DESC:
FIELD OF THE INVENTION
The present invention relates to process for preparation of 17-monoesters of 17a, 21-dihydroxy steroids. Further, the present invention also relates to process for the preparation of crystalline hydrocortisone valerate form L and an amorphous hydrocortisone valerate

BACKGROUND OF THE INVENTION
The corticosteroids constitute a class of primarily synthetic steroids used topically as anti-inflammatory and antipruritic agents. Hydrocortisone valerate and hydrocortisone butyrate are important synthetic corticosteroids for topical dermatologic use. These are available as cream, ointment and topical solution.

Hydrocortisone valerate is chemically known as 11,21-dihydroxy-17-[(1-oxopentyl)oxy]-(11ß)-pregn-4-ene-3,20-dione having chemical structure of formula I.

Formula I

Hydrocortisone butyrate is chemically known as 11ß,17,21-Trihydroxypregn-4-ene-3,20-dione 17-butyrate having chemical structure of formula II.

Formula II
The US patent number US 3152154 describe the process for preparation of 17-monoesters of 17a, 21-dihydroxy steroids of formula III by hydrolysis of the corresponding 17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroids of formula IV in the presence of aqueous acid as shown below.

It mentions that aqueous acid may be mineral acid such as hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, perchloric acid or organic acid such as formic acid, acetic acid, propionic acid, chloroacetic acid, oxalic acid and malonic acid.

SUMMARY OF THE INVENTION
The present invention relates to a process for preparation of 17-monoesters of 17a, 21-dihydroxy steroids of formula III
III
Wherein,
R is lower alkyl, arylalkyl, phenyl, ß-carboxyethyl or ß-carbomethoxethyl;
comprising
hydrolysis of the corresponding 17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroids of formula IV
IV
wherein
R is as defined above and
R1 is lower alkyl;
in the presence of an inorganic or organic acidic salt in a suitable solvent.
Further, the present invention also relates to process for the preparation of crystalline hydrocortisone valerate form L and an amorphous hydrocortisone valerate

BRIEF DESCRIPTION OF THE FIGURES
Figure I- X-ray diffraction spectrum of crystalline hydrocortisone valerate Form L.
Figure II- DSC thermogram of crystalline hydrocortisone valerate Form L.
Figure III- X-ray diffraction spectrum of amorphous hydrocortisone valerate.

DETAILED DESCRIPTION OF THE INVENTION
The term "lower alkyl" encompasses linear or branched alkyl having 1 to 9 carbon atoms, preferably 1 to 6 carbon atoms. Examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl.

The compound of formula IV can be obtained as described in the examples or method known in the art such as US patent number US 3147249.

The suitable solvent can be selected from water, alcohol, aromatic hydrocarbons (such as toluene), ethers, cycloalkanes, halogenated alkane and mixtures thereof.

Alcohol may be selected from methanol ethanol, n-propanol, isopropanol, cyclohexanol, benzyl alcohol and mixtures thereof.

The suitable solvent may be aqueous alcohol; preferably aqueous methanol or aqueous ethanol. The aqueous alcohol is 50- 99 % w/w alcohol in water.

The inorganic acidic salt can be selected from ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium phosphate, aluminum chloride, aluminum bromide, aluminum perchlorate, aluminum hypochlorite, ferric chloride, ferric bromide, ferric iodide, ferric perchlorate and sodium dihydrogen phosphate and the like.

The organic acidic salt can be selected from ammonium acetate, ammonium propionate, ammonium citrate, ammonium oxalate, ammonium formate, ammonium benzoate, ammonium valerate and the like.

The amount of inorganic or organic acidic salts used is approximately 1.0 to 10.0 molar equivalents; preferably 2 to 5 molar equivalents with respect to compound of formula IV.

The reaction temperature is usually 0° C to reflux temperature preferably 30-60 °C.

The product obtained according to the present process may be purified by heating the crude product in a suitable solvent, cooling the mixture and isolating the product.

The solvent used may be C1-C4 alcohol is selected from methanol ethanol, n-propanol or isopropanol, esters is selected from ethyl acetate, alkanes is selected from pentane, hexane, cyclohexane, ketones is selected from acetone, ethylmethyl ketone.

The present invention further relates to a process for the preparation of 17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroid of formula IVa
IVa
Wherein,
R is n-propyl or n-butyl and R1 is lower alkyl;
comprising
reacting hydrocortisone with compound of formula V
V
Wherein,
R and R1 are defined as above;
in the absence of solvent.

The present invention also relates to a process for the preparation of 17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroid of formula IVa
IVa
Wherein,
R is n-propyl or n-butyl and R1 is lower alkyl;
comprising
reacting hydrocortisone with compound of formula V
V
Wherein,
R and R1 are defined as above;
in 1,4-dioxane as a solvent.

The compound of formula V used is approximately 1.0 to 10.0 molar equivalents with respect to compound of formula IVa.

The reaction temperature is usually 0° C to reflux temperature preferably 25-60 °C.

The present invention also relates to a process for the preparation of hydrocortisone valerate compound of formula I or compound of formula II

Formula I Formula II

Comprising hydrolysis of the
17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroid of formula IVa

IVa
wherein
R is n-propyl or n-butyl and R1 is lower alkyl;
in the presence of an inorganic or organic acidic salt in a suitable solvent.

In one embodiment, the present invention an inorganic acid salt is selected from ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium phosphate, aluminum chloride, aluminum bromide, aluminum perchlorate, aluminum hypochlorite, ferric chloride, ferric bromide, ferric iodide, ferric perchlorate and sodium dihydrogen phosphate and the like
In another emdodiment, the present invention organic acid salt is selected from ammonium acetate, ammonium propionate, ammonium citrate, ammonium oxalate, ammonium formate, ammonium benzoate and ammonium valerate.

Yet another emdodiment, the present invention solvent is selected from C1-C4 alcohol selected from methanol ethanol, n-propanol or isopropanol, esters solvent is selected from ethyl acetate, alkanes is selected from pentane, hexane, cyclohexane, ketones solvent is selected from acetone, ethyl methyl ketone and mixture thereof.

In one embodiment, the present invention provides crystalline hydrocortisone valerate Form L which is characterized by X-ray diffraction spectrum comprising peaks at 8.13, 12.7, 14.6, 15.2 and 17.2 ± 0.2 degree 2?.

In another embodiment, the present invention provides crystalline hydrocortisone valerate Form L which is characterized by X-ray diffraction spectrum substantially as shown in figure I.

In another embodiment, the present invention provides crystalline hydrocortisone valerate Form L which is characterized by endotherm peak at about 162 °C in differential scanning calorimetry (DSC).

In another embodiment, the present invention provides crystalline hydrocortisone valerate Form L which is characterized by DSC thermogram substantially as shown in figure II.

In another embodiment, the present invention provides a process for the preparation of hydrocortisone valerate of Form L is characterized by the Powder X-ray diffraction having characteristic peaks at about 8.13, 12.7, 14.6, 15.2 and 17.2 ± 0.2 °2? comprising the steps of:
a) dissolving hydrocortisone valerate in an alcoholic solvent at a temperature 40-60°C
b) cooling the reaction mass to room temperature, and
c) isolating the crystalline hydrocortisone valerate of Form L

In another embodiment, the present invention dissolving hydrocortisone valerate in an alcoholic solvent at a temperature 40-60°C, stirred the mass for 30 min, cooling the reaction mass to room temperature at 25 to 35°C, isolating crystalline hydrocortisone valerate of Form L.

The alcoholic solvent solvent selected from methanol, ethanol, n-propanol or isopropanol, most preferably n-propanol, esters solvent is selected from ethyl acetate, alkanes is selected from pentane, hexane, cyclohexane, ketones solvent is selected from acetone, ethyl methyl ketone and mixture thereof.

In another embodiment, the present invention provides amorphous hydrocortisone valerate which is characterized by X-ray diffraction spectrum substantially as shown in figure III.

In yet another embodiment, the present invention provides a process for preparation of amorphous hydrocortisone valerate comprising dissolving hydrocortisone valerate in a suitable solvent and removing the solvent by thin film drying (rotay evaparation, agitated thin film drying) or spray drying.

The solvent is selected from chlorinated hydrocarbons such as chloroform, dichloromethane, trichloromethane, carbon tetrachloride.

The product such as hydrocortisone valerate (Formula III wherein R = n-butyl) or hydrocortisone butyrate (Formula III wherein R = n-propyl) obtained according to the present invention may be further micronized by suitable techniques known in the art such as milling or grinding.

The product such as hydrocortisone valerate or hydrocortisone butyrate obtained according to the present invention may be further used in the preparation of pharmaceutical compositions such as creams, ointments, topical solutions. The particle size of hydrocortisone valerate or hydrocortisone butyrate required for the preparation of pharmaceutical compositions may be obtained by the suitable techniques known in the art.

The present invention is described in the following examples, however it should be noted that the scope of present invention is not limited by the examples.

Experimental
Example 1
Preparation of 17a, 21-(1’-methoxy)-1-pentylidenedioxy-1,4-pregnadiene-11ß-ol-3, 20-dione.
A mixture of hydrocortisone (5 g, 0.0138 mol), trimethyl orthovalerate (20 ml) and p-toluene sulphonic acid (0.06 g, 0.00034 mol) was heated at 90 °C for 24 hours. The mixture was cooled to 0-5 °C. The product was filtered, washed with methanol (10 ml) and dried under vacuum at 45°C.
Yield:
HPLC purity: 97.72 %

Example 2
Preparation of 17a, 21-(1’-methoxy)-1-pentylidenedioxy-1,4-pregnadiene-11ß-ol-3, 20-dione.
A mixture of hydrocortisone (30 g, 0.082 mol), trimethyl orthovalerate (82.8 g, 0.51 mol) and 2-naphthalene sulphonic acid (0.096 g, 0.00046 mol) in 1,4-dioxane (300 ml) was stirred at room temperature for 24 hours. The solvent was distilled off, methanol (300 ml) was added to the residue anf stirred for 30 min. The solid was filtered, washed with methanol (60 ml) and dried under vacuum at 45 °C.
Yield: 31 g
HPLC purity: 95.77 %

Example 3
Preparation of hydrocortisone valerate
17a, 21-(1’-methoxy)-1-pentylidenedioxy-1,4-pregnadiene-11ß-ol-3, 20-dione (97 g, 0.21 mol) was added to ethanol (970 ml). To this mixture, ammonium chloride (33.48 g, 0.63 mol) and water (97 ml) were added. The mixture was heated at 45-50 °C for 5 hours. Water (970 ml) was added and mixture was stirred for 2 hours. The product was filtered and dried under reduced pressure at 45°C.
Yield: 77.4 g
HPLC purity: 97.78 %
Hydrocortisone 21-valerate impurity = 1.61 %
Hydrocortisone = 0.19 %

Example 4
Preparation of hydrocortisone valerate
17a, 21-(1’-methoxy)-1-pentylidenedioxy-1,4-pregnadiene-11ß-ol-3, 20-dione (25 g, 0.054 mol) was added to methanol (375 ml). A solution of ammonium chloride (8.7 g, 0.16 mol) in water (25 ml) was added. The mixture was heated at 45-50 °C for 23 hours. Water (250 ml) was added and mixture was stirred for one hour. The product was filtered and dried under reduced pressure at 45°C.
Yield: 18.9 g
HPLC purity: 97.98 %
Hydrocortisone 21-valerate impurity = 1.13 %
Hydrocortisone = 0.4 %

Example 5
Preparation of crystalline hydrocortisone valerate Form L
Hydrocortisone valerate (59 g, 0.13 mol) was dissolved in n-propanol (295 ml) at 60-65 °C. The mixture was cooled to room temperature and the solid was filtered, washed with n-propanol (59 ml) and dried under reduced pressure at 45°C.
Yield: 44.1 g
HPLC purity: 99.75 %
Hydrocortisone 21-valerate impurity = 0.04 %
Hydrocortisone = 0.05 %

Example 6
Preparation of amorphous hydrocortisone valerate
Hydrocortisone valerate (2 g) was dissolved in dichloromethane (10 ml). The solvent was distilled of under reduced pressure to get amorphous hydrocortisone valerate.
Yield: 1.9 g
,CLAIMS:Claim 1. A process for preparation of 17-monoesters of 17a, 21-dihydroxy steroids of formula III

III
Wherein;
R is lower alkyl, arylalkyl, phenyl, ß-carboxyethyl or ß-carbomethoxethyl;
Comprising;
hydrolysis of the corresponding 17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroids of formula IV

IV
Wherein is as defined above and R1 is lower alkyl;
in the presence of an inorganic or organic acidic salt in a suitable solvent.

Claim 2. The process as claimed in claim 1 wherein the inorganic acidic salt is selected from ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium phosphate; organic acidic salt is selected from ammonium acetate, ammonium propionate, ammonium citrate, ammonium oxalate, ammonium formate, ammonium benzoate, ammonium valerate and mixture thereof.

Claim 3. The process as claimed in claim 1 wherein the suitable solvent is selected from water, alcohol is selected from methanol ethanol, n-propanol, isopropanol and mixtures thereof.

Claim 4. A process for preparation of hydrocortisone valerate compound of formula I or hydrocortisone butyrate of formula II

Formula I Formula II

Comprising; hydrolysis of the
17a, 21-(1’-alkoxy)-1-substituted methylenedioxy steroid of formula IVa
IVa
Wherein;R is n-propyl or n-butyl and R1 is lower alkyl;
in the presence of an inorganic or organic acidic salt in a suitable solvent.

Claim 5. The process as claimed in claim 4 wherein the inorganic acidic salt is selected from ammonium chloride, ammonium bromide, ammonium iodide, ammonium nitrate, ammonium phosphate and mixture thereof.

Claim 6. The process as claimed in claim 4 wherein the organic acidic salt is selected from ammonium acetate, ammonium propionate, ammonium citrate, ammonium oxalate, ammonium formate, ammonium benzoate, ammonium valerate and mixture thereof.

Claim 7. The process as claimed in claim 4 wherein the suitable solvent is selected from water, methanol, ethanol, n-propanol, isopropanol and mixtures thereof.

Claim 8. A process for the preparation of hydrocortisone valerate of Form L is characterized by the Powder X-ray diffraction having characteristic peaks at about 8.13, 12.7, 14.6, 15.2 and 17.2 ± 0.2 °2? comprising the steps of:
a) dissolving hydrocortisone valerate in an alcoholic solvent at a temperature 40-60°C
b) cooling the reaction mass to room temperature, and
c) isolating the hydrocortisone valerate of Form L

Claim 9.The process according to claim 8, wherein alcoholic solvent is selected from methanol, ethanol, n-propanol, isopropanol or mixture thereof.

Claim 10. The process according to claim 9, wherein alcoholic solvent is n-propanol.