DESC:Field of the Invention
The present disclosure relates to a process for the preparation of a starting material and an intermediate in the synthesis of Glucocorticoids, and particularly to a process for the synthesis of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate from Prednisolone.

Background of the invention
21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I), is a key intermediate in the synthesis of many of potent anti-inflammatory steroids, having the structure:

The conventionally known processes discloses six step transformations of Prednisolone or similar analogues to 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate, that too with an unoptimized yield of 13% only. Further, it has been reported that the 17a-acylates are conveniently prepared through the 17a,21-ortho esters by heating the ortho ester with oxalic acid-water-methanol. However, a major weakness of this reported method is the formation of the isomeric 17-hydroxy-21-acylate during hydrolysis of 17,21-orthoacetate. It was also found that hydrolysis can be effected in a pH 3 phthalate buffer without acyl migration, even on prolonged exposure. Furthermore, it was observed that when prednisolone 17,21-diacetate, was heated for 8 hours with potassium acetate in dimethylformamide, prednisolone 17,21-diacetate was quantitatively converted into 16,17-anhydro- prednisolone 21-acetate, however with the product of lesser yield.

In one of the known processes, the synthesis of 16-carboxylate ester was disclosed and it was observed that synthesis of 16-carboxylate ester was possible using the key intermediates, 16,17-unsaturated corticosteroids. Further, acylation of 17a-OH involves the synthesis of 17a,21-orthoester, which on hydrolysis yields the desired 17a-acetate, in addition to some 21-acetate side product. However, with these aforesaid processes, the deacylation of 17a-OH is affected due to heating at high temperature in dimethylformamide solution with potassium acetate (KOAc).

Furthermore, it is known that the synthesis of corticosteroids requires functionalization of the C-9 and C-11 positions of the steroid molecule. The functionality is generally introduced via 9, 11 steroid intermediates. Methods for preparing steroids having a 9,11 double bond are known in the art. For example, an 11-hydroxy steroid can be converted to the corresponding mesylate (by treating with mesyl chloride) which is transformed into a 9,11 steroid via an elimination reaction. However, the prior art methods are not regiospecific in the case of 11a-hydroxy steroids and typically lead to mixtures of 9,11 steroid containing 10-15% of the analogous steroids. Separation of these regio-isomeric products is difficult, generally requiring laborious physical separation procedures, resulting in increased costs and lower yields. It would therefore be desirable to develop an efficient regioselective method for preparing ?9,11 steroids, from either 11 a- or 11ß-hydroxy steroids, for use as intermediates in the synthesis of corticosteroids. Also, separation of these regio-isomeric products is difficult and generally requires laborious physical separation procedures, resulting in increased costs and lower yields.

The introduction of a 21-chloro group is also of commercial importance, e.g. for preparing intermediates and therapeutically important compounds. The conversion of 21-hydroxy steroids to the analogous 21-chloro steroid by chloride displacement of a 21-methanesulfonyl intermediate is known. However, this reaction is not regioselective in the case of 11-hydroxy steroids, as methanesulfonyl chloride reacts with both the 11- and 21-hydroxy groups. In addition, there are known methods for preparing 21-chloro steroids using the Vilsmeier reagent (prepared from DMF and phosphorus oxychloride (POCl3) or phosgene). In view of the importance of both 21-chloro groups and 9, 11-double bonds it is desirable to develop a one-step process for efficiently introducing both functional groups in a single steroid molecule.

Most of the conventional methods result into low product yields. Further, there are difficulties with the process for formation of isomeric 17-hydroxy-21-acylate during hydrolysis of 17,21-orthoacetate. Higher costs for route of synthesis, difficulties in the separation of regio-isomeric products and maintaining regioselectivity in the case of 11-hydroxy steroids are difficult.

In order to overcome the drawbacks of the aforesaid processes, there is a need for an improved process for preparation of 21-hydroxypregna 1,4,9(11), 16- tetraene- 3,20-dione 21-acetate.

Summary of the invention
In one aspect, the present invention relates to a process for preparation of compound of Formula (I) from compound of Formula (II) in a single pot reaction.

In another aspect, the present invention relates to a process for preparation of a compound of Formula (I) from a compound of Formula (II) by direct double dehydration.

In yet another aspect, the present invention relates to a process for preparation of a compound of Formula (I) from compound of Formula (III) in a single pot reaction.

In a preferred embodiment, a process for preparation of a compound of Formula (I)

from a compound of Formula (II)

comprises:
(a) dehydrating a compound of Formula (II) with a dehydrating agent in a solvent and cooling to a temperature to obtain a reaction mixture;
(b) adding a base to the reaction mixture and forming an organic layer;
(c) quenching the organic layer with an acid or an alkali and water;
(d) acylating the organic layer with an acylating agent in presence of a solvent and a base forming an acylated mixture; and
(e) heating the acylated mixture in presence of a solvent and a base to obtain a compound of Formula (I).

In an embodiment, the cooling in step (a) is done to a temperature of 0°C to 15°C. The quenching in step (c) is done with 10% aqueous hydrochloric acid (HCl), 10% sodium chloride (NaCl) and water. Heating the acylated mixture is done to a temperature of 50°C to 60°C. The dehydrating agent is selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), and the like. The acylating agent is selected from the group comprising of acetyl chloride, acetic anhydride, isopropenyl acetate and like. The solvent is selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) and the like. The base is selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), and the like.

In another embodiment, a process for preparation of a compound of Formula (I)

from a compound of Formula (II)

comprises:
a) acylating a compound of Formula (II) with an acylating agent in a solvent and a base under cooling to a temperature to obtain an intermediate compound of Formula (III);

b) dehydrating the compound of Formula (III) with a dehydrating agent in a solvent and a base and cooling to a temperature to obtain an intermediate compound of Formula (IV); and

c) further dehydrating the compound of Formula (IV) with a dehydrating agent in a solvent and a base to obtain a compound of Formula (I).

In an embodiment, the acylating agent is selected from the group comprising of acetyl chloride, acetic anhydride, isopropenyl acetate and like. The cooling in step (a) is done to a temperature of -5°C to 0°C. The dehydrating agent is selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), and the like. The cooling in step (b) is done to a temperature of 0°C to 5°C. The solvent is selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) and the like. The base is selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), and the like.

In yet another embodiment, a process for preparation of a compound of Formula (I)

from a compound of Formula (III)

comprises:
a. dehydrating a compound of Formula (III) with a dehydrating agent in a solvent and a base under cooling to a temperature to obtain a compound of Formula (I).

In an embodiment, the dehydrating agent in step (1) is selected from the group of comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), and the like. The cooling in step (1) is done to a temperature of 0°C to 20°C. The solvent is selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN)and the like. The base is selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), and the like.

Description of the invention
The present invention provides a process for preparation of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I) from Prednisolone of Formula (II) in a single pot reaction.

The process provides a regioselective process for the preparation of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I) from Prednisolone of Formula (II) which involves direct double dehydration of Prednisolone or protected Prednisolone at lower temperatures.

The present invention also provides a process for preparation of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I) from 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione of Formula (III) in a single pot reaction.

All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.
References in the specification to “preferred embodiment” means that a particular feature, structure, characteristic, or function described in detail thereby omitting known constructions and functions for clear description of the present invention.

In an aspect, a process for preparation of a compound of Formula (I) from a compound of Formula (II) in a single pot reaction has been provided.

In an embodiment, the process for preparation of a compound of Formula (I)

from a compound of Formula (II)

is provided. The process comprising the steps of:
(a) dehydrating a compound of Formula (II) with a dehydrating agent in a solvent and cooling to a temperature to obtain a reaction mixture;
(b) adding a base to the reaction mixture and forming an organic layer;
(c) quenching the organic layer with an acid or an alkali and water;
(d) acylating the organic layer with an acylating agent in presence of a solvent and a base forming an acylated mixture; and
(e) heating the acylated mixture in presence of a solvent and a base to obtain a compound of Formula (I).

In an embodiment, the compound of Formula (I) is 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate. The compound of Formula (II) is Prednisolone. The known glucorticoids synthesized from the compound of Formula (I) of the present invention are selected from Budesonide, Desonide, Ciclesonide, Flumethasone, Fluticasone propionate, Betamethasone, Clobetasole propionate, Mometasone furoate, Beclomethasone dipropionate, Triamcinolone, Fluticasone furoate, and the like.
In step (a) the solvent can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) or like. The dehydrating agent can be selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), or like. Further during dehydration cooling of the first reaction mixture in step (a) can be done at a predefined temperature of 0°C to 15°C. The base can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The quenching in step (c) can be done with 10% aqueous hydrochloric acid (HCl), 10% sodium chloride (NaCl) and water. The pH of the reaction mixture in step (c) can be adjusted to a predefined pH of 7 to 8. The process further comprises a step of filtering out the quenched organic layer, separating the layers or comprises a step of distilling the quenched organic layer for acylation. The acylating agent in step (d) can be selected from the group of acetyl chloride, acetic anhydride, isopropenyl acetate, or like. The solvent in step (d) can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile(ACN)or like. The base in step (d) can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The heating in step (e) can be done to a predefined temperature of 50°C to 60°C and maintained for a predefined period of 2 to 4 hours. The solvent in step (e) can be selected from the group of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), or like. The base in step (e) can be selected from the group of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. Isolation of compound of Formula (I) can be done in a solvent selected from alcohols selected from the group comprising of isopropanol, ethanol, methanol and the like and with 10% aqueous hydrochloric acid (HCl) or 10% sodium chloride (NaCl) and water and also using ethers as single solvents like diethyl ether, diisopropyl ether and methyl tertiary-butyl ether (MTBE) and the like. The compound of Formula (I) has a purity of 95% to 99% HPLC purity and % yield of 75% to 85%.
In an embodiment, the compound of Formula (I) prepared by the process of the present disclosure has a purity of 95% to 99% HPLC purity and % yield of 75% - 80%.

In another aspect, a process for preparation of a compound of Formula (I) from a compound of Formula (II) by direct double dehydration has been provided.
In an embodiment, the process for preparation of a compound of Formula (I)

from a compound of Formula (II)

is provided. The process comprising the steps of:
a) acylating a compound of Formula (II) with an acylating agent in a solvent and a base under cooling to a temperature to obtain an intermediate compound of Formula (III);

b) dehydrating the compound of Formula (III) with a dehydrating agent in a solvent and a base and cooling to a temperature to obtain an intermediate compound of Formula (IV); and

c) further dehydrating the compound of Formula (IV) with a dehydrating agent in a solvent and a base to obtain a compound of Formula (I).

In this embodiment, in step (a) acylation of compound of Formula (II) to obtain an intermediate compound of Formula (III) comprising the steps of:

(i) dissolving the compound of Formula (II) in a solvent in presence of a base to obtain a first reaction mixture;
(ii) cooling the first reaction mixture to a temperature to obtain a second reaction mixture;
(iii) acylating the second reaction mixture with a acylating agent to obtain an acylated mixture; and
(iv) heating the acylated mixture to a predefined temperature for a predefined period of time to obtain a compound of Formula (III).
Further, in this embodiment, the dehydration in step (b) of the compound of Formula (III) to obtain an intermediate compound of Formula (IV) comprising the steps of:

(i) dissolving the compound of Formula (III) in a solvent to obtain a first reaction mixture;
(ii) cooling the first reaction mixture in a base to a predefined temperature to obtain a second reaction mixture;
(iii) dehydrating the second reaction mixture with a dehydrating agent to obtain a dehydrating mixture; and
(iv) heating the dehydrating mixture to a predefined temperature for a predefined period of time to obtain a compound of Formula (IV).
Furthermore, in this embodiment, in step (c) the dehydration in step (c) of the intermediate compound of Formula (IV) to obtain a compound of Formula (I) comprising the steps of:

(i) dissolving the compound of Formula (IV) in a solvent to obtain a first reaction mixture;
(ii) cooling the first reaction mixture in a base to a predefined temperature to obtain a second reaction mixture;
(iii) dehydrating the second reaction mixture with a dehydrating to obtain a compound of Formula (I).
In an embodiment, the compound of Formula (I) is 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate. The compound of Formula (II) is Prednisolone. The compound of Formula (III) is 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione. The compound of Formula (IV) is 21-Acetoxy-17a-hydroxypregna-1,4,9(11)-triene-3,20-dione. The known glucorticoids synthesized from the compound of Formula (I) of the present invention are selected from Budesonide, Desonide, Ciclesonide, Flumethasone, Fluticasone propionate, Betamethasone, Clobetasole propionate, Mometasone furoate, Beclomethasone dipropionate, Triamcinolone, Fluticasone furoate, and the like.
In step a) (i) the solvent can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) or like. The base can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The cooling of the first reaction mixture in step a) (ii) can be done at a predefined temperature of -5°C to 0°C. The acylating agent in step a) (iii) can be selected from the group of acetyl chloride, acetic anhydride, isopropenyl acetate, or like. The heating in step a) (iv) can be done to a predefined temperature of 40°C to 80°C and maintained for a predefined period of 3 to 4 hours. The compound of Formula (III) prepared by the process of the present disclosure has a purity of 85% to 95% HPLC purity and % yield of 65% to 85%.
In step b) (i) the solvent can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN)or like. The cooling of the first reaction mixture in step b) (ii) can be done at a predefined temperature of 0°C to 5°C. The base can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene(DBN), N,N-Diisopropylethylamine(DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The dehydrating agent in step b) (iii) can be selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), or like. The heating in step b) (iv) can be done to a predefined temperature of 50°C to 90°C and maintained for a predefined period of 1 to 4 hours. The compound of Formula (IV) prepared by the process of the present disclosure has a purity of 90% to 95% HPLC purity and % yield of 65% to 85%.
In step c) (i) the solvent can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) or like. The cooling of the first reaction mixture in step c) (ii) can be done at room temperature. The base can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene(DBN), N,N-Diisopropylethylamine(DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The dehydrating agent in step c) (iii) can be selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), or like. The compound of Formula (I) prepared by the process of the present disclosure has a purity of 85% to 95% HPLC purity and % yield of 65% to 95%.

In yet another aspect, a process for preparation of a compound of Formula (I) from compound of Formula (III) in a single pot reaction has been provided.
In an embodiment, the process for preparation of a compound of Formula (I)

from a compound of Formula (III)

is provided. The process comprising the steps of:
a. dehydrating a compound of Formula (III) with a dehydrating agent in a solvent and a base under cooling to a temperature to obtain a compound of Formula (I).

In an embodiment, the compound of Formula (I) is 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate. The compound of Formula (III) is 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione. The known glucocorticoids synthesized from the compound of Formula (I) of the present invention are selected from Budesonide, Desonide, Ciclesonide, Flumethasone, Fluticasone propionate, Betamethasone, Clobetasole propionate, Mometasone furoate, Beclomethasone dipropionate, Triamcinolone, Fluticasone furoate, and the like.
The solvent can be selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) or like. The cooling can be done at a predefined temperature of 0°C to 20°C. The bases can be selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The dehydrating agent can be selected from the group of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), or like. The compound of Formula (I) prepared by the process of the present disclosure has a purity of 90% to 95% HPLC purity and % yield of 65% to 95%.

In a further embodiment, a process for preparation of a compound of Formula (III) by acylation of a compound of Formula (II) is provided.
The process for preparation of a compound of Formula (III)

by acylation of a compound of Formula (II)

comprising the steps of:
(i) dissolving the compound of Formula (II) in a predefined solvent in presence of a predefined base to obtain a first reaction mixture;
(ii) cooling the first reaction mixture to a predefined temperature to obtain a second reaction mixture;
(iii) acylating the second reaction mixture with a predefined acylating agent at the same predefined temperature for a predefined period of time to obtain an acylated mixture; and
(iv) heating the acylated mixture to a predefined temperature for a predefined period of time followed by cooling to a predefined temperature for a predefined period of time to obtain a compound of Formula (III).

The compound of Formula (II) is Prednisolone. The compound of Formula (III) is 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione. In step (i) the predefined solvent can be selected from the group of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) or like. The bases can be selected from the group of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), or like. The cooling of the first reaction mixture in step (ii) can be done at a predefined temperature of -5°C to 0°C. The acylating agent in step (iii) can be selected from the group of acetyl chloride, acetic anhydride, isopropenyl acetate, or like. The addition of the acylating agent can be done at the same predefined temperature of -5°C to 0°C for a predefined period of time of 15 to 30 minutes.
The heating in step (iv) can be done to a predefined temperature of 40°C to 80°C and maintained for a predefined period of 3 to 4 hours. Further the cooling in step (iv) can be done to a predefined temperature of 0°C to 35°C and maintained for a predefined period of 30 minutes to 60 minutes.
The compound of Formula (III) prepared by the process of the present disclosure has a purity of 97% to 99% HPLC purity and % yield of 95% - 100%.

In an embodiment, the known glucorticoids synthesized from the compound of Formula (I) of the present invention are selected from Budesonide, Desonide, Ciclesonide, Flumethasone, Fluticasone propionate, Betamethasone, Clobetasole propionate, Mometasone furoate, Beclomethasone dipropionate, Triamcinolone, Fluticasone furoate, and the like.

In an embodiment, the acylating agents are selected from group comprising of acetyl chloride, acetic anhydride, isopropenyl acetate, and the like.

In another embodiment, the dehydrating agents are selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), and the like.

In another embodiment, the solvents are selected from the group comprising of ethyl acetate (EtOAc); acetic acid (HOAc); tetrahydrofuran (THF); dimethylsulfoxide (DMSO); methanol (MeOH); diglyme, dioxane, CCl4, diisopropyl ether; dimethoxyethane; t-butylmethyl ether (t-BuOMe); dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) and the like.

In another embodiment, the bases are selected from the group comprising of N.N-dimethylaminopyridine DMAP); pyridine; triethylamine (Et3N); diisopropylethylamine; 1,8-Diazabicyclo[5.4.0] undec-7-ene(DBU),1,5-Diazabicyclo[4.3.0]non-5-ene (DBN),N,N-Diisopropylethylamine (DIPEA),1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU); hexamethyl phosphoramide (HMPA) and the like.

In another embodiment, the quenching can be done using 10% aqueous hydrochloric acid (HCl), 10% sodium hydroxide (NaOH), 10% sodium chloride (NaCl), water, and the like.

In another embodiment, isolation of compound of Formula (I) can be done in a solvent selected from alcohols selected from the group comprising of isopropanol, ethanol, methanol and the like and with 10% aqueous hydrochloric acid (HCl) or 10% sodium chloride (NaCl) and water and also using ethers as single solvents like diethyl ether, diisopropyl ether and methyl tertiary-butyl ether (MTBE) and the like.

In the context of the present invention, the process of the present invention is an improved routes to synthesize 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate from Prednisolone in a single pot reaction and by double dehydration. The process of the present invention is an improved routes to synthesize 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate from 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione in a single pot reaction. Advantageously, using Prednisolone as the starting material for the process of the present invention provides for a shorter route as compared to routes from sapogenins that are used in conventional processes. The process of the present invention advantageously maintains the regiospecificity of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate. The process of the present invention advantageously includes a single pot synthesis of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate. The advantage of the preferred single pot synthesis over the double dehydration process is that drying operations can be avoided. Further the crude compounds after distillations can directly be converted to the required product without isolation and use of acetic anhydride can be avoided. This process gives improvement in the yield and product quality. The process of the present invention results in high yield of the end product of the present invention with maximum purity. The process of the present invention is an eco-friendly and a cost-effective process.

EXAMPLES
Examples and implementations are provided herein below for the illustration of the invention. Variations, modifications, and enhancements to the described examples and implementations and other implementations can be made based on what is disclosed.
Examples are set forth herein below and are illustrative of different amounts and types of reactants and reaction conditions that can be utilized in practicing the disclosure. It will be apparent, however, that the disclosure can be practiced with other amounts and types of reactants and reaction conditions than those used in the examples, and the resulting devices various different properties and uses in accordance with the disclosure above and as pointed out hereinafter.

I) Single-Pot Synthesis of 21-Hydroxypregna-1,4,9(11),16-Tetraene-3,2-Dione 21-Acetate of Formula (I) from Prednisolone of Formula (II)

Example-1: 50.0 gram of Prednisolone of Formula (II) was taken into a RB flask and 500ml of DCM was added. Reaction mass was cooled to 0 ± 5°C. 33.25ml of thionyl chloride was added at 0 ± 5°C for 15 to 30 minutes. The reaction mass was stirred at the same temperature for 10 to 15 minutes and added 300ml of triethyl amine at below 15°C. TLC was checked for reaction completion. The organic layer was washed using water followed by 10%NaCl solution. The organic layer was taken and adjusted the reaction mass pH 7 - 8 using 10% aq HCl solution. The two layers were separated. The solvent was distilled off under vacuum at below 45°C. 500ml of fresh DCM and 26.0 ml Triethylamine were added and 13.25 ml of acetyl chloride was slowly added for 15 to 20 minutes at room temperature. The reaction mass was stirred at the same temperature for 15 to 30 minutes. TLC was checked for reaction completion. The reaction mass was washed using water and separated the layers. The solvent was distilled off the under vacuum at below 45°C. 250 ml ethyl acetate, 14.25 ml DBU were added to the crude compound at room temperature and heated the reaction mass to 60 ± 5°C for 2 to 4 hours. The reaction mass was cooled to room temperature and decant the ethyl acetate layer into another RB flask. 10% aq. HCl solution was added and stirred the reaction mass and separated the layers. The aq. layer was extracted with 2 x 100ml of ethyl acetate. All the ethyl acetate layers was combined and washed with 500ml water. The solvent was distilled off under vacuum.
a. The crude compound was dissolved into 150 ml isopropyl alcohol at 45°C and given carbon treatment. The carbon was washed using 100 ml isopropyl alcohol. This isopropanol filtrate was added to 1000 ml 2% aq. HCl solution slowly for 30 minutes. The reaction mass was stirred at the same temperature for 10 to 15 minutes. The product was filtered and washed using water. The product was dried at 45°C to obtain compound of Formula (I). Yield obtained was 36 – 42 grams
b. The crude compound was stirred using 200ml of diisopropyl ether at room temperature for 1 – 2hours. Filtered and washed the separated product using 100ml of the same ether. The product was dried at 45°C to obtain compound of Formula (I). Yield obtained was 36 – 42 grams

Example-2: 5.0 gram of Prednisolone of Formula (II) was taken into a RB flask and 50ml of ACN was added. Reaction mass was cooled to 0 ± 5°C. 3.5ml of thionyl chloride was added at 0 ± 5°C for 15 to 30 minutes. The reaction mass was stirred at the same temperature for 10 to 15 minutes and 30ml of triethyl amine was added at below 15°C. TLC was checked for reaction completion. 100ml 10% NaCl solution was added. The reaction mass was stirred at room temperature for 30 to 60 minutes. The separated solid was filtered and washed with 50 ml water. The solid is dissolved in 50ml DCM and the water layer was separated. The solvent was distilled off under vacuum at below 45°C. 50ml of fresh DCM was added and further 2.2grams DMAP was added and 2.0ml of acetic anhydride was slowly added for 15 to 20 minutes at room temperature. The reaction mass was stirred at the same temperature for 15 to 30 minutes. TLC was checked for reaction completion. The solvent was distilled off under vacuum at below 45°C. 50 ml ACN, 0.1ml DBU was added and the reaction mass was heated to 70 ± 5°C for 2 – 4hours. The reaction mass was cooled to room temperature and 10%NaCl solution was added and the reaction mass was stirred at room temperature till free solid separates. The reaction mass was stirred at the same temperature for 10 for 15 min. The product was filtered and washed using water. The product was dried aerially to obtain compound of Formula (I). Yield obtained was 3.6 – 4.1 grams.

Example-3: 50 gram of Prednisolone of Formula (II) was taken into a RB flask and 500ml of THF was added. Reaction mass was cooled to 0 ± 5°C. 35ml of thionyl chloride was added at 0 ± 5°C for 15 to 30 minutes. The reaction mass was stirred at the same temperature for 10 to 15 minutes and 300 ml of triethyl amine was added at below 15°C. TLC was checked for reaction completion. 1000 ml 10% NaCl solution was added. The reaction mass was stirred at room temperature for 30 to 60 minutes. ~50% of the solvent was distilled under vaccum and 500 ml water was added. The reaction mass was stirred at room temperature for clear separation of the product. The separated solid was filtered and washed with 500 ml water. The solid was dissolved in 500 ml DCM and the water layer was separated. The solvent was distilled off under vacuum at below 45°C. 50ml of fresh DCM and 22 grams of DMAP was added and 20 ml of acetic anhydride was slowly added for 15 to 20 minutes at room temperature. The reaction mass was stirred at the same temperature for 15 to 30 minutes. TLC was checked for reaction completion. The solvent was distilled off under vacuum at below 45°C. 250 ml THF and 1ml DBU were added and the reaction mass was heated to 70 ± 5°C for 2 to 4 hours. The reaction mass was cooled to room temperature and 10%NaCl solution was added and the product was extracted using into 250 ml DCM. The solvent was distilled off under vacuum at below 50°C. 250 ml n-hexane was added and the reaction mass was stirred at room temperature to get free solid. The reaction mass was stirred at the same temperature for 10 to 15 minutes. The product was filtered and washed using 3 x 50ml n-hexane. The product was dried aerially to obtain compound of Formula (I). Yield obtained was 36 – 45 grams.

II) Preparation of a compound of Formula (I) from a compound of Formula (II) by direct double dehydration

Step 1. Synthesis of 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione of Formula (III) from Prednisolone of Formula (II)

Example - 50.0 grams of Prednisolone (II) was dissolved in 250ml of DMF, the reaction mixture was cooled and 44 ml of pyridine was added under cooling at temperature -5 to 0°C). Further under nitrogen atmosphere 31 ml of acetic anhydride was added at the same temperature for about 30 minutes. The contents of the flask were heated to about 50°C and maintained at the same temperature for 4 hours. Reaction completion was monitored by TLC. If TLC shows absence of starting material, the reaction mass was cooled and 1000 ml chilled water was added at room temperature and stirred at the same temperature for another 30-60 minutes and the precipitated compound was filtered off and the product was washed using 500ml water. The wet product was dried at 60°C to obtain compound of Formula (III). Yield obtained was 52 - 58 grams.

Step 2. Synthesis of 21-Acetoxy-17a-hydroxypregna-1,4,9(11)-triene-3,20-dione of Formula (IV) from 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione of Formula (III)

Example - 50 grams of the compound (III) was taken into a RB flask and 250 ml DMF was added. The reaction mass was cooled to 0 - 5°C. 4.0 mole equivalents pyridine was added and further 2.5 mole equivalents mesyl chloride was added at the same temperature. Contents of the flask were stirred for 10 minutes at the same temperature. The reaction mass was heated to 80°C. Reaction completion was checked with TLC for completion once the temperature is reached. If starting material was found absent in TLC, the reaction mass was cooled to room temperature and 500 ml water was added and the reaction mass was stirred at room temperature for 60 minutes. The product was filtered and washed with 500 ml water followed by hexane. The product was dried at 60°C to obtain compound or Formula (IV). Yield obtained was 40 - 45 grams.

Step 3. Synthesis of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I) from 21-Acetoxy-17a-hydroxypregna-1,4,9(11)-triene-3,20-dione of Formula (IV)

Example - 20.0 gram of the compound (IV) was taken into a RB flask and 200ml of DMF was added. 20.0 ml Pyridine was added. 1.5 mole equivalent of thionyl chloride was added at the same temperature for about 15 – 30 minutes. Immediately after addition of thionyl chloride, reaction was checked with TLC. If TLC showed absence of starting material, the reaction mass was quenched (at temperature below 40°C) using 1000ml of water. The reaction mass was stirred at room temperature for 15 to 30 minutes. The product was filtered and washed using 500 ml water. The product was dried aerially to obtain compound of Formula (I). Yield obtained was 15 – 18 grams.

III) Single pot Synthesis of 21-Hydroxypregna-1,4,9(11),16-tetraene-3,20-dione 21-acetate of Formula (I) from 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione of Formula (III)

Example 1 - 10.0 grams of 21-Acetoxy-1,4-pregnadiene-11ß,17a-diol-3,20-dione of Formula (III) was taken into a clean and dry RB flask. 100 ml of DMF was added and the reaction mass was cooled to 15°C to 20°C. 20ml Pyridine was added at the same temperature for 10 minutes. 4.4 ml thionyl chloride was added at the same temperature for 15 – 30 min. The reaction mass was stirred at the same temperature for 15 - 30 minutes. The reaction mass was checked with TLC for the completion of the reaction. If TLC showed absence of starting material reaction mass was quenched 25°C to 40°C using 1000 ml of 10% aqueous HCl solution. The reaction mass was stirred at room temperature for 15 – 30 minutes. The product was filtered and washed 500 ml with water to obtain compound of Formula (I). Yield obtained was 5.5 – 9.0 grams.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.
The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.
It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.

,CLAIMS:

1. A process for preparation of a compound of Formula (I)

from a compound of Formula (II)

comprising:
(a) dehydrating a compound of Formula (II) with a dehydrating agent in a solvent and cooling to a temperature to obtain a reaction mixture;
(b) adding a base to the reaction mixture and forming an organic layer;
(c) quenching the organic layer with an acid or an alkali and water;
(d) acylating the organic layer with an acylating agent in presence of a solvent and a base forming an acylated mixture; and
(e) heating the acylated mixture in presence of a solvent and a base to obtain a compound of Formula (I).

2. The process as claimed in claim 1, wherein cooling in step (a) is done to a temperature of 0°C to 15°C.

3. The process as claimed in claim 1, wherein the quenching in step (c) is done with 10% aqueous hydrochloric acid (HCl), 10% sodium chloride (NaCl) and water.
4. The process as claimed in claim 1, wherein heating the acylated mixture is done to a temperature of 50°C to 60°C.

5. A process for preparation of a compound of Formula (I)

from a compound of Formula (II)

comprising:
a) acylating a compound of Formula (II) with an acylating agent in a solvent and a base under cooling to a temperature to obtain an intermediate compound of Formula (III);

b) dehydrating the compound of Formula (III) with a dehydrating agent in a solvent and a base and cooling to a temperature to obtain an intermediate compound of Formula (IV); and

c) further dehydrating the compound of Formula (IV) with a dehydrating agent in a solvent and a base to obtain a compound of Formula (I).

6. The process as claimed in claim 5, wherein the cooling in step (a) is done to a temperature of -5°C to 0°C.

7. The process as claimed in claim 5, wherein the cooling in step (b) is done to a temperature of 0°C to 5°C.

8. A process for preparation of a compound of Formula (I)

from a compound of Formula (III)

comprising:
a. dehydrating a compound of Formula (III) with a dehydrating agent in a solvent and a base under cooling to a temperature to obtain a compound of Formula (I).

9. The process as claimed in claim 8, wherein the cooling is done to a temperature of 0°C to 20°C.

10. The process as claimed in claim 1, 5 and 8, wherein the dehydrating agent is selected from the group comprising of p-toluenesulfonyl chloride (TsCl); mesyl chloride, thionyl chloride, phosphosyl chloride (POCl3), phosphorus pentachloride (PCl5), phosphorus trichloride (PCl3), sulfuryl chloride (SO2Cl2), lithium chloride (LiCl), and the like.

11. The process as claimed in claim 1 and 5, wherein the acylating agent is selected from the group comprising of acetyl chloride, acetic anhydride, isopropenyl acetate and like.

12. The process as claimed in claim 1, 5 and 8, wherein the solvent is selected from the group comprising of ethyl acetate (EtOAc), acetic acid (HOAc), tetrahydrofuran (THF), dimethylsulfoxide (DMSO), methanol (MeOH), diglyme, dioxane, carbon tetrachloride (CCl4), diisopropyl ether, dimethoxyethane, t-butylmethyl ether (t-BuOMe), dimethylformamide (DMF), dichloromethane (DCM), chloroform (CHCl3), acetonitrile (ACN) and the like.

13. The process as claimed in claim 1, 5 and 8, wherein the base is selected from the group comprising of N.N-dimethylaminopyridine (DMAP), pyridine, triethylamine (Et3N), diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-Diazabicyclo[4.3.0] non-5-ene (DBN), N,N-Diisopropylethylamine (DIPEA), 1,3-Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), and the like.