CLIAMS:- ,TagSPECI:FORM 2

THE PATENTS ACT, 1970
(39 OF 1970)

PROVISIONAL SPECIFICATION
(See section 10 and rule 13)

A process for the preparation of fluticasone propionate

CADILA PHARMACEUTICALS LIMITED
Cadila Corporate Campus, Sarkhej – Dholka Road, Bhat, Ahmedabad – 382210, Gujarat, India

The following specification describes the invention.

FIELD OF THE INVENTION
The present invention relates to a process for preparation of Fluticasone Propionate having structural Formula-1 with substantially free of Ester impurity.

BACKGROUND OF THE INVENTION
Fluticasone propionate is a corticosteroid of androstane family which is having potent anti inflammatory activity. It is widely accepted as a useful therapy for the treatment of inflammatory and allergic conditions such as asthma and chronic obstructive pulmonary disease (COPD).

Fluticasone propionate is chemically known as 6a,9a-difluoro-17a-(((fluoromethyl)sulfanyl)carbonyl)-11ß-hydroxy-16a-methyl-3-oxoandrosta-1,4-dien-17a-yl-propionate and structurally represented as shown in formula 1.

US4335121 discloses process for the preparation of Fluticasone propionate as depicted in scheme-1, wherein 6a,9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyloxy)androsta-1,4-diene-17ßcarboxylicacid of formula IV is treated with dimethylthiocarbamoyl chloride to yield 17ß-(N,N(dimethyl-carbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyl-oxy-3-oxoandrosta-1,4-diene of formula III. The compound of formula III is hydrolysed by refluxing in diethylamine to give corresponding thioacid of formula II. The thioacid of formula II is further treated with bromochloromethane in presence of sodium bicarbonate to give a chloromethylester of formula IIa. The compound of formula IIa is converted to an iodomethylester using sodium iodide reagent and subsequently treated with silver fluoride to yield the Fluticasone propionate of formula I.

Scheme-1: Process for the preparation of Fluticasone propionate

Fluticasone propionate prepared as per scheme-1, is resulting following drawbacks:
a) At each stage the intermediate product was crystallized leading to substantially low yields of all the intermediates.
b) There are five steps with purification, the steps resulting in increase numbers of steps and low yields.
c) Silver Fluoride (AgF) is a toxic reagent
d) Use of Diethyl amine leads to formation of impurities.

US7208613 discloses the process for preparation of Fluticasone propionate as depicted in scheme-2, wherein 6a,9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyloxy)androsta-1,4-diene-17ß-carboxylic acid of formula IV is treated with dimethylthiocarbamoyl chloride, Triethyl amine, Tetrahydrofuran and Tetra butyl ammonium iodide (TBAI) to give 17ß-(N,N(dimethyl-carbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene of formula III, which is hydrolysed by refluxing in K2CO3 and MeOH at room temperature to give the thioacid of formula II. The compound of formula II is then reacted with bromofluoromethane in presence of potassium carbonate to give a Fluticasone propionate of formula I.

Scheme-2: Process for the preparation of Fluticasone propionate

Fluticasone propionate prepared as per scheme-2, is resulting following drawbacks:
a) Using combination of triethylamine and tetrahydrofuran, leads to formation of impurities.
b) Significant ester impurity is generated during preparation of formula-II.

WO2012029077 discloses process for preparation of Fluticasone propionate as depicted in scheme-3, wherein 6a,9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyloxy)androsta-1,4-diene-17ß-carboxylic acid of formula IV is treated with dimethylthiocarbamoyl chloride, Triethyl amine, Tetrahydrofuran and Sodium iodide at 75-76oC temperature to give 17ß-(N,N(dimethyl-carbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene of formula III, which is hydrolyzed by reacting with Morpholine for 3 hrs to give the thioacid of formula II. The compound of formula II is then reacted with bromofluoromethane in presence of potassium carbonate and acetone to give a Fluticasone propionate of formula I.

Scheme-3: Process for the preparation of Fluticasone propionate

Fluticasone propionate prepared as per scheme-3 results the following drawbacks:
a) Use of Morpholine as a base during preparation of thioacid (formula-II).
b) Use of tetrahydrofuran during preparation of formula-III, increases the reaction time.
c) Over all low yields and purity obtained in all stages.

US20080125407 discloses the process for preparation of Fluticasone propionate as depicted in scheme-4, wherein 6a,9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyloxy)androsta-1,4-diene-17ß-carboxylic acid of formula IV is treated with dimethylthiocarbamoyl chloride, dimethyl amino pyridine and butanone stirred at room temperature to give 17ß-(N,N(dimethyl-carbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene of formula III, which is hydrolyzed by reacting with metal phosphate in alcohol for 3 hrs to give the alkali salt of formula IIa, which is neutralized with acid to give the thioacid of formula II. The compound of formula II is then reacted with bromofluoromethane in presence of dimethyl amino pyridine and acetone to give a Fluticasone propionate of formula I. The Fluticasone propionate of formula I is also obtained directly from formula IIa, when it is reacted with bromofluoromethane.

Scheme-4: Process for the preparation of Fluticasone propionate

Fluticasone propionate prepared as per scheme-4, is resulting following drawbacks:
a) Excess solvent used during preparation of compound of formula-III.

US7214807 discloses process for preparation of Fluticasone propionate as depicted in scheme-5, wherein 6a,9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyloxy)androsta-1,4-diene-17ß-carboxylic acid of formula IV is treated with dimethylthiocarbamoyl chloride, triethylamine, anhydrous sodium iodide, 2-butanone, water and DMA stirred for 2 hours at 0oC temperature to give 17ß-(N,N(dimethyl-carbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-hydroxy-16a-methyl-17a-propionyloxy-3-oxoandrosta-1,4-diene of formula III, which is hydrolyzed by reacting with sodium hydrosulfide hydrate in dimethylacetamide at 0oC for 2 hrs to give the alkali salt of formula IIa, which is treated slowly with a solution of chlorofluoromethane in dimethyl acetamide to give a Fluticasone propionate of formula I.

Scheme-5: Process for the preparation of Fluticasone propionate

Fluticasone propionate prepared as per scheme-5, is resulting following drawbacks:
a) At each stage the intermediate product was crystallized leading to substantially low yields of all the intermediates.
b) Reaction time is very long.

SUMMARY OF THE INVENTION
A main object of the present invention is to provide an improved process for the preparation of Fluticasone propionate with reduced level of Ester impurity.
Yet another object of the present invention is provide a simple, efficient and economical method to produce Fluticasone propionate on commercial scale.
Yet another object of the present invention is provide a method to produce Fluticasone propionate without purification of the intermediates in each steps.
Yet another object of the present invention is provide a method to produce Fluticasone propionate avoiding hazardous solvents and reagents.
Yet another object of the present invention is provide a method to produce Fluticasone propionate with higher yield and purity.

DETAILED DESCRIPTION OF THE INVENTION

The process for the preparation of Fluticasone propionate as depicted in Scheme-6 comprises:
a) reacting compound of formula IV with dimethylthiocarbamoyl chloride in presence of an inorganic base and phase transfer catalyst in an organic solvent to get the compound of formula III,
b) converting compound of formula III to formula II using lithium hydroxide hydrate and alcohol
c) reacting compound of formula II with bromofluoromethane in presence of base,
d) isolating Fluticasone propionate

Scheme-6: Process for the preparation of Fluticasone propionate

According to the present invention compound of formula IV is reacted with dimethylthiocarbamoyl chloride, inorganic base and organic solvent reflux at temperature of 55-60oC for 2-4 hours. The inorganic base used during the reaction is sodium carbonate, potassium carbonate, lithium carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate. The inorganic base is preferably anhydrous potassium carbonate.

The compound of formula II is prepared form compound of formula III using lithium hydroxide monohydrate and alcohol at room temperature. The alcohol used in the reaction is methanol, ethanol, isopropyl alcohol. The alcohol is preferably methanol.

The compound of formula III when treated with lithium hydroxide hydrate-alcohol system such as lithium hydroxide monohydrate-methanol, will generate low levels of an ester impurity, such as the methyl ester impurity, a compound of formula V, which can be detected by HPLC.


The term “substantially free of impurities” means less than 0.2% of ester impurity as measured by area percentage HPLC., preferably less than 0.1% of ester impurity as measured by area percentage HPLC, most preferably less than detectable level of ester impurity as measured by area percentage HPLC.

Table-1: HPLC results for Ester impurity level:
S.
No. % of Ester impurity present during reaction % of Ester impurity after isolation of compound of formula-II
Rel. Area (%) RRT Rel. Area (%) RRT
1 3.17 0.94 0.04 0.94

From the above mentioned HPLC data in table-1, it is observed that, the level of ester impurity decreases to 0.05 level to below detection level. i.e. serial number-1 maximum relative area of ester impurity during reaction monitoring is 3.17 % at 0.94 RRT, while ester impurity after isolation of compound of formula-II relative area is 0.04% at 0.94 RRT.

The present invention is illustrated with following examples without limiting the scope of the invention.

Example-1: 6a, 9a-difluoro-11ß-17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid
A solution of periodic acid (43.11gm, 0.1897 moles) in water (110ml) is prepared. This solution is added dropwise to a stirred suspension of Flumethasone (50gm, 0.1216 moles) in tetrahydrofuran (250ml) at 0 to 5°C. The reaction mixture for 3.0 hrs after aqueous periodic addition. Reaction mass is poured into pre-cooled purified water (2500ml) is stirred at 5-10°C and stirred for 1 hrs and filtered to obtain white solid. The product 6a, 9a-difluoro-11ß-17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid is washed with water and dried at 50-55°C. Yield: 47.95g (Yield: 99.29%,HPLC: NLT 99.50% and KF: 0.33% )

Example-2: 6a, 9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyl)androsta-1,4-diene-17ß -carboxylic acid
To a suspension of 6a, 9a-difluoro-11ß-17a-dihydroxy-16a-methyl-3-oxoandrosta-1,4-diene-17ß-carboxylic acid (48.30gm, 0.1216 moles) in acetone (241ml) at room temperature is added Triethylamine ( 28.32gm, 0.2798 moles) and cooled it to 0-5°C. Propionyl chloride (25.88gm, 0.2798 moles) is added dropwise into the reaction mixture. After propionyl chloride addition completion the stirred reaction mixture is stirred for 1.0 hr at 0-5°C. Diethylamine (20.46gm, 0.2798 moles) is added and stirred for 1 hour at room temperature. Water (483ml) is added and then reaction mass is acidified with 2N hydrochloric acid to obtain pH between 1-2 at 0-5°C. The precipited product is stirred and filtered, washed with water and dried at 50-55°C. Yield: 53.95gm (Yield: 99%,HPLC: 99.37% and KF: 0.37% )

Example-3: 17ß-(N,N-(dimethylcarbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-17a-propio- nyloxy-16a-methyl-3-oxoandrosta-1,4-diene
To a suspension of 6a, 9a-difluoro-11ß-hydroxy-16a-methyl-3-oxo-17a-(propionyl)androsta-1,4-diene-17ß -carboxylic acid (53.85gm, 0.1188 moles), N,N diemethylthiocarbamoyl chloride (32.32gm, 0.2615 moles), anhydrous Potassium carbonate (36.14gm, 0.2615 moles) and tetrabutylammonium iodide (4.38gm, 0.0118 moles) in acetone (807ml) at room temperature. Reaction mass is warmed to 55°C for 2 hrs and treated sequentially with N,N dimethylacetamide (269ml) and water (2692ml) is cooled to 0-5°C and stirred for 1 hr and isolated product is filtered and washed with water and dried at 50-55°C. Yield: 63.10gm (Yield: 99%,HPLC: 98.87% and KF: 0.37% )

Example-4: 6a, 9a-difluoro-11ß-hydroxy-16a-methyl -17a-propionyloxy-3-oxoandrosta-1,4-diene-17ß-carbothioc acid
To a suspension of 17ß-(N,N-(dimethylcarbamoyl)thio)carbonyl-6a,9a-difluoro-11ß-17a-propionyloxy-16a-methyl-3-oxoandrosta-1,4-diene (62.80gm, 0.1163 moles) and lithium hydroxide monohydrate (9.81gm, 0.2326 moles in methanol (628ml) at room temperature. Reaction mass is stirred at ambient temperature for 3 hrs and treated sequentially with water (628ml) and washed with toluene (188ml) for 6 times. Aqueous layer containing the product is cooled to 0-5°C and acidified with 2N HCl to obtain pH between 1-2 at 0-5°C to obtained white solid. Reaction mass stirred for 1 hr and isolated product is filtered and washed with water and dried at 50-55°C. Yield: 63.10gm (Yield: 97%,HPLC: NLT 97.4% and KF: 2.78% )

Example-5: S-Fluoromethyl 6a,9a -difluoro-11ß-hydroxy-16a -methyl-3-oxo-17a -propionyloxyandrosta-1,4-diene-17ß-carbothioate (Fluticasone Propionate)
To a suspension of 6a, 9a-difluoro-11ß-hydroxy-16a-methyl -17a-propionyloxy-3-oxoandrosta-1,4-diene-17ß-carbothioc acid (52.40gm, 0.1118 moles) and anhydrous potassium carbonate (15.46 gm, 0.1118 moles) is taken in acetone (262ml) at room temperature under inert atmosphere and cooled to 0 to -5°C. Bromofluromethane (15.15gm, 0.1342 moles) in acetone (52.4ml) is added. Stirred the reaction mass at 0 to -5°C for 5hrs and treated sequentially with water (628ml) at 0-5°C to obtained white solid. Reaction mass stirred for 1 hr and isolated product is filtered and washed with water and dried at 50-52°C. Yield: 52.70gm (Yield: 96%, HPLC:98.68% and KF: 0.45%)

For, Cadila Pharmaceuticals Limited,

Date: 16th October 2014
Dr. Unnat P. Pandit
Dy. General Manager – IPR Cell