DESC:FILED OF THE INVENTION
The present invention relates, in general to the pharmaceutical field, and more precisely it relates to the corticosteroids and processes for the preparation thereof. In particular, the present invention relates to processes for the preparation of Fludroxycortide (also known as Flurandrenolide and Flurandrenolone) and Fludroxycortide prepared according to the processes of the invention. The present invention also relates to the intermediates which are useful for the preparation of Fludroxycortide.

BACKGROUND OF THE INVENTION
Fludroxycortide also known as Flurandrenolide and Flurandrenolone is a potent corticosteroid intended for topical use. Fludroxycortide occurs as white to off-white, fluffy, crystalline powder and is odourless. Fludroxycortide is practically insoluble in water and in ether. One gram of Fludroxycortide dissolves in 72 mL of alcohol and in 10 mL of chloroform. The molecular weight of Fludroxycortide is 436.52 gm/mol. The chemical name of Fludroxycortide is Pregn-4-ene-3, 20-dione, 6-fluoro-11, 21-dihydroxy-16, 17-[(1-methylethylidene) bis (oxy)]-, (6a, 11ß, 16a)-; its empirical formula is C24H33FO6. The structural formula of Fludroxycortide is as follows:

Figure 1
Fludroxycortide has a chemical formula of 6a-fluoro-16a-hydroxyhydrocortisone-16, 17-acetonide. It is distinguished from hydrocortisone by the presence of 2 activity-enhancing groupings, a 6a-fluorine and a 16a-OH. Substitution of an alpha-fluorine atom for hydrogen at the sixth position and a hydroxyl group at the 16a position, as well as the acetonide function linkage at both the 16a- and 17a-hydroxyl groups, are new substituents designed to impart maximum potency as an anti-inflammatory agent. At the same time, the salt-retaining property of the parent compound is decreased (J. Amer. Chem. Soc. 81: 1264-1265, 1959).
Glucocorticosteroids (GCs) that have anti-inflammatory properties are known and are widely used for the treatment of diseases such as inflammatory arthritides, other rheumatoid diseases such as systemic lupus erythematosis, scleroderma, vascutitides including temporal arteritis and polyarteritis nodosa, inflammatory bowel diseases such as crohn’s disease and ulcerative colitis, lung diseases such as asthma and chronic obstructive airways disease, as well as many other conditions such as polymyalgia rheumatica. Topical corticosteroids of low to medium potency are indicated in the treatment of corticosteroid-responsive dermatologic disorders. Fludroxycortide (Flurandrenolide/Flurandrenolone) shares the actions of the other topical corticosteroids and is used for the relief of the inflammatory manifestations of corticosteroid-responsive dermatoses.

Fludroxycortide is known from 1960’s and is approved in the United States for topical administration in the form of tape, ointment & lotion (CORDRAN) and cream (CORDRAN SP) prior to 1982. Fludroxycortide is indicated for the relief of the inflammatory and pruritic manifestations of corticosteroid-responsive dermatoses.

Fludroxycortide was disclosed and claimed in the United States Patent No. 3,126,375 (herein incorporated by reference) as cyclic ketal of 6-halo corticoid. The process for the preparation of cyclic ketals of 6-halo corticoids as disclosed in the United States Patent No. 3,126,375 is illustrated in Figure 2 below.

Figure 2
In the above figure, R and R1 may be hydrogen or the residue of a hydrocarbon of up to 8 carbon atoms of straight, branched, cyclic or mixed aliphatic-cyclic chain, saturated or unsaturated including aromatic groups. X represents fluorine or chlorine. X1 represents hydrogen, fluorine or chlorine. Y represents =O or ß-OH. Z represents a double bond between C-1 and C-2. R2 represents hydrogen or a hydrocarbon carboxylic acyl group of up to 12 carbon atoms. Acyl represents a hydrocarbon carboxylic acyl group of up to 12 carbons.

United States Patent No. 5,888,995 (herein incorporated by reference) discloses steroid esters. The process for the preparation of Fludroxycortide is described in Example-20 of the United States Patent No. 5,888,995. As per the process described in Example-20, A suspension of 2.1 g of tris(triphenylphosphine)rhodium chloride in 500 ml of toluene was hydrogenated at room temperature and atmospheric pressure for 45 min, when the catalyst was in solution. A solution of 2.0 g of 6a-fluoro-11ß, 21-dihydroxy-16a, 17a-[(1-methylethylidene) bis (oxy)]pregna-1, 4-diene-3, 20-dione in 1000 ml of absolute ethanol was added and the hydrogenation was continued for another 65 h. The reaction mixture was evaporated and the residue purified on a Sephadex LH-20 column (71×6.3 cm) using chloroform as mobile phase. The fraction 2010-2445 ml was collected and evaporated, yielding 1.51 g of 6a-fluoro-11ß, 21-dihydroxy-16a, 17a-[(1-methylethylidene) bis (oxy)] pregn-4-ene-3, 20-dione.

International Publication WO 2009/082342 (herein incorporated by reference) discloses steroid derivatives acting as glucocorticosteroid receptor agonists. The process for the preparation of Fludroxycortide is disclosed therein as Intermediate-11 wherein the Flucroxycortide was prepared from (4aR, 4bS, 5S, 6aS, 6bS, 9aR, 10aS, 10bS, 12S)-12-fluoro-6b-glycoloyl-5-hydroxy-4a, 6a, 8, 8-tetramethyl-4a, 4b, 5, 6, 6a, 6b, 9a, 10, 10b, 11, 12-dodecahydro-2H-naphtho [2’, 1’:4, 5] indeno [1, 2-d][1, 3] dioxol-2-one, i.e. Flunisolide having structural formula as shown in Figure 3.

Figure 3
According to the process described in International Publication WO 2009/082342, the compound Flunisolide was dissolved in a mixture of ethanol and toluene. Tris(triphenylphosphine)rhodium(I)chloride was added and the mixture was stirred under hydrogen atmosphere for 40 hours. After completion, monitored by LC-MS, the solvent was evaporated and the residue was re-dissolved in CH2Cl2. Heptane was added and the mixture was stirred for 1 hour. The precipitate was filtered off and washed with CH2Cl2/heptane.

As can be seen from the prior art, preparation of Fludroxycortide is not much explored. Few prior art reveals preparation of Fludroxycortide using Flunisolide ((4aR, 4bS, 5S, 6aS, 6bS, 9aR, 10aS, 10bS, 12S)-12-fluoro-6b-glycoloyl-5-hydroxy-4a, 6a, 8, 8-tetramethyl-4a, 4b, 5, 6, 6a, 6b, 9a, 10, 10b, 11, 12-dodecahydro-2H-naphtho [2’, 1’:4, 5] indeno [1, 2-d][1, 3] dioxol-2-one). Therefore the present inventors have now developed process for the preparation of Fludroxycortide which does not use Flunisolide as starting material but uses hydrocortisone as starting material. The process of the present invention involves generation and use of one or more novel intermediates as described henceforth.

OBJECTS OF THE INVENTION
The primary object of the present invention is to provide new process for the preparation of glucocorticosteroidal analogues, i.e. 6-fluoro-17ß-keto derivatives such as Fludroxycortide. The glucocorticosteroid compounds are characterized by anti-inflammatory actions.

A yet another object of the present invention is to provide preferred mode of administration of the compounds prepared by the processes of the present invention, which is by topical application on the desired application-site.

More particularly the present invention relates to newer methods of synthesis of steroidal 6-fluoro-17ß-keto derivatives, such as Fludroxycortide, using hydrocortisone as starting material as shown below in Scheme-1.

Reaction Scheme-1

A yet another object of the present invention is to provide a newer method for the chemical synthesis of compound (A) using multistep reactions.

wherein each substituent is independently selected from;
R1 is H or lower alkyl group preferably CH3;
R2 is C1-C6 linear or branched alkyl, alkynyl or cycloalkyl group; aryl or heteroaryl group; or R1 and R2 combine to form C3-C6 saturated, unsaturated cyclic or heterocyclic ring;
R3 is OH or OCOR4 wherein R4 represents H or C1-C6 linear or branched alkyl, alkynyl or cycloalkyl group;

In yet another object, the present invention describes a novel process for the preparation of compound of formula (A),
1. Acetylation of hydrocortisone (2) to get its tetraacylated product (3),
2. Fluorination of the compound (3) to get 6-F derivative (4),
3. Resolution of compound (4) to get 6-a fluoro analogue (5),
4. Deacetylation of compound (5) to obtain the compound (6),
5. Dihydroxylation of compound (6) to get its diol compound (7),
6. Protection of diol to obtain the acetonide (8) and
7. Hydrolysis of compound (8) under basic condition to obtain compound (A) or Fludroxycortide (1).

DETAILED DESCRIPTION OF THE INVENTION
The starting material used in the process of the present invention for the preparation of Fludroxycortide is hydrocortisone. First step of the Scheme-1 involves protection of alcohol groups of hydrocortisone by acetylation using acetic anhydride and acetyl chloride under refluxing condition to produce compound (3).

Second step of the reaction involves electrophilic fluorination of the compound (3) using Selectfluor to produce compound (4). The reaction can be carried out in polar aprotic solvents such as dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile (ACN), tetrahydrofuran (THF), dimethyl acetamide (DMA/DMAc) or mixture thereof.

Third step of the reaction involves resolution of the compound (3) to produce compound (4), which is an alpha isomer (>90 %). The isomerization can be carried out under acidic conditions using mineral acids such as hydrochloric acid (HCl), sulfuric acid (H2SO4) and nitric acid (HNO3) or organic acid such acetic acid, trifluoracetic acid in alcoholic solvents such as methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and the like, more preferably in isopropyl alcohol (IPA). The reaction is carried out at temperature between 0°C to room temperature (RT).

Fourth step of the reaction involves elimination of 17-acetoxy group from the compound (5) using potassium acetate, or potassium carbonate in alcoholic solvents such as methanol (MeOH), ethanol (EtOH), isopropyl alcohol (IPA) and the like to produce compound (6).

Fifth step of the reaction involves oxidation of the compound (6) by oxidizing agent such as potassium permanganate and the like to produce diol compound (7).

Sixth step of the reaction involves protection of diols at 16-17 position of the compound (7) by using aldehyde such as acetaldehyde, 1,1-dimethoxypropane, 2,2-dimethoxypropane or ketone such as acetone under acidic conditions using catalyst such as para-toluene sulfonic acid (PTSA), sulfuric acid (H2SO4), or perchloric acid to produce compound (8).

Final step of the reaction involves deacetylation of the compound (8) to produce compound (A) by hydrolysis under basic conditions. The hydrolysis can be carried out using base from the alkali or alkaline earth metals such as sodium hydroxide (NaOH), potassium hydroxide (KOH) and the like in alcoholic solvents such as methanol (MeOH), ethanol (ETOH), isopropyl alcohol (IPA) and the like, or mixture of alcoholic and chlorinated solvents such as dichloromethane (DCM), chloroform (CHCl3), 1,2-dichloroethane (EDC) and the like.

Sometimes it may also happen that the compound of formula (8) may get partially hydrolyzed to form the compound of formula (9) (as shown below) which upon further hydrolysis under suitable conditions produces the compound of formula (A).

wherein R1 and R2 are similar to those mentioned in forgoing paragraphs, preferably methyl groups.
Thus, preparation of the compound of formula (9) is also within the scope of the present invention. The compound of formula (9) can be prepared using the same process as shown above. If such, monoacetylated intermediate is generated, the same may be further hydrolyzed using alkaline conditions to produce the compound of formula (A).

BEST MODE OF CARRYING OUT THE INVENTION
EXAMPLES
The present invention can further be described by way of following examples. These examples are provided by way of illustration only and should not be construed as to limit the scope or spirit of the claims of the present invention in any manner.

Fludroxycortide Manufacturing Process:
Reaction Scheme:

(Ac)2O = Acetic anhydride, AcCl = Acetyl chloride, ACN = Acetonitrile, MeOH = Methanol, EtOH = Ethanol, IPA = Isopropanol, DCM = Dichloromethane, PTSA = p-toluenesulfonic acid, HCl = Hydrochloric acid, H2SO4 = Sulfuric acid, HNO3 = Nitric acid, AcOK = Potassium acetate, K2CO3 = Potassium carbonate, NaOH = Sodium hydroxide, KOH = Potassium hydroxide, DMF = Dimethylformamide, KMnO4 = Potassium permanganate

Preparation of Intermediates
Example-1: Preparation of (10R, 13S)-17-(2-acetoxyacetyl)-10, 13-dimethyl- 2, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-dodecahydro-1H-cyclopenta [a] phenanthrene-3, 11, 17-triyl triacetate (compound of formula (3))

To a suspension of hydrocortisone (2) (25 g) in acetic anhydride (417.3 mL) add acetyl chloride (206.7 mL) under stirring at 20-25°C within 15 minutes and keep the reaction mixture under stirring at the same temperature for 20 minutes. Reflux the reaction mixture (85-90°C) for 3-4 hours. After completion of the reaction (by monitoring through TLC), cool down the reaction mixture to 10-15°C. Slowly pour the reaction mixture into ice-water (5L) and stir the mixture at 5-10°C for 1-1.5 hours. Filter the material, wash with cold water (200 mL) and dry the compound under vacuum at 45-50°C to get the crude tetra-acetylated compound (3) (45 g). Dissolve the crude tetra-acetylated compound in IPA (120 mL) under refluxing condition and cool the mixture to 0-5°C. Keep the mixture under stirring at the same temperature (0-5°C) for crystallization. Filter the compound, wash with cold IPA (50 mL) and dry the compound under vacuum at 45-50°C to get the pure tetra-acetylated compound (3) (25 g).

Example-2: Preparation of (10R, 13S)-17-(2-acetoxyacetyl)-6-fluoro-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta [a] phenanthrene-11, 17-diyl diacetate (compound of formula (4))

To a suspension of compound (3) (25 g) in acetonitrile (250 mL) add Selectfluor (16.7 g) at -5-0°C under stirring within 20 minutes to get the clear solution. Stir the reaction mixture at the same temperature (-5-0°C) for 2-3 hours. After completion of the reaction, pour the reaction mixture into ice-water (1.5 L) and keep the mixture under stirring at 0-5°C for 1.2 hours. Filter the precipitated product, wash with cold water (100 mL) and dry the compound under vacuum at 45-50°C to get the compound (4) (25.7 g).

Example-3: Preparation of (6S, 10R, 13S)-17-(2-acetoxyacetyl)-6-fluoro-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta [a] phenanthrene-11, 17-diyl diacetate (compound of formula (5))

To the 15% HCl in IPA solution (25 mL) add compound (4) (5 g) under stirring at 5-10°C. Stir the suspension at the same temperature (5-10°C) for 4-5 hours. After obtaining 90% conversion to the desired alpha isomer (monitoring through HPLC) filetr the reaction, wash with cold IPA (20 mL) and dry the compound under vacuum at 45-50°C to get the compound (5) (4.3 g).

Example-4: Preparation of 2-((6S, 10R, 13S)-11-acetoxy-6-fluoro-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15-dodecahydro-1H-cyclopenta [a] phenanthren-17-yl)-2-oxoethyl acetate (compound of formula (6))

The solution of compound (5) (9.6 g) in DMF (96 mL) and potassium acetate was heated under stirring at 120-125°C for 3 hours. After completion of the reaction (monitoring through TLC) cool the reaction mixture to 0-5°C and pour the reaction mixture into ice-water (2 L) under stirring. Keep the reaction mixture under stirring at the same temperature for 1 hour. Filter the compound, wash with cold water (50 mL) and dry the compound under vacuum at 45-50°C to get the compound (6) (6.3 g).

Example-5: Preparation of 2-((6S, 10R, 13S, 16R, 17S)-11-acetoxy-6-fluoro-16, 17-dihydroxy-10, 13-dimethyl-3-oxo-2, 3, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17-tetradecahydro-1H-cyclopenta [a] phenanthren-17-yl)-2-oxoethyl acetate (compound of formula (7))

Prepare solutions A, B and C is as under:
Solution A: Compound (6) (6.2 g) + Acetone (280 mL) + Formic acid (0.46 mL)
Solution B: KMnO4 (3.65 g) + Acetone (10 mL) + Water (10 mL)
Solution C: 10% Sodium sulphite solution (50 mL)
Cool the solution A to 0-5°C and drop wise add solution B into it under stirring within 5 minutes. Stir the reaction mixture at the same temperature (0-5°C) for 5 minutes and add solution C into it at once. Filter the reaction mixture through celite and wash it with acetone (20 mL). Distill out volatiles from the filtrate under reduced pressure and extract the compound in DCM (2 x 50 mL). Wash the DCM layer with water (2 x 40 mL) and distill out solvent under reduced pressure to get crude diol (7). The crude diol was triturated in n-hexane (40 mL) and filter the product, wash with cold n-hexane and dry the compound under vacuum at 45-50°C to get the compound (7) (4.0 g).
Example-6: Preparation of 2-((2S, 6aR, 6bS, 7S, 8aS, 8bS, 11aR, 12aS)-2-fluoro-7-hydroxy-6a, 8a, 10, 10-tetramethyl-4-oxo-2, 4, 5, 6, 6a, 6b, 7, 8, 8a, 8b, 11a, 12, 12a, 12b-tetradecahydro-1H-naphtho [2', 1':4, 5] indeno [1, 2-d] [1, 3] dioxol-8b-yl)-2-oxoethyl acetate (compound of formula (8))

Add p-toluene sulfonic acid (PTSA) (2.35 g) to the solution of compound (7) (3.5 g) in acetone (88 mL) under stirring at 5-10°C. The reaction mixture was stirred at the same temperature (5-10°C) for 3-4 hours. After completion of reaction (monitoring through TLC) distill out the volatiles under reduced pressure. The residue was suspended in water (50 mL) and stirred at room temperature for 30 minutes. Filter the product, wash with cold water (25 mL) and dry the compound under vacuum at 45-50°C to get the crude compound (8) (3.4 g). The crude compound was purified by column chromatography over silica gel using 30% ethyl acetate (EtOAc) in n-hexane as an eluent to get pure compound (8) (2.3 g).

Preparation of Fludroxycortide
Example-7: Preparation of (4aR, 4bS, 5S, 6aS, 6bS, 9aR, 10aS, 10bS, 12S)-12-fluoro-6b-glycoloyl-5-hydroxy-4a, 6a, 8, 8-tetramethyl-3, 4, 4a, 4b, 5, 6, 6a, 6b, 9a, 10, 10a, 10b, 11, 12-tetradecahydro-2H-naphtho [2’, 1’:4, 5] indeno [1, 2-d] [1, 3] dioxol-2-one (compound of formula (1))

Dissolve the compound (8) (0.3 g) in the mixture of MeOH (3 mL) and DCM (3 mL) at room temperature and cool the solution to 0-5°C. Add solution of NaOH (5 mg) in MeOH (0.3 mL) to the above solution under stirring and continue the reaction at the same temperature for 4-5 hours. After completion of reaction (monitoring through TLC) add 10% acetic acid in MeOH (5 mL) to adjust the pH around 7.0. Distill out the volatiles under reduced pressure and suspend the residue in cold water (5 mL). Keep the suspension under stirring at 5-10°C for 1 hour. Filter the product, wash with cold 10% MeOH in water (5 mL) and dry the compound under vacuum at 45-50°C to get the crude Fludroxycortide (1) (0.32 g). The crude Fludroxycortide was purified by column chromatography over silica gel using 35% EtOAc in n-hexane as an eluent to get pure Fludroxycortide (1) (0.22 g).

In the above mentioned process, it may also happen that the compound of formula (8) partially hydrolyses to produce the compound of formula (9) as shown below. If the compound of formula (9) is produced, it may further be hydrolyzed using the same conditions as used in Example-7 to produce the compound of formula (1), i.e. Fludroxycortide. Thus, preparation of the compound of formula (9) is also within the scope of the present invention.

It should be understood that various changes and modifications to the embodiments described herein will be apparent to those skilled in the art. Such changes and modifications can be made without departing from the spirit and scope of the subject matter of the present invention and without diminishing its intended advantages. It is therefore intended that such changes and modifications be covered within the scope of the present invention. ,CLAIMS:WE CLAIM,
1. A process for the chemical synthesis of the compound 6-Fluoro-11, 21-dihydroxy-16, 17-[(l-methylethylidene)bis(oxy)]-(6a, 11ß, 16a)-pregn-4-ene-3, 20-dione (Fludroxycortide) comprising following steps:
Step (A): Protection of alcohol groups of hydrocortisone (2) by acetylation using suitable acetylating agents to produce compound (3).

Step (B): Fluorination of the compound (3) using suitable fluorinating agents to produce compound (4).

Step (C): Resolution of compound (4) under acidic condition to produce compound (5).

Step (D): Elimination of 17-acetoxy group from compound (5) under basic condition to produce compound (6).

Step (E): Oxidation of compound (6) using suitable oxidizing agents to produce compound (7).

Step (F): Formation of acetonides at 16-17 position of compound (7) by acetone or 2, 2-dimethoxypropane to produce acetonide compound (8).

Step (G): Deacetylation of compound (8) to produce compound (1) by hydrolysis under basic conditions.

2. The compound of formula (9)

3. The process for the preparation of the compound of formula (9) as claimed in claim 2 comprising following steps:
Step (A): Protection of alcohol groups of hydrocortisone (2) by acetylation using suitable acetylating agents to produce compound (3).

Step (B): Fluorination of the compound (3) using suitable fluorinating agents to produce compound (4).

Step (C): Resolution of compound (4) under acidic condition to produce compound (5).

Step (D): Elimination of 17-acetoxy group from compound (5) under basic condition to produce compound (6).

Step (E): Oxidation of compound (6) using suitable oxidizing agents to produce compound (7).

Step (F): Formation of acetonides at 16-17 position of compound (7) by acetone or 2, 2-dimethoxypropane to produce acetonide compound (8).

Step (G): Deacetylation of compound (8) to produce compound (9) by hydrolysis under basic condition.

4. The compound of formula (8)

5. The compound of formula (7)

6. The compound of formula (6)

7. The compound of formula (5)

8. The compound of formula (4)

9. Use of the compound according to any one of claim 2 and claims 4 to 8 for the preparation of Fludroxycortide.
10. Fludroxycortide prepared according to the process as claimed in claim 1 or using intermediate according to any one of claim 2 and claims 4 to 8.

Dated this 26th day of May 2018

[KETANA BABARIA]
IN/PA-660
ATTORNEY FOR THE APPLICANTS