FIELD OF THE INVENTION
The present invention relates to a chemoselective, economic and industrially advantageous process for preparation of Loteprednol Etabonate of Formula-I.
The present invention further relates to a process of purification of Loteprednol Etabonate of Formula-I to obtain pure Loteprednol Etabonate which is substantially free from the impurities.
Formula-I
BACKGROUND OF THE INVENTION
Loteprednol Etabonate, chloromethyl 17a-[(ethoxycarbonyl)oxy]-lip-hydroxy-3-oxoandrosta-l,4~diene-17p-carboxylate represented by Formula-I, a C-20 ester based derivative of prednisolone, offers potent anti-inflammatory efficacy. Loteprednol Etabonate was first approved in the USA on March 19, 1998 under the brand name LOTEMAX® and since then marketed by Bausch and Lomb as suspension/drops in 0.5% strength for anti-inflammatory ophthalmic uses. Subsequent to the first approval, Loteprednol was further approved in different dosage forms like ointment and gel and presently being marketed worldwide.
Loteprednol Etabonate and related compounds were first disclosed in GB patent No. 2079755. GB'755 also discloses an analogous process for preparation of Loteprednol Etabonate summarized herein below in Scheme-1. Scheme 1:



Formula-IV

NalO,
Step-I

Formula-V

NEt,
C!C02Et

Step-II


NaOH
CICH2I
Step-III Formula-VI
In the above process, prednisolone of Formula-IV was first reacted with sodium metaperiodate in a suitable solvent to obtain corresponding 17-beta carboxylic acid of Formula-V, which on reaction with ethyl chloroformate in presence of a suitable base produces 17-beta carboxylic acid-17 alpha-carbonate of Formula-VI. The 17-beta carboxylic acid-17 alpha-carbonate thus obtained was reacted with chloroiodo methane to produce crude Loteprednol Etabonate of Formula-I, which was then purified by crystallization using a mixed solvent of tetrahydrofuran and n-hexane.
Inventors of present invention have found that the process disclosed in GB'755 patent is not chemoselective and unwanted mixed anhydride of Formula-VI (I) was produced as a byproduct during the reaction step II, and is difficult to remove. Further, purification of crude Loteprednol Etabonate using a mixed solvent of tetrahydrofuran and n-hexane gives a product that contains lot of impurities and require separation and purification by column chromatography which makes the process unsuitable for industrial production.


H3C^°-f
FormuIa-VI (I)
J Steroid Biochem Mol Biol 1991, 38: 149-154 discloses another method of purification of Loteprednol Etabonate using acetone. Loteprednol Etabonate obtained from the said process was having purity upto 98% (HPLC), but there are nearly 2% of the impurities in the final product which are difficult to remove and the final product cannot achieve ICH specification / guidelines.
Chinese patent No. 101942001 discloses a process for purification of Loteprednol Etabonate using alcohols as an organic solvent, specially ethanol, isopropyl alcohol or methanol. Although, following the process disclosed in CN'001, the purity of final product can reach around 99.5% but it was found that in protic solvent like methanol, ethanol, isopropanol etc. the final product is hydrolyzed to some extent and results into formation of compound of Formula-VI, which reduces overall yield of the product.
In view of aforesaid drawbacks, the present invention is focused to develop a process for preparation and purification of Loteprednol Etabonate that would be chemoselective and produces the final product with high yield and purity.
OBJECT OF THE INVENTION
The main object of the present invention is to provide a chemoselective process of preparation of Loteprednol Etabonate wherein said process is economical and industrially advantageous.
The another object of the present invention is to provide a process of purification of crude Loteprednol Etabonate in order to obtain Loteprednol Etabonate of

Formula-I with high purity and substantially free from impurities of Formula-II, III and X.
SUMMARY OF THE INVENTION
The present invention relates to a chemoselective process for preparation and purification of Loteprednol Etabonate of Formula-I wherein the Loteprednol Etabonate so obtained is pure and substantially free from the impurities of Formula-II, III and X.
Accordingly, the main aspect of the present invention is to provide substantially pure Loteprednol Etabonate comprising less than about 0.5% of dimer impurity of Formula-II,
Formula-H
Other aspect of the present invention is to provide a process for preparation of Loteprednol Etabonate of Formula-I;
Formula-I
comprising the steps of:
a) reacting Prednisolone of Formula-IV

Formula-IV
with sodium metaperiodate in presence of suitable solvent to obtain a compound of Formula-V;
Formula-V
b) reacting the compound of Formula-V with ethyl chloroformate in presence of 4-dimethylaminopyridine (DMAP) to obtain a compound of Formula-VI; and
Formula-VI
c) reacting compound of Formula-VI with chloroiodomethane in N-methyl pyrrolidone in presence of a base to obtain crude Loteprednol Etabonate.
Another aspect of the present invention is to provide a process of preparation of impurity of Formula-II; wherein said impurity is prepared by the process comprising the steps of: a) reacting a compound of Formula-VI

FormuIa-VI
with Loteprednol Etabonate of Formula I
Formula-I
in presence of a base and solvent to obtain the crude compound of Formula-II; and
Formula-II
b) purifying the crude compound thus obtained by column chromatography.
Another aspect of the present invention provides a process of preparation of impurity of Formula-Ill, wherein said impurity is prepared by the process comprising the steps of:
Formula-Ill
a) reacting hydrocortisone of Formula VII

Formula-VII
with sodium metaperiodate in presence of suitable solvent to obtain compound of Formula-VIII;
Formula-VIII
b) reacting compound of Formula VIII with ethyl chloroformate in presence of 4-dimethylaminopyridine (DMAP) to obtain a compound of Formula IX;
Formula-IX
c) reacting compound of Formula-IX with chloroidomethane in a suitable solvent
in presence of a base to get a solid compound; and
d) crystallizing the solid compound in ester solvent to obtain hydrocortisone
related impurity of Formula-Ill.
One more aspect of the present invention is to provide an isolated compound of Formula-II

Formula-II
DESCRIPTION OF THE INVENTION
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
The present invention can comprise or consist essentially of the components of the present invention as well as other ingredients or elements described herein.

As used herein, "comprises or comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited.
The terms "having" and "including" are also to be construed as open ended unless the context suggest otherwise.
All ranges recited herein include the endpoints, including those that recite a range "between" two values. Terms such as "about", "generally", "substantially," and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein "crude Loteprednol Etabonate" refers to product having purity < 99% (HPLC), wherein the impurities of Formula-II, III and X may be present in an amount more than 0.5% (HPLC).
As used herein, "substantially free" refers to Loteprednol Etabonate having purity more than 99% (HPLC), wherein, the impurities of Formula-II, III and X may be present in an amount less than about 0.5% (HPLC), preferably may be present in an amount less than about 0.2%, most preferably, may be present in an amount less than about 0.05% (HPLC).
As used herein, impurity of Formula-II refers to Dimer impurity of Loteprednol Etabonate.
As used herein, impurity of Formula-Ill refers to the Hydrocortisone related impurity of the Loteprednol Etabonate.

As used herein, impurity of Formula-X refers to the Loteprednol related impurity of Loteprednol Etabonate.
Inventors of present invention have earnestly found that use of DMAP (4-dimethyl amino pyridine) reduces the formation of mixed anhydride of Formula VI (I) and hence it reduces the consumption of ethylchloroformate, which makes the process chemoselective and also very economical.

Formula-VI (I)
Further, the inventors of the present invention have further explored aprotic solvents such as acetonitrile for purification of crude Loteprednol Etabonate. It was observed that the use of acetonitrile reduce the hydrolysis of product and hence improve the yields. Crystallization of crude Loteprednol Etabonate obtained herein in acetonitrile provides highly pure Loteprednol Etabonate which is substantially free from the impurities of Formula-II, Formula-Ill and X.
Accordingly, in one embodiment, the present invention provides substantially pure Loteprednol Etabonate comprising less than about 0.5% of dimer impurity of Formula-II,

Formula-H
In one another embodiment, the present invention provides a process for preparation of Loteprednol Etabonate of Formula-I;
Formula-I
comprising the steps of:
a) reacting Prednisolone of Formula-IV
Formula-IV
with sodium metaperiodatein presence of suitable solventto obtain a compound of Formula-V;
Formula-V
b) reacting compound of Formula-V with ethyl chloroformate in presence of 4-dimethyl amino pyridine (DMAP) to obtain a compound of Formula-VI; and
Formula-VI

c) reacting compound of Formula-VI with chloroiodomethane in N-methyl pyrrolidone in presence of a base to obtain crude Loteprednol Etabonate.
The solvent used in step a) can be selected from any solvent suitable for completion of reaction, preferably, the solvent used in step a) can be selected from tetrahydrofuran, ethanol, methanol, isopropanol, butanol, 1,4-dioxane, water or a mixture thereof. More preferably, the solvent used in step a) is tetrahyrofuran, methanol and water.
The step b) is carried out in presence of solvent selected from dichloromethane, chloroform and tetrahydrofuran. More preferably, the solvent used is dichloromethane.
The base used in step c) can be selected from any base suitable for completion of reaction, preferably, the base used in step c) can be selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and potassium hydroxide. More preferably, the base used in step c) is potassium carbonate. Moreover, step c) is carried out in presence of solvent selected from N-methyl pyrrolidone, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dimethyl acetamide, 1,4-dioxane and hexamethylphosphoramide.
In one another embodiment, the present invention provides a process of preparation of Loteprednol Etabonate of Formula-1, wherein said process further comprises of purifying the crude Loteprednol Etabonate obtained in step c) by crystallizing in acetonitrile to obtain pure Loteprednol Etabonate of Formula-I.
In another embodiment, the present invention provides a process of crystallizing crude Loteprednol Etabonate comprising the steps of:
a) dissolving crude Loteprednol Etabonate in acetonitrile under heating;
b) allowing the solution to cool down to room temperature; and

c) isolating the crystalline pure Loteprednol Etabonate of Formula-I.
In preferred embodiment, the heating in step a) is performed at a temperature ranging between room temperature to reflux of solvent.
In further embodiment of the present invention, the pure crystalline Loteprednol Etabonate obtained herein is substantially free from the impurities of Formula-II, III and X.
In yet another embodiment, the Loteprednol Etabonate is isolated by filtration through celite bed or by centrifugation or by vacuum filtration.
In preferred embodiment, the crystalline Loteprednol Etabonate of the present invention is characterized by its XRPD pattern having characteristic peaks at diffraction angles 2-theta of about 7.36, 9.45, 11.82, 13.10, 13.96, 14.37, 14.83, 15.54, 15.74, 15.98, ,16.63, 17.67, 18.82, 19.03, 19.98, 21.37, 22.25, 23.09, 23.26, 23.74, 24.97, 25.12, 25.80, 26.24,27.06, 27.29, 27.83, 28.57, 29.39, 29.92, 30.48, 30.94, 31.95, 32.41, 33.59, 34.11, 34.99, 35.76, 36.28, 36.59, 37.63, 38.13, 39.04 and 39.57 ± 0.2 degrees.
In one another preferred embodiment, the crystalline Loteprednol Etabonate of the present invention is further characterized by its DSC thermogram having an endothermic peak at about 246.15°C.
In still another embodiment, the present invention provides a process of preparation of Dimer compound of Formula-II, comprising the steps of: a) reacting a compound of Formula-VI

Formula-VI
with Loteprednol Etabonate of Formula I
Formula-I
in presence of a base and solvent to obtain the crude compound of Formula-II; and
Formula-II
b) purifying the crude compound thus obtained by column chromatography.
The solvent used in step a) can be selected from any solvent suitable for completion of reaction, preferably, the solvent used in step a) can be selected from group comprising N-methylpyrrolidone, Dimethyl sulfoxide (DMSO) and Hexamethylphosphoramide (HMPA), Dimethyl formamide (DMF), Dimethyl acetamide (DMA), Tetrahydrofuran (THF)or a mixture thereof. More preferably, the solvent used in step a) is N-methylpyrrolidone (NMP).
The base used in step a) can be selected from any base suitable for completion of reaction, preferably, the base used in step a) can be selected from potassium carbonate, sodium carbonate, sodium ethoxide, potassium tert-butoxide, cesium carbonate, sodium hydroxide and potassium hydroxide. More preferably, the base used in step a) is potassium carbonate.

The dimer compound of Formula-II prepared by the process of the present invention is characterized by !H NMR, C13 NMR, IR and Mass Spectroscopy.
In preferred embodiment, the compound of Formula-II prepared as per the present invention can be used as a reference standard for identification and analysis of the dimer impurity in Loteprednol etabonate.
In one another embodiment, the present invention provides a process for preparation of Hydrocortisone related impurity of Formula III,
Formula-Ill
comprising the following steps:
a) reacting hydrocortisone of Formula-VIl
Formula-VII
with sodium metaperiodate in presence of suitable solvent to obtain compound of Formula-VIII;
Formula-VIH

b) reacting compound of Formula-VIII with ethyl chloroformate in presence of 4-dimethylaminopyridine (DMAP) to obtain a compound of Formula IX;
Formula-IX
c) reacting compound of Formula-IX with chloroidomethane in a suitable solvent
in presence of a base to get a solid compound; and
d) crystallizing the solid compound in ester solvent to obtain hydrocortisone
related impurity of Formula-Ill.
The solvent used in step a) can be selected from any solvent suitable for completionof reaction, preferably, the solvent used in step a) can be selected from tetrahydrofuran, ethanol, methanol, isopropanol, butanol, 1,4-dioxane and water or a mixture thereof. More preferably, the solvent used in step a) is tetrahyrofuran, methanol and water.
The step b) is carried out in presence of solvent selected from dichloromethane, chloroform and tetrahydrofuran. More preferably, the solvent used is dichloromethane.
The base used in step c) can be selected from any base suitable for completion of reaction, preferably, the base used in step c) can be selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and potassium hydroxide. More preferably, the base used in step c) is potassium carbonate. Moreover, step c) is carried out in presence of solvent selected from N-methyl pyrrolidone, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dimethyl acetamide, 1,4-dioxane and hexamethylphosphoramide.

The ester solvent used in step d) can be selected from any alkyl acetate with
carbon atoms C1-C6. The most preferred alkyl acetate used for crystallization of
hydrocortisone related impurity is ethyl acetate. *
In preferred embodiment, the compound of Formula-Ill prepared as per the present invention can be used as a reference standard for identification and analysis of the hydrocortisone related impurity in Loteprednol Etabonate.
In further embodiment, the present invention provides a method of preparation of compound of Formula-X, by methylation of compound of Formula-VI in presence of base and organic polar solvent,
Formula-X Formula-VI
The base used for preparation of compound of Formula-X is selected from the group comprising of potassium carbonate, sodium carbonate, cesium carbonate, sodium ethoxide, sodium hydroxide, potassium tert-butoxide and potassium hydroxide. More preferably, the base used in step c) is potassium carbonate. Moreover, said methylation is carried out in presence of solvent selected from N-methyl pyrrolidone, dimethyl formamide, dimethyl sulfoxide, tetrahydrofuran, dimethyl acetamide, 1,4-dioxane and hexamethylphosphoramide. More preferably, the solvent used is N-methyl pyrrolidone.
In preferred embodiment, the compound of Formula-X. prepared as per the present invention can be used as a reference standard for identification and analysis of the Loteprednol related impurity of Formula-X in Loteprednol Etabonate.

/
In another preferred embodiment, the present invention provides an isolated compound of Formula II.
In furthermore embodiment, the present invention provides a method for treatment of iritis, allergic conjunctivitis by administration of dosage form comprising Loteprednol Etabonate prepared by the process of the present invention.
In yet another embodiment, the present invention provides a composition
comprising pure LoteprednolEtabonate and pharmaceutically acceptable
excipients wherein the pure Loteprednol Etabonate is substantially free of
impurities of Formula-II, III and X.
The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
EXAMPLES:
Example 1: To a solution of Prednisolone (100 g) in tetrahydrofuran (800 ml), and methanol (200 ml) aqueous solution of sodium metaperiodate (130.1 g) was added. The reaction mixture was stirred for 2 to 3 hours, and then concentrated to remove the solvents. The organic solid material thus obtained was filtered out and dried under vacuum at 50°C. The compound of Formula V was obtained in approximately 97.8% (94.0 g) yield and 99.5% purity (HPLC).
Example 2: To a cold solution of Compound V (94 g) in dichloromethane (752 ml) was added ethylchloroformate (32.24 g) and 4-dimethylaminopyridine (36.5 g). The reaction mixture was stirred for 3 hours at room temperature. The reaction mass was quenched with aq. HCl solution and organic layer was washed with water. The organic layer was concentrated under vacuum and material thus obtained was dried at 50°C. The compound of Formula VI was obtained in approximately 98.5% (111.8 g) yield and 97.7 % purity (HPLC).

Example 3: To a cold solution of chloroiodomethane (187.4 g), potassium carbonate (44.02 g) and N-methylpyrrolidinone (1110 ml) was added 111.0 g of compound of Formula VI. The reaction mass was stirred for 15 hours at 0°C to 25°C and then quenched with cold water. The solid material thus obtained was filtered and the wet material was dissolved in dichloromethane. The organic layer was washed with aq. NaHCCb solution and water. The organic layer was concentrated under vacuum at 40°C to get crude Loteprednol Etabonate that was obtained in approximately 110 g. Purity: 92.2 % (HPLC) Dimer Impurity: 4 % Hydrocortisone related impurity: 0.51 %
Example 4: Crude Loteprednol Etabonate (110 g) and acetonitrile were heated to reflux and maintained till complete dissolution of material. Then allowed to cool to room temperature and stirred for 15 hours. The solid material thus obtained was filtered and dried to get 80.6 g of pure crystalline Loteprednol. Purity: 99.87 % (HPLC) Dimer Impurity: 0.03 % Hydrocortisone related impurity: 0.06 % Yield: 65 %
Example 5: Preparation of Dimer compound of Formula-II
Compound of Formula-VI (13,42 g) and Loteprednol Etabonate (10 g) were charged in RBF. N-methylpyrrolidinone (200 ml) and potassium carbonate (3.5 g) were added in the RBF. The reaction mixture was stirred for 48 hours at room temperature and then reaction mass was quenched in ice cold water. The solid material was filtered and purified by column chromatography. The pure fraction was concentrated to get off white powder of dimer compound of Formula-II. Purity: 96.1% (HPLC) Yield: 82.8%

»H NMR (CDCb): 87.19-7.16 (d, 2H), 6.24-6.21 (dd, 2H), 5.98 (S, 2H), 5.83 (S, 2H), 4.43 (S, 2H), 4.42-4.10 (q, 4H), 2.94-2.87 (M, 2H), 2.58-2.50 (M, 2H), 2.33-2.29 (M, 2H), 2.17-2.06 (M, 5H), 2.02-2.00 (M, 1H), 1.97-1.88 (M, 3H), 1.83-1.72 (M, 4H), 1.64-1.57 (M, 3H), 1.52-1.44 (M, 2H), 1.42 (S, 6H), 1.30-1.26 (t, 6H), 1.15-1.10 (M, 4H), 1.03 (S, 6H). Mass Spectroscopy: M+l = 849.49
Example-6: Preparation of Hydrocortisone related impurity of Formula-Ill
a) Preparation of compound of Formula- VIII: To a solution of hydrocortisone (15 g) in tetrahydrofuran (120 ml), and methanol (30 ml), aqueous solution of sodium metaperiodate (19.41 g) was added. The reaction mixture was stirred for 2 to 3 hours, then concentrated to remove the solvents. The solid material was filtered out and dried under vacuum at 50°C. The compound of Formula VIII was obtained in approximately 98% (16.5 g) yield and 98.7% purity (HPLC).
b) Preparation of compound of Formula-IX: To a cold solution of Compound
VIII (16.5 g) in dichloromethane (165 ml) was added ethylchloroformate (5.63 g)
and 4-dimethylaminopyridine (6.3 g). The reaction mixture was stirred for 3 hours
at room temperature. The reaction mass was quenched with aq. HC1 solution and
organic layer was washed with water. The organic layer was concentrated under
vacuum and material thus obtained was dried at 50°C. The compound of Formula
IX was obtained in approximately 98.9% (19.7 g) yield and 96.7 % purity
(HPLC).
c) Preparation of compound of Formula-IH: To a cold solution of
chloroiodomethane (33 g), potassium carbonate (7.7 g) and N-
methylpyrrolidinone (196 ml) was added 19.6 g of compound of Formula IX. The
reaction mass was stirred for 15 hours at 0°C to 25°C and then quenched with cold
water. The solid material thus obtained was filtered and the wet material was
dissolved in dichloromethane. The organic layer was washed with aq. NaHCCb
solution and water. The organic layer was concentrated under vacuum at 40°C to
get crude compound III in approximately 91.7 %(20.0 g) yield which was then

crystallized in ethyl acetate to get pure material (17 g) with 99.68% purity (HPLC).
'H NMR (CDCb): 5 5.85-5.83 (d, 1H), 5.65-5.63 (m, 2H), 4.45-4.44 (t, 1H), 4.17-4.11 (q, 2H), 2.96-2.89 (m, 1H), 2.50-2.41 (m, 2H), 2.36-2.30 (m, 1H), 2.24-2.19 (m, 1H), 2.18-2.12 (m, 1H), 2.10-2.03 (m, 2H), 2.08-1.89 (m, 2H), 1.86-1.78 (m, 2H), 1.76-1.70 (m, 1H), 1.67-1.64 (m, 1H), 1.48-1.43 (m, 1H), 1.41 (s, 3H), 1.29-1.25 (t, 3H), 1.1-1.05 (m, 2H), 1.02 (s, 3H). Mass Spectroscopy: M+l= 470.2
Example-7: Preparation of Loteprednol Impurity of Formula-X:
To a solution of compound of Formula-VI (20.0 g) in N-methyl pyrrolidone (200 ml) was added potassium carbonate (9.9 lg). Cooled the solution to 0-5°C and added iodomethane (8.15g). The reaction mixture so obtained was stirred at room temperature for 3 to 4 hours. After completion of reaction, quenched the reaction mass with water and extracted the compound in ethyl acetate. Concentrated the organic layer to obtain crude compound. Added water (400ml) to the crude compound and stirred at room temperature for 3-4 hrs. Filtered the solid and dried to get another lot of crude mass which is then crystallized in acetonitrile to get pure compound of Formula-X. The compound of Formula X was obtained in approximately 70.1% (14.5 g) yield and 99.69% purity (HPLC). 'H NMR (DMSO): 8 7.31-7.29 (d, 1H), 6.17-6.14 (dd, 1H), 5.91 (s, 1H), 4.78-4.77 (d, 1H), 4.29-4.28 (t, 1H), 4.08-4.02 (q, 2H), 3.63 (s, 3H), 2.78-2.71 (m, 1H), 2.56-2.51 (m, 1H), 2.31-2.26 (m, 1H), 2.10-2.00 (m, 2H), 1.86-1.78 (m, 1H), 1.77-1.71 (m, 2H), 1.67-1.63 (m, 1H), 1.51-1.40 (m, 2H), 1.38 (s, 3H), 1.18-1.15 (t, 3H), 1.08-0.93 (m, 2H), and 0.91 (s, 3H).
IR: 3349.64 cm'1, 2934.7cm"1, 1747.39 cm"1, 1655.04 cm"1, 1613.49 .cm"1, 1600.92 cm"1, 1372.34 cm'1, 1293.40 cm"1, 1269.34cm"1, 1245.10 cm"1, 1072.25 cm"1, 886.29 cm"1, 793.87 cm"1, and 481.65 cm"1. Mass Spectroscopy: M+l= 433

We-Claim:
1. A process for preparation of Loteprednol Etabonate of Formula-I;
Formula-I
comprising the steps of:
a) reacting Prednisolone of Formula-IV
Formula-IV
with sodium metaperiodate in presence of suitable solvent to obtain a compound of Formula-V;
Formula-V
b) reacting compound of Formula-V with ethyl chloroformate in presence of 4-dimethylaminopyridine (DMAP) to obtain a compound of Formula-VI; and
Formula-VI

c) reacting compound of Formula-VI with chloroiodomethane in N-methyl pyrrolidone in presence of a base to obtain crude Loteprednol Etabonate.
2. The process as claimed in claim 1, wherein said process further comprises of purifying the crude Loteprednol Etabonate obtained in step c) by crystallizing in acetonitrile to obtain pure Loteprednol Etabonate of Formula-I.
3. The process as claimed in claim 2, wherein said process of crystallizing crude Loteprednol Etabonate comprises the steps of:

a) dissolving crude Loteprednol Etabonate in acetonitrile under heating;
b) allowing the solution to cool down to room temperature; and
c) isolating the crystalline pure Loteprednol Etabonate of Formula-I.
4. The process as claimed in claims 2 and 3, wherein said pure Loteprednol
Etabonate is substantially free of impurities of Formula-II, Formula-Ill and
Formula-X
Formula-II

Formula-Ill

>

Formula-X
5. A process of preparation of ^impurity of Formula II, wherein said process
comprising the steps of:
a) reacting a compound of Formula-VI
FormuIa-VI
with Loteprednol Etabonate of Formula I
Formula-I
in presence of a base and solvent to obtain the crude compound of Formula-II; and
Formula-II
b) purifying the crude compound thus obtained by column chromatography.

6. The process as claimed in claim 5, wherein said solvent used in step a) is selected from group comprising of N-methylpyrrolidone, Dimethyl sulfoxide (DMSO), Hexamethylphosphoramide (HMPA), Dimethyl formamide (DMF), tetrahydrofuran (THF), Dimethyl acetamide (DMA) or a mixture thereof; and wherein said base used in step a) is selected from potassium carbonate, sodium carbonate, sodium ethoxide, potassium t-butoxide, cesium carbonate, sodium hydroxide and potassium hydroxide.
7. A process of preparation of impurity of Formula-Ill, wherein said process comprising the steps of:
Formula-HI
a) reacting hydrocortisone of Formula VII
Formula-VII
with sodium metaperiodatein presence of suitable solvent to obtain compound of Formula-VIII;
Formula-VHI

b) reacting compound of Formula VIII with ethyl chloroformate in presence of 4-dimethyl amino pyridine (DMAP) to obtain a compound of Formula IX;
Formula-IX
c) reacting compound of Formula-IX with chloroidomethane in a suitable solvent in presence of a base to get a solid compound; and
d) crystallizing the solid compound in ester solvent to obtain hydrocortisone related impurity of Formula-Ill.

8. The process as claimed in claim 8, wherein said ester solvent used in step d) is selected from C1-C6 alkyl ester.
9. Substantially pure Loteprednol Etabonate comprising less than about 0.5% of dimer impurity of Formula-II,
Formula-II
10. An isolated compound of Formula-II

Formula-II