Claims:1. A process for purification of Methylprednisolone Aceponate comprising;
a) Dissolving crude Methylprednisolone Aceponate in a mixture of alcohol and chlorinated hydrocarbon solvents;
b) Distilling the solvents to obtain solid mass;
c) Adding alcohol and ether solvents to the solid mass; and
d) Isolating the pure Methylprednisolone Aceponate product.
2. The process according to claim 1, wherein the alcohol solvent is selected from the group consisting of methanol, ethanol, n-propanol, isopropanol, n-butanol, iso butanol and tertiary butanol.
3. The process according to claim 2, wherein the alcohol solvent is methanol.
5. The process according to claim 1, wherein the hydrocarbon solvent is selected from the group consisting of methylene dichloride, ethylene dichloride, chloroform and carbon tetrachloride.
6. The process according to claim 5, wherein the hydrocarbon solvent is methylene dichloride.
7. The process according to claim 1, wherein the ether solvent is selected from the group consisting of Tetrahydrfuran, dioxane, ethyl ether, methyl t-butyl ether, 1,2-dimethoxyethane, methyl ether and diisopropyl ether.
8. The process according to claim 7, wherein the ether solvent is diisopropyl ether.
9. The process according to claim 1, wherein the process comprises a step of treating the step a) with charcoal prior to distillation.
10. The process according to claim 1, wherein the isolation of the pure Methylprednisolone Aceponate in step d) is carried out by cooling the reaction of mass of step c) to a temperature of 0 to 5°C.
11. The process according to claim 1, wherein, the crude Methylprednisolone Aceponate is prepared by a process comprising;
a) reacting 6a-methylprednisolone with Triethyl orthoformate in presence of Pyridinium p-toluenesulphonate at a temperature of -2°C to -5°C in Dimethylformamide to obtain cyclic derivative of 6a-methylprednisolone;
b) hydrolysing the cyclic derivative of 6a-methylprednisolone using 2N sulphuric acid to obtain 6a-methylprednisolone-17-propionate; and
c) reacting 6a-methylprednisolone-17-propionate with acetic anhydride in presence of Triethyl amine base in methylene dichloride to obtain Methylprednisolone Aceponate crude and
d) isolating the Methylprednisolone Aceponate by dissolving Methylprednisolone Aceponate in Methanol to get clear solution followed addition of demineralized water to cooled clear solution to obtain the Methylprednisolone Aceponate crude.
, Description:Field of invention:
The present invention relates to economical and commercial manufacturing process of Methylprednisolone Aceponate and its purification.

Background of the invention:
Methylprednisolone Aceponate (MPA; CAS: 86401-95-8) is chemically known as Pregna-1,4-diene-3,20-dione, 21-(acetyloxy)-11-hydroxy-6-methyl-17-(1-oxopropoxy)-, (6a,11ß) and its structural formula is as follows:

Methylprednisolone Aceponate:
Methylprednisolone Aceponate is a Glucocorticosteroid used for the treatment of skin diseases particularly for eczema. Methylprednisolone Aceponate along with other 6-Methylprednisolone derivatives was first disclosed in US4587236 by Schering Aktiengesellschaft, Germany. It was reported in this patent that Methylprednisolone was reacted with Triethyl orthopropionate in mixture of Dimethylformamide and benzene solvent in presence of Pyridinium-p-toluene sulphonate catalyst to obtain cyclic derivative. The cyclic derivative was hydrolysed with aqueous acetic acid to obtain Methylprednisolone-17-propionate which was purified using column chromatography and then was subjected to further reaction with acetic anhydride in presence of pyridine base to obtain Methylprednisolone Aceponate crude. The crude Methylprednisolone Aceponate was purified using acetone/hexane.
The process mentioned in this patent suffers from a main drawback of column chromatography involved in the purification step of the intermediate. Column chromatography for purification is not industrially/commercially feasible.

Another patent, US4567172, filed by Ohta Seiyaku, Japan reported the preparation of Methylprednisolone Aceponate, wherein 6a-Methylprednisolone was reacted with Triethyl orthopropionate in Dimethylformamide solvent in presence of p-toluene sulphonic acid catalyst to obtain cyclic derivative. The cyclic derivative, 17a-methylprednisolone 17a, 21-ethyl orthoprionate, thus obtained was crystallized from ether solvent and further the cyclic derivative was hydrolysed with 2N oxalic acid in methanol solvent to obtain 11ß,21-dihydroxy-6a-methyl-17a-propinoyloxy-1,4-pregnadiene-3,20-diene, which was purified by subjecting the same to preparative thin layer chromatography on silica gel. The product was further subjected to acylation reaction with acetic anhydride in presence of Triethylamine base to obtain Methylprednisolone Aceponate crude. The crude Methylprednisolone Aceponate was purified by preparative thin layer chromatography and then recrystallized from ether.

The process mentioned in this patent also involves lengthy work up procedure and industrially inapplicable purification method- preparative thin layer chromatography.

Another patent application, CN1931870, also reported a process for preparation of Methylprednisolone Aceponate wherein, Methylprednisolone was reacted with Triethyl orthopropionate in Dimethylformamide solvent using p-toluene sulphonic acid catalyst to obtain cyclic derivative. The cyclic derivative was isolated by adding ethyl acetate and sodium bicarbonate solution followed by separation of layers. The organic layer was concentrated and then methanol and water were added to the concentrated mass and isolated the cyclic derivative. The cyclic derivative was hydrolysed using G-type silica gel in methanol at reflux to obtain Methylprednisolone-17-propionate which was further reacted with acetic anhydride in presence of Triethylamine base in methylene dichloride solvent to obtain Methylprednisolone Aceponate.

The process mentioned in this patent suffers lengthy work up procedures for isolation of the cyclic derivative and use of G-type silica gel for hydrolysis. The type of silica gel G is also not defined. When we repeated the preparation of the Methylprednisolone Aceponate using the process of CN1931870, desired purity of Methylprednisolone Aceponate was not obtained and meeting the requirement of stringent impurity profile at final API stage is difficult and critical.

Yet another Chinese patent application, CN104974208, reported purification of Methylprednisolone Aceponate from mixture of acetone and n-hexane solvents in 1:0.5 to 1.5 ratios. After purification, the obtained Methylprednisolone Aceponate was subjected for one more purification to obtain purified Methylprednisolone Aceponate having purity of 99.7% purity and 0.11 % of single impurity.

The purification process in this patent application suffers repeated purifications which lead to loss of time, productivity and loss of yield of Methylprednisolone Aceponate.

Therefore, there is very much necessity in the art to develop an improved industrially feasible and economically viable process to prepare Methylprednisolone Aceponate having purity conforming to the stringent impurity profile (ICH guidelines) specification by overcoming the problems of the prior art. The present invention addresses the need by providing cost effective method for the production of Methylprednisolone Aceponate by employing readily available cheaper solvents thereby eliminating the need for chromatographic purification methods unlike the prior arts.

Summary of the invention:
Accordingly, in one aspect, the present invention provides a simple process for manufacturing of Methylprednisolone Aceponate crude avoiding use of solvents like Benzene, Ether and use of column chromatography or preparative column chromatography for purification.

In another aspect, the present invention provides a novel purification method for Methylprednisolone Aceponate by dissolving crude Methylprednisolone Aceponate in mixture of alcohol and chlorinated hydrocarbons solvents followed by precipitating from mixture of alcohol and ether solvents. The purification process according to the present invention gives pure Methylprednisolone Aceponate product which is in compliance as per the stringent impurity profile (ICH guidelines) specification.
Accordingly, present invention provides a process for purification of Methylprednisolone Aceponate which comprises (a) dissolving the crude Methylprednisolone Aceponate in a mixture of alcohol and chlorinated hydrocarbon solvents followed by activated carbon treatment; (b) distilling the solvents to obtain solid mass, (c) adding alcohol and ether solvents to the mass followed by stirring the mass; and (d) isolating the pure Methylprednisolone Aceponate product.
In one aspect, the invention provides a process for preparation of crude Methylprednisolone Aceponate which process comprises;
a) Reacting 6a-methylprednisolone with Triethyl orthoformate in presence of Pyridinium p-toluenesulphonate at a temperature of -2°C to -5°C in Dimethylformamide to obtain cyclic derivative of 6a-methylprednisolone;
b) Hydrolysing the cyclic derivative of 6a-methylprednisolone using 2N sulphuric acid to obtain 6a-methylprednisolone-17-propionate; and
c) Reacting 6a-methylprednisolone-17-propionate with acetic anhydride in presence of Triethyl amine base in methylene dichloride to obtain Methylprednisolone Aceponate and
d) Isolating the Methylprednisolone Aceponate crude.
In an aspect, the isolation of Methylprednisolone Aceponate comprise a step of dissolving Methylprednisolone Aceponate obtained from c) in Methanol to get clear solution followed by addition of demineralized water to cooled clear solution to obtain the crude Methylprednisolone Aceponate with a purity of above 98%.

In another aspect, the crude Methylprednisolone Aceponate thus obtained is dissolved in a mixture of methanol and methylene chloride. The obtained solution is treated with activated carbon followed by distillation of the filtrate to remove solvents. To the obtained mass added methanol and Isopropyl ether and isolated the pure Methylprednisolone Aceponate.

Detailed description of the invention:
Unless specified otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art, to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the invention, the preferred methods and materials are described. To describe the invention, certain terms are defined herein specifically as follows.

Unless stated to the contrary, any of the words "including," "includes," "comprising," and "comprises" mean "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. The term "consists essentially of” means excluding other materials that contribute to function.

Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth in the appended claims.

Accordingly, the present invention provides process for purification of Methylprednisolone Aceponate. The purification process comprises a) dissolving crude Methylprednisolone Aceponate in a mixture of alcohol and chlorinated hydrocarbon solvents followed by activated carbon treatment; b) distilling the solvents to obtain solid mass, c) adding alcohol and ether solvents to the mass followed by stirring the mass; and d) isolating the pure Methylprednisolone Aceponate product.

The alcohol solvents used for the dissolution of the crude Methylprednisolone Aceponate include methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol and tertiary butanol etc. However, the preferred solvent is methanol. The chlorinated hydrocarbons include methylene dichloride, ethylene dichloride, chloroform and carbon tetrachloride etc. However, the preferred solvent is methylene dichloride. Ether solvents include Tetrahydrfuran, 1, 4-dioxane, ethyl ether, methyl t-butyl ether, 1,2-dimethoxyethane, Dimethyl ether and Diisopropyl ether etc. However, the preferred solvent is diisopropyl ether.

According to the invention, the crude Methylprednisolone Aceponate is dissolved in a mixture of alcohol and chlorinated hydrocarbon solvents. Alternatively, the crude may be added in to alcohol followed by addition of chlorinated hydrocarbon solvent. The alcohol solvent may be used in 4 to 8 volumes of the crude Methylprednisolone Aceponate and chlorinated hydrocarbon solvents can be used in 2 to 6 volumes of the crude Methylprednisolone Aceponate. After treatment with charcoal, the solvents are distilled and then added mixture of alcohol and ether solvents. While the alcohol solvents can be used in 1 to 4 volumes of the precipitated solids; the ether solvent can be used in 1 to 4 volumes of the precipitated solids.

For example, the alcohol solvent may be used in the range of 4 mL/gm. to 8 mL/gm. of substrate, crude Methylprednisolone Aceponate. However, preferably about 3 mL alcohol per gm of Methylprednisolone Aceponate is used. Similarly the chlorinated solvent may be used in totality in the range of 2 mL/gm to 6 mL/gm of substrate, crude Methylprednisolone Aceponate. However, 3 mL/gm of Methylprednisolone Aceponate is preferably used.

After mixing the crude with solvents, reaction mass may be heated to reflux or may be stirred at ambient temperature to obtain clear solution. Activated carbon is added to the solution and the reaction mass is maintained for a period of half an hour. After completion of maintenance, the reaction mass is filtered on hyflow and the filtrate is subjected for distillation by heating under vacuum. Solvent is removed till some solids are precipitated. Then, further added about 1 mL/gm alcohol to the mass for stripping dichloromethane. To the solid mass added 1 mL./gm alcohol and 1 mL to 3 mL/gm Ether. However, 2 mL/gm ether is preferably added. After addition, reaction mass is maintained further for about an hour and then cooled the mass to 0-5°C and equilibrated the mass for about an hour and filtered. The obtained cake is washed with ether and dried in oven.

Accordingly, in a preferred embodiment, crude Methylprednisolone Aceponate is dissolved in a mixture of methanol and methylene dichloride. The obtained solution is treated with activated carbon followed by distillation of the filtrate to remove solvents completely. To the solid mass, methanol was added for stripping of the remaining Dichloromethane. To the obtained solid mass Methanol and Isopropyl ether are added and isolated the pure precipitated Methylprednisolone Aceponate.

In the purification process according to the invention, the pure Methylprednisolone Aceponate is precipitated at 0-5°C.
The purified Methylprednisolone Aceponate so obtained as per the invention is having more than 99.0 % purity by HPLC with less impurities and the product conforms to the stringent impurity profile (ICH guidelines) as per IHT specifications.

In another preferred embodiment, the Methylprednisolone Aceponate is prepared as per the process detailed below.

According to this process, 6a-methylprednisolone is dissolved in Dimethylformamide and the solution is reacted with Triethyl orthoformate in presence of Pyridinium p-toluenesulphonate (PPTS) at -2°C to -5°C to obtain cyclic derivative of 6a-methylprednisolone (6a-methylprednisolone 17a, 21-ethyl orthopropionate).

The cyclic derivative is hydrolysed with 2N sulphuric acid in presence of water to obtain 6a-methylprednisolone 17-propionate. After conversion, the product is isolated by usual procedures such as extraction with suitable solvent, such as methylene dichloride. The extract is concentrated under vacuum and distilled the methylene dichloride to isolate crude 6a-methylprednisolone-17-propionate. The crude 6a-methylprednisolone 17-propionate is crystallised using acetone solvent. Filtrate may be concentrated to recover the product as crop-2 and recycled to get 6a-methylprednisolone (starting material).

The obtained 6a-methylprednisolone-17-propionate is dissolved in methylene dichloride and reacted with acetic anhydride in presence of Triethyl amine base. Usually the reaction is conducted at ambient temperature for a period of one hour till showed absence of starting material. After completion of reaction, distilled the solvent, added methanol to residue, slowly cooled, diluted the solution with water to precipitate the product. The precipitate is filtered and washed with water dried in oven to obtain crude Methylprednisolone Aceponate having purity above 98%.

The route of synthesis of the preparation of Methylprednisolone Aceponate is represented in following scheme.

Stage-1: 6a-Methylprednisolone to 6a-Methylprednisolone-17-Propionate

Stage-2: 6a-Methylprednisolone-17-Propionate to Methylprednisolone Aceponate

Stage-3:
Methylprednisolone Aceponate Crude to Methylprednisolone Aceponate Pure

The following examples, which include preferred embodiments, intended to illustrate the practice of this invention. It is being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

EXAMPLES:

Example-1
Stage-1:6a-methylprednisolone to 6a-methylprednisolone 17a, 21-ethyl orthopropionate (cyclic compound) to 6a-methylprednisolone 17-propionate.
100 gms 6a-methylprednisolone (0.267 mole), 400 ml of Dimethylformamide were charged in four neck round bottom flask under nitrogen blanketing. Reaction mass was cooled to 20°±2°C., 125 ml. of Triethyl orthoformate (0.621mole) was added and reaction mass cooled to -2°C to -5°C. 15.0 gms Pyridinium p-toluenesulphonate was added and reaction mass stirred for 2 hrs. till TLC shows complete conversion of 6a-methylprednisolone to cyclic compound.
For hydrolysis of cyclic compound, added slowly 20.0 ml water and 15.0 ml 2N sulphuric acid. Reaction mass was stirred till complete conversion of cyclic compound to 6a-methylprednisolone 17-propionate. After completion of reaction, 90 ml water and 500 ml dichloromethane were added and stirred. Organic layer was separated from aqueous layer. Aqueous layer was again extracted with 100 ml dichloromethane. The obtained organic layers were combined, made neutral by water wash and distilled dichloromethane till solid mass obtained. 400 ml acetone was added, refluxed for 20-30 mins. Then cooled the reaction mass 0°C and stirred for 30 mins, filtered the product, washed with chilled acetone and dried.
Dry wt.:70.0 gms

Stage-2:6a-methylprednisolone 17-propionate to 6a-methylprednisolone 17-propionate-21-acetate.
Dissolved 70.0 gms of 6a-methylprednisolone 17-propionate in 700 ml dichloromethane, fed into round bottom flask and cooled the mass to 20°C. To the cooled reaction mass added 105 ml of acetic anhydride (0.755 mole) and 104 ml of Triethyl amine (0.510 mole). Maintained the reaction mass till TLC shows absence of starting material. Distilled the solvent till dry product obtained. 70 ml Methanol was added to the dry product obtained to get clear solution. Reaction mass was cooled and D.M. water was added slowly. Product filtered, washed with water and dried in oven.
Dry Wt.:72 gms.

Stage-3: Purification of 6a-methylprednisolone 17-propionate-21-acetate (Methylprednisolone Aceponate)
Methylprednisolone Aceponate crude (72.0 gms) was dissolved in mixture of Methanol (216 ml) and dichloromethane (216 ml). Activated carbon 10.0 gm added and stirred for 30-40 mins. Filtered and washed with mixture of Methanol and dichloromethane(72 ml+72 ml). Distilled the filtrate till solid mass obtained. Added 72 ml Methanol for stripping of Dichloromethane till solid mass obtained. Methanol (70 ml) and Isopropyl ether (140 ml) were added to the solid mass and stirred at temperature of 0° to 5°C. Filtered the mass, washed the cake with Isopropyl ether and dried in oven. Dry wt.:65 gms + 5.0 gms purified second crop. The product passes the test as per stringent impurity profile (IHT specification).

Reference example:
Purification of Methylprednisolone Aceponate using mixture of acetone and hexane was performed as per prior art, US 4587236 in which ratio of Acetone: hexane is not mentioned to compare with the present invention.

Methyl prednisolone Aceponate Crude 10.0 gms dissolved in 20 mL of acetone. To the acetone solution, added activated carbon (0.1 gm.), stirred for 30 min and filtered and washed with acetone. Distilled the filtrate till solid mass obtained. Added Acetone (20 ml). Cooled the reaction mass to 0±2°C, added 40 mL of n-hexane and stirred for 30-40 mins. at 0±2°C, filtered the product, washed with n-hexane and dried.

Dry wt.: 6.2 gms but impurities like, Methylprednisolone Acetate (Impurity-B) and Methylprednisolone 21-propionate (Impurity-D) are more than the specified limits i.e NMT: 0.5%.
Comparison chart of purification using Acetone+ n-Hexane of prior art vis-à-vis Methanol + Isopropyl Alcohol of the present invention is given below.

Purification using Acetone +Hexane on 10.0gms scale Purification using Methanol+MDC+IPE
on 100 gms scale
Limits in %(w/w) Rf values
Methyl prednisolone
Impurity-A NMT: 0.5(%w/w) 0.74 0.00 0.00
Methyl prednisolone
21-Acetate Impurity-B NMT: 0.5(%w/w) 0.83 0.56 0.37
Methyl prednisolone 17-propionate Impurity-C NMT: 0.5(%w/w) 0.85 0.14 0.12
Methyl prednisolone
21-propionate Impurity-D NMT: 0.5(%w/w) 0.8 0.60 0.38
Methyl prednisolone
17-propionate-11,21-diacetate
Impurity-E NMT:
0.5(%w/w) 1.16 0.00 0.00
Maximum unspecified NMT: 0.10(%w/w) NA 0.03 0.04
Total Impurities NMT:
2.0 (%w/w) NA 1.34 0.94
Purity % --- --- 98.66 99.06
Yield/output --- --- 6.2 gms 65.0 gms + 5.0 gms second crop of passing quality as per IHT specification.

Conclusion: Purification of Methylprednisolone Aceponate crude using solvents methanol and diisopropyl ether, gives better results (Quality and Quantity wise)

It is also observed that purification using mixture of acetone and hexane gave product which is failed as per IHT (In-house testing) specification.

Example-2
Stage-1:6a-methylprednisolone to 6a-methylprednisolone 17a,21-ethyl orthopropionate(cyclic compound) to 6a-methylprednisolone 17-propionate.
1000 gms 6a-methylprednisolone (0.267 mole), 4000 ml of Dimethylformamide were charged in four neck round bottom flask under nitrogen blanketing and made clear solution. The solution was cooled to 20°±2°C and added 1250 ml of Triethyl orthoformate (0.621mole) slowly. The reaction mass was cooled to -2°C to -5°C and added 150 gms Pyridinium-p-toluenesulphonate. Then maintained the reaction mass for 2 hrs till TLC shows complete conversion of 6a-methylprednisolone into cyclic compound.

To the cyclic compound, slowly added 200 ml water and 150 ml 2N sulphuric acid. Reaction mass was stirred till complete conversion of cyclic compound into 6a-methylprednisolone 17-propionate. After completion of reaction, water and dichloromethane were added and stirred. Organic layer was separated from aqueous layer. Aqueous layer again extracted with dichloromethane. The obtained organic layers are combined, made neutral by water wash and distilled the dichloromethane till solid mass obtained. To the reaction mass, added 4000 ml acetone, refluxed for 20-30 mins, cooled the mass, filtered, washed with chilled acetone and dried.
Dry wt.:700 gms

Stage-2:6a-methylprednisolone-17-propionate to 6a-methylprednisolone-17-propionate-21-acetate.
6a-methylprednisolone-17-propionate (700 gms) and 7000 ml dichloromethane are charged into round bottom flask and cooled the reaction mass to 20°C. To the cooled reaction mass, added 1050 ml acetic anhydride (0.755 mole) and 1040 ml of Triethyl amine (0.510 mole). Stirred the reaction mass till TLC shows absence of starting material. After completion of reaction, distilled solvent till dry product is obtained. To the concentrated mass, added 700 ml methanol to make clear solution. Reaction mass was cooled and D.M.water slowly. Product filtered, washed with water and dried in oven to obtain crude Methylprednisolone Aceponate.
Crude dry Wt.:710 gms.

Stage-3: Purification of 6a-methylprednisolone 17-propionate-21-acetate
Methylprednisolone Aceponate crude (710.0 gms) dissolved in mixture of methanol (2130 ml) and dichloromethane (2130 ml). To the solution, activated carbon (100.0 gm) was added and stirred for 30-40 mins. Filtered the activated carbon and washed with mixture methanol and dichloromethane. Distilled filtrate (solvent) till solid mass was obtained. To the solid mass added 7oo ml methanol and again distilled till solid mass obtained. To the solid mass methanol (700 ml) and diisopropyl ether (1400 ml) added and stirred at low temperature of 0° to 5°C. Filtered the mass to obtain cake, washed the cake with Isopropyl ether and dried in oven.
Dry wt.:650 gms + Second crop purified 50.0 gms. (Passes as per the required specification)
Purity: Above 99.0%
Since it is not pharmacopeial product:
In-house-Specification(IH): Impurities:
Methyl prednisolone: Impurity-A: NMT: 0.5%,
Methyl prednisolone 21-Acetate: Impurity-B: NMT: 0.5%,
Methyl prednisolone 17-propionate: Impurity-C: NMT: 0.5%,
Methyl prednisolone 21-propionate: Impurity- : NMT: 0.5%,
Methyl prednisolone17-propionate-11,21-diacetate: Impurity-E : NMT: 0.5%,
Unspecified Impurity: NMT: 0.1%,
Total Impurity: NMT: 2.0%