FIELD OF THE INVENTION
The present invention relates to an improved and industrially viable process for the preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (11ß, 16α) also known as ciclesonide, having a structure as shown in Formula -1:
(Formula Removed)
Formula -1
Ciclesonide is a novel, non-halogenated, new-generation inhaled glucocorticoid with good local antiinflammatory properties which is primarily useful against the symptoms of allergic rhinitis and asthma.
BACKGROUND OF THE INVENTION
Ciclesonide is a novel and effective non-halogenated glucocorticoid developed for the treatment of asthma. Asthma is a chronic lung disease caused by airway inflammation and results in airway constriction in response to certain stimuli. It is characterized by a variety of symptoms including wheezing, coughing and a tightening of the airways, which causes shortness of breath and can be life-threatening.
Ciclesonide has low glucocorticoid receptor affinity. It undergoes conversion to its high affinity active metabolite desisobutyryl-ciclesonide via esterases in the lung thereby minimizing effects on endogenous Cortisol. When ciclesonide is inhaled into the lungs, it is absorbed into the cells of the lungs and airways. It works by preventing the release of certain chemicals from the cells. These chemicals are normally involved in producing immune and allergic responses that result in inflammation. By decreasing the release of these chemicals in the lungs and airways, inflammation is reduced.
The novel inhaled corticosteroid Ciclesonide (Alvesco®) for the treatment of asthma is now approved in almost 25 countries worldwide including Europe, Latin America, and Australia. It
has been found that the 2'S-epimers are always significantly less potent than the 2'R-epimers which is also stated in J. Pharmacol. Exp. Ther., 2004 Apr, 309(1), 249-58.
The US patent no. 4,404,200 discloses 4-Pregnene derivatives, a process for the synthesis of compound in the form of a stereoisomeric mixture or an epimer of the R or S type regarding the orientation of the substituents in the carbon atom at position 22 including the separation of the obtained stereoisomeric mixture into its separate components (diastereoisomers), composition and method for the treatment of inflammatory conditions.
The US patent no. 4,695,625 discloses a process for the preparation of 16,17-acetals of pregnane derivatives. The said invention describes a process for the preparation of 16, 17-acetals of pregnane derivatives starting from the corresponding 16, 17-acetonides more particularly to the synthesis of 16.alpha.17.beta.-butylidendioxy-ll.beta., 21-dihydroxypregna-l, 4-diene-3, 20-dione (budesonide), wherein the process involves a direct transketalization reaction with aldehydes on 16,17-acetonides, in the presence of hydrohalogen acids.
The US patent no. 5,733,901 discloses prednisolone derivatives and process for the preparation of such prednisolone derivatives by the missing acyl radical on C-21 hydroxyl group; wherein the process comprises reacting 16-hydroxyprednisolone with cyclohexanecarboxaldehyde.
The German patent no. 2448548 discloses process for the preparation of 16α,17e cyclic acetals or ketals of 9α-halo-llss,16α,17α,-trihydroxy steroids of the pregnane series, which comprises treating the 9ss,llss-epoxides of the 16e,17e dihydroxy derivatives with a minimum quantity of aqueous hydrogen halide as long as this quantity is not below the amount stoichiometrically required for the hydrohalogenation reaction, in the presence of the necessary quantity of the selected aldehyde or ketone, and carrying out simultaneously the double reaction of hydrohalogenation and acetalization or ketalization at a temperature between -150 and +20°C.
The US patent No. 5,482,934 discloses the compound ciclesonide which is chemically (22R)-pregna-1, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-1-oxopropoxy) (11ß, 16α) and is useful for the treatment of allergic rhinitis and asthma. The process described in the said patent results in the (22S)- epimer or (22R,S)- mixtures of acetals from triesters. The said patent mentions about the use of isobutyric anhydride and
pyridine; but pyridine is a costlier and hazardous material. Handling of high quantities of pyridine required as solvent at industrial scale is not viable as it leads to toxicities such as impotency in humans. Moreover, anhydrides are costlier than corresponding acids or acid chlorides. Furthermore, the 16-hydroxyprednisolone reported as starting material in the said patent is a very costly chemical.
The German publication no. 10055820 discloses the preparation of 16, 17-cyclohexylmethylene-dioxy-pregnadiene derivative, useful as glucocorticoid, by reacting 16, 17-ketal with cyclohexanecarboxaldehyde to yield a product possessing high epimeric purity particularly in at least 90% of R epimeric form using desonide as the starting material. The said process provides an epimeric ratio of 97.8/2.2 for R/S epimers, whereas the process invented by the inventors of the present invention provides at least 99.5% of R epimeric form with about 0.5% or less of the S epimeric form, which is the better epimer ratio than that mentioned in the said German publication given the fact that the R epimer is more potent than the S epimer. In the said publication, the end product obtained at ambient temperature conditions is sticky and contains various impurities thus requiring further purification using dimethyl formamide (DMF), whereas the end product using the present improved process by the inventors is a highly pure free flowing crystalline solid material which is easy to handle and does not require any further purification step(s).
Hence, based on the discussions provided pertaining to the various prior arts available for preparation of ciclesonide, it can be clearly implied that there still exists a need for developing an efficient, commercially viable and cost-effective process for the synthesis of ciclesonide. The present invention overcomes such drawbacks of the prior art by providing an improved cost-effective process which avoids use of potentially hazardous chemicals and yields a highly pure product without the requirement of additional purification step(s).
Summary of the invention
It is an objective of the present invention to provide an improved process for the preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-1-oxopropoxy) (l1ß, 16α) of Formula-I comprising the following steps:
(Formula Removed)
Formula -1
(i) Reacting prednisolone-16, 17-ketals of Formula-II taken as starting material in a suitable solvent with acid halide or acid optionally in the presence of at least one catalyst to obtain prednisolone -16,17-ketals - 21-ester; and
(Formula Removed)
Formula - II
(ii) Reacting prednisolone-16, 17-ketals - 21-ester so obtained with cycloalkanecarboxaldehyde in a suitable solvent using an acidic substance as catalyst to obtain the desired product of Formula-I.
It is also an objective of the present invention to provide an improved process for the preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (llß,16α) of Formula-I comprising of the following steps:
(i) Reacting budesonide of Formula-Ill taken as starting material with isobutyryl halide in the presence of triethylamine using dichloromethane as solvent to obtain budesonide-21-ester; and
(ii) Reacting the budesonide-21 -ester so obtained, with cyclohexanecarboxaldehyde in 2-nitropropane using perchloric acid as catalyst to obtain the desired product of Formula-I.
(Formula Removed)
It is also an objective of the present invention to provide an improved process for the preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (11ß, 16α) of Formula-I comprising of the following steps:
(i) Reacting desonide of Formula-IV taken as starting material with isobutyryl chloride in the presence of diisopropylethylamine using chloroform as solvent to obtain desonide-21 -ester; and
(Formula Removed)
Formula - IV
(ii) Reacting the desonide-21-ester so obtained, with cyclohexanecarboxaldehyde in dimethyl formamide using methane sulphonic acid as catalyst to obtain the desired product of Formula-I.
It is also an objective of the present invention to provide a process for the preparation of ciclesonide which yields a substantially pure epimeric form, particularly the R epimer, which is specifically useful for the treatment of asthma.
It is a further objective of the present invention to provide an efficient and cheaper method that primarily comprises use of non-hazardous chemicals for preparation of ciclesonide of Formula-I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for the preparation of ciclesonide of Formula-I as herein described by using cheaper and non-hazardous chemicals. The process of the present invention leads to the formation of the more active R epimer in a highly pure form, particularly useful for the treatment of asthma.
The present invention provides an improved process for the preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-11 -hydroxy-21 -(2-methyl-1 -oxopropoxy) (l1ß, 16α) also known as ciclesonide of Formula-I as herein described. According to the present invention, the said process comprises the following steps:
(i) Reacting prednisolone-16, 17-ketals of Formula-II as described herein taken as starting material in a suitable solvent with acid halide or acid optionally in the presence of at least one catalyst to obtain prednisolone-16,17-ketals - 21-ester; and
(ii) Reacting prednisolone-16, 17-ketals - 21-ester so obtained, with cycloalkanecarboxaldehyde in a suitable solvent using an acidic substance as catalyst to obtain the desired product of Formula-I as described herein.
According to a preferred embodiment of the present invention, the process enables the formation of compound of Formula-I as herein described substantially as single "R" epimer.
In an essential embodiment, the purity of the R epimer of ciclesonide formed by using the process of the present invention is at least 97%, preferably 99.5%, most preferably 99.8%.
In another embodiment of the present invention, the stereoselective synthesis of ciclesonide can be carried out in a single pot by choosing a solvent system that will provide specifically the R epimer having a substantially high yield and purity.
According to an embodiment of the present invention, the starting material used in the present process for the preparation of ciclesonide is selected from but not limited to a group comprising prednisolone derivative-16, 17-ketals of Formula-II as herein described. Preferably the starting material is budesonide or desonide.
In another embodiment of the present invention, the present process comprises esterification of prednisolone derivative-16, 17-ketals of Formula-II as herein described first at C-21 with isobutyryl halide or isobutyric acid.
In a further embodiment of the present invention, the present process comprises the use of acid such as isobutyric acid or acid halides selected from but not limited to a group comprising isobutyrylhalides such as isobutyrylchloride, isobutyrylbromide, isobutyryliodide, and the like or suitable mixtures thereof.
In a further embodiment of the present invention, the present process comprises the use of at
least one catalyst selected from but not limited to a group comprising pyridine hydrochloride,
piperazine hydrochloride, morpholine hydrochloride, 4-pyrrolidinopyridine,
dimethylaminopyridine, perchloric acid, methanesulphonic acid, orthophosphoric acid, hydrochloric acid and the like or mixtures thereof.
In a further embodiment of the present invention, the solvent used in the process is selected from but not limited to a group comprising tetrahydrofuran, diethylether, diisopropylether, dimethyl formamide, dimethyl sulfoxide, ethylacetate, dioxane, 1-nitropropane, 2-nitropropane, dichloromethane and the like or mixtures thereof.
In a further embodiment of the present invention, additional compounds such as a coupling agent selected from but not limited to a group comprising cycloalkylcarbodiimides e.g. dicyclohexylcarbodiimide or l-ethyl-3,3-(dimethylamino)propylcarbodiimide can be used during the preparation of prednisolone -16,17-ketals - 21-ester from prednisolone -16, 17-ketals.
In another embodiment of the present invention, the present process comprises the use of cycloalkanecarboxaldehyde, preferably cyclohexanecarboxaldehyde.
In an embodiment of the present invention, the isobutyrylchloride reacts with budesonide in the presence of organic amine bases selected from but not limited to a group comprising dialkylamines such as diphenylamine, methylethylamine, methylbutylamine, methylpropylamine and trialkylamines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, diethylaniline and the like or mixtures thereof by using organohalogenated solvents such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like or mixtures thereof so as to form Budesonide-21-ester which is subsequently reacted with cyclohexanecarboxaldehyde to obtain ciclesonide of Formula-I as described herein.
The examples of process of preparation of ciclesonide of Formula-I provided herein serve to illustrate embodiments of the present invention. However, they do not intend to limit the scope of invention.
Example-1:
(i) Preparation of (l1ß, 16α) - 16, 17-[butylidenebis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1,4-diene-3,20-dione i.e. Budesonide C-21 isobutyryl ester: 500 mg (1.163 mmol) of (11ß, 16α)-16, 17 - [butylidenebis(oxy)]- 11, 21-dihydroxypregna-l, 4-diene-3, 20-dione in 8 ml of dichloromethane was cooled to 0°C and 176.2 mg (1.745 mmol) of triethylamine was added at this temperature. Reaction mixture was stirred for 10-15 min at 0° -5°C and 186 mg (1.745 mmol) of isobutyrylchloride was added to the reaction mixture at 0° -5°C. The resulting reaction mass was stirred at 5°-10°C for 30 mins followed by its stirring at room temperature for 2 hrs. After 2 hrs stirring at room temperature, 10 ml of DM water was added to the reaction mixture and the organic layer was separated. Organic phase was again washed with 8 ml of DM water followed by 10 ml of brine solution. The organic layer was dried over MgSO4 and recovered in vacuo to get crude material which was purified by subjecting to chromatography on silica gel (65/35 hexane/ethyl acetate) so as to produce (l1ß, 16α) - 16,17-[butylidenebis(oxy)]-l1-hydroxy-21 -(2-methyl-1-oxopropoxy) pregna-1, 4-diene-3, 20-dione as pure white solid material (400 mg, 68.79%). IR(m"1): 3494,2957,1750,1723, 1667,1625,1601,1098 (Bd.)
(ii) Preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (l1ß, 16α) i.e. Ciclesonide:
100 mg (0.20 mmol) of (l1ß, 16α) - 16,17-[butylidenebis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1, 4-diene-3, 20-dione in 5 ml of 2-nitropropane was cooled to 0°-5°C and 30.15 mg (0.30 mmol) of 70% perchloric acid was added at 0°-5°C. Reaction mixture was stirred for 30 mins at this temperature and 33.6 mg (0.30 mmol) of cyclohexanecarboxaldehyde was added. The resulting reaction mixture was stirred overnight at 20° - 22°C and the crude material so separated was filtered followed by its purification from column chromatography on silica gel (65/35 Hexane/ ethyl acetate) so as to produce (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[cyclohexylmethylene-bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (l1ß, 16α) as a white
solid (70 mg, 65%) in a purity greater than 99.5%. The purified product was dried under vacuum
at4 0°-45°C for 4-5hrs.
IR (cm"1): 3388,2933,2854, 1747, 1730,1655,1614, 1602, 1059
1HNMR (ppm): δ 7.35 (1H, d), 6.30 (1H, d), 6.05 (1H, s), 4.85 (3H, m), 4.50 (1H, s), 4.35 (1H,
d), 2.71 - 2.54 (3H, m), 2.19 - 2.03 (4H, m), 1.74 - 1.46 (11H, m)
The process flow chart for Example-1 showing steps (i) & (ii) is provided in Figure-1.
Example-2:
(i). Preparation of (l1ß, 16α) - 16,17-[butylidenebis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1,4-diene-3,20-dione i.e. Budesonide C-21 isobutyryl ester: 50 mg (0.57 mmol) of Isobutyric acid in 5 ml of ethyl acetate was added to 147mg (0.713 mmol) of dicyclohexylcarbodimide and the resulting clear solution was stirred for 30 mins at room temperature. Turbidity appeared during the stirring and after 30 mins, 245 mg (0.57 mmol) of (lip,16a)-16, 17 -[butylidenebis(oxy)]- 11, 21-dihydroxypregna-l, 4-diene-3, 20-dione was added followed by the addition of a small quantity of dimethylaminopyridine. The resulting suspension was stirred for 2 hrs at room temperature and the reaction mixture was filtered. The filtrate was concentrated in vacuo and the crude material so obtained was subjected to column chromatography on silica gel (70/30 Hexane/ethyl acetate) so as to produce (11ß, 16α) - 16,17-[butylidenebis(oxy)]-ll- hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1, 4-diene-3, 20-dione as pure white solid material (171.5 mg, 60.2%). IR(m"1): 3494,2957,1750,1723,1667,1625,1601,1098
(ii) Preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (l1ß, 16α) i.e. Ciclesonide:
100 mg (0.20 mmol) of (l1ß, 16α) - 16,17-[butylidenebis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1, 4-diene-3, 20-dione in 5 ml of 2-nitropropane was cooled to 0°-5°C and 30.15 mg (0.30 mmol) of 70% perchloric acid was added at 0°-5°C. Reaction mixture was stirred for 30 mins at this temperature and 33.6 mg (0.30 mmol) of cyclohexanecarboxaldehyde was added. The resulting reaction mixture was stirred overnight at 12° - 15°C and the crude material so separated was filtered followed by its purification from column chromatography on neutral activated aluminium oxide (70/30 Hexane/ ethyl acetate) so as to produce (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-l l-hydroxy-21-(2-methyl-l-
oxopropoxy) (l1ß, 16α) as a white solid material (70 mg, 65%) having a purity of 99.8%. The
purified product was dried under vacuum at 40°-45°C for 4-5 hrs.
IR (cm-1): 3388,2933,2854,1747,1730,1655,1614,1602,1059
!HNMR (ppm): δ 7.35 (1H, d), 6.30 (1H, d), 6.05 (1H, s), 4.85 (3H, m), 4.50 (1H, s), 4.35 (1H,
d), 2.71-2.54 (3H, m), 2.19-2.03 (4H, m), 1.74 - 1.46 (11H, m)
The process flow chart for Example-2 showing steps (i) & (ii) is provided in Figure-2.
Example-3:
(i) Preparation of (l1ß, 16α) - 16,17-[(l-methylethylidene)bis(oxy)]-ll-hydroxy-21-(2-methyl-1-oxopropoxy) pregna-1,4-diene-3,20-dione i.e. Desonide C-21 isobutyryl ester: 500 mg (1.202 mmol) of (l1ß, 16α) - 16,17-[(l-methylethylidene)bis(oxy)]-ll, 21-dihydroxypregna-1, 4-diene-3, 20-dione in 8 ml of chloroform was cooled to 0°C and 232.6 mg (1.803 mmol) of diisopropylethylamine was added at this temperature. Reaction mixture was stirred for 10-15 minutes at 0°-5°C and 192 mg (1.803 mmol) of isobutyrylchloride was added to the reaction mixture at this temperature. The resulting reaction mass was stirred at 5-10°C for 30 mins followed by its stirring at room temperature for 2 hrs. After 2 hrs stirring at room temperature, 10 ml of DM water was added to the reaction mixture and the organic layer was separated. Organic phase was again washed with 8 ml of DM water followed by 10 ml of brine solution. The organic layer was dried over MgSO4 and recovered in vacuo to get crude material which was purified by subjecting to chromatography on silica gel (65/35 Hexane/ ethyl acetate) so as to afford (11α, 16α) - 16,17-[(l-methylethylidene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) pregna-1,4-diene-3,20-dione as a pure white solid (400 mg, 68.5%). IR(cm'1): 3389,2983,2937,2873,1750,1728,1655,1615,1605,1373,1087,1059
(ii) Preparation of (22R)-pregna-l, 4-diene-3, 20-dione-16, 17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (l1ß, 16α) i.e. Ciclesonide:
200 mg (0.412 mmol) of (l1ß, 16α) - 16,17-[(l-methylethylidene)bis(oxy)]-ll-hydroxy-21-(2-methyl-1-oxopropoxy) pregna-1, 4-diene-3,20-dione in 8 ml of dimethyl formamide was cooled to 0°-5°C and 60 mg (0.618 mmol) of methane sulphonic acid was added at this temperature. Reaction mixture was stirred for 30 mins at this temperature and 69.2 mg (0.618 mmol) of cyclohexanecarboxaldehyde was added. The resulting reaction mixture was stirred overnight at 12° - 15°C and added into the mixture of 25 ml of DM water and 20 ml of ethyl acetate. The
organic layer was separated and the aqueous layer was extracted twice with 10 ml each of ethyl
acetate. The whole combined ethyl acetate layer was washed with 50 ml of DM water followed
by 50 ml of brine solution. The separated organic layer was dried over MgSO4 and recovered in-
vacuo to get crude material which was purified by subjecting to column chromatography on
silica gel (65/35 Hexane/ ethyl acetate) so as to yield (22R)-pregna-l, 4-diene-3, 20-dione-16,
17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (l1ß, 16α) as a
white solid material (140 mg, 62.9%) in a purity greater than 99.5%. The purified product was
dried under vacuum at 40°-45°C for 4-5 hrs.
IR(cm-1): 3388,2933,2854,1747, 1730, 1655,1614, 1602, 1059
'HNMR (ppm): δ 7.35 (1H, d), 6.30 (1H, d), 6.05 (1H, s), 4.85 (3H, m), 4.50 (1H, s), 4.35 (1H,
d), 2.71 -2.54 (3H, m), 2.19-2.03 (4H, m), 1.74- 1.46 (11H, m)
The process flow chart for Example-3 showing steps (i) & (ii) is provided in Figure-3.

We claim:
1. An improved process for the preparation of (22R)-pregna-l,4-diene-3,20-dione-16,17-
[(cyclohexylmethylene)bis(oxy)]-11 -hydroxy-21 -(2-methyl-1 -oxopropoxy) (11ß, 16α) of
Formula-I as herein described wherein the process comprises of the following steps:
i) Reacting prednisolone-16,17-ketals of Formula-II as herein described taken as starting material in a suitable solvent with acid halide or acid optionally in the presence of at least one catalyst and/or other compound(s) to obtain prednisolone-16,17-ketals-21-ester; and
ii) Reacting prednisolone-16,17-ketals-21 -ester with cycloalkanecarboxaldehyde in a suitable solvent using an acidic substance as catalyst to obtain the desired product of Formula-I as herein described.
2. A process according to claim 1, wherein the prednisolone-16,17 ketals is selected from a group comprising budesonide or desonide, or its pharmaceutically acceptable salts, esters, amides, solvates, hydrates, analogues, enantiomers, or derivatives.
3. A process according to claim 1, wherein the solvent is selected from a group comprising tetrahydrofuran, diethylether, diisopropylether, dimethyl formamide, dimethyl sulfoxide, ethylacetate, dioxane, 1-nitropropane, 2-nitropropane, dichloromethane, ethylene chloride, carbon tetrachloride, chloroform, or mixtures thereof.
4. A process according to claim 1, wherein the acid halide is an isobutyrylhalide(s) selected from a group comprising isobutyrylchloride, isobutyrylbromide, isobutyryliodide, or mixtures thereof.
5. A process according to claim 1, wherein the catalyst is selected from a group comprising pyridine hydrochloride, piperazine hydrochloride, morpholine hydrochloride, 4-pyrrolidinopyridine, dimethylaminopyridine, perchloric acid, methanesulfonic acid, orthophosphoric acid, hydrochloric acid, or mixtures thereof.
6. A process according to claim 1, wherein the other compounds(s) is organic aminic base(s) selected from a group comprising dialkylamines or trialkylamines, or mixtures
thereof and/or coupling agent(s) selected from a group comprising cycloalkylcarbodimide(s), or mixtures thereof.
7. A process according to claim 1, wherein the process comprises the use of cycloalkanecarboxaldehyde.
8. A process according any of the preceding claims, wherein the process enables the formation of compound of Formula-I as herein described substantially as "R" epimer.
9. A process according any of the preceding claims, wherein the purity of the "R" epimer of the compound of Formula-I is at least about 95%.
10. An improved process for the preparation of (22R)-pregna-l,4-diene-3,20-dione-16,17-[(cyclohexylmethylene)bis(oxy)]-ll-hydroxy-21-(2-methyl-l-oxopropoxy) (11ß,16α) of Formula-I as described herein by examples and illustrations.