PROCESS FOR PREPARING EXEMESTANE AND RELATED INTERMEDIATES

FILED OF THE APPLICATION

The present invention relates to processes for the preparation and purification of Exemestane and intermediate compounds useful for its preparation.

BACKGROUND OF THE APPLICATION
Exemestane is 6-methylene androst-1,4-dien-3,17-dione and is represented by the structural Formula I.

Exemestane is an oral steroidal aromatase inactivator and is used in the adjuvant treatment of hormonally-responsive (also called hormone-receptor-positive, estrogen-responsive) breast cancer in postmenopausal women.

The main source of estrogen formation is the ovaries in premenopausal women, while in post-menopausal women most of the body's estrogen is produced in the adrenal gland from the conversion of androgens into estrogen by the aromatase enzyme. Exemestane is an irreversible, steroidal aromatase inactivator, structurally related to the natural substrate androstenedione. It acts as a false substrate for the aromatase enzyme, and is processed to an intermediate that binds irreversibly to the active site of the enzyme causing its inactivation. Hence, exemestane, by being structurally similar to the target of the enzymes, permanently binds to those enzymes, thereby preventing them from ever completing their task of converting androgens into estrogens.

U.S. Patent No. 4,808,616 discloses exemestane, its pharmaceutically acceptable salts, and processes for its preparation, wherein one of the processes involves reacting 6-methylene androst-4-en-3,17-dione with dichlorodicyano benzoquinone in the presence of anhydrous dioxane at reflux temperature for about 15 hours to form exemestane. The process may be summarized by the reaction scheme-l as given below:

6-Methylenandrost-4-ene-3,17-dione Exemestane

Scheme-I

The purification of the product obtained is carried out by silica gel chromato-graphy using hexane/ethyl acetate.

U.S. Patent No. 4,876,045 ("the '045 process") discloses a process for the preparation of exemestane by reacting 6-methylene androst-1,4-dien-17p-ol-3-one with Jones reagent in acetone at -10°C. The '045 process may be summarized by the reaction scheme-ll as given below:

6- Methylenandrost-1,4-diene-17b-ol-3-one Exemestane

Scheme-II

The product obtained is crystallized from 65:35 mixture of ethanol and water.

U.S. Patent No. 4,990,635 ("the '635 process") discloses a process for preparing exemestane which involves reacting androst-4-en-3,17-dione with triethylorthoformate and p-toluenesulphonic acid at 40°C to give the corresponding dienol ethers, followed by reaction with N-methylaniline, 40% formic aldehyde aqueous solution to give 6-methylene androst-4-en-3,17-dione which is dehydrogenated by a three step process employing a bromination, denomination, and dehydrobromination sequence to give exemestane. The '635 process may be summarized by the reaction scheme-Ill as given below:

Scheme-Ill

The present inventors have discovered that carrying out the process disclosed in the '635 process does not facilitate a complete reaction. Also, in-situ preparation of 6-methylene androst~4-ene-3,17-dione results in an increased level of process related impurities. Further, dehydrogenation by a three-step process reduces the yield of exemestane and may not be suitable for an industrial-scale.

International Application Publication No. WO 01/04342 discloses a process for the preparation of exemestane which involves contacting 6-methyleneandrost-4-ene-3,17-dione with ∆1-dehydrogenating enzymes of A. simplex in the presence of a water-immiscible organic solvent and an exogenous electron carrier. It also discloses the use of toluene/octane as the solvents for the isolation of crystalline exemestane.

International Application Publication No. WO 2005/070951 discloses a two step process for making exemestane starting with 6-hydroxylmethyl androst-1,4-dien-3,17-dione. It also discloses the use of methanol/water and acetonitrile/ water (1:1) as the solvents for crystallization of exemestane.

There is an ongoing need for processes for the preparation of exemestane and its intermediates with improved purity and yield, which processes are eco-friendly, cost-effective, and well suited for an industrial scale.

SUMMARY OF THE INVENTION

The present invention includes process for preparing exemestane, which process comprises the steps of:

(a) reacting 3-methoxy androst-3,5-diene-17-one of Formula II

with aqueous formaldehyde and N-methylaniline to obtain 6-methylene androst-4-en-3,17-dione of Formula III; and

b) reacting the compound of Formula III with DDQ and an organic acid in the presence of an organic solvent to provide exemestane.

The present invention includes process for purifying exemestane, which processes comprises the steps of:

(a) providing a solution or suspension of exemestane in dimethylformamide, optionally in combination with a nitri/e or an alcohol;

(b) optionally adding water to precipitate solid exemestane; and

(c) isolating solid exemestane from the solution or suspension obtained in steps a) or b).

The present invention includes 3,17-dimethoxy androst-3,5,16-triene of Formula IV

The present invention includes 6-(N-methylphenylamino)-methyl androst-4-en-3,17-dione of Formula V

DETAILED DESCRIPTION

The present invention includes process for preparing exemestane, which process comprises the steps of:

(a) reacting 3-methoxy androst-3,5-diene-17-one of Formula II

with aqueous formaldehyde and N-methylaniline to obtain 6-methylene androst-4-en-3,17-dione of Formula III; and

b) reacting the compound of Formula III with DDQ and an organic acid in the presence of an organic solvent to provide exemestane.

Step (a) involves reaction of the compound of Formula II with aqueous formaldehyde and N-methylaniline to obtain a compound of Formula III. The reaction mixture may optionally comprise an acid, such as an inorganic acid.

The compound of Formula II may be obtained by the processes known in the art or by the process as disclosed in Example 3 of the present application, which process involves reacting androst-4-en-3,17-dione with 2,2-dimethoxypropane and

p-toluenesulfonic acid in the presence of dimethylformamide and methanol as summarized in the scheme below

The organic solvents that may be used for providing a solution or suspension of the compound of Formula II include and are not limited to: alcohols such as, for example, methanol, ethanol, isopropanol, and the like; nitriles, such as, for example, acetonitrile, propionitrile, and the like; and combinations thereof. For example, the organic solvent may be methanol.

The amount of solvent used may not be a critical parameter, however, the quantity of solvent employed is usually kept to a minimum and the solution of Formula II in the solvent selected may be provided at a temperature of about 20°C to about the reflux temperature of the solvent used.

The formaldehyde used may have a concentration of about 37% to 40% in water.

The amount of the formaldehyde used in Step (a) may range from about 0.1 to 4 volumes with respect to the weight of the compound of Formula II. For example, 0.5 volumes of formaldehyde may be used.

The amount of N-methylamine utilized in Step (a) may be about 0.5-3 molar equivalents per mole of the compound of Formula II. For example, 1.5 moles of N-methylamine per mole of the compound of Formula II may be used.

The addition of aqueous formaldehyde and N-methyl aniline to the solution of Formula II may be carried out at a temperature of about 0-65°C, about 30-55°C, or about 40-45°C.

The addition may be drop-wise over a period of about 5 minutes to about 1 hour.

The inorganic acids that may be used in the process of the present invention include and are not limited to hydrochloric acid, hydrobromic acid, hydrofluoric acid, HI, sulfuric acid, nitric acid, and phosphoric acid. For example, the acid may be hydrochloric acid. The acid may be neat or in the form of solution. For example, a solution of the acid is used.

The amount of the acid used may range from about 0.1 to about 12 volumes, or about 2 to about 8 volumes with respect to the weight of the compound of Formula II.

The acid may be added drop-wise over a period of about 5 minutes to about 1 hour. The addition may be carried out at a temperature of about 10°C to a temperature of about 80°C.

After the completion of addition, the reaction mixture is maintained at a temperature of about 10-60°C or about 35-50°C for a sufficient period of time to facilitate the conversion of the compound of Formula II. Optionally, the reaction mixture may be further be cooled to a temperature of about 5°C to about 35°C and maintained for a sufficient period of time.

For example, when the solvent is methanol, the reaction mixture may be maintained at a temperature of about 40°C to about 50°C, followed by a temperature of about 5°C to about 35°C.

The compound of Formula Ml may then be recovered from the reaction mixture. The recovery may be carried by any method known in the art, such as extraction or evaporating the solvent. For example, the compound of Formula III may be recovered by the process as disclosed in the Example 4.

The compound of Formula III may optionally be further purified by crystallization from solvents including and not limited to aromatic hydrocarbons, such as, for example, toluene and xylenes; aliphatic hydrocarbons, such as, for example, n-pentane, n-hexane, n-heptane, cyclohexane or mixture thereof; ketones, such as, for example, acetone, methyl isobutyl ketone, ethyl methyl ketone, and the like; and water. For example, the compound of Formula IN may be purified by crystallization from toluene and n-heptane, acetone and water, or both.

Step (b) involves reacting a compound of Formula III with DDQ and an organic acid in the presence of an organic solvent to provide exemestane.

The present inventors have found that the use of DDQ in combination with an organic acid results in an improved yield and purity of exemestane as compared to the known processes that involve the use of DDQ alone.

Organic acids that may be used in Step (b) include and are not limited to organic sulfonic acids such as methylsulfonic acid, toluenesulfonic acid; haloacetic acids, such as trifluoroacetic acid, trichloroacetic acid; and acetic acid. For example, the acid may be methylsulfonic acid or trifluroacetic acid.

Organic solvents that may be used in Step (b) include and are not limited to: aromatic hydrocarbons, such as, for example, toluene and xylenes.

The amount of the DDQ used in Step (b) may range from about 0.05 to about 4 molar equivalents, per molar equivalent of the compound of Formula III. For example, about 1.0 to about 2.0 molar equivalents may be used.

The amount of organic acid utilized in Step (b) may be about 0.01 -1.0 molar equivalents per mole of the compound of Formula III For example, about 0.2 molar equivalents of organic acid may be used.

The present inventors have found that carrying the reaction of Step (b) in stages, i.e., lot wise addition of DDQ and organic acid, facilitates the complete conversion of Formula III. The amount of DDQ that may be used in each stage or lot of Step (b) may range from about 0.1 to 1.5 molar equivalents with per molar equivalent of the compound of Formula III. The amount of organic acid that may be used in each stage of Step (b) may range from about 0.01 to 0.1 molar equivalents per molar equivalent of the compound of Formula III. The number of stages depends on the consumption of the starting material after each lot wise addition of DDQ and organic acid.

In a particular embodiment, the first lot involves the use of 0.5-1.2 molar equivalents of DDQ and 0.03-0.06 molar equivalents of organic sulfonic acid or haloacetic acid, per mole of the compound of Formula III.

Any addition of DDQ and organic acid may be carried out at a temperature of about 10°C to about 95°C. For the example, the addition may be carried out at a temperature of about 25°C to about 35°C.

After any addition of DDQ and organic acid, the reaction mixture may be optionally heated. The reaction mixture may be heated to a temperature of about 30-95°C, or about 65-80°C, or about 70-75°C. The reaction mixture is maintained at such temperature for a sufficient period of time to allow the conversion of the compound of Formula (II to exemestane.

After any stage, the reaction mixture may be optionally filtered, e.g., by cooling the reaction mixture to a temperature of about 20-40X, and washed with the reaction solvent.

After completion of the reaction, the reaction mixture is cooled to a temperature of about 20-40°C and a base is added. The base may be an organic or inorganic base or basic alumina. Preferably, an inorganic base, such as, for example, sodium hydroxide or potassium hydroxide either as a solid or solution may be used as the base. Subsequently, the reaction mixture may be maintained at a temperature of about 20-40°C, and filtered.

The exemestane may then be recovered. The recovery may be carried out by any method known in the art, such as extraction or evaporating the solvent. For example, the compound of Formula I may be recovered by an adding an aqueous solution of inorganic base to the reaction mass or filtrate to obtain a two phase system comprising an organic phase and of an aqueous phase, separating the aqueous phase, washing the organic phase with water, optionally distilling off the organic phase to minimum volume, and adding a suitable anti-solvent for precipitating the exemestane.

Useful anti-solvents include and are not limited to: alkanes, such as, for example, n-heptane, n-hexane, cyclohexane, and the like; ethers, such as, for example, diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 1,4-dioxane, dimethoxyethane, methyl tertiary-butyl ether, and the like; and combinations thereof. For example, an alkane may be used as the anti-solvent.

Typically, the suspension is maintained at a temperature of about 0°C to about 35*C for about 30 minutes to about 3 hours to increase the yield of the precipitated Formula I, which may be recovered from the suspension by filtering it, washing the filtered product, and drying.

The recovered exemestane of Formula I may optionally be further purified by crystallization.

In one of the particular embodiment, the present invention includes a process for preparing exemestane comprising the steps of:

(a) reacting androst-4-en-3,17-dione with 2,2 DMP/methanol, PTSA, and DMF to obtain 3-methoxy androst-3,5-dien-17-one of Formula II

(b) reacting the compound of Formula II with aqueous formaldehyde and N-methylaniline to obtain 6-methylene androst-4-en-3,17-dione of Formula III; and

(c) reacting Formula III with DDQ and an organic acid in the presence of an organic solvent to obtain exemestane.

The present invention includes process for purifying exemestane, which processes comprises the steps of:

(a) providing a solution or suspension of exemestane in dimethylformamide, optionally in combination with a nitrile or an alcohol;

(b) optionally adding water to precipitate solid exemestane; and

(c) isolating solid exemestane from the solution or suspension obtained in steps a) or b).

Purification step (a) involves providing a solution or suspension of exemestane in dimethylformamide, optionally in combination with a nitrile or an alcohol.

Nitrile solvents that may be used include but are not limited to acetonitrile and propionitile. An alcohol solvent that may be used includes but are not limited to methanol, ethanol, and isopropanol or mixtures thereof.

For example, a solution of exemestane may be provided by dissolving exemestane in dimethylformamide, or dimethylformamide and an alcohol. For another example, a suspension of exemestane may be provided in dimethylformamide and a nitrile solvent.

The solution or suspension of exemestane may be provided at a temperature of about 20°C to a temperature up to the boiling point of the solvent used. Preferably, the solution or suspension of exemestane is provided at a temperature of about 25°C to about 35°C. Undissolved particles in the solution may be removed by filtration, centrifugation, decantation, and other techniques.

The solution or suspension of exemestane may be maintained at the selected temperature for about 5 minutes to about 5 hours or more. For example, as Step (b) is optional, and water may not be added to a suspension of exemestane in .dimethylformamide and a nitrile solvent, a suspension of exemestane may be maintained at the selected temperature for the required time, and then directly isolated as described in Step (c).

Purification step (b) involves optionally adding water to precipitate solid exemestane. For example, water is added to a solution of exemestane in dimethylformamide or dimethylformamide and an alcohol.

The quantity of water needed for precipitation may be readily determined by a person ordinary skilled in the art and depends on factors including the concentration of exemestane in the solution and the temperature of the solution.

The temperature at which the water may be added ranges from about 0°C to 35°C. After the addition of water, the solution or suspension may be maintained at the selected temperature for about 30 minutes to about 5 hours or more. For example, the solution of exemestane may be maintained at a temperature of about 25°C to about 35°C for 2 to 3 hours to affect complete precipitation.

Purification step (c) involves isolating solid exemestane from the solution or suspension.

The exemestane may be separated by the techniques known in the art. For example it may be separated through filtration by gravity or by suction, centrifugation, decantation, and the like. After separation, the wet solid obtained may be dried in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer, and the like. The drying may be carried out at a temperature of about 35-65°C, e.g., about 50°C, optionally under reduced pressure for a sufficient period of time.

The present invention also includes a process for purifying exemestane, comprising the steps of:

a) obtaining the solution of exemestane in toluene and adding n-heptane to precipitate the solid;

b) crystallizing the solid obtained in step a) from dimethylformamide and acetonitrile;

c) recrystallizing the solid obtained in step b) from acetonitrile;

d) dissolving the solid obtained in step c) In methanol and adding water to precipitate the solid;

e) isolating purified exemestane.

The purity of exemestane obtained by the processes of the present invention may be equal to or greater than about 99.7%.

The present invention includes substantially pure exemestane, wherein the amount of each of the impurities listed in Table 1 is less than about 0.15 % and/or the sum of all the impurities is less than 0.3%.


Table 1

The present invention includes 3,17-dimethoxy androst-3,5,16-triene of Formula IV

which compound is useful as a marker in the processes of the present invention.
The present invention includes 6-(N-methylphenylamino)-methyl androst-4-en-3p17-dione of Formula V

which compound is useful as a marker in the processes of the present invention.

Exemestane obtained by the process of the present application may have a particle size D90 in the range of about 60-90 microns, D50 in the range of about 30-50 microns, and D10 in the range of about 5-20 microns.

Exemestane obtained by the process of the present application may have a mean particle size in the range of about 30-50 microns.

Certain aspects of the processes of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES

Example 1: Method of Analyzing the Compound of Formula 111 by HPLC

The compound of Formula III may be analyzed by HPLC under the following set of conditions.
Column: ACE 3 C18,150x4.6 mm, 3 urn
Mobile Phase A: Filtered and degassed water
Mobile Phase B: Filtered and degassed mixture of acetonitrile and methanol (1:1 v/v)
Flow rate: 0.8 mL/min
Wavelength of detection: 247 nm by UV
Column temperature: Ambient
Injection volume; 10 mL
Gradient Program
Under these conditions, the relative retention times listed in Table 2 are obtained for certain impurities (relative to the retention time for the compound of Formula III (RRT=1)).

Table 2

Example 2: Method of Analyzing Exemestane by HPLC
Exemestane may be analyzed by HPLC utilizing the following conditions:
Column: BDS C-18, 150x4.6 mm, 3 urn
Mobile Phase A: Filtered and degassed water
Mobile Phase B: Filtered and degassed methanol
Flow rate: 1.0 mL/min
Wavelength of detection: 247 nm by UV
Column temperature: 45°C
Injection volume: 10 mL
Diluent: WaterAcetonitrile (1:1, v/v)
Gradient Program
Under these conditions, the relative retention times listed in Table 3 are obtained for certain impurities (relative to the retention time for the compound of Formula I (RRT=1)).

Table 3

Example 3: Process for the preparation of the compound of Formula II

450 mL of dimethylformamide and 90 g of the androstenedione are charged into a round bottom flask at 28°C and stirred. 270 mL of 2,2-dimethoxypropane, 2.99 g of p-toluenesulphonic acid, and 18 ml of methanol are charged and stirred to obtain a reaction mixture. The obtained reaction mixture is heated to a temperature of 75±5°C and maintained for 6 hours. The reaction mixture is cooled to a temperature of 25-30°C and a saturated solution of sodium bicarbonate (obtained by dissolving 13.7 g of sodium bicarbonate in 196 m|_ of water) is charged to the reaction mixture and stirred for 15 minutes. 900 mL of water is added to a second round bottom flask and cooled to a temperature of 0-5°C. The reaction mixture is added slowly to the water at a temperature of 0-5°C under stirring. The obtained suspension is maintained at a temperature of 0-5°C for 1 hour, filtered, washed with 180 ml_ of water, and suction dried. The wet material and 450 ml_ of methanol are charged into a third round bottom flask and stirred at 28°C for about 1 hour. The suspension is filtered, washed with 90 mL of methanol, and dried at a temperature of 45°C for about 2 hours.

Yield: 72.0g
Purity by HPLC: 92.02%

Example 4: Process for the preparation of the compound of Formula III
570 mL of methanol and 68 g of the compound of Formula II prepared according to Example 3 are charged to a round bottom flask at 28°C and stirred for 5 minutes. 36.7 mL of N-methylaniline is added followed by 34 mL of aqueous formaldehyde (40%) to obtain a reaction mixture. 2.36 mL of cone. HCI is added. The reaction mixture is heated to a temperature of 42.5±2.5°C and maintained at the same temperature for 3 hours. The reaction mixture is cooled to a temperature of 12.5±2.5°C and 140 mL of cone, hydrochloric is added slowly. The reaction mixture is maintained at a temperature of 27.5±2.5°C for about 6 hours and then cooled to a temperature of 0-5°C. 1190 mL of water is added to the reaction mixture and the reaction mixture is maintained at 0-5°C for 1 hour. 680 mL of toluene is charged to the reaction mixture. The organic layer is separated. The aqueous layer is charged into another round bottom flask and extracted with 680 mL of toluene. The organic layers are combined and distilled under vacuum at a temperature of about 46°C to obtain about 170 mL of the reaction product. 340 mL of n-heptane is added to the reaction product at a temperature of 28°C and stirred for about 2 hours. The obtained solid is filtered and suction dried under vacuum.

The wet compound and 442 mL of acetone are charged into a round bottom flask and stirred for 10-15 minutes. 190 mL of water is added, cooled to 0-5°C, and maintained for about 3 hours. The suspension is filtered and the obtained compound is washed with 70 mL of water and dried at 40°C under vacuum for 6 hours.

Yield: 22.5 g
Purity by HPLC: 98.38%

Example 5: Process for the preparation of exemestane.

1000 mL of toluene and 100 g (1.0 M) of the compound of Formula III are charged into a round bottom flask and stirred for 5 minutes. 76.17 g (1.0 M) of DDQ, 1.28 mL (0.05 M) of trifluoroacetic acid, and 25 g of flux calcined diatomaceous earth (i.e., CELITE® HYFLO® SUPER CEL) are added to the reaction mixture. The reaction mixture is heated to a temperature of 70-75°C and maintained for 8 hours. The reaction mixture is cooled to 25-30°C, filtered, and the filtrate is washed with 200 mL of toluene. The filtrate is charged into a round bottom flask with 19.04 g (0.25 M) of DDQ, 1.28 mL (0.05 M)of trifluoroacetic acid, and 25 g of flux calcined diatomaceous earth. The obtained reaction mass is heated to a temperature of 70-75°C and maintained for 4 hours. The reaction mass is cooled to 25-30X, filtered, and washed with 200 mL of toluene. The filtrate is charged into a round bottom flask and 19.04 g (0.25 M) of DDQ, 1.28 mL (0.05 M) of trifluoroacetic acid, and 25 g of flux calcined diatomaceous earth are added. The obtained reaction mass is heated to a temperature of 70-75°C and maintained for 4 hours. The reaction mass is cooled to 25-30°C, filtered, and washed with 200 mL of toluene. The filtrate is charged into a round bottom flask and 11.4 g (0.15 M) of DDQ, 0.77 mL (0.03 M) of trifluoroacetic acid, 25 g of flux calcined diatomaceous earth are added. The obtained reaction mass is heated to a temperature of 70-75°C and maintained for 4 hours. The reaction mass is cooled to 25-30°C, 200 g of basic alumina is charged to the reaction mass and stirred for 10-15 minutes. The reaction mass is filtered and washed with 500 mL of toluene. The obtained filtrate and 1000 mL of 0.3 N sodium hydroxide solution are added into a round bottom flask, stirred for 10-15 minutes, and the aqueous layer is separated. The organic layer is washed with water and distilled under vacuum at 45-50°C to 300 mL. 800 mL of n-heptane is charged to the reaction mass and distilled off under vacuum at 45-50°C to 300 mL. A further 800 mL of n-heptane is charged to the crude and distilled off under vacuum at 45-50°C to 300 mL. The reaction mass is cooled to 25-30°C and maintained for 60-90 minutes. The obtained solid is filtered and suction dried. 50 mL of DMF:acetonitrile (1:9) is added to the obtained solid. The reaction mass is cooled to 0-5°C and maintained for 60-90 minutes. The solid is filtered, washed with acetonitrile precooked to 0-5°C, and dried at a temperature of 45-50°C under high vacuum for 6 hours.

Yield: 20.2 g
18
Purity by HPLC: 98.78%

Example 6: Process for purifying exemestane

10.0 g of exemestane (Purity: 98.78%) and 70 mL of acetonitrile are charged into a round bottom flask and heated to a temperature of 65-70°C for dissolution. The reaction mass is stirred for 10-15 minutes. The solution is filtered through a 0.45 micron filter. The filtrate is charged into a round bottom flask, cooled to 25-30°C, and stirred for 4 hours. The obtained suspension is filtered, washed with 10 mL of acetonitrile precooled to 0-5°C, and dried at a temperature of 45-50°C under high vacuum for 6 hours.

Yield: 6.6 g
Purity by HPLC: 99.55%

6.0 g of exemestane (Purity: 99.55%) and 84 mL of methanol are charged into a round bottom flask and heated to a temperature of 50-55°C for dissolution. The obtained solution is filtered through a 0.45 micron filter. The filtrate is charged into a round bottom flask. 72 mL of water at a temperature of 25-30°C is slowly added to the solution and the reaction mixture is stirred for 3 hours. The obtained suspension is filtered, washed with 6 mL of water, and dried at a temperature of 45-50°C under high vacuum for 6 hours.

Yield: 4.62 g
Purity by HPLC: 99.77%

Formula II: Not Detected, Formula IV: Not Detected, Formula V: Not Detected, Formula III: 0.02%, Formula VI: 0.02%, Formula VII: 0.05%, Formula VIII: 0.05% and 0.07%

Particle Size: D90 = 75.53 microns, D50 = 36.96, D10 = 11.65.
Mean particle size: 40.78 microns.

Claims:
1. A process for preparing exemestane, comprising the steps of:

a) reacting androst-4-en-3,17-dione with 2,2-dimethoxypropane and p-toluenesulfonic acid in the presence of dimethylformamide and methanol to obtain 3-methoxy androst-3,5-dien-17-one of Formula II

b) reacting the compound of Formula II with formaldehyde and N-methylaniline to obtain 6-methylene androst-4-en-3,17-dione of Formula III; and

c) reacting the compound of Formula III with DDQ and organic sulfonic acid or haloacetic acid, in the presence of an aromatic hydrocarbon solvent to provide exemestane.

2. The process of claim 1, wherein organic sulfonic acid in step c) is selected from
methylsulfonic acid, toluenesulfonic acid or haloacetic acid is selected from trifluoroacetic acid, trichloroacetic acid.

3. The process of claim 1, wherein in the the amount of the DDQ in step c) ranges
from about 0.1 to about 4 molar equivalents, and the amount of the organic sulfonic acid or haloacetic acid ranges from about 0.01 -1.0 molar equivalents, per mole of the compound of Formula III.

4. The process of claim 1, wherein the reaction of step c) involves lot wise addition of DDQ and the organic sulfonic acid or haloacetic acid.

5. The process of claim 4, wherein at least three lots of DDQ and the organic sulfonic acid or haloacetic acid are used and the first lot involves the use of 0.5-1.2 molar
equivalents of DDQ and 0.03-0.06 molar equivalents of sulfonic acid or haloacetic acid, per mole of the compound of Formula III.

6. A process for purifying exemestane, comprising the steps of:

a) obtaining the solution of exemestane in toluene and adding n-heptane to precipitate the solid;

b) crystallizing the solid obtained in step a) from dimethylformamide and acetonitrile;

c) recrystallizing the solid obtained in step b) from acetonitrile;

d) dissolving the solid obtained in step c) in methanol and adding water to precipitate the solid;

e) isolating purified exemestane.

7. A process for purifying exemestane, comprising the steps of:

a) providing a solution or suspension of exemestane in dimethylformamide, in combination with a nitrile or an alcohol solvent;

b) optionally adding water to precipitate solid exemestane; and

c) isolating solid exemestane from the solution or suspension obtained in steps a) orb).

8. The process of claim 7, wherein the nitrile solvent used is selected from acetonitrile and propionitrile and the alcohol solvent used is selected from methanol, ethanol, and isopropanol.

9. Exemestane having a purity of greater than about 99.7% and the each of the impurities Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII less than about 0.15 %.

10. Exemestane having a mean particle size between about 30 µm and about 50 µm and a particle size distribution of D90 in the range of about 60-90 microns, D50 in the range of about 30-50 microns, and D10 in the range of about 5-20 microns.