FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, Rule 13]
IMPROVED PROCESS FOR PREPARATION OF 6α-FLUORINATED CORTICOSTEORID INTERMEDIATE;
AARTI INDUSTRIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, WHOSE ADDRESS IS 71, UDYOG KSHETRA, 2ND FLOOR, MULUND GOREGAON LINK ROAD, MULUND (W), MUMBAI, 400080, INDIA
THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

Field of the invention
The present invention relates to processes for corticosteroid intermediates and more particularly to an improved process for preparation of a 6α-fluorinated corticosteroid intermediate, which is useful in the synthesis of several corticosteroids such as Fluocinonide, Flucinoloneacetonide, diflorasonediacetate, Flumethasone Pivalate, Halobetasol, Ulobetasol, Flunisolide and the like.
Background of the invention
Corticosteroids represent a broad class of agents employed in the treatment of individuals suffering from variety of disorders. In the treatment of an individual suffering from arthritis, administration of a corticosteroid may reduce inflammation. In addition, individuals suffering from autoimmune disorders often benefit from the administration of a corticosteroid. Other applications in which corticosteroids have been used include the treatment of allergic reactions, ankylosing spondylitis, asthma, Crohn's disease, dermatological disorders and psoriasis. As a class, corticosteroids represent an important and widely used tool in pharmacotherapy as corticosteroids are involved in wide range of physiological process such as stress response and immune response, carbohydrate metabolism, protein metabolism, blood electrolyte levels.

In particular, 6α-fluorinated corticosteorid intermediate chemically described as 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate compound, is represented as structure of formula (A)-
Inclusion of halogen, particularly fluorine, at either C-6 or C-9 positions in the cortisone molecule increases potency. However, combination of these potentiating groups in the same molecule leads to an additive influence on potency. In general, various laboratory scale methods have been reported in the prior art for the synthesis of 6α-fluoro-9β,11β-epoxypregna-1,4,16-triene-3,20-dione-21 -acetate compound of formula (A).
For example, U.S. Patent No. 3,178,459 discloses a process for preparation of compound of formula (A). As per cited process, the solution of N-bromoacetamide in pyridine is added to 6α-fluoro-17α,21-dihydroxy-1,4,-9(11)-pregnatriene-3,20-dione-21-acetate with stirring and the reaction mixture is added to cooled saturated solution of sulfur dioxide in pyridine. The resulting mixture is stirred and poured in ice-water. The solid which separated is isolated by filtration, washed with water, and dried. The material so obtained is dissolved in a small quantity of methylene chloride and chromatographed on a column of alumina. The column is eluted with benzene containing increasing proportions of acetone and those fractions which, on the basis of infrared analysis that is found to contain 6α-fuoro-21-

acetoxy-1,4,9(11),16-pregnatetraene-3,20-dione, are combined and evaporated to dryness. The 6α-fuoro-21-acetoxy-1,4,9(11),16-pregnatetraene-3,20-dione obtained is reacted with N-bromoacetamide in t-butyl alcohol followed by a solution of 70% perchloric acid to form 6α-fuoro-21-acetoxy-1,4-dihydro-9β-bromo,11β-hydroxy,16-pregnatetraene-3,20-dione. The compound is treated with anhydrous potassium acetate and acetone to form6α-fluoro-9β,11β-epoxypregna-1,4,16-triene-3,20-dione-21 -acetate.
In addition, U.S. Patent No. 2,838,499 cited in U. S. Patent No. 3,178,459 teaches the process for preparation of starting compound 6α-fluoro-17α,21-dihydroxy-1,4,-9(11)-pregnatriene-3,20-dione 21-acetate. The cited process involves fermentation of 6α-fluorohydrocortisone acetate using Septomyxaaffinis, A. T. C. C. 6737 as one of the steps. U.S. Patent No. 3,210,341 claims 6α-fluoro-9β,11β-epoxy-16α,17α-dihydroxypregna-1,4,16-triene-3,20-dione-21-acetate compound and also discloses processes for preparation thereof. The cited process involves reaction of 6α-fluoro-21-hydroxy-1,4,9(11), 16-pregnatetraene-3,20-dione-21-acetate with N-bromoacetamide in presence of methylene dichloride and 70% perchloric acid. The reaction yields 9α-bromo-11β-hydroxy derivative (bromohydrin) which is treated with potassium acetate in acetone to obtain a gummy product. The gummy product obtained was chromatographed on column of Florisil. The 6α-fluoro-9β,11β-epoxy-16α,17α-dihydroxy pregna-1,4,16-triene-3,20-dione-21 -acetate compound was eluted with 70% yield. The process involves use of 6α-fluoro-9β,11β-epoxy-16α,17α-dihydroxy pregna-1,4,16-triene-3,20-dione-21-acetate as a starting material, which is substantially costlier. Also, the process needs chromatography for separation and purification. Thus, overall the process is found to be costlier.

Accordingly, there is a need of an improved process for preparation of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate of formula (A) which gives better yield and higher purity of the product. Moreover, there is need of an improved process for preparation of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate that avoids use of expensive reagents thereby having industrial advantage on commercial scale.
Objects of the invention
An object of the present invention is to provide 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate compound of formula (A) with higher yield and purity.
Another object of the present invention is to provide 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate compound of formula (A) which avoids fermentation process.
Yet another object of the present invention is to provide process which is cost effective and industrially feasible.
Still another object of the present invention is to provide a process for preparation of corticosteroids from 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate compound of formula (A) prepared by the process of the present invention. One more object of the present invention is to provide a stable polymorphic Alpha (α) form of Fluocinonide.
Summary of the invention
The present invention provides a process for preparation of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate of formula (A).

In one aspect, the present invention provides a process for preparation of compound of formula (A), said process comprising the steps of:
a) reacting 9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate of formula (I) with an acylating agent to yield 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II); and
b) reacting 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II) with a fluorinating agent for obtaining the compound of formula (A) of the present invention.
In another aspect, the present invention further provides use of compound of formula (II) and compound of formula (A) in preparation of corticosteroid compounds.
In yet another aspect, the present invention describes a polymorphic Alpha (α) form of Fluocinonide and process for preparation thereof.

Detailed description of the invention
In one aspect, the present invention provides a process for preparation of compound of formula (A),
wherein the process comprising the steps of:
a) reacting 9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate of formula (I) with an acylating agent to yield 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II); and
b) reacting 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II) with a fluorinating agent for obtaining the compound of formula (A). Accordingly, the detailed process for preparation of compound of formula (A) is
described hereinafter:
In an initial step, 9β, 11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate of
formula (I) is reacted with acylating agent such that said acylation reaction is optionally

carried out in presence of a catalyst and an inert solvent. The acylation reaction is preferably carried out at a temperature in a range of about 10-70°C, most preferably at a temperature in a range of about 30-40°C.
The acylating agent in accordance with the present invention is selected from acetic anhydride, acetyl chloride and isopropenyl acetate, preferably isopropenyl acetate. The solvent in accordance with the present invention is an inert solvent selected from the group consisting of halogenated solvent, hydrocarbon solvent, ester solvent, nitrile solvent and aprotic polar solvent. The halogenated solvent is optionally selected from dichloromethane, ethylene dichloride and chloroform. The hydrocarbon solvent is optionally selected from toluene, xylenes, n-hexane, n-heptane and cyclohexane. The ester solvent is optionally selected from ethyl acetate, isopropyl acetate and tert-butyl acetate. The nitrile solvent is optionally selected from acetonitrile, propionitrile and butyronitrile. The aprotic polar solvent is optionally selected from dimethyl sulfoxide, N,N-dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidone and mixtures thereof.
In next step, the catalyst is added to a reaction mixture obtained in earlier step. It is understood here that the catalyst is acid or salt thereof with a base and is preferably selected from p-toluene sulfonic acid and pyridine-p-toluene sulfonic acid salt. The reaction is carried out at a temperature of about -25 to 100°C, preferably at 70 to 90°C. In next step, an oily mass obtained in earlier step is dissolved in a solvent selected from methylene dichloride (MDC, hereinafter), ethylene dichloride and chloroform, most preferably MDC. In next step, chilled solution of an inorganic base is added in said oily mass to obtain organic and aqueous layers. In next step, the organic and aqueous layers are separated and the organic layer is

distilled under vacuum. It is understood here that the inorganic base is selected from sodium bicarbonate and potassium bicarbonate.
In next step, the compound of formula (II) with or without isolation is treated with a fluorinating agent. The fluorinating agent is stereo-selective fluorinating agent in accordance with the present invention. It is understood here that the stereo-selective fluorinating agent is a compound that fluorinates enolized 21-esters of 9β,11β-epoxy-3,20-dione and related compounds in the 6-position to stereoselectively produce α-epimer. These compounds are capable of donating an electrophilic fluorine moiety. The fluorinating agent is selected from N-fluoro-N-chloromethyltriethylenediaminebistetrafluoroborate (Selectfluor®), Octan-di-tetrafluoroborate (AccufluorTM), 1-fluoro-benzenesulfonamide and mixture thereof.
In this step, said reaction is carried out in a dipolar aprotic solvent selected from acetonitrile, dimethylformamide (DMF), N,N-dimethyl acetamide and mixtures thereof. It is understood however that the temperature of said reaction is maintained in the range of about -25 to 50°C, and most preferably at a temperature in the range of about -15 to 25°C.
In next step, the pH of the reaction mass is adjusted between 7 and 8 after completion of the reaction. In next step, distilled water is added to said reaction mass and the reaction mixture is stirred to obtain free-flowing powder of compound of formula (A).
In an embodiment, the compound of formula (A) is oxidized to yield 6α-fluoro-9β, 11β-epoxy-16α, 17α-dihyhdroxy pregna-1,4,16-triene-3,20-dione-21 -acetate of formula (III).

It is understood here that oxidation reaction in above step is carried out in presence of oxidizing agents selected from potassium permanganate, Osmium Tetroxide and Metachloroperbenzoic acid.
In this embodiment, the compound of formula (III) is converted to 6α-fluoro-9β,11β-epoxy-16α, 17α-(1-methylethylidenedioxy) pregna-1,4,16-triene-3,20-dione-21-acetate of formula (IV).
It is understood here that conversion in above step proceeds in presence of suitable acid and suitable ketonic solvent at a lower temperature in a range of about 0 to 30 °C, and most preferably ay a temperature in a range of about 0 to 5 °C . The acid is selected from hydrochloric acid, sulfuric acid, perchloric acid, p-toluene sulfonic acid (PTSA), benzene

sulfonic acid (BSA), methane sulfonic acid (MSA) and formic acid. The ketonic solvent is selected from butanone, acetone, methyl isobutyl ketone (MIBK), dicyclopropyl ketone, cyclopropyl methyl ketone, p-chloroacetophenone and α-thienyl methyl ketone.
The compound of formula (IV) is finally converted to Fluocinonide of formula (F) by treating with hydrofluoric acid.
The hydrofluoric acid used is aqueous hydrofluoric acid, preferably 60-80% hydrofluoric acid. The reaction proceeds well at lower temperature range in a range of about -25 to 0°C. The low temperature is preferably maintained using brine solution.
In another aspect, the present invention provides polymorphic form Alpha (α) of Fluocinonide. The Alpha (α) crystalline form is stable and is characterized by an X-ray Powder Diffraction (XRPD) Pattern which includes the characteristic 2θ values as shown in Table-1 below:
Table-1: X-ray Powder Diffraction (XRPD) Pattern data Alpha (α) crystalline form of Fluocinonide

2 Theta I/I1 Value
8.73 37
11.18 92
13.89 26
15.30 12
16.81 100
17.70 16
17.94 13
22.83 23
24.36 10
25.21 17
29.05 19
31.67 42
Accordingly, the detailed process for preparation of Fluocinonide Alpha (α) form is described hereinafter-
In an initial step, Fluocinonide is crystallized by water miscible organic solvent such that Fluociononide is refluxed in a water miscible organic solvent with constant stirring to obtain a reaction mass. In next step, the reaction mass is heated to yield a clear solution. Optionally, activated charcoal is added to the solution for purification.
In next step, the reaction mass is heated, filtered and washed with solvent to obtain a solution that is cooled gradually at a room temperature and chilled further to precipitate out Fluocinonide in crystalline form. It is understood here that the solvent is selected from

methylene dichloride, methanol, ethanol and/or mixtures thereof and their mixture with water.
EXAMPLES
Only a few examples and implementations are disclosed. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.
EXAMPLE 1
Synthesis of 9a-bromo-lip-hydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate-
Perchloric acid (30 ml) was added to water (140 ml) under nitrogen atmosphere. N-bromosuccinamide (73 g) was added and reaction mixture was stirred at a temperature of about 25°C to 30°C for 45 minutes. The reaction mixture was gradually chilled to a temperature of about 0°C to -5°C. A solution of Pregna-1,4,9(11),16-tetraene-3,20-dione-21-acetate was prepared separately by charging 21-(Acetyloxy)-pregna-1,4,9(11),16-tetraene-3,20-dione (100 g) to acetone (1L) and heated to a temperature of about 40 °C to 45°C with stirring for 30 minutes. This solution was slowly added to above chilled reaction mixture in a

time period of about 2-3 hours and the temperature was throughout maintained to 0°C during said addition. pH of the reaction mass was adjusted to 7-7.5 by drop wise addition of Sodium sulfite solution prepared by dissolving sodium sulfite (105 g) in water (420 ml). The temperature was maintained to -5°C to 0°C. Acetone was distilled from the reaction mass under vacuum at 40°C to 45°C to obtain sticky slurry. Distilled water was added drop wise at a temperature of about 20°C to 25°C for 1 hour and reaction was maintained for 3 hours. Distilled water (1L) was added to the reaction mass and stirred for 2 hours. The reaction mass was filtered, washed with water (100 ml) and suck dried well. The wet cake was dried at a temperature of about 45 °C to 50°C till the water content is less than 1%. Accordingly, 9α-bromo-11β-hydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (120 gm) was obtained with HPLC purity of 92%.
EXAMPLE 2
Synthesis of 9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate (Compound I)
9α-bromo-11β-hydroxy-pregna-1,4,16-triene-3,20-dione-21-acetate obtained in Example-1 was charged to acetone (600 ml) and stirred for 15 minutes to form a reaction mixture. Potassium acetate (63.4 gm) was added to the reaction mixture and reaction mixture was heated to a temperature of about 55°C to 57°C and maintained for 16 hours. The reaction mixture was filtered and washed with acetone (60 ml). The filtrate was distilled under vacuum at a temperature of about 30°C to 35°C. Distilled water (900 ml) was charged to the reaction mixture at a temperature of about 15°C to 20°C and mixture was stirred for a period of 4 to 6 hours at the room temperature. The suspension was filtered, washed with water (60 ml) and suck dried well. The precipitate obtained was dried at a temperature of about 45°C to

50°C for 10 hours to yield 9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate (44 gm) as free flowing powder having HPLC purity of 99 %.
EXAMPLE 3
Isolation of 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate
(Compound II)
9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate (50 g) obtained in Example-2 was charged to isopropenyl acetate (250 ml) and stirred for 10 minutes to form a reaction mixture. P-toluene sulfonic acid (1.2 g) was added to the reaction mixture and stirred to obtain a clear solution. The reaction mixture was heated to a temperature of about 85 °C to 90 °C for a period of 30 minutes. The pH of the reaction mixture was adjusted to 7-8 using triethylamine. Isopropenyl acetate was distilled under vacuum at a temperature of 50°C till the thick browny mass was obtained. The oily mass was dissolved in Methylene dichloride (500 ml) and 10% chilled NaHCO3 (50 ml) was added to the solution. The mixture was stirred for 15 minutes at a temperature of about 5°C to 10°C and aqueous layer was separated. The MDC layer was washed with chilled 10% NaHCO3 (50 ml x 2). The MDC layer was dried on sodium sulfate and distilled under vacuum to obtain 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate as (74gm) oily thick mass having LC purity of 78.77 %
EXAMPLE 4
Isolation of 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate
(Compound II)

9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate (50 g) obtained in Example-2 was charged to isopropenyl acetate (1200 ml) and stirred for 10 minutes. P-toluene sulfonic acid (1.2 g) was added to the reaction mixture and stirred to obtain a clear solution. The mixture was heated to a temperature of about 85°C to90°C and maintained for 4 hours thereafter. The pH of the reaction mixture was adjusted to 7-8 using triethylamine. Isopropenyl acetate was distilled under vacuum at a temperature of 50°C till a thick brown mass was obtained having LCMS [M]+=425.16.
EXAMPLE 5
Synthesis of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate
(Compound A).
21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate (240 g) isolated in Example- 4 was taken in acetonitrile (1200 ml) and stirred for 30 minutes under nitrogen atmosphere to obtain a clear solution. Selectfluor® (240 g) was added to acetonitrile (1200 ml) under nitrogen atmosphere. 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate solution in acetonitrile was added dropwise to Selectfluor® solution at -12°C within 20-25 min. The temperature of the reaction mixture was raised to 0 °C and maintained for 1 hour. Acetonitrile was distilled under vacuum below 40°C till 2 about volumes remained in the vessel. 10% sodium bicarbonate solution (240 ml) was added to the reaction mixture. Distilled water (2400 ml) was added to the reaction mixture and stirred for a period of 4-6 hours in order to obtain a free suspension. The reaction mass was filtered and washed with distilled water (480 ml) and suck dried well. The precipitate of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate obtained (400 g) was dried well at a temperature

of about 40-45°C for a period of 10 hours having dry weight 225 gm and HPLC purity of 86.97% for alpha isomer and 13.02% for beta isomer.
EXAMPLE 6
Synthesis of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate
(Compound A).
9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate (240g) obtained in Example-2 was charged to isopropenyl acetate (1200 ml) and stirred for 10 minutes. P-toluene sulfonic acid (12 g) was added to the reaction mixture and stirred to get clear solution. The mixture was heated to 84°C for 4 hours. The reaction mixture was cooled to a temperature of about 45°C to 50°C and stirred for 30 minutes. Triethylamine (40 ml) was added gradually to adjust the pH in between 7-8. Isopropenyl acetate was distilled under vacuum at a temperature of 50°C and degassed well for 45 minutes. The reaction mixture was cooled to a temperature of about 30°C to 35°C and acetonitrile (1200 ml) was added. The mixture was stirred for 30 minutes to obtain a clear solution. Selecfluor® (240 g) was added to acetonitrile (1200 ml) under nitrogen atmosphere at room temperature and stirred well for 30 minutes to get a clear solution. The solution was chilled to a temperature of -15°C. The reaction mixture was added drop-wise to Selectfluor® solution by maintaining the temperature below -12°C within a period of 20-25 minutes. The temperature of the reaction mixture was raised to 0°C and maintained for 1 hour. The pH was adjusted to 7-8 by adding 10% sodium bicarbonate solution. Distilled water (2400 ml) was added and mixture was stirred for 4-6 hours. The suspension was filtered and washed with water (480 ml). The wet cake was dried at a temperature of about 40°C to 45°C for a period of 10 hours to yield 6α-fluoro-9β,11β-epoxy-

pregna-1,4,16-triene-3,20-dione-21 -acetate (225 g) as a pale yellow powder having HPLC Purity of 75.19% for alpha isomer and 15.36% for beta isomer. Accordingly, the NMR data was observed to be 1.101 (s, 3H, H-18), 1.762-1.423 (m, H-7, H-12, H-15, H-19, 7H), 2.176 (s, 3H, H-23), 2.443-2.794 (m, 4H, H-7, H-8, H-12, H-14), 3.233 (bs, 1H, H-11), 5.018-4.836 (dd, J=16.2Hz, H-21, 2H), 5.601-5.378 (qd, J=49.2 hz, 6H2, 1.5Hz, H-6, 1H), 6.277-6.237 (dd, J=10.2 Hz, 1.8 Hz, 1.8 Hz, H-16, 1H), 6.6464-6.453 (t, H-4, 1H), 6.583-6.545 (dd, J=10.2 Hz, 1.2Hz, H-2, 1H), 6.689-6.683 (q, H-1, 1H). The melting point was 157 °C.
EXAMPLE 7
Synthesis of 6α-fluoro-9β,11β-epoxy-16α,17α-dihydroxypregna-1,4,16-triene-3,20-dione-
21-acetate (Compound III)
Acetone (2000 ml) was charged to 6α-fluoro-9β, 11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate (225 gm) obtained in Example-3. Acetone (250 ml) was flushed and the mixture was stirred well to obtain a clear solution. The solution was chilled to a temperature of about -10°C to -15°C. Formic acid (48 ml) was charged at a temperature of -5° and stirred for a period of 30 minutes. Potassium permanganate solution, prepared by dissolving potassium permanganate (90 g) in distilled water (405 ml) and acetone (405 ml), was added to the reaction mixture at -15°C to -10°C within 30 minutes.
Sodium metabisulfite solution prepared by dissolving sodium metabisulfite (281 gm) in distilled water (1128 ml) was added to the reaction mixture gradually by maintaining temperature below 0°C. The reaction mixture was maintained for 1 hour, filtered and washed with acetone (450 ml) and dried well. Acetone was distilled to get thick slurry and water (2250 ml) was charged drop wise with constant stirring for a period of 25-30 minutes. The

mixture was further stirred for 1 hour. The suspension was filtered, washed with water (450 ml) and suck dried well. The wet cake was dried at a temperature of about 40°C to 45°C for a period of 8 hours to yield 6α-fluoro-9β,11β-epoxy- 16α,17α-dihyhdroxy-pregna-1,4,16-triene-3,20-dione-21 -acetate (210 g).
EXAMPLE 8
Synthesis of 6α-fluoro-9β,11β-epoxy-16α,17α-(1-methylethylidenedioxy)pregna-1,4,16-
triene-3,20-dione-21-acetate (Compound IV)
Acetone (500 ml) was charged to 6α-fluoro-9β,11β-epoxy-16α,17α-dihyhdroxy-pregna-1,4,16-triene-3,20-dione-21-acetate (100 g) obtained in Example-4. The reaction mass was stirred for 15 minutes and cooled to a temperature of about 0°C to 5°C. Perchloric acid (26 ml) was added drop wise at a temperature of about 0°C to 5°C within a time period of 30 to 40 minutes thereby maintaining the temperature below 5°C. The reaction mass was maintained for 1 hour. The pH of the reaction mass was adjusted to 7-7.5 by drop wise addition of sodium bicarbonate solution. The mixture was stirred for 30 minutes. The reaction mass was quenched in chilled distilled water and stirred at 5-10°C for 1 hour. The suspension was washed with chilled distilled water (200 ml) and suck dried well. The wet cake was dried at a temperature of 50°C for a period of 12 to 15 hours to produce 6α-fluoro-9β,11β-epoxy-16α,17α-(1 -methylethylidenedioxy)pregna-1,4,16-triene-3,20-dione-21 -acetate(79 gm) having HPLC Purity of 87.41% for alpha isomer and 12.58% for beta isomer.

EXAMPLE 9
Synthesis of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate
(Compound A).
21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate (74 g) isolated in example 3 was taken in acetonitrile (250 ml) and stirred for 30 minutes under nitrogen atmosphere to get clear solution. Selectfluor® (50 g) was added to acetonitrile (250 ml) under nitrogen atmosphere. 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate solution in acetonitrile was added dropwise to Selectfluor® solution at a temperature of -12°C within a time period of 20 to 25 min. The temperature of the reaction mixture was raised to 0°C and maintained for 1 hour. Acetonitrile was distilled under vacuum below 40°C till about 2 volumes thereof were remained. 10% sodium bicarbonate solution (50 ml) was added to reaction mixture. Distilled water (500 ml) was added to the reaction mixture and stirred for 4-6 hours to obtain a free suspension. The reaction mass was filtered and washed with distilled water (100 ml) and suck dried well. The turmeric color precipitate of 6α-fluoro-9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21 -acetate obtained (73 g) was dried well at a temperature of about 40 to 45°C for a period of 10 hours thereby obtaining dry weight of 47g with HPLC Purity of 65.48% for alpha isomer and17.34% for beta isomer.
EXAMPLE 10 Synthesis of Fluocinonide
6α-fluoro-9β,11β-epoxy-16α,17α-(1 -methyl ethylidenedioxy)pregna-1,4,16-triene-3,20-dione-21-acetate (140 g) as prepared in Example-5 was added to stirred and chilled solution of 72% HF at a temperature of about -12°C to -10°C. The temperature was gradually raised to a

temperature range of -5°C to 0°C and maintained thereafter for a time period of 4 to 5 hours. Acetone (420 ml) was added to the reaction mixture and stirred for 3-4 hours at a temperature of about 0°C to 5°C. The reaction mass was subsequently quenched by ice cold water. The pH of the reaction mixture was adjusted to 6 thereby using NaOH. Further pH of the reaction mass was adjusted to 7-8 by drop-wise addition of sodium bi-carbonate solution. The reaction mass was maintained for next 30 minutes, filtered out and suck dried well. The precipitate was washed with water (240 ml x 2) thereby obtaining wet wt. of 275 gm and dry weight of 115 gm with HPLC Purity of 89.43% for alpha isomer and HPLC purity of 10.56% for beta isomer.
EXAMPLE 11
Synthesis of Fluocinonide Alpha (α) Form
MDC (800 ml) was added to crude Fluocinonide (100 g) obtained in Example-9. Methanol (400 ml) was added to the reaction mixture and stirred for 15 minutes to obtain clear solution. Activated charcoal (10 g) was added to the solution and heated to a temperature of 40°C for 1 hour. The reaction mass was filtered and washed with mixture of methanol (40 ml) and MDC (80 ml). The filtrate was distilled under vacuum at 40°C. The reaction mass was cooled to room temperature when 2 volumes of the reaction mass was obtained. The mass was stirred for 30 minutes and filtered. The precipitate was washed with chilled methanol (100 ml) and suck dried well for 30 minutes and further dried at a temperature of about 50-55°C under vacuum for 6 hours to yield Fluocinonide Alpha (α) form (69 gm).
EXAMPLE 12

Synthesis of Fluocinonide Alpha (α) Form
Fluocinonide (10 g) obtained in Example 9 was added to methanol (1 lit) and refluxed at a temperature of about 25-30°C. The reaction mixture was stirred at a temperature of 25-30°C for 30 minutes. The reaction mass was subsequently heated to a temperature of about 55-60°C till the clear solution was observed. The reaction mass was maintained for 1 hour and cooled gradually to a temperature of about 25-30°C. The reaction mass was chilled to a temperature of 0-5°C and maintained for 1 hour thereafter. The suspension was filtered, suck dried and the cake was washed with chilled methanol. The cake was suck dried. The product was further dried at a temperature of about 50-55°C under vacuum to obtain dry weight of 8.80 gm.
EXAMPLE 13
Synthesis of Fluocinonide Alpha (α) Form
Fluocinonide (10 g) obtained in Example- 9 was added to ethanol (1.5 lit) and refluxed at a temperature of about 25-30 °C. The reaction mixture was stirred thereafter at a temperature of about 25-30 °C for a time period of about 30 minutes. The reaction mass was heated to a temperature of about 55-60°C till the clear solution was observed. The reaction mass was maintained for 1 hour and cooled gradually to a temperature of about 25-30°C. The reaction mass was chilled to a temperature of about 0-5°C and maintained for 1 hour thereafter. The suspension was filtered, suck dried and the cake was washed with chilled ethanol. The cake was suck dried. The obtained product was further dried at a temperature of about 50-55°C under vacuum to obtain dry weight of 8.70 gm.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

We Claim:
1) A process for preparation of a compound of formula (A)
wherein said process comprising the steps of:
a) reacting 9β,11β-epoxy-pregna-1,4,16-triene-3,20-dione-21-acetate of formula (I) with an acylating agent in an inert solvent and a catalyst to afford 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II); and
b) reacting 21-(acetyloxy)-9β,11β-epoxy-pregna-1,3,5,16-tetraene-3-oxo-acetate of formula (II) with a fluorinating agent in presence of a dipolar aprotic solvent for obtaining the compound of formula (A).
2) The process as claimed in claim 1, wherein the acylating agent is selected from
acetic anhydride, acetyl chloride and isopropenyl acetate.
3) The process as claimed in claim 1, wherein the acylating agent is isopropenyl acetate.

4) The process as claimed in claim 1, wherein the inert solvent selected from the group of halogenated solvent, hydrocarbon solvent, ester solvent, nitrile solvent, aprotic polar solvent and/or mixtures thereof.
5) The process as claimed in claim 4, wherein the halogenated solvent is selected from dichloromethane, ethylene dichloride and chloroform.
6) The process as claimed in claim 4, wherein the hydrocarbon solvent is selected from toluene, xylene, n-hexane, n-heptane and cyclohexane.
7) The process as claimed in claim 4, wherein ester solvent is selected from ethyl acetate, isopropyl acetate and tert-butyl aceatate.
8) The process as claimed in claim 4, wherein the nitrile solvent is selected from acetonitrile, propionitrile and butyronitrile.
9) The process as claimed in claim 4, wherein the aprotic polar solvent is selected from dimethyl sulfoxide, N,N-dimethyl formamide, dimethyl acetamide and N-methyl pyrolidinone.
10) The process as claimed in claim 1, wherein the catalyst is selected from p-toluene sulfonic acid and pyridine-p-toluene sulfonic acid salt.
11) The process as claimed in claim 1, wherein the fluorinating agent used in is selected from N-fluoro-N-chloromethyltriethylenediaminebistetrafluoroborate, Octan-di-tetrafluoroborate and 1-fluoro-benzenesulfonamide.
12) The process as claimed in claim 1, wherein the dipolar aprotic solvent selected from acetonitrile, dimethylformamide, N,N-dimethyl acetamide andmixtures thereof.
13) A process for preparation of Fluocinonide comprising the steps of:

i) reacting a compound of formula (A) with potassium permanganate to form
16,17-dihydroxy compound of formula (III);
ii) reacting compound of formula (III) with a suitable acid in presence of ketonic
solvent to form compound of formula (IV) ; and
iii) reacting compound of formula (III) with hydrofluoric acid to form
Fluocinonide of formula (F)

14) The process as claimed in claim 13, wherein the acid is selected from hydrochloric acid, sulfuric acid, perchloric acid, p-toluene sulfonic acid, benzene sulfonic acid, methane sulfonic acid and formic acid.
15) The process as claimed in claim 13, wherein the acid is perchloric acid.
16) The process as claimed in claim 13, wherein the ketonic solvent is selected from butanone, acetone, methyl isobutyl ketone, dicyclopropyl ketone, cyclopropyl methyl ketone, p-chloroacetophenone and α-thienyl methyl ketone.
17) The process as claimed in claim 13, wherein the ketonic solvent is acetone.
18) A process for preparation of Alpha (α) polymorph of Fluocinonide exhibiting an XRD pattern with 2θ values at 8.73, 11.18, 16.81, 31.67, said process comprising the step of crystallizing said Fluocinonide from water miscible organic solvent.

19) The process as claimed in claim 18, wherein the solvent is selected from methylene
dichloride, methanol, ethanol, and/or mixtures thereof.