TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved and industrially advantageous process for the preparation of (11β, 16α)-Pregna4,4-diene-3,20-dione-l methylethylidene)bis(oxy)]-21-(phosphonooxy) disodium salt given by formula (I), commonly known as desonide sodium phosphate!
The process provides desonide sodium phosphate of formula (I) in higher yield and purity compared to the previously known processes.

(I)
BACKGROUND OF THE INVENTION
Desonide sodium phosphate is a synthetic nonfluorinated corticosteroid. Therapeutically desonide has been used to treat atopic dermatitis (eczema), seborrheic dermatitis, contact dermatitis and psoriasis in both adults and children. Desonide sodium phosphate is used topically.as anti-inflammatory and antipruritic agent.
Desonide is chemically 11β 21-dihydroxy-16α, iya-isopropylidenedioxy-1,4-pregnadiene-3, 20-dione given by formula (III) and is disclosed first time in U.S. Patent No. 2,99.0,401 which also discloses its method of preparation by reacting lip, 16a, 17a, 2l-tetrahydr6xy-l,4-pregnadiehe-3,20-dione of formula (II) with acetone and mineral acid as catalyst, as shown below.

OH

OH

.'"■: :0D■■'.'". (,M)
However, the process for preparation of desonide disclosed in above patent suffers from the drawbacks like long reaction time, excessive use of solvents and lower yield.
U.S. Patent No. 4,839,282 discloses preparation of desonide of by fermenting corresponding 3-oxorA^steroids with living cultures of Arthrobacter simplex in the presence of cobalt(II) ions.
U.S. Patent No. 5,310,896 discloses preparation of desonide by subjecting (11β, 16α)-11 -(formyloxy)-16,17-[(l -methylethylidene)-bis(oxy)-21-(acetyloxy)- AI,4pregnadiene-3,20-dione of formula (a) to alcoholysis in presence of methanolic solution of potassium hydroxide and dioxane as cosolvent.
'■''■■■■"■..■ "■'■■■CH'3 - ■
. .■■■.■; o ; ■

Chinese Publication No. 101885751 discloses process of synthesizing the desonide by reacting 16α-hydroxyhydrogenated prednisone of formula (II) with acetone in presence of acidic ionic liquid. ,

OH

-Overall;- the processes for preparation of desonide described in prior arts are not suitable for, large scale production due to use of excessive of solvent, long reaction time and lower yield. Therefore there is a need for a simple, efficient and commercially viable process for preparation of desonide arid desonide sodium phosphate with shorter reaction time arid higher yield and also which does not involve use excessive reagents.
The present invention provides such an alternative process for the preparation of desonide , and desonide sodium phosphate which is applicable to industrial scale and gives desonide and desonide sodiurii phosphate with high purity.
SUMMARY OF THE INVENTION
The present invention provides an improved process for preparation of desonide sodium phosphate, represented by formula (I) comprising,

(a) reacting. 11α, 16β, 17, 2l-;tetrahydroxy-pregna-l,4-diene-3,20-dione of formula(II) with acetone in presence of an acid catalyst to give desonide of formula (III),

(b) reacting desonide with a phosphorylating agent.to give desonide phosphate of
: formula (IV), '.
(c) converting desonide phosphate to desonide sodium phosphate of formula (I) using
suitable base.
Desonide sodium phosphate obtained after step (c) is isolated and purified to give pure desonide sodium phosphate.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for preparation of desonide sodium phosphate, represented by formula (I) comprising, .

(a) reacting11α, 16β, 17, 21-tetrahydroxy-pregna4,4-diene-3,20-dione of formula (II)
with acetone in presence of an acid catalyst to give desonide of formula (III),
(b) reacting desonide: with a phosphorylating agent to give desonide phosphate of
. : fbrmula(lV),
(c) converting desonide phosphate to desonide sodium phosphate of formula (I) using
; suitable base.

: HO*
H3C

OH
■O ■OH
■OH
H

Acetone
Perchloric acid

OH

(II)

(III) ,
Pyrophosphoryl chloride /THF


Instep (a), desonide is prepared by reacting 11α, 16β,, 17, 21-tetfahydroxy-pregna-l,4-diene-3,20-dione With acetone, in presence of the acid catalyst in polar aprotic solvent.
In one of the embodiment, suitable acid catalyst can be selected from the group consisting of hydrochloric acid, p-toluenesulfohic acid, boron trifluoride etherate, perchloric, acid and mixture thereof. More preferably the acid, catalyst is perchloric acid.
In one of the embodiment, polar aprotic solvent for above reaction can be selected from the group consisting of tetrahydrofuran, ethyl, acetate, acetone, dimethylformamide, acetonitrile, dimethyl sulfoxide, dimethylacetamide, , N-methylpyrrolidene, toluene, benzene and the like. More preferably the polar aprotic solvent

In one of the embodiment, the molar ratio of the acid catalyst to 11α, 16β, 17, 21-tetrahydroxy-pregna-l,4-diene-3,20-dione is in the range from 0.10 to 1, more preferably in the range from 0.1 to 0.5.
In one of the embodiment, the volume ratio of acetone to 11α, 16β,, 17, 21-tetrahydroxy-pregha-l,4-diehe-3,20-dione is in the range of 5 to 15, more preferably in the range of 8 to 12;
In another embodiment, the reaction temperature for the reaction between (11α, 16β, 17, 2l Ttetrahydrbxy-pregria-l,4-diene-3,20-dione and acetone is about 0°C to about 35°C. More preferably the reaction temperature is about 20°C to about 25°C. The reaction is completed within 2 to 3 hours. :.
Desonide formed in step (a) can be purified by techniques known in the art. In one of the ernbodiment, desonide having high purity can be obtained by directly precipitating it from the reaction mixture by adding water after completion of the reaction and collecting the precipitated desonide.
In step (b) desonide is reacted with a suitable phosphorylating agent to give desonide ' phosphate;
In one of the embodiment, phosphorylating agent is selected from the group consisting of cyclo-triphpsphate, methylene diphosphonate, ethyl dichlorothiophosphate, dimethyl chlorothiophosphate, pyrophosphoryl chloride, 0,0'-diethyl chlorothiophosphate and the like.; More preferably phosphorylating agent is pyrophosphoryl chloride.;
In another embodiment, suitable solvent for phosphorylation is polar aprotic solvent and can be selected from the group consisting of tetrahydrofuran, dimethyl sulfoxide, dimethylforrnamide, dimethylacetamide, N-methylpyrrbliderie, toluene, benzene and the ' iike. More preferably the solvent for phosphorylation's tetrahydrofuran.
In one of the ernbodiment, the molar ratio of desdnide to pyrophosphoryl chloride is in the range of 2 to 5, more preferably in the range of 2.5 to 3.5.

In one of the embodiment, desonide is reacted with pyrophosphoryl chloride in presence of solvent, at about -60°C to about -40°C.
In step (e), the obtained desonide phosphate is reacted with suitable base in solvent to precipitate out crude desonide sodium phosphate.
In one of the embodiment, the suitable base used is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium acetate, sodium phosphate and the like. More preferably the suitable base is sodium hydroxide.
In one of the embodiment, the solvent used for salt formation is selected from the group consisting of methanol, ethahol, isopropyl alcohol or mixture thereof. More preferably the Solvent for salting is methanol.
In one of the embodiment, the molar ratio of desonide phosphate to sodium hydroxide is in the range of 2 to 5, more preferably in the range of 2.2 to 3.2.
Desonide sodium phosphate obtained can be isolated and purified using known techniques. In one of the embodiment, obtained crude desonide sodium phosphate is purified by recrystallization technique using a suitable solvent selected from the group consisting of ethanpl, isopropyl alcohol, ethyl acetate or mixture thereof. More preferably the solvent for recrystallization is a mixture of;methahorand ethanol,
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.
Example 1: Preparation of Despnicie
In a solution of 11α, 16β,, 17, 21-tetrahydroxy-pregna-l,4-diene-3,20-dione'(50 g, 0,133 mole) in acetone (500:mL, 10 vol.) was added perchloric acid (16.7 g; 0.166 mole) at 15°C to 25°C in 20 to 25 min and stirred at 20°C to 30°C for 2 to 3 h: The:progress of reaction was monitored through TLC, After completion of the reaction, water (500 mL) was added to the. reaction mixture and stirred for 1 to 2 h at 5°C to 10°C. Precipitated product was then filtered, washed with water (100 mL x 3) and dried at 55°C to 65QCto obtain desonide as white solid (Yield 50 g, purity 99.5%).
..

Example-2: Preparation of Desonide Sodium Phosphate
Mixtureof desonidfe (50 g, 0.12mole) in THF.(550 mL, 11 vol.) was cooled up to -60°C ; to -50PC. To the above mixture was added solution of pyrophosphoryl chloride (82 g, 0.326 mole) in THF (150 mL, 3 vol.) over a period of 1 to 2 h and stirred at -50°C to -40°C for 2 to 2.5 h. The progress of reaction was monitored through TLC. After completion of reaction, water (100 mL) was; added slowly maintaining reactions temperature between -50 to -10°C. Solution of sodium bicarbonate (200 g) in water (500 mL) was added slowly to trie above mixture arid stirred for 10 min. Solution of sodium hydroxide (27 g) in water (50 mL) was then added and stirred for another 2 to 3 h. Then reaction mixture was saturated with sodium chloride (30 g) and stirred for 10 min. Organic layer was separated from the resulted biphasic layer and washed with 20% brine solution. ■Remaining aqueous layer was extracted with THF (100 mL). THF layer was washed with 20% brine solution (150 mL x 3) and combined with the organic layer separated above. The resulting combined organic layer was dried over anhydrous sodium sulfate, distilled out under vacuum and stripped out with ethyl acetate (3 x 100 mL). The residue was dissolved in acetone (250 mL), filtered through hyflow and the filtrate was distilled out under vacuum. The residue was again dissolved in methanol (500 mL) and pH of the solution was adjusted at 8 to 10 with 10% sodium hydroxide solution in methanol followed by stirring for 0.5 h. The reaction mixture was filtered through hyflow and methanol was distilled out under vacuum. Ethanol (500 mL) was added to the residue and resulting suspension was stirred for 1 to 2 h, filtered and residues were dried at 60°C to 65°C for 10 to 15 h to'obtain thetitle compound (Yield 55 g).
ExampIe-3: Purification of Desonide Sodium Phosphate
Solution of desonide sodium phosphate (55 g) in methanol (550 mL) was stirred at room temperature for 30 to 45 min. To the above mixture was added Amberlite IR120H (55 g) : and stirred for 1 h followed by filtration through hyflow. From the filtrate, methanol was distilled out under vacuum and to the residue methanol (550 mL) was added. Resulting mixture was pooled to 10 to 20°C and to it was added 10% aqueous sodium hydroxide solution to adjust pH about 8 to 10. The reaction mass was stirred for 30 to 45 min,

filtered through hyflow and from the filtrate, methanol was distilled out under vacuum. Ethanol (500 mL) was added to the residue followed by stirring for 1 to 2 h at room temperature, filtration and washing with ethanol to get wet cake. The obtained wet cake was then dried at 60oC to 65°C to obtain pure desoriide sodium phosphate as white solid. (Yield48g, purity99.5%);

Weclaim:
1. A process for preparation of desonide sodium phosphate of formula (I) comprising,

(a) reacting 11α, 16β,, 17, 21-tetrahydroxy-pregna-l,4-diene-3,20-dione of formula
(II) with acetone in presence of acid catalyst to give desonide of formula (III);
-,OH.- ■ ' ■ OH


" 11:
(b) reacting desonide of formula (III) with a phosphorylating agent to give desonide phosphate of formula (IV);


(c) converting desonide phosphate of formula (IV) to desonide sodium phosphate using suitable base.
2. A process according to claim 1, wherein acid catalyst used in step (a) is selected from group consisting of hydrochloric acid, p-toluenesulfonic acid, boron trifluoride etherate and perchloric acid,
3. A process according to claim 1, wherein volume of acetone to compound of formula (II) is in the range of 5 to 15.
4. A process according to claim 1, wherein reaction temperature for the reaction between compound of formula (II) and acetone is about 0°C to about 35°C.
5. A process according to claim 1, wherdn phosphorylatihg agent used in step (b) is
selected from group consisting of cycio-triphosphate, methylene diphosphonate, ethyl dichiorothiophosphate, dimethyl chlorothiophosphate, pyrophosphoryl chloride and O,O-diethyl chlorothiophosphate.
6. A process according to claim1, wherein suitable base used in step (c) is selected from
the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate,
sodium acetate and sodium phosphate.

0 12
7. -,. A process for preparation of desonide sodium phosphate of formula (I) comprising,

(a) reacting 11α, 16β,, 17, 21rtetrahydroxy-pregha-l,4-diene-3;20-dione with acetone in presence of'an acid catalyst to give desonide,
(b) reacting desonide with pyropnosphoryl chloride to give desonide phosphate,
(c) preparing sodium salt of desonide phosphate using sodium hydroxide and methanol and, further isolating the product using ethanol to give desonide sodium phosphate.