FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(SECTION 10 and Rule 13) TITLE OF THE INVENTION
"A Novel Process for Raloxifene Hydrochloride"
Emcure Pharmaceuticals Limited, an Indian company, registered under the Indian Company's Act 1957 and
having its registered office at
Emcure House, T-184, M.I.D.C, Bhosari, Pune-411026, India.
THE FOLLOWING SPECIFICATION DESCRIBES THE INVENTION AND THE MANNER IN
WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The present invention relates to an economical and convenient process for the preparation of raloxifene of formula (I). The process comprises reaction of 2-(4-hydroxyphenyl) benzo [b] thiophene of formula (II) with 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid (III) in presence of methanesulfonic acid and phosphorous pentoxide to give 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl] benzo[b] thiophene of formula (IV), which, after deprotection of the methanesulfonyl groups and treatment with hydrochloric acid yields raloxifene hydrochloride of formula (la) conforming to regulatory specifications.
BACKGROUND OF THE INVENTION
Raloxifene of formula (I), chemically known as 6-hydroxy-2-(4-hydroxyphenyl)-benzo-[b]thien-3-yl]-4-[2-(l-piperidinyl)-ethoxy]-phenyl] methanone, is an oral selective estrogen receptor modulator (SERM) which is used in the prevention of osteoporosis. Raloxifene, which is administered as its hydrochloride salt, is marketed under the name Evista (Eli Lilly and Company) and was approved in the United States by'USFDA on December 9, 1997 for the treatment and prevention of osteoporosis in postmenopausal women. On September 13, 2007, the USFDA approved raloxifene hydrochloride tablets for reduction in the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer.

Raloxifene and its pharmaceutically acceptable salts were first disclosed genetically in US 4,133,814 and specifically in US 4,418,068.
Various synthetic processes are reported in the literature for the preparation of raloxifene. US 4,133,814, which discloses synthesis of 2-phenyl-3-aroylbenzothiophenes, exemplifies the key step of benzoyl coupling in raloxifene synthesis as follows. 2-(4-methoxyphenyl)-6-methoxybenzothiphene is reacted with 4-anisoyl chloride in presence of aluminium chloride to give 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxy- benzothiophene, which is deprotected using sodium hydride and further reacted with N-2-chloroethylpiperidine to afford raloxifene.
A multi-step route of synthesis involving various protecting groups and their subsequent deprotection methods along with the associated unit operation processes, use of hazardous reagents such as sodium hydride and requirement of column chromatographic purifications at different stages of synthesis render this process unsuitable for industrial application.
US 4,418,068 discloses a synthetic method wherein the hydroxyl groups in the dihydroxyl-phenyl-benzothiophene starting materials are protected with alkyl, carboxyalkyl or alkylsulfonyl moieties. The protected derivatives such as 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene are then reacted with activated 4-(2-piperidinoethoxy) benzoic acids using classical Friedel-Craft catalysts. While the F-C catalyst are selected from zinc chloride , aluminium chloride or proton acid catalysts like polyphosphoric acid, the activating groups for benzoic acids comprise halogens like chlorine, bromine or ester forming agents such as hydroxybenzotriazole or dicyclohexylcarbodiimide. After the reaction, further deprotection of the resultant condensation product yields the desired product, raloxifene.
WO 2005/003116 discloses a synthetic strategy for raloxifene wherein 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene is reacted with 4-2-(piperidinoethoxy benzoyl chloride), in presence of aluminium chloride followed by alkaline hydrolysis of the resulting acetoxy protected derivative to afford raloxifene. The intermediate 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene used in this strategy is synthesized from demethylation of corresponding methoxy compound and subsequent acetylation of the resultant hydroxylated benzothiophene derivative.

The above-mentioned reaction sequence also involves various protecting groups, their corresponding deprotection strategies and hazardous reagents such as aluminium chloride wherein the disposal of resulting sludge of aluminium hydroxide poses serious problems to the environment. Factors such as these hamper commercial viability of the process.
WO 2009/008000 discloses a process for deprotection of 6-methanesulfonyloxy-2-(4-
methanesulfonyloxyphenyl)-3 [4-(2-piperidinoethoxy) benzoyl] benzo[b]thiophene
hydrochloride using a base such as sodium hydroxide in dimethylsulfoxide to get raloxifene. According to the disclosure in this application, the methanesulfonyloxy protected intermediate is prepared by methods known in the art such as those described in US 4,418,068.
US 6,723,739 and US 6,756,388 disclose the preparation of raloxifene free base by hydrolysis of 6-methanesulfonyloxy-2-(4- methanesulfonyloxyphenyl)-3[4-(2-piperidinoethoxy) benzoyl] benzo[b]thiophene using alkali metal hydroxide as base in presence of mixture of solvents.
WO2011/029088 discloses a process wherein 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3[4-(2-piperidinoethoxy) benzoyl] benzo[b]thiophene is hydrolyzed in presence of aqueous base like alkali metal hydroxides, carbonates or bicarbonates.
It may be noted that in most of the synthetic routes disclosed in prior art for synthesis of raloxifene, the key step is that of benzoylation of hydroxyl-protected benzothiophene compound to give the benzoyl-benzothiophene derivative. For this reaction, the benzothiophene reactant is first treated with hydroxyl protecting reagents and the protected derivative is isolated and further reacted with benzoic acid compounds with an activated carbonyl functionality, usually in presence of reagents like aluminium chloride. These multi-step synthetic strategies include separate steps for protection of hydroxyl groups in the reactant benzothiophene derivative, carbonyl activation of the substituted benzoic acid derivatives and subsequent removal of the protecting groups after the coupling reaction, which make the processes uneconomical, cumbersome and energy-intensive.

From the prior art references it is clear that various hydroxyl protecting groups, carbonyl activating groups and different strategies for their deprotection after the benzoylation reaction have been explored to obtain the raloxifene free base.
Thus, there still exists a need for a simple and convenient process for synthesis of raloxifene (I) which avoids hazardous reagents such as aluminium chloride and employs a cost-effective synthetic approach wherein auxiliary synthetic steps such as hydroxyl group protection, carbonyl activation are kept at a minimum possible level.
The present inventors have developed a novel process for synthesis of raloxifene (I) in which the key benzoylated intermediate is synthesized without prior activation of substituted benzoic acid derivative and without the requirement of a separate step for protection of 2-(4-hydroxyphenyl)benzo [b] thiophene in the synthetic strategy. Thus, 2-(4-hydroxyphenyl)benzo[b] thiophene of formula (II) is reacted with 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid in presence of Eaton's reagent to give the corresponding benzoyl compound of formula (IV), which, upon deprotection of the methanesulfonyl group and treatment with hydrochloric acid yields raloxifene hydrochloride conforming to regulatory specifications.
OBJECT OF THE INVENTION
An objective of the present invention is to provide raloxifene hydrochloride of formula (la) having desired purity by a safe and economical process which does not involve use of hazardous and toxic reagents such as sodium hydride or aluminium chloride.
Another objective df the present invention is to provide an efficient and convenient process for preparation of raloxifene hydrochloride (la) wherein 2-(4-hydroxyphenyl)benzo(b) thiophene-6-ol of formula (II) is reacted with the carboxylic compound 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III), in presence of Eaton's reagent avoiding separate steps of prior hydroxyl-protection or carboxyl activation, followed by facile deprotection of the resultant compound (IV) and subsequent treatment with hydrochloric acid.

SUMMARY OF THE INVENTION
The present invention relates to a novel method for synthesis of 6-hydroxy-2-(4-hydroxyphenyl) - benzo-[b] thien-3-yl]-4-[2-(l-piperidinyl)-ethoxy]-phenyl] methanone hydrochloride of formula (la) having desired purity.
An aspect of the invention relates to a process for preparation of raloxifene hydrochloride (la) comprising reaction of 2-(4-hydroxyphenyl)benzo(b) thiophene -6-ol of formula (II) with 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III) in presence of methanesulfonic acid and phosphorous pentoxide, optionally in presence of an organic solvent, to give 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b]thiophene of formula (IV), which, after reaction with alkali metal hydroxide followed by treatment with hydrogen chloride in alcoholic solvent yields raloxifene hydrochloride (la) having purity conforming to regulatory specifications.
The objectives of the present invention will become more apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
As evident from the study of prior art, benzoylation of the hydroxyl-protected benzothiophene derivative using activated benzoic acid intermediates is a key step in the various synthesis strategies disclosed for raloxifene . Apart from the use of environmentally hazardous Lewis acid catalysts like aluminium chloride, the separate steps and various associated unit operations for hydroxyl protection and activation of benzoic acid render these synthesis processes cumbersome.
The present inventors, while developing a cost effective, convenient approach for the benzoylation step in synthesis of raloxifene, surprisingly found that the reaction sequence could be significantly shortened with use of Eaton's reagent, wherein separate steps for hydroxyl protection in benzothiophene reactant or carboxyl activation of benzoic acid derivative were no longer required. The sequence also avoided use of environmentally hazardous Lewis acid catalyst in the said benzoylation reaction. As a result, the final product raloxifene was obtained in a cost-effective, economical manner and was found to possess

desired purity without resorting to elaborate, time-consuming purification procedures like chromatographic separation at any of the intermediate stages.
During the extensive experimentation carried out for synthesis of raloxifene, it was surprisingly found that Eaton's reagent, which is prepared by mixing methanesulfonic acid and phosphorous pentoxide was an excellent agent for the benzoylation of the dihydroxylated benzothiophene derivative for the reasons given below.
• Separate step for prior protection of 2-(4-hydroxyphenyl)benzo(b) thiophene -6-ol in benzoylation reaction was eliminated due to the presence of methanesulfonic acid in the reagent. Otherwise, hydroxyl protection is an essential step in benzoylation of hydroxylated derivatives to avoid undesired reactions of hydroxyl functionalities.
• Without incurring a separate step, the mesylated benzothiophene derivative was generated in-situ in the present reaction. Due to electron-withdrawing effect of two mesyl group, undesired side reactions in benzoylation which are likely in alkylated hydroxy-benzothiophenes were reduced, leading to purer benzoylated intermediate.
• Reagents like aluminium chloride, zinc chloride were avoided in benzoylation reaction, since the reaction of in-situ generated mesyl protected benzothiophene compound with substituted benzoic acid in presence of Eaton's reagent did not require Lewis acid catalysis.
• In benzoylation reaction, Eaton's reagent proved to be a good alternative for proton acids such as polyphosphoric acid which, due to its high viscosity, poses operational issues on commercial scale.
• Prior activation of the carboxylic acid reagent, 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid (III) in benzoylation reaction was eliminated because of Eaton's reagent. In the absence of such effective reagent, carboxyl activation was a prerequisite for benzoylation wherein the carbonyl group was converted to corresponding chloride type derivative using hazardous reagents like thionyl chloride.
• By avoiding separate reactions for hydroxyl protection and carbonyl activation, the number of synthetic steps and the associated unit operations for preparation and isolation of intermediates were reduced, which significantly lowered the batch time and most importantly, the project cost.

• Due to high solubility of the reactants in methanesulfonic acid, benzoylation reaction was possible with lower solvent volumes, and also at milder conditions, with a significant control on impurities, as compared to prior art.
Scheme 1: Method embodied in the present invention for the preparation of raloxifene hydrochloride (la)

In an embodiment, 2-(4-hydroxyphenyl) benzo [b] thiophene-6-ol of formula (II) was added to the mixture of phosphorous pentoxide and methanesulfonic acid. The stirred reaction mixture was heated in the temperature range of 70 to 95 C, till completion of formation of 2-(4-methanesulfonyloxyphenyl)-l-benzothiophen-6-ylmethanesulfonate, as monitored by HPLC. A stirred mixture of 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III) in methanesulfonic acid was gradually added to the reaction mass at 70 to 95°C, followed by addition of phosphorous pentoxide to the reaction mixture. The reaction was carried out in the temperature range of 70 to 95°C. After completion of reaction as monitored by HPLC, the reaction was quenched with ice-water followed by extraction with dichloromethane. Separation and concentration of the organic layer gave 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b]thiophene of formula (IV).
Optionally, the above reaction could also be carried out in presence of an organic solvent, either at atmospheric pressure or under pressure. In that case, 2-(4-hydroxyphenyl) benzo [b] thiophene-6-ol of formula (II) was added to the mixture of phosphorous pentoxide, methanesulfonic acid and an organic solvent. The stirred reaction mixture was heated in the temperature range of 60 to 95°C, depending upon the solvent used, till completion of formation of 2-(4-methanesulfonyloxyphenyl)-l-benzothiophen-6-ylmethanesulfonate, as monitored by HPLC. A stirred mixture of 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III) in methanesulfonic acid was gradually added to the reaction mass at 60 to 95°C, followed by addition of phosphorous pentoxide to the reaction mixture.
After completion of reaction as monitored by HPLC, the reaction was quenched with ice-water and the organic layer was separated. Concentration of the organic layer gave 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3 -[4-(2-piperidino ethoxy) benzoyl] benzo [b]thiophene of formula (IV).
The organic solvent was selected from a group of halogenated hydrocarbons comprising dichloromethane, dichloroethane, chloroform, carbon tetrachloride, dichlorobenzene etc. or substituted aromatics such as nitrobenzene and mixtures thereof.
The quantity of P2O5 in the reaction could be varied ranging from 5 to 40% weight /volume with respect to methanesulfonic acid.
Compound (IV) was treated with a base using organic or aqueous solvents or mixtures thereof in the temperature range of 50 to 90°C. The base was selected from alkali metal alkoxides such

as sodium and potassium methoxide, alkali metal hydroxides such as sodium and potassium
hydroxide and the like and mixtures thereof while the organic solvent was selected from
dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide and the like and mixtures
thereof.
After completion of the reaction as monitored by HPLC, the reaction mixture was quenched
with water, and treated with hydrochloric acid till it attained the pH between 9 to 10.5. The
reaction mixture was stirred, followed by filtration to give raloxifene (I).
Raloxifene base was further dissolved in methanol and treated with hydrochloric acid to give
raloxifene hydrochloride (la) having desired purity.
Alternatively, both the reactions, benzoylation and deprotection of the methanesulfonyl group
were carried out in-situ wherein the organic layer which contained the desired compound 6-
methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3 - [4-(2-piperidino ethoxy) benzoyl]
benzo[b]thiophene of formula (IV) was concentrated and further deprotection reaction was
carried out in the same reactor, by adding the base/s and solvent/s in requisite quantities.
The reactants, 2-(4-hydroxyphenyl) benzo [b] thiophene-6-ol of formula (II) and 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid hydrochloride of formula (III) were prepared by following the methods known in the prior art. For example, 3-methoxybenzenethiol was reacted with a-bromo-4-methoxyacetophenone in presence of potassium hydroxide and solvent ethanol to give a-(3-methoxyphenylthio)-4-methoxyacetophenone which was treated with polyphosphoric acid to give 6-methoxy-2-(4-methoxyphenyl) benzo [b] thiophene. The dimethoxylated intermediate was further treated with pyridine hydrochloride at around 220°C to give the desired hydroxyphenyl benzothiophene reactant.
4-(2-piperidinoethoxy)benzoic acid hydrochloride was similarly prepared following procedures known in the art. For example, methyl 4-hydroxybenzoate was treated with 0-chloroethylpiperidine hydrochloride at around 75-80°C in presence of potassium carbonate and isopropyl acetate to give 4-(2-piperidinoethoxy)benzoic acid, which on further reaction with hydrochloric acid gave the desired benzoic acid hydrochloride.
The following examples are meant to be illustrative of the present invention. These examples exemplify the invention and are not to be construed as limiting the scope of the invention.

EXAMPLES
Example 1: Preparation of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b]thiophene (IV)
Phosphorous pentoxide (146.3 g) was added to methanesulfonic acid (800 ml) at 25-35°C followed by addition of 2-(4-hydroxyphenyl) benzo [b] thiophene-6-ol of formula (II) (100.1 g) to the mixture at the same temperature. The reaction mass was heated to 70 -90 C with continued stirring till completion of formation of 2-(4-methanesulfonyloxyphenyl)-l-benzothiophen-6-ylmethanesulfonate, as monitored by HPLC.
4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid hydrochloride of formula (III), (123.8 g) was added to methanesulfonic acid (200 ml) with stirring and the resultant mixture was gradually added to the stirred reaction mass at 70 -90 °C. Phosphorous pentoxide (74.0 g) was then added to the mixture and the reaction was continued till completion as monitored by HPLC. After completion of the reaction, the cooled reaction mixture was gradually added to ice-water, stirred and extracted with dichloromethane. Separation and concentration of the organic layer gave 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b] thiophene of formula (IV). Yield: 215. 6 g(78.4 %)
Example 2: Preparation of 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo [b]thiophene (IV)
Phosphorous pentoxide (146.3 g) was added to mixture of ethylene dichloride (400 ml) and methanesulfonic acid (400 ml) at 25-35°C followed by addition of 2-(4-hydroxyphenyl) benzo [b] thiophene-6-ol of formula (II) (100.1 g) to the mixture at the same temperature. The reaction mass was heated to 60 -80 °C with continued stirring till completion of formation of 2-(4-methanesulfonyloxyphenyl)-l-benzothiophen-6-ylmethanesulfonate, as monitored by HPLC.
4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid hydrochloride of formula (III), (123.8 g) was added to methanesulfonic acid (200 ml) with stirring and the resultant mixture was gradually added to the stirred reaction mass at 60 -80 °C. Phosphorous pentoxide (74.0 g) was then added to the mixture and the reaction was continued till completion as monitored by HPLC.

After completion of the reaction, reaction mixture was gradually added to the ice cooled -water, followed by extraction with dichloromethane. Separation and concentration of the organic layer gave 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b] thiophene of formula (IV). Yield: 210. 6 g(76.4 %)
Example 3: Preparation of Raloxifene hydrochloride (la)
6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl]
benzo[b]thiophene hydrochloride (100.2 g) was treated with a mixture of potassium hydroxide
(68.3 g) in water (115 ml) and dimethyl sulfoxide (400 ml). The reaction mixture was heated to
60-80°C and stirred at the same temperature till completion of the reaction, as monitored by
HPLC. After completion, water was added and the reaction mass was cooled to 20-25°C,
followed by addition of aqueous hydrochloric acid till it attained the pH between 9 to 10.5. The
reaction mass was stirred at 20-25°C, filtered and dried to give raloxifene free base.
The free base (60.2 g) was added to methanol (300 ml), followed by treatment with
concentrated hydrochloric acid at room temperature.
After completion of the salt formation as monitored by TLC, the reaction mass was cooled,
filtered and dried to yield raloxifene hydrochloride (la)
Yield: 57.6 g (75.3%)

CLAIMS
We claim,
1. A process for preparation of raloxifene hydrochloride (la) comprising reaction of 2-(4-hydroxyphenyl)benzo(b) thiophene -6-ol of formula (II) with 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III) in presence of methanesulfonic acid and phosphorous pentoxide, optionally in presence of an organic solvent, to give 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3 - [4-(2-piperidino ethoxy) benzoyl] benzo[b]thiophene of formula (IV), which, after reaction with alkali metal hydroxide followed by treatment with hydrogen chloride in alcoholic solvent yields raloxifene hydrochloride (la) having purity conforming to regulatory specifications.
2. A process as claimed in claim 1 wherein 2-(4-hydroxyphenyl)benzo(b) thiophene -6-0I of formula (II) is treated with methanesulfonic acid and phosphorous pentoxide to give 2-(4-methanesulfonyloxyphenyl)-1 -benzothiophen-6-ylmethanesulfonate, which upon in-situ reaction with 4-[2-(l-piperidinyl)-ethoxy]-phenyl] benzoic acid of formula (III) in presence of methanesulfonic acid and phosphorous pentoxide gives 6-methanesulfonyloxy-2-(4-methanesulfonyloxyphenyl)-3-[4-(2-piperidino ethoxy) benzoyl] benzo[b]thiophene of formula (IV).
3. A process as claimed in claim 1 wherein the reaction to give compound IV is carried out in the temperature range of 60 to 95 °C.
4. A process as claimed in claim 1 wherein the organic solvent is selected from the group of halogenated hydrocarbons comprising dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, dichlorobenzene or nitrobenzene and mixtures thereof.