WO2011132194A1

WO2011132194A1 - Process for the preparation of raloxifene hydrochloride

Info

Publication number: WO2011132194A1
Application number: PCT/IN2010/000247
Authority: WO
Inventors: Bandi Parthasaradhi Reddy; Kura Rathnakar Reddy; Dasari Muralidhara Reddy; Rapolu Raji Reddy; Matta Ramakrishna Reddy; Bandi Vasmi Krishna
Original assignee: Hetero Research Foundation
Priority date: 2010-04-19
Filing date: 2010-04-19
Publication date: 2011-10-27

Abstract

The present invention provides an improved process for the preparation of α-(3- methoxyphenylthio)-4-methoxyacetophenone. The present invention also provides a process for the preparing free flowing solid of 6-methoxy-2-(4-methoxyphenyl)- benzo[b]-thiophene. The present invention further provides a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene. The present invention further provides a process for purification of raloxifene hydrochloride.

Description

PROCESS FOR THE PREPARATION OF RALOXIFENE HYDROCHLORIDE

Field of the Invention

The present invention provides an improved process for the preparation of a-(3- methoxyphenylthio)-4-methoxyacetophenone. The present invention also provides a process for the preparing free flowing solid of 6-methoxy-2-(4-methoxyphenyl)- benzo[b]-thiophene. The present invention further provides a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene. The present invention further provides a process for purification of raloxifene hydrochloride.

Background of the Invention

Raloxifene, its pharmaceutically acceptable salts thereof and process for their preparation were first disclosed in U.S. Patent No. 4,418,068 (herein after refer to '068 patent). Raloxifene hydrochloride is chemically, [6-hydroxy-2-(4-hydroxyphenyl)- benzothiophen-3-yl]-[4-[2-(l-piperidyl)ethoxy]phenyl]methanone hydrochloride and has the structural formula:

Raloxifene is an oral selective estrogen receptor modulator (SERM) that has estrogenic actions on bone and anti-estrogenic actions on the uterus and breast. It is used in the prevention of osteoporosis in postmenopausal women. Raloxifene is marketed under the brand name is Evista by Eli Lilly.

Process for the preparation of raloxifene hydrochloride was described in Ό68 patent.

According to the Ό68 patent disclosed a process for the preparation of a-(3- methoxyphenylthio)-4-methoxyacetophenone which comprises reacting 3- methoxybenzenethiol with potassium hydroxide in water and denatured ethanol and was slowly added a-bromo-4-methoxyacetophenone, the solvent was then evaporated off in vacuum, and water was added. Isolating the crude a-(3-methoxyphenylthio)-4- methoxyacetophenone, this was recrystallized from methanol.

According to the Ό68 patent disclosed a process for the preparation of 6- methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene which comprises adding slowly polyphosphoric acid to a-(3-methoxyphenylthio)-4-methoxyacetophenone, water was added. Isolating the crude 6-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene. The crude product was slurried in hot methanol and isolating the 6-methoxy-2-(4- methoxyphenyl)-benzo[b]thiophene and this was recrystallized from ethyl acetate.

According to the '068 patent disclosed a process for purification of raloxifene hydrochloride which comprises dissolving raloxifene hydrochloride in methanol and water, isolating.

Process for the preparation of raloxifene hydrochloride and its intermediates were disclosed in Journal of Medicinal Chemistry, 1984, Vol. 27, No. 8. According to the article disclosed a process for the preparation of 6-methoxy-2-(4-methoxyphenyl)- benzo[b]thiophene which comprises adding slowly polyphosphoric acid to a-(3- methoxyphenylthio)-4-methoxyacetophenone, water was added. Isolating the crude 6- methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene. The crude product was slurried in acetone and isolating.

PCT publication no. WO 2005/0031 16 a multi-step process for obtaining raloxifene hydrochloride is described, which is characterized by a step of hydrolyzing 6- acetoxy-2-(4-acetoxyphenyl)3-[4-(2-piperidioethoxy)benzoyl]-benzo[b]thiophene with alkaline hydroxide in an alcoholic solvent and subsequent acidification of the obtained product with concentrated hydrochloric acid. According to that described in the international patent application, crude raloxifene hydrochloride is obtained with a purity equal to about 98% and a yield of about 65-70%.

U.S. patent application no. 2007/0100147 disclosed a process for the preparation of raloxifene hydrochloride which comprises:

a) demethylation of 6-methoxy-2-(4-methyoxyphenyl)benzo[b]thiphene in pyridine hydrochloride to obtain 6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene; b) acetylating of 6-methoxy-2-(4-methyoxyphenyl)benzo[b]thiphene with acetic anhydride in the presence of triethylamine in ethyl acetate to obtain 6-acetoxy-2- (4-acetoxyphenyl)benzo[b]thiophene;

c) acylation of 6-acetoxy-2-(4-acetoxyphenyl)benzo[b]thiophene with 4-(2- piperidinoethoxy)benzoyl chloride and aluminium chloride in methylene chloride to obtain 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]- benzo[b]thiophene; and

d) hydrolysis of 6-acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]- benzo[b]thiophene with sodium hydroxide in methanol to obtain raloxifene and optionally converted to raloxifene hydrochloride.

Yields obtained by the prior art processes for the preparation of a-(3- methoxyphenylthio)-4-methoxyacetophenone are below 70%, where as the yields obtained by the process of the present invention is above 75%.

We have also discovered a process for preparing free flowing solid of 6- methoxy-2-(4-methoxyphenyl)-benzo [b] -thiophene.

It has been found that the 6-methoxy-2-(4-methoxyphenyl)-benzo[b] -thiophene produced according to the prior art procedures result in the formation of impurities. According to the present invention which process yields 6-methoxy-2-(4- methoxyphenyl)-benzo[b] -thiophene in a better purity when compared with that obtained by the prior art procedures.

According to the prior art processes raloxifene hydrochloride is purified by crystallizing raloxifene hydrochloride from methanol having the moisture content of about 1.3% and such processes required multiple recrystallizations to obtain a pure raloxifene hydrochloride. The multiple recrystallizations result in low yields of pure raloxifene hydrochloride. According to the present invention pure raloxifene hydrochloride can be obtained in higher yields then the prior art processes.

Thus, one object of the present invention is to provide an improved process for the preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone.

Another object of the present invention is to provide a process for the preparing free flowing solid of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene. Another object of the present invention is to provide a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene.

Yet another object of the present invention is to provide a process for purification of raloxifene hydrochloride.

Summary of the Invention

In one aspect, the present invention provides an improved process for the preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone, which comprise: a) reacting 4-methoxyacetophenone with bromine in an organic solvent at below 20°C; ·

b) reacting brominated compound obtained in step (a) with 3-methoxybenzenethiol in the presence of a base;

c) isolating the a-(3-methoxyphenylthio)-4-methoxyacetophenone from the reaction mass characterized in that the quantity of bromine used in step (a) is 1 to 2 moles with respect to 4-methoxyacetophenone.

In another aspect, the present invention provides a process for the preparing of free flowing solid of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene, which comprises:

a) reacting a-(3-methoxyphenylthio)-4-methoxyacetophenone with polyphosphoric acid;

b) adding 5 to 50 ml of water per 100 gm of a-(3-methoxyphenylthio)-4- methoxyacetophenone to the reaction mass obtained in step (a);

c) pouring the reaction mass to the water; and

d) isolating the solid to obtain free flowing solid of 6-methoxy-2-(4- methoxyphenyl)-benzo [b] -thiophene.

In another aspect, the present invention provides a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene, which comprise:

a) slurring the 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene with ketonic solvent;

b) separating the 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene as solid; c) slurring the isolated solid obtained in step (b) with ester solvent; and

d) separating the resulting solid to obtain substantially pure 6-methoxy-2-(4- methoxyphenyl)-benzo [b] -thiophene .

Yet another aspect, the present invention provides a process for purification of raloxifene hydrochloride, which comprises crystallizing raloxifene hydrochloride from a solution of raloxifene hydrochloride in methanol moisturized with at least 2.5% of water.

Detailed Description of the Invention

According to one aspect of the present invention, there is provided an improved process for the preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone, which comprise:

a) reacting 4-methoxyacetophenone with bromine in an organic solvent at below 20°C;

The organic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from alcoholic solvents such as methanol, ethanol and isopropanol. More preferable organic solvent is methanol. Still more preferably methanol is used in the entire process.

The temperature of the reaction in step (a) may preferably be carried out at below 15°C and more preferably at below 12 C.

Preferably the base used in step (b) is an inorganic base or organic base such as potassium hydroxide or sodium hydroxide and more preferably the base is potassium hydroxide.

Isolation of a-(3-methoxyphenylthio)-4-methoxyacetophenone in step (c) may preferably be carried out by the methods known such as filtration or centrifugation. According to another aspect of the present invention, there is provided a process for the preparing of free flowing solid of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene, which comprises:

c) pouring the reaction mass to the water; and

d) isolating the solid to obtain free flowing solid of 6-methoxy-2-(4- methoxyphenyl)-benzo[b]-thiophene.

The water used in step (b) may preferably be 10 to 40 ml of water per 100 gm of a-(3-methoxyphenylthio)-4-methoxyacetophenone and more preferably 20 to 30 ml of water per 100 gm of a-(3-methoxyphenylthio)-4-methoxyacetophenone.

The temperature of the reaction in step (b) is maintained at elevated temperature. The term "elevated temperature" refers to temperature at above 25°C. Preferably the maintaince may be carried out at about 40 to 100°C, more preferably at about 60 to 90°C and still more preferably at about 70 to 90°C.

Preferably reaction mass in step (b) is stirred for 5 minutes to 1 hour of the addition of water.

Preferably quantity of water used in step (c) may be in an excess quantity and more preferably above 10 volumes to the a-(3-methoxyphenylthio)-4- methoxyacetophenone by weight.

Preferably water used in step (c) may be ice water.

The reaction mass in step (c) may preferably be stirred for at least 30 minutes. Isolation of free flowing solid of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene in step (d) may preferably be carried out by the methods known such as filtration or centrifugation.

According to another aspect of the present invention, there is provided a process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene, which comprise: a) slurring the 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene with ketonic solvent;

The ketonic solvent used in step (a) may preferably be a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone, and more preferable ketonic solvent is acetone.

The ester solvent used in step (c) may preferably be a solvent or mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate, and more preferable ester solvent is ethyl acetate.

The separated solid may preferably be collected by the method known such as centrifugation or filtration.

According to another aspect of the present invention, there is provided a process for purification of raloxifene hydrochloride, which comprises crystallizing raloxifene hydrochloride from a solution of raloxifene hydrochloride in methanol moisturized with at least 2.5% of water.

Preferably the solution of raloxifene hydrochloride is prepared by dissolving raloxifene hydrochloride in methanol moisturized with at least 2% of water at elevated temperature and more preferably under reflux conditions.

Preferably water content of the solution is 3 to 5% and more preferably 3.5 to

4.5%.

The term "% of water" refers to volume of the water per 100 volumes of methanol (v/v).

Crystallization of raloxifene hydrochloride from the solution of raloxifene hydrochloride in methanol can be performed by conventional methods such as cooling, partial removal of solvents, seeding or a combination thereof. The separated solid may be collected by the method known such as centrifugation or filtration.

The invention will now be further described by the following examples, which are illustrative rather than limiting. Examples

Example 1 :

Preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone

4-Methoxyacetophenone (100 gm) was dissolved in methanol (500 ml) and cooled to 10°C, and then added bromine (120 gm) for 2 hours. Then the contents were maintained for 30 minutes at 10°C and water (300 ml) was added to the reaction mass. The reaction mass was stirred for 30 minutes, filtered and dried at room temperature for 2 hours to obtain a solid. A mixture of water (300 ml), potassium hydroxide (42 gm) and 3-methoxybenzenethiol (84 gm) was added to the above solid at 0°C. The temperature of the reaction mass was raised to room temperature and maintained for 3 hours at room temperature. Water (420 ml) was added to the reaction mass and stirred for 1 hour, filtered. The solid obtained was dried at room temperature for 2 hours to obtain a solid. To the solid was added methanol (440 ml) and stirred for 1 hour, filtered. The solid obtained was dried under vacuum at 35 to 40°C for 6 hours to obtain 163 gm of a-(3- methoxyphenylthio)-4-methoxyacetophenone.

Example 2:

Preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone

4-Methoxyacetophenone (200 gm) was dissolved in methanol (1000 ml) and cooled to 10°C, and then added bromine (300 gm) for 2 hours. Then the contents were maintained for 30 minutes at 15°C and water (300 ml) was added to the reaction mass. The reaction mass was stirred for 30 minutes, filtered and dried at room temperature for 2 hours to obtain a solid. A mixture of water (600 ml), potassium hydroxide (80 gm) and 3-methoxybenzenethiol (170 gm) was added to the above solid at 0°C. The temperature of the reaction mass was raised to room temperature and maintained for 3 hours at room temperature. Water (850 ml) was added to the reaction mass and stirred for 1 hour, filtered. The solid obtained was dried at room temperature for 2 hours to obtain a solid. To the solid was added methanol (900 ml) and stirred for 1 hour, filtered. The solid obtained was dried under vacuum at 35 to 40°C for 6 hours to obtain 330 gm of a-(3- methoxyphenylthio)-4-methoxyacetophenone. Example 3:

Preparation of free flowing solid of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene

Polyphosphoric acid (250 gm) was taken and heated to 65°C, and then slowly added a-(3-methoxyphenylthio)-4-methoxyacetophenone (100 gm) as obtained in example 1 under stirring. Then the contents were maintained for 2 hours at 90°C and were added water (25 ml), and continued the stirring for 10 minutes. The reaction mass was poured to the ice water (2475 ml) and stirred for 4 hours. The separated free flowing solid was filtered to obtain 87 gm of 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene containing 4-methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene.

Example 4:

Polyphosphoric acid (120 gm) was taken and heated to 65°C, and then slowly added a-(3-methoxyphenylthio)-4-methoxyacetophenone (50 gm) under stirring. Then the contents were maintained for 1 hour 30 minutes at 90°C and were added water (20 ml), and continued the stirring for 10 minutes. The reaction mass was poured to the ice water (1300 ml) and stirred for 3 hours. The separated free flowing solid was filtered to obtain 42 gm of 6-methoxy-2-(4-methoxyphenyl)-benzo[b] -thiophene containing 4- methoxy-2-(4-methoxyphenyl)-benzo[b]thiophene.

Example 5:

Preparation of substantially pure 6-methoxy-2-(4-methoxypheny.)-benzo[b]- thiophene

6-Methoxy-2-(4-methoxyphenyl)-benzo [b] -thiophene containing 4-methoxy-2- (4-methoxyphenyl)-benzo[b]thiophene (85 gm) as obtained in example 3 was added acetone (300 ml) at room temperature. The suspension was heated to reflux and maintained for 1 hour at reflux. The suspension was cooled to room temperature and stirred for 1 hour, filtered. The solid obtained was added ethyl acetate (250 ml) at room temperature. The suspension was heated to reflux and maintained for 1 hour at reflux. The suspension cooled to room temperature and stirred for 1 hour. The separated solid was filtered and dried at 55 to 60°C for 6 hours to obtain 60 gm of substantially pure 6- methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene (High Performance Liquid Chromatography (HPLC) Purity: 99.9%).

Example 6:

Preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)-benzo[b]- thiophene

6-Methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene containing 4-methoxy-2- (4-methoxyphenyl)-benzo[b]thiophene (40 gm) was added acetone (150 ml) at room temperature. The suspension was heated to reflux and maintained for 1· hour at reflux. The suspension was cooled to room temperature and stirred for 1 hour, filtered. The solid obtained was added ethyl acetate (120 ml) at room temperature. The suspension was heated to reflux and maintained for 1 hour at reflux. The suspension cooled to room temperature and stirred for 1 hour. The separated solid was filtered and dried at 55 to 60°C for 6 hours to obtain 26 gm of substantially pure 6-methoxy-2-(4-methoxyphenyl)- benzo[b]-thiophene (HPLC Purity: 99.85%).

Example 7:

Preparation of raloxifene hydrochloride

4-(2-Piperidinoethoxy)-benzoic acid hydrochloride (120 gm) was added to toluene (600 ml) and then added dimethylformamide (2 ml) and thionyl chloride (160 gm) under stirring. The temperature of the reaction mass was raised to 80°C and maintained for 2 hours. The reaction mass was distilled off solvent completely under vacuum at 65° to obtain residue. To the residue was added methylene chloride (1500 ml) and then added 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene (100 gm). To the reaction mass was added aluminum chloride (360 gm) for 1 hour and maintained for 2 hours at room temperature. The reaction mass was cooled to 10°C and then added propanethiol (100 ml) for 1 hour 30 minutes under stirring. The temperature of the reaction mass was gradually raised to room temperature and maintained for 1 hour 30 minutes. The reaction mass was cooled to 5°C and then added methanol (600 ml). The reaction mass was stirred for 30 minutes at 5 C and then added dilute hydrochloric acid (2N, 800 ml). To the reaction mass was added saturated sodium chloride solution (800 ml) and water (800 ml). The reaction mass was stirred for 2 hours and filtered. To the wet solid was added diluted hydrochloric acid (IN, 800 ml) and stirred for 1 hour, filtered. To the wet solid was added acetone (500 ml) and heated to reflux, and maintained for 30 minutes. The suspension was cooled to room temperature and stirred for 1 hour 30 minutes. The separated solid was filtered and dried at 55 to 60°C for 2 hours to obtain 220 gm of raloxifene hydrochloride. Example 8:

Preparation of purification of raloxifene hydrochloride

Raloxifene hydrochloride (220 gm) as obtained in example 7 was dissolved in 4% moisturized methanol (4000 ml) and heated to reflux to obtain solution. To the solution was added activated carbon (5 gm) and distilled off methanol until about 600 ml of solvent left under vacuum at 50°C. The separated solid was filtered and dried at 55 to 60°C for 9 hours to obtain 120 gm of raloxifene hydrochloride (HPLC Purity: 99.8%).

Example 9:

Preparation of purification of raloxifene hydrochloride

Raloxifene hydrochloride (100 gm) was dissolved in 3.5% moisturized methanol

(1800 ml) and heated to reflux to obtain solution. To the solution was added activated carbon (5 gm) and distilled off methanol until about 300 ml of solvent left under vacuum at 50°C. The separated solid was filtered and dried at 55 to 60°C for 8 hours to obtain 52 gm of raloxifene hydrochloride (HPLC Purity: 99.7%).

Claims

We claim:

1. A process for the preparation of a-(3-methoxyphenylthio)-4-methoxyacetophenone, which comprise:

a. reacting 4-methoxyacetophenone with bromine in an organic solvent at below 20°C;

b. reacting brominated compound obtained in step (a) with 3-methoxybenzenethiol in the presence of a base;

c. isolating the a-(3-methoxyphenylthio)-4-methoxyacetophenone from the reaction mass characterized in that the quantity of bromine used in step (a) is 1 to 2 moles with respect to 4-methoxyacetophenone.

2. The process according to claim 1, wherein the organic solvent used in step (a) is a solvent or mixture of solvents selected from alcoholic solvents are methanol, ethanol and isopropanol.

3. The process according to claim 2, wherein the organic solvent is methanol.

4. The process according to claim 3, wherein the methanol is used in entire process.

5. The process according to claim 1 , wherein the temperature of the reaction in step (a) is carried out at below 15°C.

6. The process according to claim 5, wherein the temperature of the reaction at below 12°C.

7. The process according to claim 1, wherein the base used in step (b) is an inorganic base or organic base is potassium hydroxide or sodium hydroxide.

8. The process according to claim 7, wherein the base is potassium hydroxide.

9. A process for the preparing of free flowing solid of 6-methoxy-2-(4- methoxyphenyl)-benzo[b]-thiophene, which comprises:

a. reacting a-(3-methoxyphenylthio)-4-methoxyacetophenone with polyphosphoric acid;

b. adding 5 to 50 ml of water per 100 gm of a-(3-methoxyphenylthio)-4- methoxyacetophenone to the reaction mass obtained in step (a);

c. pouring the reaction mass to the water; and

d. isolating the solid to obtain free flowing solid of 6-methoxy-2-(4- methoxyphenyl)-benzo[b]-thiophene.

10. The process according to claim 9, wherein the water used in step (b) is 10 to 40 ml of water per 100 gm of a-(3-methoxyphenylthio)-4-methoxyacetophenone.

1 1. The process according to claim 10, wherein the water is 20 to 30 ml of water per 100 gm of a-(3-methoxyphenylthio)-4-methoxyacetophenone.

12. The process according to claim 9, wherein the temperature of the reaction in step (b) is maintained at elevated temperature.

13. The process according to claim 12, wherein the maintaince is carried out at about 40 to 100°C.

14. The process according to claim 13, wherein the maintaince is carried out at about 60 to 90°C.

15. The process according to claim 14, wherein the maintaince is carried out at about 70 to 90°C.

16. A process for the preparation of substantially pure 6-methoxy-2-(4-methoxyphenyl)- benzo[b]-thiophene, which comprise:

a. slurring the 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene with ketonic solvent;

b. separating the 6-methoxy-2-(4-methoxyphenyl)-benzo[b]-thiophene as solid; c. slurring the isolated solid obtained in step (b) with ester solvent; and

d. separating the resulting solid to obtain substantially pure 6-methoxy-2-(4- methoxyphenyl)-benzo [b] -thiophene .

17. The process according to claim 16, wherein the ketonic solvent used in step (a) is a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone and diethyl ketone.

18. The process according to claim 17, wherein the ketonic solvent is acetone.

19. The process according to claim 16, wherein the ester solvent used in step (c) is a solvent or mixture of solvents selected from ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate and ethyl formate.

20. The process according to claim 19, wherein the ester solvent is ethyl acetate.

21. A process for purification of raloxifene hydrochloride, which comprises crystallizing raloxifene hydrochloride from a solution of raloxifene hydrochloride in methanol moisturized with at least 2.5% of water.

22. The process according to claim 21, wherein the solution of raloxifene hydrochloride is prepared by dissolving raloxifene hydrochloride in methanol moisturized with at least 2% of water at elevated temperature.

23. The process according to claim 21, wherein the water content of the solution is 3 to 5%.

24. The process according to claim 23, wherein the water content of the solution is 3.5 to 4.5%.