

Info

Publication number: WO2011022596A2
Application number: PCT/US2010/046091
Authority: WO
Inventors: Rakeshwar Bandichhor; Amarnath Reddy Lekkala; Pranab Haldar; Ravi Kumar Mylavarapu; China Malakondaiah Golla; Raghunath Vagwala; Vijaya Kumar Karri; Swapna Akula
Original assignee: Dr. Reddy's Laboratories Ltd.; Dr. Reddy's Laboratories, Inc.
Priority date: 2009-08-21
Filing date: 2010-08-20
Publication date: 2011-02-24
Also published as: WO2011022596A3

Abstract

Processes for preparing bazedoxifene and its pharmaceutically acceptable salts, substantially free from process related impurities and process intermediates.

Description

PREPARATION OF BAZEDOXIFENE AND ITS SALTS

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-1 H-indol-5-ol acetic acid, and has the chemical structure shown below as Formula I.

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 postmenopausal 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. lnternational 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., Λ/-(4-benzyloxyphenyl)-α-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-i -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 HCI and thionyl chloride to conduct the chlohnation 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 α- 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.

-A-

Scheme A: Preparation of Compound of Formula Il

Scheme B: Preparation of Compound of Formula I

(Formula VII)

IMA

Scheme C: Preparation of Compound of Formula I

Formula IV Formula V Formula I where Bn = benzyl

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-1 /-/-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-1 /-/-indole of Formula IV;

Formula III

(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

Formula IV Formula V

(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-1 H-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 Vl) 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

F

ormula Vl Formula VII 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 IMA).

Formula INA

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 Ka 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-1 H-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-1 H-indole of Formula IV;

Formula Il

Formula III

(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

Formula IV Formula V

(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-1 H- 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 0-10⁰C.

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 20^0⁰C.

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, Ci-C₄ alcohols; C2-C6 ketones, such as, for example, acetone, ethyl methyl ketone, and diethyl ketone; halogenated hydrocarbons, such as, for example, Ci-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, propionithle, 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-1 H- 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.

Formula IX

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; nithles such as acetonithle; 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 thethylamine, 4-dimethylaminopyhdine (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.

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 Vl) 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

Formula VII 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 IMA).

Formula INA

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-dimethylaminopyhdine (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), thethylbenzylammonium 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, Ci-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), N₁N- 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 IMA).

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 Ci-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), N₁N- dimethylformannide (DMF), N,N-dimethylacetannide (DMAC), N-methylpyrrolidone (NMP), and the like; and any mixtures thereof.

Step b) may be conducted at temperatures about 0⁰C up to the reflux temperature of the solvent, or about 0-50⁰C, 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 200⁰C, or about 20⁰C to about 80°C, or about 30°C to about 60⁰C, 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, (150x4.6 mm, 3.5 μm) column with the following parameters:

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, thcalcium 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-1 H-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 100⁰C, 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 50-55⁰C 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-1 H-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 100-105⁰C, and maintained at that temperature until reaction completion as verified using thin layer chromatography (TLC). The mixture is cooled to 50-55⁰C 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 NaCI in 490 L of water).The ethyl acetate is distilled under vacuum below 70⁰C (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% NaCI solution (100 mL) at 50⁰C. 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 HCI 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 0-5⁰C 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 50-55⁰C 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% NaCI solution (1 Kg NaCI in 10 L of water) at 55-60⁰C. 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 HCI 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 HCI 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 50-55⁰C 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 HCI gas is passed through the mixture at 0-5⁰C 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 0-5⁰C 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 60⁰C 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 0-5⁰C 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 50⁰C 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]-1 H-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-1 H-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-dimethylforπnannide (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 50⁰C to form a residue. Methanol (120 mL) is added to the residue and the mixture is stirred for 30 minutes at 25-30⁰C. 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 50⁰C 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]-1 H-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-1 H-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 N₁N- 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 N₁N- 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 50⁰C 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 50⁰C 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-1 H-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 45-50⁰C 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 (~11 N, 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 70⁰C 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-1 H-indole (10 g) and ethyl acetate (100 mL) is heated to 40⁰C 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 (~11 N, 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-1 H-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 (~11 N, 2.5 ml_) and L-ascorbic acid (0.01 g) 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 50⁰C 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-1 H-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 (~11 N, 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 50⁰C 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 50⁰C 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^χ350 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 50⁰C 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 50⁰C 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 HCI 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 50⁰C 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 (~1 1 N, 5.5 mL). The mixture is stirred for 1 -2 hours. The solid is filtered and washed with methanol (7 mL), then dried at 50⁰C 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 50⁰C 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-1 H-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 (~11 N, 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 50⁰C 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-1 H-indole (30 g), acetone (450 mL), and methanol (150 mL) is stirred at 40⁰C. 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 (~11 N, 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 50⁰C 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 25-30⁰C, 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 40-50⁰C. THF (16 mL) is added and the mixture is cooled to 25-30⁰C, 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 50⁰C 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-1 H- 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-1 H-indole (20 g), methanol (200 ml_), 10% palladium on carbon (8.0 g), and ammonium formate (9.7 g) is heated to 50-55⁰C 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-1 H-indole (5 g) is heated to reflux and maintained until completion of the reaction (~1 hour). The mixture is cooled to 25-30⁰C 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- 1 H-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 25-30⁰C 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 0-5⁰C 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).

Claims

CLAIMS:

1. A process for preparing bazedoxifene or a salt thereof, comprising: (a) reacting 5-benzyloxy-2-(4-benzyloxyphenyl)-3-methyl-1 /-/-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-1 /-/-indole of Formula IV;

Formula

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

Formula IV Formula V

(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 a solvent in (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 an acid is hydrochloric acid.

9. The process according to claim 6, wherein a base in (c) is an organic base.

10. The process according to claim 6, wherein a base in (c) comprises triethylamine, morpholine, or ammonium hydroxide.

11. 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), purifiying the product of (a) by crystallization.

12. The process of claim 11 where an acid in (a) is hydrochloric acid.

13. Crystalline bazedoxifene hydrochloride having a powder X-ray diffraction pattern with peaks located substantially in accordance with the pattern of Fig. 1.

14. The crystalline bazedoxifene hydrochloride of claim 13, having a differential scanning calorimetry curve with a peak located substantially in accordance with the curve of Fig. 2.