Claims:1. A process for the preparation of 3, 3-dichloro-1-(4-iodophenyl)piperidin-2-one or salts thereof, compound of Formula II

Formula-II
Theprocess includes the step of;
a) dissolving 1-(4-iodophenyl)piperidin-2-one in toluene at temperature about 0°C to 10°C,
b) treating the reaction mixture of step (a) with phosphorous pentachloride attemperature about 60°C to 65°C,
c) isolating3, 3-dichloro-1-(4-iodophenyl)piperidin-2-one or salt thereof.

2. The process of claim 1, wherein step (c) is carried out at low temperature -10°C to 0°C.

3. The process of claim 1, wherein step (c) involves extraction of 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salt thereof by means of phase separation technique.

4. The process of claim 3, wherein phase separation is carried out in dichloromethane and water solvent system.

5. The process of claim 1,wherein isolated 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salt thereof is further purified in ether solvent.

6. The process of claim 5, wherein ether solvent is isopropyl ether.

7. The process of claim 1, wherein 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereof has purity more than 99 %, when measured by HPLC.

8. The process of claim 1, wherein 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereof is further converted to Apixaban.
, Description:Field of Invention

The present invention relates to a process for the preparation Apixaban Intermediate. The present invention specifically directs to process for the preparation of 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereof. The present invention process is very simple cost effective and may be employed at commercial scale. The product obtained by using an improved process has purity more than 99.9 %, when measured by HPLC.

Background of the invention

Apixabanis an anticoagulant for the treatment of venous thromboembolic events, indicated for the treatment of venous thromboembolic events. Apixabanis a factor Xa inhibitor, is chemically described as 1-(4methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridine-3-carboxamide.

Formula-I
US Patent No. 6,967,208 describes the Apixabanand its process for the preparation.

US Patent Nos. 6,919,451; 7,153,960; 7,396,932;8,969,561 and 8,884,016 describevarious processes for the preparation of Apixaban and other pyrazole-pyridine derivatives.There are also some pending US Patent application describe processes for the preparation of Apixaban US20070027186 and US 20070203178.

Summary of the Invention

The present invention provides a process for the preparation of Apixaban Intermediate.

In an aspect, the present invention is to provide a process for the preparation of 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereof, compound of Formula II

Formula-II
Theprocess includes the step of;
a) dissolving 1-(4-iodophenyl)piperidin-2-one in toluene at temperature about 0-10?C,
b) treating the reaction mixture of step (a) with phosphorous pentachloride attemperature about 60-65?C,
c) isolating3, 3-dichloro-1-(4-iodophenyl)piperidin-2-oneor a salt thereof.

In an aspect, the present invention is to provide a 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-oneor a salt thereofhas purity more than 99.5 % when measured by HPLC.
Description of the Invention

For purposes of the present invention, the following terms are defined below.

The3, 3-dichloro-1-(4-iodophenyl) piperidin-2-oneof the present invention may be prepared/used as free bases or its salts.

The salt used is pharmaceutically acceptable salt and it refers to inorganic or organic salt. Inorganic salt may include hydrochloride, hydrobromide, and the like; organic salt may include acetate, mesylate, tosylate, trifluoroacetate, fumarate, mandalate, lactate, glutamate, ascorbate, citrate and the like.
In an aspect, the present invention is to provide a process for the preparation of 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereof, compound of Formula II

Formula-II
Theprocess includes the step of;
a) dissolving 1-(4-iodophenyl)piperidin-2-one in toluene at temperature about 0-10?C,
b) treating the reaction mixture of step (a) with phosphorous pentachloride attemperature about 60-65?C,
c) isolating3, 3-dichloro-1-(4-iodophenyl)piperidin-2-oneor salt thereof.

The present invention process for the preparation of involves dissolving 1-(4-iodophenyl) piperidin-2-one in toluene at temperature in between range of 0-10 °C, followed by treatment with phosphorous pentachloride. The reaction is heated in between range of 60-65 °C for the period of 4 to 6 hours.

The resulting reaction mass is cooled at temperature in between range of -5 to 0 °C, followed by slowly addition of water and dichloromethane. The reaction mixture is stirred. The layers are separated. Organic layer is preserved and aqueous layer is extracted again in dichloromethane. Layers separated, aqueous layer discarded. Both organic layers are combined and washed with water organic layer is concentrated under vacuum at temperature in between range of 50-60 °C to get thick semi solid mass.

The resulting semisolid mass is charged with isopropyl ether, followed by stirring for the period of 1 hour. The reaction mass is filtered and washed with Isopropyl ether and the obtained solid material is dried at temperature in between range of 45-50 °C under vacuum to get highly pure 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one.

In an aspect, the present invention is to provide a 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one or salts thereofhas purity more than 99.5 % when measured by HPLC.

The present invention may further be illustrated by the following examples which may be provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents may be apparent to those skilled in the art and may be intended within the scope of the present invention.

EXAMPLES

Example 1: Preparation of 3, 3-dichloro-1-(4-iodophenyl) piperidin-2-one

Charged 800 ml toluene and 100 gm (0.270 moles) 1-(4-iodophenyl) piperidin-2-oneat temperature about 5 °C. To the above suspension 196.8 gm (242gm) (0.945 moles) phosphorous pentachloridewas added, followed by heating the reaction mixtureat temperature to about 60?C to 65 °C for the period of 2 hours. Resulting reaction mass was cooled to temperature -5?C to 0 °C, followed by slowly addition of 500 mL water, followed by 1000 ml dichloromethane and stirred. Layers were separated and organic layer was preserved and aqueous layer again extracted with 200 ml dichloromethane under stirring. Layers were separated and aqueous layer was discarded. Both organic layers were combined and washed with water and aqueous layer was discarded. Organic layer was concentrated under vacuum at temperature 50-60 °C to get thick semi solid mass. To the resulting semisolid mass, charged with 200 ml of isopropyl ether, stirred for 1 hour, filtered and washed with 200 ml isopropyl ether. Thus obtained solid material dried at temperature 45°C -50 °C under vacuum to get titled compounds.
Yield: 99gm
HPLC purity: > 99%