FIELD OF THE INVENTION
The present invention relates to an industrially advantageous and efficient process for the preparation of 2-phenyl-3-aroylbenzothiophenes. Particularly the present invention relates to an industrially advantageous and efficient process for the preparation of raloxifene of formula I or pharmaceutically acceptable salts thereof.
(Formula Removed)
BACKGROUND OF THE INVENTION
Raloxifene of formula I, chemically known as [6-hydroxy-2-(4-hydroxyphenyl) benzothiophen-3 -yl] [4-[2-( 1 -piperidyl)ethoxy]phenyl] -methanone,
(Formula Removed)
is marketed under the name EVISTA® in the form of its hydrochloride salt.
Raloxifene is known to have antiestrogene and antiandrogene activity. Raloxifene
hydrochloride salt has proved useful for the preparation of pharmaceutically
compositions for the treatment of cancer, osteoporosis and cartilage degradation.
Raloxifene and its pharmaceutically acceptable salts were first disclosed generically
in US patent 4,133,814 and specifically described in US patent 4,418,068.
US patent 4,133,814 describes the synthesis of various 2-phenyl-3-
aroylbenzothiophenes. In exemplified process, 2-(4-methoxyphenyl)-3-(4-
hydroxybenzoyl)-6-methoxy benzothiophene, a key intermediate for raloxifene is prepared by the reaction of 4-anisoyl chloride with 2-(4-methoxyphenyl)-6-, methoxybenzothiphene in the presence of aluminium chloride to give 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxybenzothiophene followed by its purification using chromatography and then deprotection using sodium hydride and ethanethiol, and subsequent purification using silica gel chromatography and re-crystallization. The overall yield of hydroxyl intermediate from starting product is
about 50%, which is quite low. Further process involves purification by using
chromatographic techniques, which are time consuming and not suitable at industrial
scale.
US patent 4,418,068 discloses the preparation of raloxifene by a number of processes
as shown below.
(Formula Removed)
In exemplified processes, most of the intermediates and raloxifene are purified using column chromatographic technique which is a cumbersome process and thus makes the process unsuitable for commercial use.
US patent 5,567,828 discloses the process for the preparation of various 2-phenyl-3-
aroylbenzothiophenes other than raloxifene and exemplified the preparation of 2-(4-
methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzothiophene, a key
intermediate for raloxifene. The process involves the reaction of 4-anisoyl chloride with 2-(4-methoxyphenyl)-6-methoxybenzothiophene in the presence of aluminium chloride to give 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxybenzo thiophene and purification by flash chromatography. The intermediate thus prepared is then deprotected using sodium ethanethiolate and N,N- dimethylformamide to give 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzothiophene which is isolated by radial chromatography. Again this process involves and additional step of selective demethylation and use of chromatographic techniques, which makes the process unattractive from industrial point of view.
US patent 5,808,061 discloses the process for the preparation of raloxifene of formula I or its pharmaceutically acceptable salts thereof. According to process, raloxifene of formula I is prepared by the reaction of substituted benzo[b]thiophene with p-anisoyl chloride in the presence of aluminium chloride and dichloromethane to form an intermediate followed by selective demethylation using sodium ethane thiolate in dimethylformamide to give 2-(4-methoxyphenyl)-3-(4-hydroxybenzoyl)-6-methoxybenzothiophene which is then converted to raloxifene by the two methods as described below:
(Formula Removed)
In one of the processes, the process involves more number of steps like addition of piperidine side chain by two step process, first addition of ethyl group followed by addition of piperidine. In another process, Mitsunobu reaction is carried out, which requires the use of triphenylphosphine which has neurotoxic effects and diethyl azodicarboxylate (DEAD) which is a toxic, shock sensitive and thermally unstable compound. Further the bye product triphenylphosphine oxide formed during the said reaction is difficult to remove and results in yield loss and hence makes the process insignificant at industrial synthesis.
US patent 6,025,495 exemplified the process for the preparation of raloxifene of formula I, as shown below:
(Formula Removed)
Raloxifene is prepared via acylation of the substituted benzo[b]thiophene with p-anisoyl chloride to form 2-(4-methoxyphenyl)-3-(4-methoxybenzoyl)-6-methoxybenzothiophene followed by deprotection to give 2-(4-hydroxyphenyl)-3-(4-hydroxybenzoyl)-6-hydroxybenzothiophene, with all three hydroxy groups free for further reaction. The above intermediate is then converted to raloxifene by the reaction with 2-chloroethylpiperidine in the presence of sodium hydride to give raloxifene which is purified by flash chromatography. The process involves the use of strong base such as sodium hydride during the reaction which is very hazardous. Further the use of flash chromatography for the purification of intermediate suffers from disadvantages in convenience, safety and reliability.
In view of above, we have not found any prior art reference wherein the Friedal craft acylation has been carried out using 2-phenyl benzothiophene derivative and p-hydroxy benzoyl derivative. In all the references, Friedal craft acylation is carried out by using hydroxyl protected benzoyl derivative, which needs deprotection in next step and an addition step is carried out in prior art processes. So, there is a need to develop a process for the synthesis of raloxifene or pharmaceutically acceptable salts thereof that will overcome the prior art disadvantages and avoid the need of chromatographic purification, hazardous reagents such as sodium hydride, DEAD etc, and involves less number of steps. Thus, present invention fulfills the need in the art and provides an improved, simple and commercially viable process for the preparation of highly pure raloxifene or pharmaceutically acceptable salts thereof.
OBJECTIVE OF THE INVENTION
The principal objective of the present invention is to provide an efficient and
industrially advantageous process for the preparation of raloxifene or pharmaceutically
acceptable salts thereof.
Another objective of the present invention is to provide an improved process for the
preparation of raloxifene hydrochloride involving less number of steps.
Yet another objective of the present invention is to provide a process for the
preparation of benzothiophene intermediate, a key intermediate for raloxifene.
Yet another objective of the present invention is to provide a process for the preparation
of benzothiophene intermediate, which involves less number of steps.
Yet another objective of the present invention is to provide a process for the
purification of benzothiophene intermediate.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved and industrial advantageous
process for the preparation of raloxifene of formula I,
(Formula Removed)
or a pharmaceutically acceptable salt thereof, comprises the steps of: a). reacting 4-hydroxy benzoic acid of formula I,
(Formula Removed)
with a suitable activating agent to activate carboxyl group selectively to form intermediate of formula III,
(Formula Removed)
wherein X is selected from halogen such as chloro, bromo or iodo and the like b). condensing intermediate of formula III with compound of formula IV,
(Formula Removed)
wherein both R can be same or different and is H or any hydroxy protecting group; each R can independently selected from hydrogen, alky I, atyl, cychalkyl, aralkyl, -SO2R1 or -COR1; wherein R1 is alkyl, haloalkyl, alkoxy, alkyl aryl, alkoxy aryl, substituted or unsubstituted atyl; substituent can be at one or more position of atyl group and selected amongst alkyl, alkoxy, hydroxy, nitro, halo, or trihaloalkyl; more preferably R can be acetyl, benzyl, benzenesulfonyl, methane sulphonyl, ethoxycarbonyl, methyl, benzoyl, dodecanoyl and the like in the presence of a suitable catalyst to form benzothiophene intermediate of formula V,
(Formula Removed)
wherein R is as defined above c). optionally, purifying the benzothiophene intermediate of formula V; and d). converting benzothiophene intermediate of formula V to raloxifene
hydrochloride. According to other embodiment, the present invention provides a process for the purification of benzothiophene intermediate of formula V, comprising the steps of: a). providing a solution comprising benzothiophene intermediate of formula V and a
water immiscible solvent; b). treating the solution with a suitable base; c). separating the layers;
d). optionally, washing the aqueous layer with a suitable water immiscible solvent, e). acidifying the aqueous layer with a suitable acid; f). extracting the aqueous layer using an organic solvent; g). isolating the purified benzothiophene intermediate of formula V there from; and
h). optionally, crystallizing benzothiophene intermediate of formula V from a
suitable solvent. According to another embodiment, present invention provides a process for the preparation of raloxifene of formula I or a pharmaceutically acceptable salt thereof, comprising the steps of: a). reacting benzothiophene intermediate of formula V,
(Formula Removed)
wherein R is as defined above with compound of formula VI,
(Formula Removed)
wherein Hal is selected from chloro, bromo, iodo and the like
in the presence of base to form intermediate of formula VII or acid addition salts
thereof;
(Formula Removed)
wherein R is as defined above b). deprotecting the intermediate of formula VII or acid addition salts thereof using a
suitable deprotecting reagent; and c). isolating raloxifene of formula I or a pharmaceutically acceptable salt thereof. According to yet another embodiment, present invention provides a process for the preparation of raloxifene of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of: a). reacting 4-hydroxy benzoic acid of formula I,

(Formula Removed)
with a suitable activating agent to activate carboxyl group selectively to form intermediate of formula III,
(Formula Removed)
wherein X is as defined above b). condensing intermediate of formula III with compound of formula IV,
(Formula Removed)
wherein R is as defined above
in the presence of a suitable catalyst to form benzothiophene intermediate of
formula V,
(Formula Removed)
wherein R is as defined above c). optionally, purifying the benzothiophene intermediate of formula V, d). reacting the benzothiophene intermediate of formula V with compound of
formula VI,
(Formula Removed)
wherein Hal is selected from chloro, bromo, iodo and the like
in the presence of base to form intermediate of formula VII or acid addition salts
thereof;
(Formula Removed)
wherein R is as defined above e). deprotecting the intermediate of formula VII or acid addition salts thereof using a
suitable deprotecting reagent; and f). isolating raloxifene of formula I or a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved, efficient and industrially viable process for the preparation of raloxifene of formula I or a pharmaceutically acceptable salt thereof.
According to one embodiment of the present invention, raloxifene or a pharmaceutically acceptable salt thereof can be prepared starting from 4-hydroxy benzoic acid through benzothiophene intermediate of formula V. The process involves the synthesis of intermediate of formula V by selectively activating the carboxyl group of 4-hydroxy benzoic acid of formula II to form activated compound of formula III followed by its reaction with compound of formula IV, which forms the inventive part of the process. Intermediate of formula V is then converted to raloxifene or raloxifene hydrochloride.
Generally, the process involves the reaction of 4-hydroxy benzoic acid of formula II using a suitable activating agent, which selectively activates the carboxyl group. Usually, the reaction is carried out at a temperature of 0 to 80 °C for few minutes to several hours, preferably at a 20 to 25 °C till the completion of the reaction. Activating agent includes oxalyl halide such as oxalyl chloride and the like. The reaction can be carried out in the presence of a suitable solvent that includes halogenated solvent such as dichloromethane, dichloroethane, chlorobenzene, chloroform, carbon tetrachloride; aprotic solvent such as N,N-dimethylformamide, dimethylsulfoxide and the like or mixture thereof. It is preferable to use catalytic amount of N,N-dimethylformamide for the reaction. After the completion of the reaction, the intermediate of formula III can be isolated from the reaction mixture by suitable techniques or can be used as such for the further reaction. It is preferable to concentrate the reaction mixture by the partial or complete removal of solvent and then used for the further reaction or reaction mixture as such without solvent removal can be used for the further reaction.
The reactive derivative of formula III or reaction mixture is then made to react with intermediate of formula IV in the presence of a suitable catalyst.
The process involves the reaction of intermediate of formula III with compound of formula IV in the presence of suitable catalyst at a temperature of 0 to 50 °C for few minutes to several hours, preferably the reaction is carried out 20 to 30°C for 4 to 12 hours. More preferably, the reaction mixture is maintained till the completion of the reaction. Catalyst employed for the reaction can be selected from any catalyst known in the art that can effectively serve the purpose; preferably, catalyst used can be Lewis acid catalyst such as aluminum chloride, aluminum bromide, zinc chloride, boron trifuoride, boron trichloride, boron tribromide, titanium tetrachloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, ferric chloride and the like. The reaction can be carried out in the presence of a suitable solvent. Suitable solvent includes halogenated solvent such as dichloromethane, dichloroethane, carbon tetrachloride and the like or mixture thereof. After the completion of the reaction, the reaction mixture can be optionally quenched using a suitable quenching agent depending upon the reagent employed for the reaction. Quenching agent employed for the reaction includes ether solvent such as tetrahydrofuran or tetrahydrofuran followed by ice cooled water and the like. The desired product of formula V can be isolated from the reaction mixture by the suitable techniques. Specifically, the benzothiophene intermediate of fonnula V can be isolated by the addition of water to the reaction mixture. Thereafter, organic layer can be separated and optionally washed with water and/or brine. The intermediate of fonnula V can be recovered from the resulting organic layer by the removal of solvent by techniques such as distillation, evaporation and the like. According to another embodiment, present invention provides a process for the purification of benzothiophene intemiediate of fonnula V that makes the intennediate free from the impurities.
Specifically, a solution of intermediate of formula V in a water immiscible solvent can be treated with a suitable base and stirred for few minutes to several hours; preferably reaction mixture is stirred for 30 minutes to 1 hour or till layer formation. The solution of benzothiophene intermediate of fonnula V can be obtained by
dissolving the benzothiophene intermediate of formula V in water immiscible solvent. Aqueous layer can be separated from the reaction mixture. It is advantageous to wash the aqueous layer with water immiscible solvent to minimize the quantity of undesired impurities in the reaction mixture. Washing of the aqueous layer with water immiscible solvent can be optionally repeated. Water immiscible solvent includes halogenated solvents such as dichloromethane, dichloroethane, chloroform; esters such as ethyl acetate; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof. Suitable base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. Thereafter, resulting aqueous layer can be acidified using a suitable acid till the reaction mixture become acidic, preferably till the pH 2 to 3. Suitable acid employed for the reaction includes inorganic acid such as hydrochloric acid, sulfuric acid or organic acid such as carboxylic acids (acetic acid), sulfonic acid (benzene sulfonic acid, p-toluene sulfonic acid) and the like. The resulting mixture is then extracted with a suitable organic solvent. Organic solvent can be selected from the solvent in which benzothiophene intermediate of formula V have more solubility. Suitable organic solvent includes ester such as ethyl acetate; halogenated solvents such as dichloromethane, dichloroethane, chloroform; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof. Resulting organic layer can be optionally washed with sodium bicarbonate solution and/or water and/or brine and the like. The benzothiophene intermediate of formula V can be isolated from the resulting organic layer by the removal of solvent by techniques such as distillation, evaporation and the like.
In another alternate way, benzothiophene intermediate of formula V can be purified by crystallization with a suitable solvent.
Specifically, the benzothiophene intermediate of formula V is dissolved in a suitable solvent at temperature of about 40 to 80 °C for few minutes to several hours, preferably for 1 to 2 hours, more preferably till the complete dissolution of the product. Suitable solvent includes aliphatic or aromatic hydrocarbon solvent such as
toluene; halogenated solvent such as chlorobenzene; ester such as ethyl acetate; nitriles such as acetonitrile; alcohols such as methanol, ethanol, isopropanol and the like or mixture thereof. Crystallization of product can be initiated by reducing the temperature of the reaction mixture or by adding anti-solvent or by reducing the volume of solvent. Suitable anti solvent that can be used to precipitate the compound can be selected from the solvents in which the desired compound has low solubility or no solubility and preferably selected from aliphatic hydrocarbon such as heptane, cyclohexane, hexane, n-heptane; ethers such as isopropyl ether, methyl tert-butyl ether; and the like or mixture thereof. The product thus crystallized can be isolated by suitable techniques such as filtration, centrifugation and the like. Benzothiophene intermediate of formula V, prepared by using the process of present invention is highly pure and high yield (more than 90%). It has purity greater than 99 area % and more preferably greater than 99.5 area % having single known impurity not greater than 0.15 area % and unknown impurity not greater than 0.10 area % by HPLC. The process described is highly advantageous as it avoids deprotecting step as described in the prior art wherein hydroxyl protected benzothiophene intermediate of formula V is prepared, starting from hydroxy protected starting material. The present invention provides the selective activation of carboxyl group in starting compound of fonrmula II which avoids the need to protect the hydroxy group. Thus, process of present invention has advantage of reduction in the number of steps. Benzothiophene intennediate of formula V thus isolated from reaction mixture is found to be free from undesired organic impurities which is achieved by preparing metal salt with intermediate of fonnula V to make it soluble in aqueous layer and thereafter giving washing with water immiscible organic solvent to remove the impurities and thereby converting the metal salt to free hydroxyl compound i.e. pure benzothiophene intermediate of formula V by treating with suitable acid.
According to another embodiment, present invention provides a process for the conversion of benzothiophene intermediate of formula V in to raloxifene or a pharmaceutically acceptable salt by the condensation of benzothiophene intermediate
of formula V with a compound of formula VI using a base, (which is not hazardous), in suitable aprotic solvent to give intermediate of formula VII, which forms another novel feature of the invention.
Generally, the process involves reaction of intermediate of formula V with compound of formula VI in the presence of suitable base in a solvent at a temperature of 50 to 120 °C for few minutes to few hours. Preferably, reaction can be carried out at temperature 90 to 105°C for 30 minutes to 2 hours, more preferably till the completion of the reaction. Suitable base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides such as potassium carbonate, potassium bicarbonate, cesium carbonate and the like. Suitable solvent includes aprotic solvent as N,N-dimethylformamide, dimethylacetamide, dimethyl sulfoxide; esters such as amyl acetate; nitriles such as acetonitrile and the like or mixture thereof. After the completion of the reaction, the intermediate of formula VII can be isolated from the reaction mixture using suitable techniques. Specifically, reaction mixture can be cooled to a temperature of 30 to 40 °C followed by filtration to remove undissolved impurities like inorganic salts, if any, from the reaction mixture. The intermediate of formula VII can be recovered from the resulting filtrate by the removal of solvent using techniques such as distillation, evaporation and the like. The reaction mixture can yield directly raloxifene or a pharmaceutically acceptable salts thereof, wherein reaction is carried out by using intermediate of formula V (where R is hydrogen). The intermediate of formula VII, thus obtained, can be optionally purified to enhance the purity of the product, if desired.
Specifically, intermediate of formula VII can be dissolved in a suitable solvent selected from ester such as ethyl acetate; halogenated solvent such as dichloromethane, dichloroethane, chlorobenzene; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof. The resulting organic layer can be optionally washed with brine and/or water. Intermediate of formula VII can be recovered from the resulting organic layer by the removal of solvent using techniques such as distillation, evaporation and the like.
The intermediate of formula VII can be optionally converted to acid addition salts thereof or can be isolated from the reaction mixture as acid addition salts. Specifically, the intermediate of formula VII or reaction mass containing intermediate of formula VII can be made to react with a suitable source of acid. Source of an acid includes but not limited to inorganic acid such as hydrochloric acid, hydrobromic acid, , sulphuric acid, phosphoric acid; or organic acids such as sulfonic acids like methane sulfonic acid, p-toluene sulfonic acid; carboxylic acid like tartaric acid, succinic acid, formic acid, citric acid, benzoic acid, maleic acid, acetic acid, and the like. Usually, salt formation can be carried out at 0 to 35 °C. Suitable solvent employed includes halogenated solvent such as dichloromethane, dichloroethane,; esters such as ethyl acetate, isopropyl acetate; alcohol such as methanol, ethanol, isopropanol, ketone such as acetone, methyl ethyl ketone and the like or mixture thereof. The acid addition salt of intermediate of formula VII can be isolated from the reaction mixture by the conventional methods known in the art. Preferably, hydrochloride salt of intermediate of formula VII can be prepared. Specifically, intermediate of formula VII can be treated with a suitable source of hydrochloric acid in a suitable solvent. The desired product can be isolated from the reaction mixture by the layer separation followed by removal of solvent.
The resulting acid addition salt of intermediate of formula VII can be optionally purified using slurry wash with suitable solvent. The solvent employed includes halogenated solvent such as chlorobenzene; aliphatic or aromatic hydrocarbon such as cyclohexane, hexane, n-heptane and the like or mixture thereof. Alternatively, resulting acid addition salt of intermediate of formula VII can be optionally purified by crystallization using a suitable solvent that includes ketone such as acetone; methyl ethyl ketone, methyl isobutyl ketone and the like. The desired product can be isolated either by initiating crystallization by reducing the temperature of the reaction mixture or by adding an anti solvent followed by filtration or centrifugation. Suitable anti solvent includes ether such as isopropyl ether, methyl tert-butyl ether and the like.
Intermediate of formula VII or acid addition salt thereof then can be deprotected to give raloxifene or pharmaceutically acceptable salt thereof by the method known in the art or specifically by the method as described herein for reference. Generally, the deprotection process involves the reaction of intermediate of formula VII with a suitable deprotecting reagent in a suitable solvent in order to remove the protecting group. The deprotecting reagent employed for the reaction can be selected from any suitable reagent known in the art for the deprotection of hydroxyl functional group. The deprotecting reagent can be selected on the basis of the nature of protecting group to be removed and are well known in the field of organic synthesis. When R is either -COR1 or -SO2R1 (wherein R1 is as defined above) then deprotection reaction can be carried out by simple hydrolysis with strong or moderately strong bases such as alkali metal hydroxides. The hydrolysis can be carried out with acid catalysts (aqueous, concentrated or gaseous) such as methane sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid or with ion exchange resin.
When R is selected from alkyl, aryl, cycloalkyl, aralkyl as group to protect the hydroxy group, then deprotection can be carried out by using any reagent known in the art that can serve the puipose. Preferably, the deprotecting reagent includes boron compounds like borane trihalide; beryllium compounds such as beryllium dihalide; thiophenol, lithium diphenylphosphide, aluminium halide thiol system, high molecular weight alkane or arene thiolate anions, trialkyl borohydride and its salts; thiophenol, sodium sulfide and the like; silyl compounds such as trimethyl silyl halides with sodium iodide in nitrile solvents; hydrobromic acid, hydrochloric acid (aqueous, concentrated or gaseous); diisobutylaluminium hydride; thioethanol in combination with sodium methoxide, aluminium halide or boron tribromide; sulphur compounds like alkyl thiol such as methanethiol, ethanethiol, isopropanethiol, butanethiol and the like; dialkyl sulfides such as diethyl sulfide, butyl s-butyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide and the like; benzenethiol; methionine; and alkyl phenyl sulfides such as methyl
phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide and the like. The deprotection reaction may also be effected by the hydrogenolysis of compound of formula VII using a suitable catalyst. The catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like. The reaction can take place over a wide range of temperature depending upon the nature of protecting group as well as on deprotecting reagent employed for the reaction. The nature of the solvent employed for deprotection reaction is not critical provided it should not have any impact on the other functionalities present in the compound. Raloxifene of formula I, thus prepared, by the deprotection reaction can be isolated from the reaction mixture using conventional methods known in the art. Preferably the intermediate of formula VII (wherein R is methyl) or acid addition salt thereof can be converted to raloxifene of formula I or pharmaceutically acceptable salt thereof, preferably raloxifene is isolated as hydrochloride salt.
Specifically, the protecting group employed for the reaction can be alkyl. The alkoxy group can be converted to hydroxy by the reaction of intermediate of formula VII or salts thereof with a suitable deprotecting reagent selected from sulphur compounds like alkyl thiol such as methanethiol, ethanethiol, isopropanethiol, butanethiol and the like; dialkyl sulfides such as diethyl sulfide, butyl s-butyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide and the like; benzenethiol; methionine; and alkyl phenyl sulfides such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide; or sulfur compound such as thioethanol in combination with sodium methoxide, aluminium halide or boron tribromide and the like. The reaction is generally carried out at a temperature of 20 to 35 °C for few minutes to few hours. Preferably, reaction can be carried out a temperature 25 °C for 2 hours, more preferably till the completion of the reaction. After the completion of the reaction, the reaction mixture can be optionally quenched using suitable quenching agent whenever required. Quenching agent employed for the reaction includes ethereal solvent such as tetrahydrofuran; acid such as hydrochloric acid and the like or combination thereof. Raloxifene of formula I can be isolated from the
resulting reaction mixture • using conventional techniques known in the art. Specifically, the product precipitated in the reaction mixture can be isolated as raloxifene hydrochloride by filtration or centrifugation and the like. Raloxifene can be converted to pharmaceutically acceptable salt thereof by the conventional methods known in the art. Source of an acid includes but not limited to inorganic acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid; or organic acids such as sulfonic acids like methane sulfonic acid, p-toluene sulfonic acid; carboxylic acid like tartaric acid, succinic acid, formic acid, citric acid, benzoic acid, maleic acid, acetic acid, and the like. Preferably, hydrochloride salt of raloxifene can be prepared. Solvent employed for the salt formation includes ether such as tetrahydrofuran; halogenated solvents as dichloromethane; alcohol such as methanol; ester such as ethyl acetate and the like or mixture thereof. Raloxifene pharmaceutically acceptable salt thereof can be optionally purified by crystallization with a suitable solvent that includes alcohol such as methanol, ethanol, isopropanol and the like.
Raloxifene hydrochloride thus prepared can be optionally converted to raloxifene by treating with a suitable base in a suitable solvent. Suitable base includes organic base such as ammonia, triethyl amine, diisopropylethyl amine and the like; or inorganic base that includes alkali or alkaline metal hydroxides, carbonates, bicarbonates or alkoxides thereof such as sodium carbonate, sodium hydroxide, potassium bicarbonate and the like. Solvent employed for the reaction includes ketones such as acetone, methyl ethyl ketone; methyl isobutl ketone; alcohol such as methanol, ethanol, isopropanol; esters such as ethyl acetate; halogenated solvents such as dichloromethane, dichloroethane, chlorobenzene; ether such as tetrahydrofuran and the like or mixture thereof. Raloxifene thus prepared can be further converted to hydrochloride salt using a suitable source of chloride ion.
Raloxifene or hydrochloride salts thereof prepared by the process of present invention is highly pure. It has purity greater than 99 area % and more preferably greater than
99.5 area % and having single known impurity not greater than 0.15 area % and unknown impurity not greater than 0.10 area % by HPLC.
The order and manner of combining the reactants at any stage of the process are not important and may be varied. The reactants may be added to the reaction mixture as solids, or may be dissolved individually and combined as solutions. Further, any of the reactants may be dissolved together as sub-groups, and those solutions may be combined in any order. Wherever required, progress of the reaction is monitored by suitable chromatographic techniques such as High performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
Isolation and purification of final compound and intermediates described here in the present invention can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, derivatisation, slurry wash, salt preparation or combination of these procedures. Acid used for the salt preparation are same as described above. The purification can be carried out at intermediate stage and/or of final product or salts thereof. However, other equivalent procedures such as acid-base treatment could, also be used, to purify the intermediates. The solvents used for the purification of final compound as well intermediates or salts thereof of the present invention can be selected from aliphatic or aromatic hydrocarbon such as toluene, cyclophexane; ester such as ethyl acetate; alcohol such as methanol, ethanol, isopropanol; ether such as methyl tertiary butyl ether and the like or mixture thereof in suitable proportion.
Major advantage realized in the present invention is that process is simple, economical, high throughput and industrial advantageous. Other advantages are that raloxifene hydrochloride is prepared in overall high yield and high purity using less number of steps without using chromatographic purification and hazardous reagent such as sodium hydride, DEAD etc.
Although, the following examples illustrate the present invention in more detail, but should not be construed as limiting the scope of the invention.
Example 1: Preparation of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene
Oxalyl chloride (45 g, 0.35 mol) was added to a solution of 4-hydroxy benzoic acid (25 g, 0.18 mol) in N,N- dimethylformamide (3 ml) and dichloromethane (250 ml) at 15-20 °C. Reaction mass was warmed to 20-25 °C and stirred for 2 hours. After the completion of the reaction (monitored by TLC), some dichloromethane was distilled off under vacuum to remove excess of oxalyl chloride. Thereafter 6-methoxy-2-(4-methoxy-phenyl)-benzo[b]thiophene (44 g, 0.16 mol) and dichloromethane (1.5 L) were added to the reaction mixture. Reaction mixture was cooled to 0-5 °C and aluminum chloride (26.2 g, 0.20 mol) was added, raised the temperature to 20-25 °C and stirred for 4-5 hours. After the completion of the reaction (monitored by TLC), reaction mass was quenched with tetrahydrofuran (200 ml) and then poured in to ice cold water. Organic layer was separated, washed with brine solution followed by washing with water. The resulting organic layer was concentrated under vacuum to give title compound.
Purification: The resulting product was dissolved in dichloromethane (350 ml) and 5% sodium hydroxide (400 ml) was added to the solution and stirred for 10 minutes. Layers were separated and aqueous layer was washed with dichloromethane (3 x 300ml) and then acidified to pH 2-3 using concentrated hydrochloric acid. Ethyl acetate (400 ml) was added to aqueous solution and stirred for 10 minutes. Organic layer was separated and washed successively with saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine solution (200 ml). The resulting organic layer was distilled off under reduced pressure to obtain 63 g of the title compound which was crystallized from toluene to give 60 g (95%) of the title compound. Example 2: Preparation of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene
Oxalyl chloride (41 g, 0.32 mol) was added to a solution of 4-hydroxy benzoic acid (22.7 g, 0.16 mol) in N,N- dimethylformamide (2.7 ml) and dichloromethane (227 ml) at 15-20 °C. Reaction mass was warmed to 20-25 °C and stirred for 2 hours.
After the completion of the reaction (monitored by TLC), 6-methoxy-2-(4-methoxy-phenyl)-benzo[b]thiophene (40 g, 0.15 mol) and dichloromethane (1.4 L) were added to the reaction mixture. Reaction mixture was cooled to 0-5 °C and aluminum chloride (23.8 g, 0.18 mol) was added, raised the temperature to 20-25 °C and stirred for 4-5 hours. After the completion of the reaction (monitored by TLC), reaction mass was quenched with tetrahydrofuran (182 ml) and then poured in to ice cold water. Organic layer was separated, washed with brine solution followed by washing with water. The resulting organic layer was concentrated under vacuum to give oil which was dissolved in dichloromethane (318 ml) and 5% sodium hydroxide (364 ml) was added to the solution and stirred for 10 minutes. Layers were separated and aqueous layer was washed with dichloromethane (3 x 273 ml) and then acidified to pH 2-3 using concentrated hydrochloric acid. Ethyl acetate (364 ml) was added to aqueous solution and stirred for 10 minutes. Organic layer was separated and washed successively with saturated sodium bicarbonate solution (182 ml), water (182 ml) and brine solution (182 ml). The resulting organic layer was distilled off under reduced pressure to obtain 57.3 g of the title compound, which was crystallized from toluene to give 52.5 g (91%) of title compound.
Example 3: Preparation of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene
Oxalyl chloride (51.1 g, 0.40 mol) was added to a solution of 4-hydroxy benzoic acid (28.3 g, 0.21 mol) in N,N- dimethylformamide (3.4 ml) and dichloromethane (284 ml) at 15-20 "C. Reaction mass was warmed to 20-25 °C and stirred for 2 hours. After the completion of the reaction (monitored by TLC), some of the solvent was distilled off from the reaction mixture. 6-Methoxy-2-(4-methoxy-phenyl)-benzo[b]thiophene (50 g, 0.19 mol) and dichloromethane (1.7 L) were added to the reaction mixture. Reaction mixture was cooled to 0-5 °C and aluminum chloride (29.8 g, 0.22 mol) was added, raised the temperature to 20-25 °C and stirred for 4-5 hours. After the completion of the reaction (monitored by TLC), reaction mass was quenched with tetrahydrofuran (227 ml) and then poured in to ice cold water. Organic
layer was separated, washed with brine solution followed by washing with water. The resulting organic layer was concentrated under vacuum. The residue thus obtained was dissolved in dichloromethane (398 ml) and 5% sodium hydroxide (454 ml) was added to the solution and stirred for 10 minutes. Layers were separated and aqueous layer was washed with dichloromethane (3 x 341 ml) and then acidified to pH 2-3 using hydrochloric acid. Ethyl acetate (454 ml) was added to aqueous solution and stirred for 10 minutes. Organic layer was separated and washed successively with saturated sodium bicarbonate solution (227 ml), water (227 ml) and brine solution (227 ml). The resulting organic layer was distilled off under reduced pressure to obtain 71.5 g (99%) of the title compound.
Example 4: Preparation of 2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]-6-methoxybenzo[b] thiophene
A mixture of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene (5g, 0.01 mol), potassium carbonate (4.4g, 0.03 mol) and dimethyl formamide (40 ml) was heated to 90-105 °C, and 2-chloroethyl piperidine (2.7 g, 0.01 mol) was added and stirred for 30 minutes. After the completion of the reaction (monitored by TLC), reaction mass was cooled to 35°C and filtered. Filtrate was distilled out under reduced pressure to give title compound which was dissolved in ethyl acetate. The resulting organic layer was washed with brine solution followed by water. Solvent was distilled off under reduced pressure to give 6 g (92 %) of pure title compound.
Example 5: Preparation of raloxifene hydrochloride
2-(4-Methoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]-6-methoxybenzo {b]
thiophene (5 gm, 0.01 mol), aluminum chloride (8g, 0.06mol), and thioethanol (3g, 0.05 mol) were added to dichloromethane (50 ml) and the reaction mass was stirred for 60 minutes at 25-30°C. After the completion of the reaction, reaction mass was quenched with tetrahydrofuran (10 ml) and 20% hydrochloric acid (30ml). To the above solution, brine solution (30ml) was added and was stirred for 20-30 minutes at
20-25 °C. The resulting reaction mixture was filtered to give 4.5 g (88 %) of the tile compound.
Example 6: Preparation of 2-(4-methoxyphenyl)-3-[4-(2-piperidinoethoxy) benzoyl]-6-methoxybenzo [b] thiophene hydrochloride
Method A: A mixture of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene (5g, 0.01 mol), potassium carbonate (4.4g, 0.03 mol) and dimethyl formamide (40 ml) was heated to 90-105 °C, and 2-chloroethyl piperidine (2.7 g, 0.014mol) was added and stirred for 30 minutes. After the completion of the reaction (monitored by TLC), reaction mass was cooled to 35°C and filtered. Filtrate was distilled out under reduced pressure to give a residue which was dissolved in dichloromethane (50ml) followed by addition of 20% hydrochloric acid (50 ml) to the reaction mixture. Organic layer was separated. Solvent was distilled off from the organic layer and the residue thus obtained was slurried in hot chlorobenzene (64 ml), cooled to 5 °C and filtered to give 6.4 g (92 %) of the tile compound. Method B: : A mixture of 2-(4-(methoxy phenyl)-3-(4-hydroxy benzoyl)-6-methoxy benzo[b] thiophene (5g, 0.01 mol), potassium carbonate (4.4g, 0.03 mol) and dimethyl formamide (40 ml) was heated to 90-105 °C, and 2-chloroethyl piperidine (2.7 g, 0.014mol) was added and stirred for 30 minutes. After the completion of the reaction (monitored by TLC), reaction mass was cooled to 35°C and filtered. Filtrate was distilled out under reduced pressure to give a residue which was dissolved in dichloromethane (50ml) followed by addition of 20% hydrochloric acid (50 ml) to the reaction mixture. Organic layer was separated. Solvent was distilled off to give title compound which was crystallized from acetone (30 ml) to give 6.7 g (97%) of title compound.
Example 7: Preparation of raloxifene hydrochloride
6-Methoxy-2-(4-methoxy-phenyl)-3-[4-(2-piperidinoethoxy)benzoyl] benzo [b] thiophene hydrochloride. (6 g, 0.01 mol), aluminum chloride (9.6 g, 0.07 mol) and thioethanol (3.6 g, 0.06 mol) were added to dichloromethane (50 ml) and the reaction mass was stirred for 60 minutes at 25-30 °C. After the completion of the reaction
(monitored by TLC), reaction mass was quenched with tetrahydrofuran (10 ml) and
20% hydrochloric acid (30 ml). Brine solution (30 ml) was added to the resulting
reaction mixture and stirred for 20-30 minutes at 20-25 °C. The resulting reaction
mixture was filtered to give 4.5 g (80%) of the title compound.
Example 8: Preparation of raloxifene
Raloxifene hydrochloride (2 g) was dissolved in acetone (20 ml) and solution was
basified with aqueous ammonia (2 ml). Acetone was distilled out from the reaction
mixture under reduced pressure. Ethylacetate (20 ml) was added to the resulting
residue and Organic layer was washed successively with water (20 ml) followed by
brine. Solvent was distilled off from the resulting layer to give 1.8 g (97%) of the title
compound.
Example 9: Preparation of raloxifene hydrochloride
Raloxifene (1.8 g) was dissolved in tetrahydrofuran (72 ml) and resulting solution
was dried over molecular sieve 4 A. Hydrogen chloride gas was passed through the
reaction mass till the precipitation of the product. The product thus precipitated was
filtered to give 1.82 g (94%) to give title compound.

We Claim:
1). A process for the preparation of raloxifene of formula I,
(Formula Removed)
or a pharmaceutically acceptable salt thereof, comprises the steps of: a), reacting 4-hydroxy benzoic acid of formula I,
(Formula Removed)
with a suitable activating agent to activate carboxyl group selectively to form of formula intermediate III,
(Formula Removed)
wherein X is selected from halogen such as chloro, bromo or iodo and the like b). condensing intermediate of formula III with compound of formula IV,
(Formula Removed)
wherein both R can be same or different and is H or any hydroxy protecting group; each R can independently selected from hydrogen, alkyl, aryl, cycloalkyl, aralkyl, -SO2R1 or -COR1; wherein R1 is alkyl, haloalkyl, alkoxy, alkyl aryl, alkoxy aryl, substituted or itnsubstituted aryl; substituent can be at one or more position of aryl group and selected amongst alkyl, alkoxy, hydroxy, nitro, halo, or trihaloalkyl; more preferably R can be acetyl, benzyl, benzenesulfonyl, methane sulphonyl, ethoxycarbonyl, methyl, benzoyl, dodecanoyl and the like
in the presence of a suitable catalyst to form benzothiophene intermediate of formula V,
(Formula Removed)
wherein R is as defined above c). optionally, purifying the benzothiophene intermediate of formula V, d). converting benzothiophene intermediate of formula V to raloxifene hydrochloride. 2). The process according to claim 1, wherein in step a) suitable activating agent is oxalyl chloride; and in step b) catalyst includes Lewis acid catalyst such as aluminum chloride, aluminum bromide, zinc chloride, boron trifuoride, boron trichloride, boron tribromide, titanium tetrachloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, ferric chloride and the like. 3). The process according to claim 1, wherein R is preferably H or alkyl and more
preferably R is methyl. 4). A process for the purification of benzothiophene intermediate of formula V, comprising the steps of: a), providing a solution comprising benzothiophene intermediate of formula V
and a water immiscible solvent; b). treating the solution with a suitable base; c). separating the layers; d). optionally, washing the aqueous layer with a suitable water immiscible
solvent, e). acidifying the aqueous layer with a suitable acid; f). extracting the aqueous layer using an organic solvent; g). isolating the purified benzothiophene intermediate of formula V there from;
and h). optionally, crystallizing benzothiophene intermediate of formula V from a suitable solvent.
5). The process according to claim 4, wherein in step a) water immiscible solvent includes halogenated solvents such as dichloromethane, dichloroethane, chloroform; esters such as ethyl acetate; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof; and in step b) base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides thereof such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.
6). The process according to claim 4, wherein in step d) water immiscible solvent includes halogenated solvents such as dichloromethane, dichloroethane, chloroform; esters such as ethyl acetate; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof; in step e) suitable acid includes inorganic acid such as hydrochloric acid, sulfuric acid or organic acid such as carboxylic acids (acetic acid), sulfonic acid (benzene sulfonic acid, p-toluene sulfonic acid) and the like; and in step f) suitable solvent includes ester such as ethyl acetate; halogenated solvents such as dichloromethane, dichloroethane, chloroform; aliphatic or aromatic hydrocarbon such as toluene and the like or mixture thereof.
7). A process for the preparation of raloxifene of formula I, or a pharmaceutically acceptable salt thereof, comprises the steps of:
a), reacting 4-hydroxy benzoic acid of formula I,
(Formula Removed)
with a suitable activating agent to activate carboxyl group selectively to form intermediate of formula III,
(Formula Removed)
wherein X is as defined above
b). condensing intermediate of formula III with compound of formula IV,
(Formula Removed)
wherein R is as defined above
in the presence of a suitable catalyst to form benzothiophene intermediate of formula V,
(Formula Removed)
wherein R is as defined above c). optionally, purifying the benzothiophene intermediate of formula V, d). reacting the benzothiophene intermediate of formula V with compound of
formula VI
(Formula Removed)
wherein Hal is selected from chloro, bromo, iodo and the like in the presence of base to form intermediate of formula VII,
(Formula Removed)
wherein R is as defined above or acid addition salts thereof e). deprotecting the intermediate of formula VII or acid addition salts thereof
using a suitable deprotecting reagent; and f). isolating raloxifene of formula I or a pharmaceutically acceptable salt thereof there from. 8). The process according to claim 7, wherein in step a) suitable activating agent is oxalyl halide and the like; and in step b) catalyst includes Lewis acid catalyst such as aluminum chloride, aluminum bromide, zinc chloride, boron trifuoride, boron trichloride, boron tribromide, titanium tetrachloride, titanium tetrabromide, stannic chloride, stannic bromide, bismuth trichloride, ferric chloride and the like. 9). The process according to claim 7, wherein in step d) base includes alkali or alkaline metal hydroxides, carbonates, bicarbonates, alkoxides such as
potassium carbonate, potassium bicarbonate, cesium carbonate and the like; and in step e) deprotecting agent includes bases such as alkali metal hydroxides; acid catalysts (aqueous, concentrated or gaseous) such as methane sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid; ion exchange resin; boron compounds such as borane trihalide; beryllium compounds such as beryllium dihalide; thiophenol, lithium diphenylphosphide, aluminium halide thiol combination, high molecular weight alkane or arene thiolate anions, trialkyl borohydride and its salts; thiophenol, sodium sulfide and the like; silyl compounds such as trimethyl silyl halides with sodium iodide in nitrile solvents; hydrobromic acid, hydrochloric acid catalyst includes transition metals with or without support (carbon) such as palladium, platinum, nickel and the like diisobutylaluminium hydride; sulphur compounds like alkyl thiol such as methanethiol, ethanethiol, isopropanethiol, butanethiol and the like; dialkyl sulfides such as diethyl sulfide, butyl s-butyl sulfide, ethyl propyl sulfide, butyl isopropyl sulfide, dimethyl sulfide, methyl ethyl sulfide and the like; benzenethiol; methionine; and alkyl phenyl sulfides such as methyl phenyl sulfide, ethyl phenyl sulfide, butyl phenyl sulfide; sulfur compounds such as thioethanol in combination with sodium methoxide, aluminium halide or boron tribromide and the like.
10). The process according to claim 7, wherein R is methyl, Lewis acid catalyst is aluminium chloride ( step b), base is potassium carbonate (step d) and deprotecting agent is ethanethiol in the presence of aluminium chloride.