Field of the invention

The present invention relates to an improved process for the preparation of Raloxifeneof formula (I).

Background of the invention

Raloxifeneis an estrogen agonist/antagonist, commonly referred to as a selective estrogen receptor modulator (SERM), which belongs to the benzothiophene class of compounds. The compound is administered as its hydrochloride.Chemically, Raloxifene is known as methanone, [6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thien-3-yl]-[4-[2-(l-piperidinyl)ethoxy]phenyl] hydrochloride. It is marketed in the US under the brand name Evista® as tablet dosage form.
Considering the importance of Raloxifene, several patents disclosesprocesses for the preparation of Raloxifene, few of them utilize the following compounds as starting materials. US 4,418,068 & US 4,380,635 disclose a process for the preparation of Raloxifene by condensing the compound of formula (II) with (III) in the presence of ethanethiol and aluminum chloride Indian patent application No. 1027/CHE/2010 disclose a process for the preparation of Raloxifene, as shown in scheme I given below :

The process for the preparation of Raloxifene as discussed in the above prior art references has one or more of the following drawbacks:

1) Utilizes the ethanethiol that has a strong, unpleasant odour even at very low concentrations,

2) Ethanethiol being lower molecular weight thiol, may vaporize to form explosive mixtures with air.

Considering the importance of Raloxifene, there is need for a simple, economical and industrially viable and odorless process for the synthesis of Raloxifene. With a view to find a simple process, the inventors of the present invention diligently worked and identified a robust and economical process for the preparation of Raloxifene using higher molecular weight thiols. Objective of the invention The main objective of the present invention is to provide an improved process for the preparation of Raloxifene that avoids the use of hazardous flammable ethanethiol. Another objective of the present invention is to provide a robust and odorless process for the preparation of Raloxifene with high purity and yield.

Summary of the invention

Accordingly, there is provided an improved process for the preparation of Raloxifene, the said process comprising the steps of: i) reacting 4-(2-piperidinoethoxy)benzoic acid chloride of formula (II) or its salt with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene of formula (III) in the presence of a aluminum chloride or aluminum bromide and in the presence of C8-C20alkylthiol or arylthio as a solvent; and ii) isolating Raloxifene of formula (I). Detailed descC8-C20ription of the invention In an embodiment of the present invention, the C8-C20alkylthiol is selected from decanethiol, dodecanethiol and the like or arylthio such as thiophenol, natphol and the like. The use of thiols like decanethiol replaces toxic & flammable ethanethiol that has a strongly disagreeable odor. Thus the use of decanethiol has been found to be an excellent as it allows an essentially odorless work-up process. Further the use of decanethiol affords Raloxifene in excellent yields. Accordingly the present invention provides eco-friendly and industrially safe process for the preparation of Raloxifene. As the acylation and subsequent dealkylation process contain complex of the acylation catalyst, the use of ethanethiol makes the workup process tedious and makes the process practically impossible in manufacturing plant. The use of decanethiol makes the workup process easier and provides odorless process. In another embodiment of the present invention the above said reaction both acylation and de-protection of methyl group occur in successive steps.

In another embodiment of the present invention, 4-(2-piperidinoethoxy)benzoic acid chloride of formula (II) may be used in the form of salts such as hydrochloric acid, hydrobromic acid and the like. In another embodiment of the present invention, the reaction is carried out at a temperature in the range of 0 to 50 °C, for a period of 30 minutes to 6 hours. In yet another embodiment of the present invention, the said reaction may optionally contain solvents such as dichloromethane, 1,2-dichloroethane, chloroform, benzene, toluene and the like during the acylation, and the decanethiol preferably added after the acylation reaction. In a preferred embodiment, the present invention provided an improved process for the preparation of Raloxifene, the said process comprising the steps of: i) reacting 4-(2-piperidinoethoxy)benzoic acid chloride of formula (II) or its salts with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene of formula (III), in the presence of a aluminum chloride or aluminum bromide and in the presence of C8-C20 alkylthiol such as decanethiol, dodecanethiol and the like or arylthio such as thiophenol, natphol as a solvent; and ii) isolating Raloxifene of formula (I). In still another embodiment of the present invention the Raloxifene is isolated from the reaction mass using conventional methods. The staring materials of compounds of formulae (II) and (III) are prepared using the process known in the literature. It will be understood that various modifications may be made to the embodiments disclosed herein. Therefore the above description should not be construed as limiting, but merely as exemplifications of preferred embodiments.

Example-1 [6-Hydroxy-2-(4-Hydroxyphenyl)benzothiophen-3-yl][4-[2-(piperidin-l- yl)ethoxy] phenyl] methanone hydrochloride A mixture of 13.0 g of 4-[2-(l-Piperidinyl)ethoxy]benzoic acid hydrochloride, 100 mL of methylene dichloride, 15 mL of thionyl chloride, and 5 drops of pyridine under protection with calcium chloride guard tube were stirred at reflux temperature for 2 hr. Excess thionyl chloride and methylene dichloride were removed by vacuum distillation. The residue was dissolved in 150 mL of methylene dichloride and cooled 0° C to +10 °C, and 10.0 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, and 37.0 g of anhydrous aluminium chloride were added. The mixture was stirred at 25-35 °C for 2 hr. Then 26 gm of of decanethiol was added and the reaction mixture was stirred at 25-35 °C for 1 hr. The mass was quenched in mixture of methanol(100 ml), ice and hydrochloric acid below 30 °C and stirred for 1 hr. The separated product was isolated by filtration, dried to yield 16 g of crude. Recrystallization of crude from methanol and water gave 9 gm of pure title compound, mp 258 °C.

Example-2 [6-Hydroxy-2-(4-Hydroxyphenyl)benzothiophen-3-yl][4-[2-(piperidin-l-yl)ethoxy] phenyl] methanone hydrochloride. A mixture of 13.0 g of 4-[2-(l-Piperidinyl)ethoxy]benzoic acid hydrochloride, 100 mL of methylene dichloride, 15 mL of thionyl chloride, and 5 drops of pyridine under protection with calcium chloride guard tube were stirred at reflux temperature for 2 hr. Excess thionyl chloride and methylene dichloride were removed by vacuum distillation. The residue was dissolved in 150 mL of methylene dichloride and cooled 0° C to -10 °C, and 10.0 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, and 37.0 g of anhydrous aluminium chloride were added. The mixture was stirred at 25-35 °C for 2 hr. Then 26 gm of of decanethiol was added and the reaction mixture was stirred at 25-35 °C for 1 hr. The mass was quenched in mixture of methanol(100 ml), ice and hydrochloric acid below 10 °C and stirred for 1 hr. The separated product was isolated by filtration, dried to yield 14 g of crude. Recrystallization of crude from methanol and water gave 8.4 gm of pure title compound, mp 258 °C.

Example-3 [6-Hydroxy-2-(4-Hydroxyphenyl) benzothiophen-3-yl][4-[2-(piperidin-l- yl)ethoxy] phenyl] methanone hydrochloride. A mixture of 13.0 g of 4-[2-(l-Piperidinyl)ethoxy]benzoic acid hydrochloride, 100 mL of methylene dichloride, 15 mL of thionyl chloride, and 5 drops of pyridine under protection with calcium chloride guard tube were stirred at reflux temperature for 2 hr. Excess thionyl chloride and methylene dichloride were removed by vacuum distillation. The residue was dissolved in 150 mL of methylene dichloride and cooled 0° C to -10 °C, and 10.0 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, and 37.0 g of anhydrous aluminium chloride were added. The mixture was stirred at 25-35 °C for 2 hr. Then 19.5 gm of of decanethiol was added and the reaction mixture was stirred at 25-35 °C for 1 hr. The mass was quenched in mixture of methanol(100 ml), ice and hydrochloric acid below 10 °C and stirred for 1 hr. The separated product was isolated by filtration dried to yield 13.5 g of crude . Recrystallization of crude from methanol and water gave 7 gm of pure title compound, mp 258 °C. Example-4 [6-Hydroxy-2-(4-Hydroxyphenyl) benzothiophen-3-yl][4-[2-(piperidin-l- yl)ethoxy] phenyl] methanone hydrochloride. A mixture of 13.0 g of 4-[2-(l-Piperidinyl)ethoxy]benzoic acid hydrochloride, 100 mL of methylene dichloride, 15 mL of thionyl chloride, and 5 drops of pyridine under protection with calcium chloride guard tube were stirred at reflux temperature for 2 hr. Excess thionyl chloride and methylene dichloride were removed by vacuum distillation. The residue was dissolved in 150 mL of methylene dichloride and cooled 0° C to +10 °C, and 10.0 g of 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene, and 37.0 g of anhydrous aluminium chloride were added. The mixture was stirred at 25-35 °C for 2 hr. Then 20 gm of thiophenol was added and the reaction mixture was stirred at 25-35 °C for 1 hr. The mass was quenched in mixture of methanol (100 ml), ice and hydrochloric acid below 30 °C and stirred for 1 hr. The separated product was isolated by filtration, dried to yield 15 g of crude. Recrystallization of crude from methanol and water gave 7 gm of pure title compound, mp 258°C.

We claim :

1. An improved process for the preparation of Raloxifene, the said process comprising the steps of:

i) reacting 4-(2-piperidinoethoxy)benzoic acid chloride of formula

(II) or its salts with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene of formula

(III), in the presence of a aluminum chloride or aluminum bromide and in the presence of C8 C20alkylthiol or arylthio as a solvent; and ii) isolating Raloxifene of formula (I).

2. The process as claimed in claim 1, wherein C8-C20 alkylthiol is selected from decanethiol or dodecanethiol.

3. The process as claimed in claim 1, wherein arylthio is selected from thiophenol or natphol.

4. The process as claimed in claim 1, wherein 4-(2-piperidinoethoxy)benzoic acid chloride of formula (II) is used in the form of salts selected from hydrochloric acid, or hydrobromic acid.
5. The process as claimed in claim 1, wherein reaction is carried out at a temperature in the range of 0 to 50 °C, for a period of 30 minutes to 6 hours.

6. The process as claimed in claim 1, wherein reaction further comprise solvent selected from dichloromethane, 1,2-dichloroethane, chloroform, benzene or toluene.

7. An improved process for the preparation of Raloxifene, the said process comprising the steps of:

i) reacting 4-(2-piperidinoethoxy)benzoic acid chloride of formula

(II) or its salt with 6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene of formula

(III) in the presence of a aluminum chloride or aluminum bromide and in the presence of C8-C20 alkylthiol selected from decanethiol, dodecanethiol or arylthio selected from thiophenol, natphol as a solvent; and ii) isolating Raloxifene of formula (I).

8. An improved process for the preparation of Raloxifene, prepared according to the examples as described herein.