DESC:
FIELD OF THE INVENTION:
The present invention relates to an improved, efficient and industrially advantageous process for the preparation of Clascoterone of Formula-I.
The present invention also relates to process for purification of Clascoterone intermediate of Formula II.
The present invention also relates to process for preparation of crystalline Form II and Form III of Clascoterone of Formula I.
BACKGROUND OF THE INVENTION:
Clascoterone is chemically known as 17a-propionyloxy-21-hydroxy-pregna-4-ene- 3,20-dione, having the structure of Formula-I,

[Formula I]
Clascoterone was initially developed by Cassiopea SpA and later on partnership with Sun Pharmaceutical Industries Ltd. launched in United States. Clascoterone was approved by United States of Food and Drug Administration (USFDA) on August 26, 2020 under the brand name Winlevi®. Winlevi® cream contain Clascoterone as an active ingredient which is an androgen receptor inhibitor indicated for the topical treatment of acne vulgaris in patients 12 years of age and older.
US patent number US 3152154 (herein after US ‘154) first discloses racemic Clascoterone and its other isomers. The US ‘154 also discloses a process for the preparation of cortexolone 17a-propionate which involves the transformation of cortexolone into the corresponding ortho-ester by reaction with an alkyl ester of an orthocarboxylic acid, under acid catalysis and subsequent hydrolysis, carried out in an acidic, mineral or organic medium, in an alcoholic medium to yield the desired 17-monoester.
US ‘154 process suffers from the major drawback such as during hydrolysis of ortho-ester compound, the desired 17-monoester product along with 10 % of the corresponding 21-monoester was also formed as by-product of the reaction, which affects the yield of the final product, Further, US ‘154 is also silent about purity and yield of 17-monoester product. Therefore, process as disclosed in US ‘154 is not attractive option for large scale industrial production of Clascoterone.
US 8143240 (herein after US ‘240) first discloses the stereospecific isomer of Clascoterone and its process for their preparation comprising selective protection of 21-hydroxyl group of cortexolone with allyl chloroformate in presence of sodium hydroxide in tetrahydrofuran and water to obtain corresponding 21-O-Alloc-cortexolone. Further, 17-alpha-hydroxyl group of resulting compounds was esterified using 2,2,2-trifluoroethyl propionate in presence of Bacillus subtilis protease enzyme and tetrahydrofuran to obtain Alloc-protected Clascoterone. Alloc group removed from the resulting compound using triphenylphosphine, palladium triphenylphosphine and dichloromethane followed by crystallization using isopropyl ether to obtain Clascoterone.
Schematic representation of process for preparation Clascoterone as disclosed in US ‘240 as given in Scheme-I,

Scheme-I
US ‘240 process suffers from the major drawback such as requires costly reagent. Also, US ‘240 process is silent about yield and purity of final Clascoterone API. Therefore, process as disclosed in US ‘240 is not attractive option for large scale industrial production of Clascoterone.
US 8785427 (herein after US ‘427) discloses the process for preparation of crystalline form III of Clascoterone comprising reacting cortexolone-17a,21-dipropionate with butanol in presence of lipase enzyme followed by crystallization from mixture of dichloromethane and n-hexane, or mixture of acetone and n-hexane, or mixture of ethanol and water to obtain crystalline form III of Clascoterone.
US ‘427 process requires lipase enzyme which is not attractive option for large scale industrial production of Clascoterone.
European patent number EP 4071160 (herein after EP ‘160) discloses the process for preparation of Clascoterone comprising reacting cortexolone with triethyl orthopropionate in presence of p-toluenesulfonic acid, pyridine and methylene chloride to obtain corresponding cortexolone orthoester. Resulting compound was hydrolysed using 80% acetic acid in presence of ethanol and water to obtain oily residue of Clascoterone, which was further crystallized from mixture of ethyl acetate and isopropyl ether, or mixture of acetonitrile and hexane to obtain Clascoterone.
EP ‘160 process is silent about purity of Clascoterone and its intermediate.
Chinese patent CN 115073546 (herein after CN ‘546) discloses the process for preparation of Clascoterone comprising hydrolysis of cortexolone orthoester using aluminium chloride and hydrolysis reagent, which is one of aqueous solutions of formic acid, acetic acid, propionic acid, a mixture of formic acid and formate, a mixture of acetic acid and acetate, a mixture of propionic acid and propionate or a mixture of phosphoric acid and dihydrogen phosphate.
CN ‘546 process requires aluminium chloride and hydrolysis reagent. Also, the process requires additional alkali treatment to neutralize the pH of reaction mixture. Therefore, process as disclosed in CN ‘546 is not attractive option for large scale industrial production of Clascoterone.
Synthesis (1982), (12), 1023-5 discloses the process for preparation of cortexolone orthoester comprising reacting cortexolone with ethyl or methyl orthoester in presence of anhydrous p-toluenesulfonic acid, dimethylformamide followed by heating at 85 °C and recrystallization from mixture of ether and hexane to obtain corresponding cortexolone orthoester.
Above journal article is silent about purity of cortexolone orthoester.
Since most of the prior art references suffers from disadvantages like use of costly reagents and are silent about either yield or purity of Clascoterone. Therefore, there is an urgent need for the process for preparation of Clascoterone which overcomes the drawbacks of prior arts processes.
The present inventors have developed an improved and cost-effective process for the preparation of Clascoterone of Formula I which gives advantages over the prior art processes in terms of higher yield, higher purity, simple work up process and industrially economical.
OBJECT OF THE INVENTION:
The main object of the present invention is to provide an efficient and industrially advantageous process for the preparation of pure Clascoterone of Formula I.
Another object of the present invention is to provide a process for purification of compound of Formula II and crystalline Form III of Clascoterone of Formula I.
A further object of the present invention is to provide a process for preparation of crystalline Form II and Form III of Clascoterone of Formula I.
SUMMARY OF INVENTION:
First aspect of the present invention is to provides a process for the preparation of Clascoterone of Formula I,

[Formula I]
comprising hydrolysis of the compound of Formula II,

[Formula II]
in the presence of boric acid and solvent to obtain Clascoterone of Formula I.
Second aspect of the present invention is to provides a process for purification of compound Formula II,

[Formula II]
comprising the steps of:
a) treating compound of Formula II with alcohol; and
b) isolating the compound Formula II.
Third aspect of the present invention is to provides a process for purification of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I in a mixture of alcohol and ether solvent; and
b) isolating Clascoterone of Formula I.
Fourth aspect of the present invention is to provides a process for preparation of crystalline Form III of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with ether solvent;
b) heating the reaction mixture of step a) at temperature of 30°C to 70°C;
c) cooling the reaction mixture of step b) below 15°C; and
d) isolating the crystalline Form III of Clascoterone of Formula I.
Fifth aspect of the present invention is to provides a process for preparation of crystalline Form II of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with cyclopentyl methyl ether solvent;
b) heating the reaction mixture of step a) at temperature of 35°C to reflux termperature;
c) cooling the reaction mixture of step b) below 10°C; and
d) isolating the crystalline Form II of Clascoterone of Formula I.
BRIEF DESCRIPTION OF DRAWINGS:
Figure 01: Illustrates the X-ray powder diffractogram (XRPD) of crystalline Form III of Clascoterone of Formula I.
Figure 02: Illustrates the X-ray powder diffractogram (XRPD) of crystalline Form II of Clascoterone of Formula I obtained according to Example 04.
Figure 03: Illustrates the X-ray powder diffractogram (XRPD) of crystalline Form II of Clascoterone of Formula I obtained according to Example 05.
DETAILED DESCRIPTION OF INVENTION:
In order to provide a clear and consistent understanding of the terms used in the present specification, a number of definitions are provided below. Moreover, unless defined otherwise, all technical and scientific terms as used herein have the same meaning as understood by the person skilled in the art.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the specification may not only mean “one”, but also encompasses the meaning of “one or more”, “at least one”, and “one or more than one”. Similarly, the word “another” may mean at least a second or more.
As used in this specification the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “consisting” (and any form of consisting, such as “consists”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “include” and “includes”) or “containing” (and any form of containing, such as “contain” and “contains”), are inclusive or open-ended and do not exclude additional, unrecited elements or process steps.
The invention will now be described in detail in connection with certain preferred embodiments, so that various aspects thereof may be fully understood and appreciated.
The best methods and materials of performing the present invention are described here.
The present invention provides a novel, efficient and industrially advantageous process for the preparation of Clascoterone of Formula-I.
According to first embodiment, the present invention is to provides a process for the preparation of Clascoterone of Formula I,

[Formula I]
comprising hydrolysis of the compound of Formula II,

[Formula II]
in the presence of boric acid and solvent to obtain Clascoterone of Formula I.
In the first embodiment, the crude compound of Formula II can be obtained process known in the prior-art.
In the first embodiment, hydrolysis reaction of the compound of Formula II in the presence of boric acid and solvent can be carried out at temperature of 30°C to reflux temperature of solvent used.
In the first embodiment, hydrolysis reaction of the compound of Formula II in the presence of boric acid and solvent can be carried out for 2 hours to 10 hours.
In the first embodiment, boric acid can be used in the proportion of 1.0 molar equivalent to 2.0 molar equivalent with respect to compound of Formula II.
In the first embodiment, the solvent can be selected from the group consisting of alcohol such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether (DIPE), methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
In the first embodiment, the solvent can be used in the proportion of 01 volume to 18 volumes with respect to compound of Formula II.
After completion of reaction, solvent can be distilled out under vacuum. Water and methylene dichloride can be added to the resulting mixture and mixture can be allowed to separate organic and aqueous layer. The resulting organic layer-1 can be kept aside and aqueous layer can be extracted using methylene dichloride. All the organic layers can be combined, filtered and filtrate can be distilled to remove solvent. Resulting distilled mass can be treated with solvent to obtain Clascoterone of Formula I.
Generally distilled mass can be treated with alcohol or mixture of alcohol and ether solvent. Particularly distilled mass can be treated with solvent by methods such as slurry wash or by heating up to reflux temperature followed by cooling to isolate Clascoterone of Formula I.
The resulting Clascoterone of Formula I may have purity greater than 99.5% by HPLC (High-performance liquid chromatography).
According to second embodiment, the present invention provides a process for purification of compound Formula II,

[Formula II]
comprising the steps of:
a) treating compound of Formula II with alcohol; and
b) isolating the compound Formula II.
In the second embodiment the compound of Formula II used can be obtained process known in the prior-art.
In the second embodiment, treatment of compound of Formula II with alcohol can be carried out by methods such as slurry wash or by heating the mixture of compound of Formula II with alcohol up to reflux temperature followed by cooling to obtain pure compound of Formula II.
In the second embodiment, alcohol can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof.
In the second embodiment, alcohol can be used in proportion of 02 volume to 05 volume with respect to compound of Formula II.
In the second embodiment, the compound of Formula II can be isolated by filtration followed by drying.
In the second embodiment, compound of Formula II may have purity greater than 99.1% by HPLC (High-performance liquid chromatography).
According to third embodiment, the present invention provides a process for purification of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating compound of Formula I in a mixture of alcohol and ether solvent; and
b) isolating Clascoterone of Formula I.
In the third embodiment of step a), compound of Formula I can be treated with mixture of alcohol and ether solvent. Particularly compound of Formula I can be treated with alcohol and ether solvent by methods such as slurry wash or by heating up to reflux temperature followed by cooling to isolate Clascoterone of Formula I.
The resulting Clascoterone of Formula I may have purity greater than 99.5% by HPLC (High-performance liquid chromatography).
In the third embodiment of step a), the alcohol solvent can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof.
In the third embodiment of step a), the alcohol solvent can be used in the proportion of 0.2 volumes to 2 volumes with respect to Clascoterone of Formula I.
In the third embodiment of step a), the ether solvent can be selected from the group consisting of diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
In the third embodiment of step a), the ether solvent can be used in the proportion of 5 volumes to 18 volumes with respect to Clascoterone of Formula I.
In the third embodiment of step b), the compound of Formula I can be isolated by filtration or removing the solvent followed by drying.
In the third embodiment, Clascoterone of Formula I may have purity greater than 99.5% by HPLC (High-performance liquid chromatography).
According to fourth embodiment, the present invention is to provides a process for preparation of crystalline Form III of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with ether solvent;
b) heating the reaction mixture of step a) at temperature of 30°C to 70°C;
c) cooling the reaction mixture of step b) below 15°C; and
d) isolating the crystalline Form III of Clascoterone of Formula I.
In the fourth embodiment of step a), the ether solvent can be selected from the group consisting of diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
In the fourth embodiment of step a), ether solvent can be used in the proportion of 03 volumes to 18 volumes with respect to Clascoterone of Formula I.
In the fourth embodiment of step b), heating of reaction mixture of step a) can be carried out at temperature of 30°C to 70°C.
In the fourth embodiment of step c), cooling of reaction mixture of step b) can be carried out at below 15°C temperature.
In the fourth embodiment of step d), the crystalline Form III of Clascoterone of Formula I can be isolated by filtration followed by drying.
In the fourth embodiment, resulting crystalline Form III of Clascoterone of Formula I may have purity greater than 99.5% by HPLC (High-performance liquid chromatography).
The crystalline Form III of Clascoterone can be characterized by X-ray powder diffractogram (XRPD) as per figure 01.
According to fifth embodiment, the present invention is to provides a process for preparation of crystalline Form II of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with cyclopentyl methyl ether solvent;
b) heating the reaction mixture of step a) at temperature of 35°C to reflux termperature;
c) cooling the reaction mixture of step b) below 10°C; and
d) isolating the crystalline Form II of Clascoterone of Formula I.

In the fifth embodiment of step a), Clascoterone of Formula I can also be treated in presence of mixture cyclopentyl methyl ether and other ether solvent selected from the group consisting of diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
In the fifth embodiment of step a), solvent can be used in the proportion of 03 volumes to 20 volumes with respect to Clascoterone of Formula I.
In the fifth embodiment of step b), heating of reaction mixture of step a) can be carried out at temperature of 35°C to reflux temperature.
In the fifth embodiment of step c), cooling of reaction mixture of step b) can be carried out at below 10°C temperature.
In the fifth embodiment of step d), the crystalline Form II of Clascoterone of Formula I can be isolated by filtration followed by drying.
In the fifth embodiment, resulting crystalline Form II of Clascoterone of Formula I may have purity greater than 99.5% by HPLC (High-performance liquid chromatography).
The crystalline Form II of Clascoterone can be characterized by X-ray powder diffractogram (XRPD) as per figure 02.
EXAMPLES:
The following examples are illustrative of some of the embodiments of the present invention described herein. These examples should not be considered to limit the spirit or scope of the invention in any way.
Example 01: Preparation of compound of Formula-II

[Formula II]
To a stirred solution of cortexolone (50.0 g) and N,N-dimethyl formamide (350 mL), triethyl orthopropionate (50.87 g) was added at temperature of 25°C to 35 °C. p-toluenesulfonic acid monohydrate (2.75 g) was added to resulting mixture at same temperature and the resulting mixture was stirred for 10 minutes. Resulting mixture was heated at 75°C to 85°C and stirred for 2 hours at same temperature. After completion of reaction, the resulting mixture was cooled at 5°C to 15°C and purified water (500 mL) was added to the mixture. 1 % aqueous sodium carbonate (25.0 mL) was added to mixture at 5°C to 15°C and pH of the mixture was adjusted to 8.5. Resulting mixture was stirred for 1 hour and filtered, washed with water (25 mL) to obtain crude.
Methanol (100 mL) was added to above obtained crude material and mixture was stirred for 30 minutes at 5°C to 15°C. Resulting mixture was filtered, washed with methanol (25.0 mL) followed by drying under vacuum at 45°C to 55°C for 8 hours to obtain title compound (57.0 g).
Yield: 91.93 %.
HPLC Purity: 99.14 %
Example 02: Preparation of Clascoterone of Formula-I

[Formula I]
To a stirred mixture of compound of Formula II (130.0 g) and methanol (1300 mL), boric acid (28.6 g) was added at temperature of 25°C to 35°C. To the resulting mixture, purified water (130 mL) was added, and mixture was heated at 60°C to 70°C and stirred for 4 hours at same temperature. After completion reaction, the resulting mixture was cooled below 45°C and solvent was distilled out. Water (390.0 mL) followed by methylene dichloride (390 mL) was added to the resulting mixture and stirred 20 minutes and allowed to separate organic and aqueous layers. The resulting organic layer-1 was kept aside, and aqueous layer was extracted with methylene dichloride (130 mL). All the organic layers were combined and purified water (260 mL) was added to the resulting mixture, and the mixture was stirred for 20 minutes, and mixture was allowed to separate organic and aqueous layers. The resulting organic layer was filtered and washed with methylene dichloride. Resulting filtrate was distilled and methanol (130 mL) was added to distilled mass. Resulting mixture was stirred for 10 minutes and distilled out methanol under vacuum below 40°C. Methanol (130 mL) was added to resulting mass at 25°C to 35°C and mixture was filtered, washed with methanol and resulting filtrate was distilled to obtained a distilled mass.
Methanol (39 mL) and diisopropyl ether (1950 mL) was added to resulting distilled mass at 25°C to 35°C. Resulting mixture was stirred for 2 hours. The mixture was then cooled to 0°C to 10°C and further stirred for 4 hours. Resulting mixture was filtered and washed with diisopropyl ether to obtain title compound (84.0 g) having HPLC Purity of 99.38%.
Example 03: Process for preparation of crystalline Form III of Clascoterone of Formula I.
Clascoterone obtained in Example 02 (84.0 g) was added in diisopropyl ether (1300 mL) at temperature of 25°C to 35°C. Resulting mixture was heated at 60°C to 70°C and stirred for 2 hours. The resulting mixture was cooled at 0°C to 10°C and further stirred for 2 hours at the same temperature. Resulting mixture was filtered, washed with diisopropyl ether (98 mL) followed by drying under vacuum to obtain title compound (78.0 g) having HPLC Purity of 99.79%.
Example 04: Preparation of crystalline Form II of Clascoterone of Formula I.
Stir a mixture of Clascoterone (10.0 g) and cyclopentyl methyl ether (20 mL) at 20°C to 30°C for 10 minutes. The resulting mixture was stirred at 0°C to 5°C for 15 hours. The obtained mixture was filtered, dried under vacuum at 40°C for 6 hours to obtain a title compound (7.2 g) having HPLC Purity of 99.70%.
Example 05: Preparation of crystalline Form II of Clascoterone of Formula I
To a stirred mixture of compound of Formula II (160.0 g), methanol (1600 mL) and water (160 mL), boric acid (35.2 g) was added at temperature of 20°C to 30°C.
The resulting reaction mixture was heated under reflux condition for 12 hours at 60°C to 65°C. After completion of the reaction, the resulting mixture was cooled to 25°C to 35°C. Cyclopentyl methyl ether (1600 mL) and water (800 mL) was added to the resulting mixture at 25°C to 35°C. The obtained mixture was allowed to separate organic and aqueous layers. The resulting organic layer-1 was kept aside, and aqueous layer was extracted with cyclopentyl methyl ether (CPME). All the organic layers were combined and washed with water and dried over sodium sulfate and filtered through a hyflo bed. Resulting filtrate was distilled partly and di-isopropyl ether (1600 mL) was added at 60°C to 65°C for 30 minutes. Resulting mixture was cooled to 0°C to 5°C and stirred for 2 hours at same temperature. The resulting solid was filtered and dried under vacuum at 30°C 35°C for 12 hours to obtain a title compound (84.0 g) having HPLC purity of 99.83%.

Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

I / We Claim:
1. A process for preparation of the preparation of Clascoterone of Formula I,

[Formula I]
comprising hydrolysis of the compound of Formula II,

[Formula II]
in the presence of boric acid and solvent to obtain Clascoterone of Formula I.
2. The process as claimed in claim 01; wherein solvent is selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, cyclopentyl methyl ether (CPME), diisopropyl ether (DIPE), methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
3. The process as claimed in claim 01; wherein hydrolysis reaction of the compound of Formula II in the presence of boric acid and solvent can be carried out at temperature of 30°C to reflux temperature of solvent used.
4. A process for purification of compound Formula II,

[Formula II]
comprising the steps of:
a) treating compound of Formula II with alcohol; and
b) isolating the compound Formula II.
5. The process as claimed in claim 04; wherein alcohol is selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof.
6. A process for purification of compound Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating compound of Formula I in a mixture of alcohol and ether solvent; and
b) isolating Clascoterone of Formula I.
7. The process as claimed in claim 06; wherein the alcohol solvent can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof; and ether solvent can be selected from the group consisting of diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
8. A process for preparation of crystalline Form III of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with ether solvent;
b) heating the reaction mixture of step a) at temperature of 30°C to 70°C;
c) cooling the reaction mixture of step b) below 15°C; and
d) isolating the crystalline Form III of Clascoterone of Formula I.
9. The process as claimed in claim 08; wherein the ether solvent can be selected from the group consisting of cyclopentyl methyl ether (CPME), diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
10. A process for preparation of crystalline Form II of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with cyclopentyl methyl ether solvent;
b) heating the reaction mixture of step a) at temperature of 35°C to reflux termperature;
c) cooling the reaction mixture of step b) below 10°C; and
d) isolating the crystalline Form II of Clascoterone of Formula I.

Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

ABSTRACT

“A PROCESS FOR THE PREPARATION OF CLASCOTERONE”
The present invention relates to an improved, efficient and industrially advantageous process for the preparation of Clascoterone of Formula-I.

[Formula I]
The present invention also relates to process for purification of Clascoterone intermediate of Formula II.

[Formula II]
The present invention also relates to process for preparation of crystalline Form II and Form III of Clascoterone of Formula I.
Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 1 of 3

Figure 01
Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 2 of 3

Figure 02
Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

Ami Lifesciences Pvt. Ltd. Sheet 3 of 3

Figure 03
Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.

,CLAIMS:
I / We Claim:
1. A process for preparation of the preparation of Clascoterone of Formula I,

[Formula I]
comprising hydrolysis of the compound of Formula II,

[Formula II]
in the presence of boric acid and solvent to obtain Clascoterone of Formula I.
2. The process as claimed in claim 01; wherein solvent is selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol or tert-butyl alcohol; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl isobutyl ketone; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, cyclopentyl methyl ether (CPME), diisopropyl ether (DIPE), methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
3. The process as claimed in claim 01; wherein hydrolysis reaction of the compound of Formula II in the presence of boric acid and solvent can be carried out at temperature of 30°C to reflux temperature of solvent used.
4. A process for purification of compound Formula II,

[Formula II]
comprising the steps of:
a) treating compound of Formula II with alcohol; and
b) isolating the compound Formula II.
5. The process as claimed in claim 04; wherein alcohol is selected from methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof.
6. A process for purification of compound Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating compound of Formula I in a mixture of alcohol and ether solvent; and
b) isolating Clascoterone of Formula I.
7. The process as claimed in claim 06; wherein the alcohol solvent can be selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, secondary-butyl alcohol, tert-butyl alcohol or mixture(s) thereof; and ether solvent can be selected from the group consisting of diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
8. A process for preparation of crystalline Form III of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with ether solvent;
b) heating the reaction mixture of step a) at temperature of 30°C to 70°C;
c) cooling the reaction mixture of step b) below 15°C; and
d) isolating the crystalline Form III of Clascoterone of Formula I.
9. The process as claimed in claim 08; wherein the ether solvent can be selected from the group consisting of cyclopentyl methyl ether (CPME), diethyl ether, n-propyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane or mixture(s) thereof.
10. A process for preparation of crystalline Form II of Clascoterone of Formula I,

[Formula I]
comprising the steps of:
a) treating Clascoterone of Formula I with cyclopentyl methyl ether solvent;
b) heating the reaction mixture of step a) at temperature of 35°C to reflux termperature;
c) cooling the reaction mixture of step b) below 10°C; and
d) isolating the crystalline Form II of Clascoterone of Formula I.

Dated this 27th day of December 2024.

Mr. Raju Sharma,
Head-IPR,
Ami Lifesciences Pvt. Ltd.