FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
"AN IMPROVED PROCESS FOR THE PREPARATION OF
URSODIOL"
AJANTA PHARMA LTD.
A company incorporated under the laws of India having their office at
98, Ajanta house, Charkop, Kandivali (West)
Mumbai - 400067, Maharashtra, India.
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a]phenanthren-17-yl]pentanoic acid represented by Formula-(I) commonly known as Ursodiol.

The process provides Ursodiol in higher yield and purity as compared to the previously known processes.
BACKGROUND OF THE INVENTION
Ursodiol (Ursodeoxycholic acid) is a secondary bile acids, which are metabolic by-products of intestinal bacteria and is marketed under brand name "Actigall" Capsule, "URSO 250" and "URSO FORTE", Oral Tablet in US market.
Ursodeoxycholic acid regulate cholesterol by reducing the rate at which the intestine absorbs cholesterol molecules while breaking up micelles containing cholesterol. Because of this property, ursodeoxycholic acid is used to treat gall stones non-surgically. Ursodiol is a synthetically-derived form of ursodiol, a bile acid produced by the liver and secreted and stored in the gallbladder. Also produced by the Chinese black bear liver, ursodiol has been used in the treatment of liver disease for centuries. This agent dissolves and/or prevents cholesterol gallstones by blocking hepatic cholesterol production and decreasing bile cholesterol.
Journal of Biochemistry (1927), Vol.7, pp.505-517 describes the process for preparation
of Ursodeoxycholic acid by reacting Chenodeoxycholic acid with barium salt.
Chenodeoxycholic acid on reaction with barium salt produces Chenodeoxycholic acid
barium salt, which on hydrolysis produces Chenodeoxycholic acid hemihydrate which

further reacts with an acid to produce Ursodeoxycholic. Crystallization of crude Ursodeoxycholic acid from dilute alcohol or acetone yields Ursodeoxycholic acid.
U.S. Patent No. 4,282,161 discloses a process for the purification of Ursodeoxycholic acid by treating with methanol to produce ester derivative, followed by crystallization and saponification with an alkali produces ursodeoxycholic acid alkali salt which on further treatment with an acid in chloroform produces crystalline ursodeoxycholic acid.
U.S. Patent No. 4,834,919 discloses a process for the preparation of Ursodeoxycholic acid by treating Potassium salt of 7-ketolithocholic acid with potassium tertiary butoxide in isopropanol, further the above reaction mass was hydrogenated using Raney nickel under hydrogen pressure to produce crude Ursodeoxycholic acid. Further, the obtained crude Ursodeoxycholic acid is purified using acetone and triethylamine to produce pure Ursodeoxycholic acid.
Chinese Publication No. 200910115155 discloses a method for the preparation of chenodeoxycholic acid and ursodeoxycholic acid magnesium salt trihydrate. This process uses chenodeoxycholic acid, ursodeoxycholic acid and magnesium sulfate heptahydrate as the raw material, with water as the solvent. This process often produces gelatinous material (which may be colloidal magnesium hydroxide), causing the subsequent filtration operation extremely difficult. Owing to this, the said process suffers from drawback like incomplete washing of the product resulting in increased residual inorganic salt impurities.
Indian Application No. 4112/CHE/2011 discloses process for preparation of ursodiol by oxidizing chenodeoxycholic acid with sodium hypochlorite in presence of ethyl acetate, sodium bromide, tert-ammonium bromide followed to yield 3a-hydroxy-7-oxo-5p-cholan-24-oic acid (7-KCA) which was further reduced using Raney nickel and converted to N,N-diisopropyl amine salt. The salt was neutralized and purified to give ursodiol.
The processes for the preparation of Ursodiol and its intermediates, as defined in the aforementioned prior arts suffer from several disadvantages such as complex reaction scheme with an indefinite reaction stages, use of a catalyst(s) which tends to form an impurities, multiple purification steps, tedious workup process. Therefore, there is a need to develop simple, efficient and a commercial viable process for preparation of Ursodiol with higher purity level along with higher yield by avoiding the above mentioned drawbacks.

The present invention provides such an improved process for the preparation of Ursodiol which is cost effective and avoids the drawbacks of the prior art processes.
SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of (R)-4-[(3R,5S,7S,8R,9S, 10S,13R,14S,17R)-hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a] phenanthren-17-yl]pentanoic acid, commonly known as Ursodiol, a compound of formula (I), comprising

a) reacting a compound of formula (A) with an oxidising agent in suitable solvent or solvent mixture to provide a compound of formula (B) in absence of phase transfer catalyst;

b) reacting the compound of formula (B) with a reducing agent in a suitable
solvent; followed by triethyl amine salt formation in a suitable solvent or solvent mixture to yield a compound of formula (C)


c) Converting the compound of formula (C) to Ursodiol of formula (I) by using a suitable neutralizing agent in presence of suitable solvent or mixture thereof
Another object of the present invention is to provide a process for the preparation of Ursodiol which is substantially free from impurity and is also industrially viable.
It has been surprisingly found that the process according to the present invention provides Ursodiol with superior impurity profile. Isolation of intermediates and final product by filtration techniques makes this process commercially viable and user friendly.
DETAILED DESCRIPTION OF THE INVENTION
As used throughout the specification, the term "suitable solvent" refers to, but is not limited to polar protic solvents such as methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol, iso-butanol, n-pentanol and the like; halogenated solvents such as methylene chloride (dichloromethane), chloroform, chlorobenzene, trichloroethylene, carbon tetrachloride, and the like; hydrocarbons solvents such as toluene, xylene, hexanes, heptanes, petroleum ether and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether (TBME), dioxane, tethydrofuran (THF) and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert. butyl acetate and the like; ketone solvents such as acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK); water or mixtures thereof.
As used throughout the specification, the term "Inorganic acids" refers to, but is not limited to hydrochloric acid, sulphuric acid, nitric acid and the like.

As used throughout the specification, the term "Phase Transfer Catalyst (PTC)" refers to, but is not limited to benzyltributylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium hydrogensulfate, tetramethylammonium bromide and the like.
In one embodiment, the present invention provides a process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a]phenanthren-17-yl]pentanoic acid, commonly known as Ursodiol, the compound of formula (I)



b) reacting the compound of formula (B) with a reducing agent in a suitable solvent followed by triethyl amine salt formation in a suitable solvent or solvent mixture to yield a compound of formula (C)


c) converting the compound of formula (C) to Ursodiol of formula (I) by using a suitable neutralizing agent in presence of suitable solvent or mixture thereof
In one embodiment, step (a) comprises reacting a compound of formula (A) with an oxidizing agent in suitable solvent or solvent mixture to provide a compound of formula (B) in absence of phase transfer catalyst.

The oxidizing agent used in step (a) is selected from hypohalous acid or a salt thereof. Preferably, the oxidizing agent used for process step (a) is selected from sodium hypochlorite, calcium hypochlorite. More preferably the oxidizing agent used is sodium hypochlorite.
The suitable solvent used in step (a) is as defined supra. Preferably, the solvent used for the process in step (a) is ketone solvent, water or mixture thereof. More preferably, the solvent used in step (a) is mixture of acetone and water thereof.
In one embodiment, the step (a) comprises, adding and stirring a compound of formula
(A) and acetic acid in acetone-water mixture in a ratio of about 7:0, preferably in a ratio
of about 6:05, more preferably in a ratio of about 5:1 and the reaction mixture was cooled
at a temperature of about-15 °C to about 15 °C preferably at a temperature of about -10

°C to about 10 °C, more preferably at a temperature of about -5 °C to about 5 °C. Further to the reaction mixture, about 4 to 6% sodium hypochlorite solution may be added at a temperature of about -15 °C to about 15 °C, preferably at a temperature of about -10 °C to about 10 °C, more preferably at a temperature of about -5 °C to about 5 °C in about 3 h, preferably in about 2 h, more preferably in about 1 h. Further, the reaction mixture may be maintained for about 3 h, preferably for about 2 h, more preferably for about 1 h.
After the completion of the reaction in step (a), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (a), the crude product obtained after the reaction in step (a) may be washed using a suitable solvent. The suitable solvent used in as defined supra. Preferably, the solvent used for washing is water. The wet cake obtained thereafter may be dried at temperature of about 40 °C to about 65 °C, preferably at a temperature of about 45 °C to about 60 °C, more preferably at a temperature of about 50 °C to about 55 °C for about 8 h to about 14 h, preferably for about 9 h to 13 h, more preferably to about 10 h to 12 h.
In one embodiment, the compound of formula (B) obtained after the completion of reaction in step (a) may be purified by techniques known in the art such as crystallization, fractional crystallization, liquid-liquid extraction and the like. The said purification may be carried out using a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an ester solvent, polar protic solvent, water or mixture thereof. More preferably, the solvent is a mixture of ethyl acetate, methanol and water.
In one embodiment, the crude was charged in to a mixture of ethyl acetate, methanol and water at 25 °C to 35 °C. The reaction mixture may be heated and stirred at a temperature of about 50 °C to about 75 °C, preferably at a temperature of about 55 °C to about 70 °C, more preferably at a temperature of about 60 °C to at about 65 °C for about 3 h, preferably for about 2 h, more preferably to about 1 h. Further the reaction mixture was cooled to a temperature of about 0 °C to about 25 °C, preferably at a temperature of about 5 °C to about 20 °C, more preferably at a temperature of about 10 °C to at about 15 °C and stirred for about 3 h, preferably for about 2 h, more preferably to about 1 h. The solid was filtered and washed with ethyl acetate.
In one embodiment, the present invention provides a process of preparation of Ursodiol of formula (I) comprising, reacting a compound of formula (A) with sodium hypochlorite

in mixture of acetone and water to provide a compound of formula (B) in absence of phase transfer catalyst.
In one embodiment, the step (b) comprises reacting the compound of Formula (B), obtained in step (a), with a reducing agent in a suitable solvent; followed by triethyl amine salt formation in a suitable solvent or solvent mixture to yield compound of formula (C).

The suitable solvent used in step (b) is as defined supra. Preferably, the solvent used for reduction in step (b) is a polar aprotic solvent and the solvent used for triethylamine salt formation is ketone solvent, water or mixture thereof More preferably the solvent used in step (b) for reduction is iso-propyl alcohol and the solvent used for triethylamine salt formation is acetone-water mixture.
In one embodiment, the step (b) comprises, adding and subsequently stirring a compound of Formula (B) in a suitable solvent such as iso-propyl alcohol at a temperature of about 15 °C to about 40 °C, preferably at a temperature of about 20 °C to about 35 °C, more preferably at a temperature of about 25 °C to about 30 °C into pressure reactor. Further Raney nickel may be added at a temperature of about 15 °C to about 40 °C, preferably at a temperature of about 20 °C to about 35 °C, more preferably at a temperature of about 25 °C to about 30 °C. The reaction mixture obtained may be maintained at a temperature of about 55 °C to about 85 °C, preferably at a temperature of about 60 °C to about 80 °C, more preferably at a temperature of about 65 °C to about 75 °C under hydrogen gas pressure of about 3 kg to about 6 kg, preferably at hydrogen gas pressure of about 3.5 to 5.5 kg, more preferably at hydrogen gas pressure of about 4 kg to 5 kg till the completion of the reaction.

After the completion of the reaction in step (b), suitable work up may be performed, as known to a skilled artisan. In one embodiment, after completion of reaction in step (b), the reaction mixture may be cooled at a temperature of about 15 °C to about 40 °C, preferably at a temperature of about 20 °C to about 35 °C, more preferably at a temperature of about 25 °C to about 30 °C and the hydrogen pressure is released.
The reaction mass obtained thereafter may be filtered through hyflo bed after unloading from autoclave. The hyflo bed is then washed with a suitable solvent. The suitable solvent used is as defined supra. Preferably, the solvent used is an alcoholic solvent. More preferably, the solvent used is iso propyl alcohol. The filtrate may be treated under vacuum, to distill off the iso propyl alcohol at a temperature of about 60 °C, preferably at a temperature of about 55 °C, more preferably at a temperature of about 50 °C to obtain an oil which was degassed further at a temperature of about 40 °C to about 65 °C, preferably at a temperature of about 45 °C to 60 °C, more preferably at a temperature of about 50 °C to about 55 °C.
In one embodiment, the oil obtained as above may be taken in a solvent and an inorganic acid may further be used to lower the pH of the solution. The solvent and an acid as used are as defined supra. Preferably, the solvent used is an ester, water or mixture thereof and an inorganic acid used is hydrochloric acid, nitric acid, sulfuric acid and mixture thereof. More preferably, the solvent used is ethyl acetate-water mixture and an inorganic acid used at a temperature of about 30 °C to about 35 °C is dilute hydrochloric acid to adjust the pH to 1. The precipitated solid may then be filtered and washed with a suitable solvent to give Crude Ursodiol. The suitable solvent used is as defined supra. More preferably, the solvent used is water.
In one embodiment, the step (b) further comprises, adding and subsequently stirring crude ursodiol in a suitable solvent as defined supra. Preferably, the solvent used for the process is a ketone solvent, water or mixture thereof. More preferably, the solvent used is a mixture of acetone and water. The crude ursodiol in water-acetone mixture may be heated to at a temperature of about 50 °C to about 55 °C and triethyl amine may be added to the reaction mixture. The obtained reaction mixture may be stirred at a temperature of about 50 °C to about 55 °C for about 30 minutes. To the reaction mixture, acetone may be added at a temperature of about 50 °C to about 55 °C; followed by cooling to a temperature of about 10 °C to about 15 °C. The obtained solid may then be filtered and washed with

suitable solvent. The solvent used for washing is as defined supra. More preferably the solvent used is acetone. The obtained reaction mass may be dried and purified using suitable solvent to get pure compound of formula (B). The solvent used is as defined supra. More preferably the solvent used is mixture of water and acetone.
In one embodiment, the present invention provides a process of preparation of Ursodiol of formula (I) comprising, reacting the compound of Formula (B), obtained in step (a), with Raney nickel in iso-propyl alcohol; followed by triethyl amine salt formation in mixture of acetone and water to yield compound of formula (C).
In one embodiment, the present invention provides a process for the preparation of Ursodiol, comprising
a) reacting compound of formula (A) with an oxidising agent in suitable solvent or solvent mixture to provide a compound of formula (B) in absence of phase transfer catalyst;
b) Reacting the compound of formula (B) with a reducing agent in a suitable solvent followed by triethyl amine salt formation in a suitable solvent or solvent mixture to yield compound of formula (C)
In one embodiment, the step (c) comprises reacting the compound of Formula (C) obtained in step (b) to Ursodiol of Formula (I) by using a suitable neutralizing agent in presence of suitable solvent or mixture thereof.

The suitable solvent used in step (c) is as defined supra. Preferably the solvent used is ketone solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; ester solvent such as ethyl acetate, methyl acetate and the like; water or mixture thereof. More preferably a solvent used is a mixture of ethyl acetate and water.

In one embodiment, the step (c) comprises, adding a compound of Formula (C) in solvent mixture of ethyl acetate and water. The pH of the reaction mixture may be adjusted to about 1 using an inorganic acid as defined supra. More preferably, an inorganic acid used is dilute hydrochloric acid. The reaction mixture may then be stirred at a temperature of about 25 °C to about 30 °C for about 4 h. The solid obtained may be filtered and washed with a suitable solvent. The suitable solvent used is as defined supra. The suitable solvent used is water. The wet cake is dried preferably at a temperature of about 45 °C to 60 °C, more preferably at a temperature of about 50 °C to 55 °C to give Ursodiol, compound of Formula (I).
In one embodiment, the present invention provides a process for the preparation of Ursodiol, comprising converting compound of Formula (C) to Ursodiol by using a suitable neutralizing agent in presence of mixture of ethyl acetate and water. The neutralizing agent used is an inorganic acid as defined supra. More preferably, the neutralizing agent used is a hydrochloric acid.
In one embodiment, the present invention provides a process for the preparation of Ursodiol, comprising
a) reacting compound of formula (A) with an oxidising agent in suitable solvent or solvent mixture to provide a compound of formula (B) in absence of phase transfer catalyst;
b) reacting the compound of formula (B) with a reducing agent in a suitable solvent; followed by triethyl amine salt formation in a suitable solvent or solvent mixture to yield compound of formula (C)
c) converting compound of formula (C) to Ursodiol by using a suitable neutralizing agent presence of suitable solvent or mixture thereof
In one embodiment the present invention provides an improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy -10,13-dimethyl-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid, Ursodiol a compound of formula (I)


comprising the steps of: a) reacting compound of formula (A) with sodium hypochlorite in acetone-water mixture solvent to provide a compound of formula (B) in absence of phase transfer catalyst;

b) reacting the compound of formula (B) with a Raney Nickel in iso propyl alcohol followed by triethyl amine salt formation in acetone-water mixture to yield compound of formula (C)

c) Converting compound of formula (C) to Ursodiol of formula (I) by using dilute hydrochloride acid in water-ethyl acetate mixture
In one embodiment the present invention provides an improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy

-10,13 -dimethyl-1H-cyclopenta[a]phenanthren-17-yl]pentanoic acid, Ursodiol a compound of formula (I)

comprising the steps of: a) reacting compound of formula (A) with sodium hypochlorite in acetone-water mixture in a ratio of about 7:05 to about 5:0 to provide a compound of formula (B) in absence of phase transfer catalyst wherein the temperature of the reaction is in the range of about -10 °C to about 10 °C

b) reacting the compound of formula (B) with a Raney Nickel in iso propyl alcohol followed by triethyl amine salt formation in acetone-water mixture to yield compound of formula (C)

c) converting compound of formula (C) to Ursodiol of formula (I) by using dilute hydrochloride acid in water-ethyl acetate mixture.
The present invention is explained in detail by referring to examples, which are not to be construed as limitative.

Example-1:(R)-4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)hexadecahydro-3-hydroxy-10,13-dimethyl-7-oxo-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (7-KCA, Formula B)
To a solution of (R)-4-((3R,5S,7R,8R,10S,13R,14S,17R)-hexadecahydro-3,7-dihydroxy-10,13-dimethyl-1H-cyclopenta[a]phenanthren-17-yl)pentanoic acid (CDCA) (300 g, 0.764 mole) in acetone (3.0 Ltr), and water (0.60 Ltr) was charged acetic acid (45.88 g, 0.764 mole) and reaction mixture was cooled to -5 °C to 5 °C. To this was added 4 to 6% sodium hypochlorite solution (1.86 kg, 0.726 mole) slowly within 60 min at -5 °C to 5 °C. The reaction mixture was then stirred at -5 °C to 5 °C for 1 h. After reaction completion, water (3.0 Ltr) was added drop wise and precipitated solid was stirred at 25 °C to 30 °C for 2 h. The precipitated solid was later filtered and the obtained cake was washed with water (300 mL x 3) and dried at 50 °C to 55 °C for 10 to 12 h to afford 276 g desired crude (R)-4-((3R,5S,8R, 10S,13R,14S,17R)-hexadecahydro-3-hydroxy-10,13-dimethyl-7-oxo-lH-cyclopenta[a] phenanthren-17-yl)pentanoic acid (7-KCA) as off-white solid (Yield - 92%, HPLC purity - 93%). The crude (276 g) was then charged into a mixture of ethyl acetate (810 mL), methanol (80 mL), and water (80 mL) at 25 °C to 30 °C and the reaction mixture was heated and stirred at 60 °C to 65 °C for 1 h. Further, the reaction mixture was cooled to 10 °C to 15 °C, stirred for 1 h and filtered. The obtained cake was further washed with ethyl acetate (270 mL) and dried at 50 °C to 55 °C for 12 h to afford 220 g desired pure (R)-4-((3R,5S,8R,10S, 13R,14S,17R)-hexadecahydro-3-hydroxy-10,13-dimethyl-7-oxo-lH-cyclopenta[a] phenanthren-17-yl)pentanoic acid (7-KCA) as white solid. Yield - 76%, HPLC purity - 98.5%
ExampIe-2:(R)-4-((3R,5S,7S,8R,10S,13R,14S,17R)-hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a]phenanthren-17-yl)pentanoic acid-Triethylamine salt (Ursodiol-TEA salt, Formula C)
A solution of (R)-4-((3R,5S,8R,10S,13R,14S,17R)-hexadecahydro-3-hydroxy-10,13-dimethyl-7-oxo-lH-cyclopenta[a]phenanthren-17-yl)pentanoic acid (7-KCA) (200 g, 0.512 mole) in isopropyl alcohol (2.0 Ltr) was charged into pressure reactor at 25 °C to 30 °C. To this were added Potassium tert-butoxide (115 g, 1.021 mole) followed by a suspension of Raney nickel (30 g) in isopropyl alcohol (0.4 Ltr) at 25 °C to 30 °C in pressure reactor. Then 4 Kg to 5 kg hydrogen pressure was applied and the reaction

mixture was heated to 65 °C to 75 °C. After this, the reaction mixture was maintained at 65 °C to 75 °C under 4 Kg to 5 kg hydrogen pressure. After reaction completion, reaction mixture was cooled at 25 °C to 30 °C, filtered through hyflo bed and washed with isopropyl alcohol (200 mL). The filtrate obtained was evaporated completely at 50 °C under vacuum to obtain oil which was further degassed at 50 °C to 55 °C under vacuum for 2 h. To this was charged water (2.0 Ltr) followed by ethyl acetate (200 mL) and reaction mixture was stirred for 0.5 h. After adjusting the pH of the reaction mixture to 1 to 2 with drop wise addition of 50% v/v hydrochloric acid (200 mL), the precipitated solid was stirred at 25 °C to 30 °C for 1 h, filtered and washed with water (600 mL x 3) to the get the wet cake which was dried at 50 °C to 55 °C for 12 h to afford 190 g desired crude (R)-4-((3R,5S,7S,8R,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a]phenanthren-17-yl)pentanoic acid (Ursodiol) as off-white solid (Yield -95%, HPLC purity - 94%).
To the crude Ursodiol (190 g, 0.48 mole), was charged acetone (570 mL), followed by
water (48 mL) at 25 °C to 30 °C and the reaction mixture was heated to 50 °C to 55 °C.
Triethylamine (60 g, 0.529 mole) was later added to this reaction mixture and stirred for
0.5 h at 50 °C to 55 °C. To this reaction mixture, was added acetone (1.9 Ltr) slowly at
50 °C to 55 °C and the same was cooled to 10 °C to 15 °C and stirred for 2 h. The obtained
reaction mass was then filtered, washed with acetone (200 mL) and suck dried. The wet
cake was further dried at 55 °C to 60 °C for 2 h, charged into a mixture of acetone (540
mL), water (48 mL) and heated upto 50 °C to 55 °C to get clear solution. To this clear
solution, acetone (1.9 Ltr) was added slowly at 50 °C to 55 °C. Then reaction mixture
was then cooled to 10 °C to 15 °C, stirred for 2 h, filtered and washed with acetone (200
mL). The wet cake obtained was dried at 50 °C to 55 °C for 12 h to afford 160 g desired
pure (R)-4-((3R,5S,7S,8R,l0S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13-
dimethyl-1 H-cyclopenta[a]phenanthren-17-yl)pentanoic acid-Triethylamine salt (Ursodiol-TEA salt) as white solid. Yield - 63%, HPLC purity - 99.9%
Example-3: 4-((3R,5S,7S,8R,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13 -dimethyl-lH-cyclopenta[a]phenanthren-17-yl)pentanoic acid (Ursodiol)
To a mixture of (R)-4-((3R,5S,7S,8R,10S,13R,14S,17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-1 H-cyclopenta[a]phenanthren-17-yl)pentanoic acid-Triethylamine salt

(Ursodiol-TEA salt) (150 g, 0.304 mole) in water (1.5 Ltr), was added charged ethyl acetate (300 mL) and pH of reaction mixture was adjusted to 1 to 2 with drop wise addition of 10% v/v hydrochloric acid (150 mL). The reaction mixture was then stirred at 25 °C to 30 °C for 4 h, filtered and washed with water (450 mL x 2) to get the wet cake. The wet cake was dried at 50 °C to 55 °C for 12 h to afford 115 g desired Ursodiol as off-white solid. Yield - 96%, HPLC purity - 99.9%

We claim:
1. An improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S, 17R)-hexadecahydro-3,7-dihydroxy-10,13 -dimethyl-1 H-cyclopenta[a]phenanthren-17-yl]pentanoic acid, Ursodiol a compound of formula (I)

comprising the steps of: a) reacting compound of formula (A) with oxidising agent in suitable solvent or solvent mixture to provide a compound of formula (B) in absence of phase transfer catalyst;

b) reacting the compound of formula (B) with a reducing agent in a suitable solvent followed by triethy] amine salt formation in a suitable solvent or solvent mixture to yield compound of formula (C)

c) Converting compound of formula (C) to Ursodiol of formula (I) by using a suitable neutralizing agent in presence of suitable solvent or mixture thereof.

2. A process as claimed in claim 1(a), wherein the oxidation is carried out by reacting the compound of formula (A) with oxidising agent comprising hypohalous acid or a salt thereof in a suitable solvent.
3. A process as claimed in claim 2, wherein the said oxidising agent is selected from the group consisting of sodium hypochlorite, calcium hypochlorite and said suitable solvent is selected from the group consisting of diethyl ether, THF, dioxane, tert butyl methyl ether; acetone, methyl isobutyl ketone; water or mixtures thereof.
4. A process as claimed in claim 1(b), wherein the reducing agent is selected from the group consisting of Raney Nickel, Pd/C, Pt and the solvent employed for reduction is selected from the group consisting of polar protic solvent, ethers, hydrocarbons.
5. A process as claimed in claim 1(b), wherein the solvent employed in triethyl amine salt formation is selected from the group consisting of ketones, esters, ethers, water or mixtures thereof.
6. A process as claimed in claim 1(c), wherein the inorganic acid employed for salt neutralization is selected from the group consisting of acid such as aqueous sulfuric acid, dilute hydrochloric acid, aqueous nitric acid.
7. A process as claimed in claim 1(c), wherein the solvent employed in the salt neutralization is selected from the group consisting esters, ethers, halogenated alkyl solvents.
8. An improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S, 17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-1 H-cyclopenta[a]phenanthren-17-yl]pentanoic acid, Ursodiol a compound of formula (I)


comprising the steps of: a) reacting compound of formula (A) with sodium hypochlorite in acetone-water mixture solvent to provide a compound of formula (B) in absence of phase transfer catalyst;

b) reacting the compound of formula (B) with a Raney Nickel in iso propyl alcohol followed by triethyl amine salt formation in acetone-water mixture to yield compound of formula (C)

c) Converting compound of formula (C) to Ursodiol of formula (I) by using dilute hydrochloride acid in water-ethyl acetate mixture
9. An improved process for the preparation of (R)-4-[(3R,5S,7S,8R,9S,10S,13R,14S, 17R)hexadecahydro-3,7-dihydroxy-10,13-dimethyl-lH-cyclopenta[a]phenanthren-17-yl]pentanoic acid, Ursodiol a compound of formula (I)


comprising the steps of: a) reacting compound of formula (A) with sodium hypochlorite in acetone-water mixture in a ratio of about 7:05 to about 5:0 to provide a compound of formula (B) in absence of phase transfer catalyst wherein the temperature of the reaction is in the range of about -10 °C to about 10 °C

b) reacting the compound of formula (B) with a Raney Nickel in iso propyl alcohol followed by triethyl amine salt formation in acetone-water mixture to yield compound of formula (C)

c) converting compound of formula (C) to Ursodiol of formula (I) by using dilute hydrochloride acid in water-ethyl acetate mixture