Claims:1. A process for the preparation of Apixaban, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof,
the process comprises of ;
a) converting ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin -1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, Formula-II

Formula-II
to 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, Formula-III,

Formula-III
b) aminating 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, formula-IV

Formula-IV
with aminating agent and coupling agent to obtain Apixaban or a pharmaceutically acceptable salt thereof.

2. The process of claim 1, wherein aminating agent is selected from the group comprising one or more ammonia gas, concentrated ammonium hydroxide ammonium salts such as ammonium carbonate and ammonium phosphate.

3. The process of claim 2, wherein aminating agent is ammonia gas.

4. The process of claim 1, wherein coupling agent is selected from the group comprising one or more N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), 1,1'-carbonyldiimidazole (CDI) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and ethyl chloroformate.

5. The process of claim 4, wherein coupling agent is ethyl chloroformate.

6. The process of claim 1, wherein Apixaban or a pharmaceutically acceptable salt thereof has purity more than 99 %, when measured by HPLC.

7. The process of claim 1, wherein 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid has purity more than 99 %, when measured by HPLC.
, Description:Field of Invention

The present invention relates to a process for the preparation of Apixaban or pharmaceutically acceptable salts thereof. The present invention provides improved process for the preparation of Apixaban or its pharmaceutically acceptable 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 more than 99 %, when measured by HPLC.

Background of the invention

Apixaban is an anticoagulant for the treatment of venous thromboembolic events, indicated for the treatment of venous thromboembolic events. Apixaban is 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 Apixaban and its process for the preparation.

US Patent Nos. 6,919,451; 7,153,960; 7,396,932; 8,969,561 and 8,884,016 describe various 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 US 20070027186 and US 20070203178.

Summary of the Invention

The present invention provides a process for the preparation of Apixaban or pharmaceutically acceptable salt thereof.

In an aspect, the present invention is to provide a process for the preparation of Apixaban, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof,
the process includes the step of;
a) converting ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, Formula-II

Formula-II
to 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, Formula-III

Formula-III
b) aminating 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, formula-IV

Formula-IV
with coupling agent to obtain Apixaban or a pharmaceutically acceptable salt thereof

In an aspect, the present invention is to provide a Apixaban has 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.

The Apixaban, intermediates thereof of 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 of the present invention provides a process for the preparation of Apixaban, compound of Formula I

Formula-I
or a pharmaceutically acceptable salt thereof,
the process includes the step of
a) converting ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin -1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, Formula-II

Formula-II
to 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, Formula-III,

Formula-III
b) aminating 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid, formula-IV,

Formula-IV
with aminating agent and coupling agent to obtain Apixaban or a pharmaceutically acceptable salt thereof.

The aminating agent is selected from the group comprising one or more ammonia gas, concentrated ammonium hydroxide (an aqueous solution of ammonia), ammonium salts (ammonium carbonate, ammonium phosphate, etc.) and the like.

The coupling agent is selected from the group comprising one or more N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), 1,1'-carbonyldiimidazole (CDI) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and ethyl chloroformate and the like.

The step (a) of present invention involves the suspending ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate in mixture of water and alcohol, wherein alcohol is selected from the group comprising one or more of methanol, ethanol, isopropanol, n-propanol, butanol, isobutanol and propylene glycol. The reaction mixture is cooled to temperature in between range of 15?C to 20°C, followed by addition of 10% to 15% aqueous hydroxide base solution, wherein base is selected from the group comprising one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate. The reaction mixture is stirred at temperature 60 °C and then washed with dichloromethane. The pH of aqueous layer is adjusted in between range of 1.5-2.5 to precipitate out the white solid compound. The reaction mass is stirred at room temperature, filtered, washed and dried at temperature in between range of 45?C to 50 °C under vacuum to get 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid.

The step (b) of present invention involves dissolving 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid in dichloromethane, followed by cooling at temperature in between range of
to -10 to 0 °C. The triethyl amine is added, followed by addition of ethyl chloroformate to the reaction mixture. The ammonia gas is purged in the reaction mixture followed by dichloromethane and water is added. The dichloromethane layer is concentrated under vacuum to get solid mass, which is dried at temperature in between range of 45?C to 50 °C under vacuum to get the Apixaban.

In an aspect, the present invention is to provide a 4,5,6,7-tetrahydro-1-(4-methoxy phenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid has purity more than 99.5 % when measured by HPLC.

In an aspect, the present invention is to provide a Apixaban has 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 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

Charged 125 gm of ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate in mixture of water (1.2 L) and methanol (800 mL). The reaction was cooled to temperature at about 15?C to 20 °C. The
10% aqueous sodium hydroxide solution (0.125 L) was added into the reaction mixture and stirred to get clear solution. Solution was filtered, followed by washed with dichloromethane. Organic layer was discarded and aqueous layer pH was adjusted to about 1.5 to 2.5 to precipitate out solid. The obtained white suspension was stirred at room temperature for the period of 30 minutes, filtered washed and dried at temperature about 45?C to 50 °C under vacuum to get titled compound.
Yield: 110 gm
HPLC purity: >99.5%

Example 2: Preparation of 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid

Charged 125 gm of ethyl-4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylate in mixture of water (1.2 L) and isopropyl alcohol (800 mL). The reaction was cooled to temperature at about 15?C to 20 °C. The
10% aqueous potassium hydroxide solution (0.125 L) was added into the reaction mixture and stirred to get clear solution. Solution was filtered, followed by washed with dichloromethane. Organic layer was discarded and aqueous layer pH was adjusted to about 1.5 to 2.5 to precipitate out solid. The obtained white suspension was stirred at room temperature for the period of 30 minutes, filtered washed and dried at temperature about 45?C to 50 °C under vacuum to get titled compound.
Yield: 110 gm
HPLC purity: >99.5%

Example 3: Preparation of 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban)]

Charged 100 gm of 4,5,6,7-tetrahydro-1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid in 1800 mL dichloromethane, followed by cooling to at temperature about -10 to 0 °C. The 46.1 gm triethyl amine was added into the reaction mixture, followed by addition of 27.0 gm of ethyl chloroformate to the reaction mixture. The ammonia gas is purged to the reaction mixture for about 60 minutes. Reaction mixture then treated with dichloromethane (1.5L) and water (1.0L). Layers were separated and organic layer was concentrated under vacuum at 45?C to 50 °C. The solid mass was treated with ethyl acetate (0.100L) filtered, washed and dried at temperature about 45?C to 50 °C under vacuum to get the titled compound Apixaban.
Yield: 95 gm
HPLC purity: >99.5%