DESC:PROCESS FOR PREPARATION OF OBETICHOLIC ACID

Dr. Reddy’s Laboratories Limited
An Indian Company having registered office at
8-2-337, Road No. 3, Banjara Hills, Hyderabad - 500 034,
Telangana, India

The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF OBETICHOLIC ACID INTRODUCTION
The present application relates to process for the preparation of intermediate of obeticholic acid and conversion thereof to obeticholic acid.
Obeticholic acid is a semi-synthetic bile acid analogue. It is an agonist of farnesoid X receptor (FXR) ligand. Obeticholic acid is under development for the treatment of primary biliary cirrhosis (PBC) and Nonalcoholic steatohepatitis (NASH). PCT patent application, WO2002072598A1 (hereinafter referred as the WO’598 application) discloses obeticholic acid and process for preparation thereof. Obeticholic acid is chemically known as 6a-ethyl-chenodeoxycholic acid and has following structural formula:

US patent, US7994352B2 (hereinafter referred as the US’352 patent) discloses a process for the preparation of obeticholic acid.
PCT patent application, WO2013192097A1 (hereinafter referred as the WO’097 application) discloses a process for preparing pure amorphous form of obeticholic acid comprising the step of converting crystalline form C of obeticholic acid to pure amorphous form. Amorphous form has been designated as Form 1 in the WO’097 application.

Obeticholic acid is synthetic bile acid and hence achieving ICH grade of purity is known to be difficult. Moreover, the starting material for the synthesis of obeticholic acid is chenodeoxycholic acid which is obtained from animal origin. Hence, the purification of obeticholic acid is essential for the use of it as drug.
Hence, there remains a need for an alternate commercially feasible process for the preparation of pure obeticholic acid which is suitable to be used as drug.
SUMMARY
One aspect of the present application relates to a process for the preparation of compound of formula (II) comprising reducing compound of formula (I) in presence of Raney nickel

wherein, P is hydrogen or a protecting group and R is C1-C5 alkyl.

Another aspect of the present application relates to a process for the preparation of compound of formula (IIA) comprising reducing compound of formula (IA) in presence of Raney nickel

DETAILED DESCRIPTION
One aspect of the present application relates to a process for the preparation of compound of formula (II) comprising reducing compound of formula (I) in presence of Raney nickel

wherein, P is hydrogen or a protecting group and R is C1-C5 alkyl.

In one embodiment, P is any nitrogen protecting group known in the art. In another preferable embodiment, P is acetyl group. In yet another embodiment, R is methyl.

Another aspect of the present application relates to a process for the preparation of compound of formula (IIA) comprising reducing compound of formula (IA) in presence of Raney nickel
One embodiment of the present application relates to a process for preparation of compound of formula (II) by reduction in presence of Raney nickel in a suitable solvent. The suitable solvent may be selected from a group of an ester solvent such as ethyl acetate, methyl acetate and the like; an alcohol solvent such as methanol, ethanol and the like; a ketone solvent such as acetone, methyl ethyl ketone and the like; water and mixture thereof. Specifically, the suitable solvent is a mixture of an ester solvent and water. More specifically, the suitable solvent is a mixture of an ethyl acetate and water.
Another embodiment of the present application relates to a process for preparation of compound of formula (II) by reduction in presence of Raney nickel in a suitable solvent at a temperature of about 30 °C to about boiling point of the solvent. Specifically, the temperature may be about 40 °C to about 60 °C.

The prior art, WO2017208165, discloses a process for preparation of compound of formula (II) by reducing a compound of formula (I) in presence of palladium/charcoal. Since, palladium is more toxic than Raney nickel and is acceptable up to 10 ppm compared to Raney nickel which is acceptable up to a level of 20 ppm as per regulatory guidelines. Moreover, it is also known that palladium is more costly than Raney nickel. Hence, the process of the present application is advantageous over prior art in terms of quality, regulatory acceptability and economic significance.
In another embodiment, the compound of formula (II) may be converted to obeticholic acid by a process, as known in WO2017208165. Specifically, the compound of formula (IIA) may be converted to obeticholic acid by a process, as known in WO2017208165.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The terms "about," "general, ‘generally," and the like are to be construed as modifying a term or value such that it is not an absolute. Such terms will be defined by the circumstances and the terms that they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25 °C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “room temperature” is taken to mean a temperature of about 20 °C to about 30 °C.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
The term “Crude” is taken to mean that the material is not pure enough to be used as drug.
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 disclosure in any manner.

Examples

Example 1: Preparation of methyl 3a-acetoxy-6-ethyl-7-keto-5ß-cholanate (IIA)
A solution of methyl 3a-acetoxy-6-ethylidene-7-keto-5ß-cholanate (IA) (15 g) and ethyl acetate (71.25 mL) was charged in an autoclave. A suspension of Raney nickel (15 g) and water (15 mL) was charged into the autoclave. The autoclave was flashed with nitrogen pressure and then with hydrogen pressure and then maintain the reaction mass with hydrogen up to a pressure of 6 – 8 kg/cm2 at 50 – 55 °C for 30 – 35 hours. The reaction mass was cooled to 25-30 °C and filtered through hyflow bed. The bed was washed with ethyl acetate (100 mL) and the organic layer was separated. The organic layer was distilled out completely at below 50 °C completely. Toluene (30 mL) was added to the residue and distilled out under vacuum up to 1-2 volumes. The step was repeated for 2 times and obtained reaction mass was carried forward to the next step.

Example 2: Preparation of methyl 3a-acetoxy-6a-ethyl-7-keto-5ß-cholanate (IIIA)
To a mixture of methyl 3a-acetoxy-6-ethyl-7-keto-5ß-cholanate (IIA), as obtained in the Example 1, in toluene (75 mL), 1,8-Diazabicyclo(5.4.0)undec-7-ene (DBU) (12.03 g) was added at 28 °C. The reaction mass was stirred for 12 hours at 105–120 °C and then allowed to cool to 10-15 °C. Acetic acid (5.69 g) was added to the reaction mass at 10-25 °C. The temperature of the reaction mass was allowed to warm up to 25 °C for and stirred for 15-30 minutes. An aqueous solution of sodium chloride (20%, 75 mL) was added and stirred for 15-45 minutes. The organic layer was separated. The aqueous layer was extracted with toluene (75mL). The combined organic layer was washed with aqueous sodium bicarbonate solution (8%, 150 mL) followed by water (75 mL). The organic layer was distilled under vacuum up to 1-1.5 volumes below 60 °C. To the residue, n-heptane (30 mL) was added and distilled under vacuum up to 1-1.5 volumes. This step was repeated once. To the residue, methanol (30 mL) was added and distilled under vacuum up to 1-1.5 volumes. This step was repeated thrice. Again methanol (22.5 mL) was added to the reaction mass and heated to reflux for 15 minutes. The reaction mass was cooled to -6 to +2 °C and stirred for 1-2 hours at that temperature. The precipitated solid was collected by filtration and washed with precooled methanol (7.5 mL). The solid was suck-dried for 20-30 minutes and then further dried in a vacuum oven at about 50-60 °C for about 8 hours.
Yield: 9.9 g
Purity (by HPLC): 95.37%

,CLAIMS:WE CLAIM:
1. A process for the preparation of compound of formula (II) comprising reducing compound of formula (I) in presence of Raney nickel
COOROPOCOOROPO(I)(II)
wherein, P is hydrogen or a protecting group and R is C1-C5 alkyl.
-9-
2. The process as claimed in claim 1, wherein R is methyl.
3. The process as claimed in claim 1, wherein P is acetyl.
4. A process for the preparation of compound of formula (IIA) comprising reducing compound of formula (IA) in presence of Raney nickel
COOMeOAcOCOOMeOAcO(IA)(IIA)
5. The process as claimed in claim 4, wherein the solvent is a mixture of ethyl acetate and water.
6. The process as claimed in claim 4, wherein the process is carried out under high pressure and in presence of hydrogen gas.
7. The process as claimed in claim 4, wherein the temperature at which the process is carried out is about 40 °C to about 60 °C.
8. The process as claimed in claim 4, is further extended to Obeticholic acid.