FIELD OF THE INVENTION

The present invention relates to novel compounds of Formula I and process of preparation and use in preparation of 6-(alpha-ethylchenodeoxycholic acid), or 3a,7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid. (Obeticholic acid) of Formula II
and pharmaceutical acceptable salts thereof,
o
M p
': J R3 ''■ /
I / °H
Formula I
Formula II
BACKGROUND OF THE INVENTION
Obeticholic acid is chemically described as 6-(a-ethylchenodeoxycholic acid), or
3a,7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid having the following structure as
shown in Formula II,
o
I /— OH
HOV,'^^T 'OH
Formula II
Obeticholic acid (OCA) is a derivative of chenodeoxycholic acid, the primary human biliar acid (BA). OCA is an FXR agonist, a nuclear receptor predominantly expressed in the gastrointestinal tract (liver and intestine) that has important role in the enterohepatic circulations of Bas. The FXR is the key intracellular BA sensor regulating several metabolic process involved in BA formation, transport and detoxification. FXR exerts its functions by eliciting transcriptional alteration. The

protein has a multidomain structure with dinstict regions engaged in DNA binding, ligand binding and transactivation. Farnesoid X-activated receptor agonists.
Obeticholic acid has been approved and marketed by Intercept Pharms Inc, for the treatment of primary biliary cholangitis (PBC) under the trade name OCALIVA® in the form of oral tablet having dosage strength as 10 mg and 5 mg.
US 8,969,330 B2 discloses the obetichloic acid and it's pharmaceutical acceptable salt. Further it dicloses a process for the preparation of the obeticholic acid, which is shown below in scheme 1:

US 7,812,011 B2 discloses a process for the preparation of obeticholic acid, as shown below in Scheme-2:



HO*'

US 8,338,628 B2 discloses a process for the preparation of obeticholic acid, as shown below in Scheme-3:
US 7,994,352 B2 discloses a process for the preparation of obeticholic acid, as shown below in Scheme 4:

OH Hydrogenating with Pd/C
Metallic hydride
wherein R is a linear or branched CM alkyl
HOs

Although there are certain processes known in the prior published references for the preparation of Obeticholic acid, however these processes involves low yields due to the formation of diastereomers, which results into additional purification steps making process commercially unsuitable. Hence there is always a need to provide a process for preparing pure Obeticholic acid, which is economical and commercially viable. The present invention is focused towards the development of Obeticholic acid in high yields and purity by using novel compounds as intermediates.
OBJECT OF THE INVENTION
The main object of the present invention is to provide novel compounds of Formula I, isomers, pharmaceutical^ acceptable salts and process of preparation thereof,

Formula I
wherein, Ri represents C=0, a-OH, P-OH, or H;
R2 represents hydroxyl protecting group, and
R3 is selected from -OR5, wherein R5 represents H, alkyl, N(ReR7), wherein R6 and
R7 are independently selected from hydrogen, C1-C6 (un)substituted alkyl, and Ci-
C6 (un)substituted alkoxyl group.
Another object of the present invention is to provide novel compounds of Formula I that can be used for the preparation of Obeticholic acid and its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
The main aspect of the present invention is to provide novel compounds of Formula I, isomers, or pharmaceutical acceptable salts thereof;

Formula I
wherein, Ri represents C=0, a-OH, P-OH, or H;
R2 represents hydroxyl protecting group, and
R3 is selected from -OR5, wherein R5 represents H, alkyl, N(ReR7), wherein R6 and
R7 are independently selected from hydrogen, C1-C6 (un)substituted alkyl, and Ci-
C6 (un)substituted alkoxyl group.
In another aspect, the present invention provides novel compounds as represented by formulas mentioned below:


Formula V Formula VI Formula VI'
5 5
O
ar)(4 Formula VII
wherein R2 and R3 are as defined above.

In another aspect, the present invention provides novel compounds as represented by formulas mentioned below:

-o-'o~-\y-

"cr "o*

^o^cy'

"0^0°

Formula V-A

Formula VI-A

Formula VT-A

to-O^
o-
"O' "O*

'OH

"cT^cr

Formula VU-A

Formula V-B

Formula VI-B

to-•ar'o-O^
O^
o-X
"O' "O'
"O' "0*

Formula VD-B

Formula V-C

Formula VI-C

Formula VI'-C

Formula VII-C



O^
io-o-AX

Formula V-D

Formula VI-D

Formula Vl'-D

K)-AX,

'OH

and

Formula VII-D

In another aspect, the present invention provides use of novel compounds of Formula I in preparation of obeticholic acid.
In another aspect, the present invention provides a process for the preparation of obeticholic acid of Formula II or its pharmaceutically acceptable salts by using novel compounds of Formula I, wherein said process comprising the steps of: a) protecting 3a-hydroxyl compound of Formula I-A with suitable hydroxyl protecting group to obtain compound of Formula I;

Formula I-A

Formula I

wherein Ri, R2 and R3 are as defined above; and
b) converting compound of Formula I to obeticholic acid of Formula II or its
pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of obetichohc acid of Formula II or its pharmaceutically acceptable salts, comprising the steps of: a) protecting 3a-hydroxyl compound of Formula IV with suitable hydroxyl
protecting group to obtain compound of Formula V,

Formula IV Formula V
wherein R2 is as defined above; and
b) converting the compound of Formula V to obetichohc acid of Formula II or its
pharmaceutically acceptable salts.
In another aspect, the present invention provides a process for the preparation of obetichohc acid of Formula II or its pharmaceutical acceptable salts, comprising the steps of: a) hydrogenating compound of Formula V with suitable hydrogenating agent to
obtain compound of Formula VI,

Formula V Formula VI
wherein R2 and R3 are as defined above; and
b) converting the compound of Formula VI to obetichohc acid of Formula II or its pharmaceutically acceptable salt.
DETAILED DESCRIPTION

"Pharmaceutically acceptable salts" as used in the context of the present invention refers to pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium, barium or zinc salts, ammonium salts; organic amines such as benethamine, benzathine, diethanolamine, dicyclohexyl amine, tromethamine, ethanolamine, 4-(2-hydroxyethyl)morpholine, l-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine and the like.
The term "isomers" as used in the context of the present invention refers to all such compounds including tautomers, cis-and trans-isomers, R- and ^-enantiomers, diastereomers, D-isomers, L-isomers, and racemic mixtures of all the compounds herein described under the definitions of compound of Formula I. Further, additional asymmetric carbon atoms may be present in a substituent such as alkyl group. The compounds herein described may have asymmetric carbon atoms and may be isolated in optically active forms by synthesis from optically active starting materials, or synthesis using optically active reagents by methods known in the prior published references.
The term "protecting group" as used in the context of the present invention refers to hydroxyl protecting group selected from methoxyethoxymethyl, ethoxymethyl, methoxypropyl, 3-methylbutanoyl, 2-tetrahydropyranyl (TFIP), substituted benzyl, unsubstituted benzyl, Boc, carbon and silyl containing moieties.
The term "optionally substituted" or "(un) substituted" as used in the context of the present invention means that substitution is optional and therefore it is possible for the designated atom or moiety to be substituted or unsubstituted.
As used herein, unless otherwise indicated, the term "alkyl" alone or in combination refers to a monovalent saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms. The alkyl groups include, but are not limited to, methyl,

ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, sec-butyl, tert-butyl, tert-pentyl, n-heptyl, and the like.
"Suitable solvent" as used in the context of the present invention refers to solvents selected from, but not limited to, the group comprising of alcohols, hydrocarbons, halogenated solvents, esters, ethers, ketones, sulfoxides, formamide, amides, nitriles, pyrrolidines, carbonates, water and the like. Specifically, the suitable solvent as used in the present invention is selected from, but not limited to, tetrahydrofuran, toluene, o/m/p-xylene, 1,4-dioxane, dichloromethane, carbon tetrachloride, dichloroethane, dichlorobenzene, chlorobenzene, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, acetone, methyl ethyl ketone, 2-methyl tetrahydrofuran, butyl acetate, isobutyl acetate, t-butyl acetate, propyl acetate, propylene acetate, butanol, t-butanol, methyl t-butyl ketone, dimethyl sulfoxide, N-methyl pyrrolidine, dimethyl acetamide, dimethyl formamide, N-methyl acetamide, acetamide, acetone, methyl isobutyl ketone, acetonitrile, propionitrile, methyl ethyl ether, methyl tert-butyl ether, dimethyl ether, diethyl ether, cyclohexane, n-heptane, water and mixture thereof.
"Suitable hydroxyl protecting group" as used in the context of the present invention refers to carbon and silyl containing moieties, preferably methoxyethoxymethyl, ethoxymethyl, methoxypropyl, 3-methylbutanoyl, 2-tetrahydropyranyl (THP), substituted benzyl unsubstituted benzyl, and tert-butoxycarbonyl.
"Suitable Base" as used in context of the present invention are selected from, but not limited to, organic and inorganic base such as pyridine, ammonia, triethyl amine, diisopropyl ethyl amine, dimethyl amino pyridine, morpholine, dicyclohexyl amine, carbonates, hydroxides, bicarbonates, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), lithium diisopropylaminde, lutidine, imidazole, guanidine and the like.

"Organic amine" as used in context of the present invention are selected from, but not limited to amines such as tert-butyl amine, propyl amine, ethylene diamine, dicyclohexyl amine, triethylamine, diisopropyl ethyl amine and the like.
In one embodiment the present invention provides novel compounds of Formula I,

Formula I
wherein, Ri represents C=0, a-OH, P-OH, or H;
R2 represents hydroxyl protecting group, and
R3 is selected from -OR5, wherein R5 represents H, alkyl, N(ReR7), wherein R6 and
R7 are independently selected from hydrogen, C1-C6 (un)substituted alkyl, and Ci-
C6 (un)substituted alkoxyl group.

Formula I-A Formula I
wherein Ri, R2 and R3 are as defined above; and
In another embodiment, the present invention provides a process for the preparation of obeticholic acid of Formula II or its pharmaceutically acceptable salts by using novel intermediate of Formula I, wherein said process comprising the steps of: a) protecting 3a-hydroxyl compound of Formula I-A with suitable hydroxyl protecting group to obtain compound of Formula I;

b) converting compound of Formula I to obeticholic acid of Formula II or its pharmaceutically acceptable salt.
In another embodiment, the present invention provides the preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, comprising the steps of: a) hydrogenating compound of Formula V with suitable hydrogenating agent to
obtain compound of Formula VI,

Formula V Formula VI
wherein R2 and R3 are as defined above; and
b) converting the compound of Formula VI to obeticholic acid of Formula II or it pharmaceutically acceptable salt.
In another embodiment, the present invention provides the preparation of obeticholic acid of Formula II and its pharmaceutically acceptable salts, comprising the steps of: a) esterifying compound of Formula III in a suitable solvent to obtain the

Formula HI Formula IV
wherein, R3 is as defined above;
compound of Formula IV,

b) protecting the 3a-hydroxyl compound of Formula IV with suitable hydroxyl protecting group to obtain compound of Formula V,
Q o
R3 <•. / R3
Formula IV Formula V
wherein R2 and R3 are as defined above;
c) hydrogenating the compound of Formula V with suitable hydrogenating agent to obtain compound of Formula VI,

Formula V
wherein R2 and R3 are as defined above; d) converting the compound of Formula VI into its corresponding isomer of compound of Formula VI' in the presence of suitable solvent,

Formula VI
wherein R2 and R3 are as defined above;
e) reducing the ketonic group at 7-position of compound of Formula VI' to obtain compound of Formula VIII,

Formula VI' Formula VII
wherein R2 and R3 are as defined above; and
f) deprotecting compound of Formula VII to obtain obeticholic acid of Formula II or pharmaceutically acceptable salt thereof.
In one another embodiment, the present invention provides a process of preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-5 below:

HO1' "--' ~^< 'OH
Formula II Formula VIII
wherein R2 is as defined above.

Formula VII

In one another embodiment, the present invention provides a process of preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-6 below:

Formula XXXII
H0V

OH

HO1'

wherein R2 is as defined above.
In one another embodiment, the present invention provides a process for the preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-7 below:


HO°

Formula XIX

Formula XXI

R2—l

HO'

'OH

'OH

Formula XXH

Formula XXI'

wherein R2 is as defined above.

In one another embodiment, the present invention provides a process for the preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-8 below:


Formula XXVI'
Formula XXVH

wherein R2 is as defined above.
In one another embodiment, the present invention provides a process of preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-9 below:

Formula XXX'
HO''

Formula XXXI]

In one another embodiment, the present invention provides a process of preparation of obeticholic acid of Formula II and its pharmaceutical acceptable salts, wherein said process comprising of reaction steps as mentioned in the scheme-10 below:

Formula XXXV
In another embodiment, the process for the preparation of obeticholic acid includes preparation of intermediates wherein said intermediates may optionally be not isolated, or may be converted to suitable salts before proceeding to next step.

In another embodiment, the process for the preparation of obeticholic acid includes preparation of intermediates wherein said intermediates may optionally be purified before the next step.
In another embodiment, the present invention provides a process of purification of obeticholic acid of Formula II or its pharmaceutically acceptable salts thereof, wherein said process comprising the steps of:
a) dissolving obeticholic acid in a suitable solvent, optionally in presence of organic amine;
b) optionally heating at a temperature in the range of 30-100°C; and
c) isolating pure obeticholic acid.
In a preferred embodiment, the obeticholic acid of Formula II is purified in a solvent selected from, but not limited to n-butyl acetate, n-heptane, isopropyl ether, n-butyl acetate/n-heptane, n-butyl acetate/organic amine, methyl isobutyl ketone, methyl isobutyl ketone /n-heptane, ethyl acetate, isopropyl acetate, acetone/water, toluene, methyl ethyl ketone, methyl isobutyl ether/n-heptane, isopropyl ether/ n-heptane and the like.
In a preferred embodiment, the obeticholic acid of Formula II may be isolated from the reaction mixture by purification, centrifugation, crystallization, filtration, extraction, evaporation and lyophilization.
In further embodiment, the present invention provides a substantially pure obeticholic acid of Formula II, wherein said obeticholic acid is free from the compounds of Formula I.
In furthermore embodiment, the present invention provides substantially pure obeticholic acid of Formula II, wherein said obeticholic acid of Formula II is substantially free of impurities of Formula (i) to (xi); wherein each impurity is less

than about 0.3% w/w or total impurity is less than about 1% w/w, more specifically less than about 0.15% w/w of any impurity;

P o
HO'
HO'"

Formula (i)

Formula (il)

Formula (iii)

HO'1

HO''

Formula (iv)

Formula (v)

Formula (vi)

HO'' "-"-" "^ 'OH Formula (vii)

HO'' "--' v 'OH Formula (viil)

HO'

Formula (xi)
Formula (x)

and

HO'

In another embodiment, the present invention provides pure obetichohc acid of Formula II, wherein said obetichohc acid is characterized by purity of 99.0%> and above.

In further embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of obeticholic acid or pharmaceutically acceptable salt thereof, comprising the steps of:
a) adding Obeticholic acid or pharmaceutically acceptable salt thereof in a suitable solvent to get a mixture;
b) providing a solution of atleast one pharmaceutically acceptable carrier in a suitable solvent and adding to the mixture obtained in step a), wherein said suitable solvent is optionally similar to the solvent used in step a); and
c) isolating to get amorphous solid dispersion of obeticholic acid or
pharmaceutically acceptable salt thereof.
In another embodiment, the obeticholic acid or salt thereof, obtained by the process of the present invention is characterized by particle size distribution of less than about 300um, preferably less than about 200um and most preferably about lOOum.
In a preferred embodiment, the obeticholic acid or salt thereof as isolated by the process of the present invention is crystalline in nature, wherein said crystalline obeticholic acid is substantially free of amorphous form.
In another preferred embodiment, the obeticholic acid or salt thereof as isolated by the process of the present invention is amorphous in nature, wherein said amorphous obeticholic acid is substantially free of crystalline peaks.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

EXAMPLES Example 1: Synthesis of 3a-hvdroxv-6-ethylidene-7-keto-5B-cholan-24-oic acid ethyl ester of Formula IV
Charged 3a-hydroxy-6-ethylidene-7-keto-5P-cholan-24-oic acid of Formula III (30 g), ethanol and sulphuric acid (cat. amount) in RBF and heated at 40-80°C. After completion of reaction, distilled out the solvent to get residue. Added water and extracted the material with ethyl acetate. Distilled out solvent to get of 3a-hydroxy-6-ethylidene-7-keto-5P-cholan-24-oic acid ethyl ester of Formula IV (28.5 g).
Example 2: Synthesis of 3a-(2-methoxvethoxv)methoxv)-6-ethylidene-7-keto-5B-cholan-24-oic acid ethyl ester of Formula V (R2 is methoxyethoxymethyl)
Charged ethyl acetate to (3a-hydroxy-6-ethylidene-7-keto-5P-cholan-24-oic acid ethyl ester of Formula IV. Cooled and added triethyl amine and l-(chloromethoxy)-2-methoxyethane. Stirred the reaction mixture at room temperature till completion of reaction. After completion of reaction, reaction mixture was quenched with water and extracted the material with ethyl acetate. Washed the organic layer with sodium bicarbonate. Separated the organic layer and used as such in the next step.
Example 3: Synthesis of 3a-(2-methoxvethoxv)methoxv)-6-ethyl-7-keto-5B-cholan-24-oic acid ethyl ester of Formula VI (R2 is methoxyethoxymethyl)
Organic layer of ethyl (3a-(2-methoxyethoxy)methoxy)-6-ethylidene-7-keto-5P-cholan-24-oic acid ethyl ester of Formula V and 10% Pd/C were charged into autoclave and hydrogenated using hydrogen gas at 40-100°C. After completion of reaction filtered the reaction mass and concentrated to get 3a-(2-methoxyethoxy)methoxy)-6-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester of Formula VI (29 g).
Example 4: Synthesis of 3a-(2-methoxvethoxv)methoxv)-6a-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester of Formula VI' (R2 is methoxyethoxymethyl)

Charged toluene and l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) into crude 3a-(2-methoxyethoxy)methoxy)-6-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester of Formula VI and heated to 50-100°C. After completion of reaction, reaction mixture was cooled and washed with saturated aq. solution of sodium chloride and then with aq. solution of sodium bicarbonate. Separated the layers and concentrated the organic layer under vacuum to get crude 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester (25.0 g) of Formula VI'.
Example 5: Synthesis of 3a-(2-methoxvethoxv)methoxv)-6a-ethyl-7a-hvdroxv-5P-cholan-24-oic acid ethyl ester of Formula VII (R2 is methoxyethoxymethyl)
Charged ethanol into 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester of Formula VI' (25.Og) and cooled to 0-10°C. Charged sodium borohydride lot wise to the reaction mixture and stirred the reaction mixture at room temperature. After completion of reaction, quenched the reaction mixture with acetic acid and water. Extracted the compound in ethyl acetate and organic layer was washed with saturated sodium chloride. Concentrated the organic layer to get crude 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7a-hydroxy-5P-cholan-24-oic acid ethyl ester of Formula VII (21.0 g).
Example 6: Synthesis of 3a-(2-methoxvethoxv)methoxv)-6a-ethyl-7a-hydroxy-5B-cholan-24-oic acid ethyl ester of Formula VII (R2 is methoxyethoxymethyl)
Added methanol and TUF to 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7-keto-5P-cholan-24-oic acid ethyl ester of Formula VI' (25.Og) and cooled to 0 to 10°C. Charged sodium borohydride lot wise to the reaction mixture under stirring. After completion of reaction, the reaction mixture was quenched with acetic acid. Distilled out the solvent and charged water to the residue thus obtained. Reaction mixture was extracted with ethyl acetate and washed the organic layer with aq. sodium bicarbonate and saturated sodium chloride. Separated the organic layer and

concentrated to get crude 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7a-hydroxy-5P-cholan-24-oic acid ethyl ester of Formula VII (20.8 g).
Example 7: Synthesis of 3a, 7a-dihvdroxv-6a-ethyl-5B-cholan-24-oic acid ethyl ester of Formula VIII
Charged dichloromethane and zinc bromide to 3a-(2-methoxyethoxy)methoxy)-6a-ethyl-7a-hydroxy-5P-cholan-24-oic acid ethyl ester of Formula VII and stirred at room temperature. After completion of reaction, quenched the reaction mixture with water and extracted with dichloromethane. Concentrated the organic layer thus obtained to get crude 3a, 7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid ethyl ester of Formula VIII.
Example 8: Synthesis of Obeticholic acid of Formula II
Added ethanol and water to crude 3a, 7a-dihydroxy-6a-ethyl-5P-cholan-24-oic acid ethyl ester of Formula VIII (15.0 g). Added 10% NaOH solution in ethanol: water to the reaction mixture and heated to reflux. After completion of reaction, reaction mixture was concentrated under vacuum followed by acidification with 10% aq. HC1. Extracted the compound with ethyl acetate. Concentrated the organic layer to get crude obeticholic acid of Formula II. Crude material was purified in methyl isobutyl ketone and dried to get Obeticholic acid of Formula II (10.0 g). Obeticholic acid so obtained is basified in aqueous solution and then acidified, filtered and dried to get final pure product.

WE CLAIM

1. Compounds of Formula I, isomers, or pharmaceutical acceptable salts thereof;
o ^R3

Formula I
wherein, Ri represents C=0, a-OH, P-OH, or H;
R2 represents hydroxyl protecting group, and
R3 is selected from -OR5, wherein R5 represents H, alkyl, N(ReR7), wherein R6 and
R7 are independently selected from hydrogen, C1-C6 (un)substituted alkyl, and Ci-
C6 (un)substituted alkoxyl group.

wherein R2 and R3 are as defined in claim 1.
2. The compounds as claimed in claim 1, wherein said compounds are represented by formulas mentioned below:

3. The compounds as claimed in claims 1 and 2, wherein said hydroxyl protecting
group of R.2 is selected from methoxyethoxymethyl, ethoxymethyl, methoxypropyl,
3-methylbutanoyl, 2-tetrahydropyranyl (THP), substituted benzyl unsubstituted
benzyl, and tert-butoxycarbonyl.
4. A process for the preparation of Obeticholic acid of Formula II or its
pharmaceutically acceptable salts by using compounds of Formula I, wherein said
process comprising the steps of:
a) protecting 3a-hydroxyl compound of Formula I-A with suitable hydroxyl protecting group to obtain compound of Formula I;

Formula I-A Formula I
wherein Ri, R2 and R3 are as defined in claim 1; and
b) converting compound of Formula I to Obeticholic acid of Formula II or its
pharmaceutically acceptable salt.
5. A process for the preparation of Obeticholic acid of Formula II or its pharmaceutically acceptable salts by using compounds as claimed in claim 2, wherein said process comprising the steps of: a) esterifying compound of Formula III in a suitable solvent to obtain the

Formula III Formula IV
compound of Formula IV,

wherein, R3 is as in defined in claim 1;
b) protecting the 3a-hydroxyl compound of Formula rV with suitable hydroxyl protecting group to obtain compound of Formula V,


Formula V

wherein R2 and R3 are as defined in claim 1;
c) hydrogenating the compound of Formula V with suitable hydrogenating agent to obtain compound of Formula VI,

wherein R2 and R3 are as defined in claim 1;
d) converting the compound of Formula VI into its corresponding isomer of
compound of Formula VI' in the presence of suitable solvent,

0 "R3
Formula VI
wherein R2 and R3 are as defined in claim 1;
e) reducing the ketonic group at 7-position of compound of Formula VI' to obtain compound of Formula VII,


Formula VI'
wherein R2 and R3 are as defined in claim 1; and
f) deprotecting compound of Formula VII to obtain Obeticholic acid of Formula II or pharmaceutically acceptable salt thereof.
5. A process of purification of Obeticholic acid of Formula II or its
pharmaceutically acceptable salts thereof, wherein said process comprising the
steps of:
a) dissolving Obeticholic acid in a suitable solvent, optionally in presence of organic amine;
b) optionally heating at a temperature in the range of 30-100°C; and
c) isolating pure Obeticholic acid.

6. The process as claimed in claim 5, wherein said suitable solvent is selected from n-butyl acetate, n-heptane, isopropyl ether, n-butyl acetate/n-heptane, n-butyl acetate/organic amine, methyl isobutyl ketone, methyl isobutyl ketone /n-heptane, ethyl acetate, isopropyl acetate, acetone/water, toluene, methyl ethyl ketone, methyl isobutyl ether/n-heptane, and isopropyl ether/ n-heptane.
7. The process as claimed in claim 5, wherein said Obeticholic acid is substantially free of impurities of Formula (i) to (xi), wherein each impurity is less than about 0.3% w/w;



H0°

HO'

Formula (i)

Formula (ii)

Formula (iii)

HO'

HO'1

Formula (iv)

Formula (v)

Formula (vi)

HO'' "-"' ^^ 'OH Formula (vii)

HO' ^ v 'OH Formula (viil)

HO'~

HO'

'OH

Formula (x)

and H3°"

Formula (xi)

8. The process as claimed in claim 5, wherein said Obeticholic acid is characterized by purity of 99.0% and above.