Claims:1. An Improved process for preparing 1-(4-iodophenyl) piperidine-2-one compound of Formula (II)

Formula-II
which is an intermediate in the synthesis of Apixaban, the said process comprising the steps of:
a) reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in tetrahydrofuran;
b) adding potassium hydroxide and then aqueous hydrochloric acid solution to the reaction mixture obtained in step a);
c) extracting the reaction mixture obtained in step b) with dichloromethane;
d) remove the solvent to get 1-(4-iodophenyl) piperidine-2-one compound of Formula (II);
e) optionally purifying the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) using ethyl acetate and isopropyl ether
f) Isolating the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) in an organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

2. The process for the purification of purification of 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) using organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

3. The process according to claim 1 and 2, wherein the organic solvent is selected from the group of C1-C4 alcohols, ketones, ethers, esters, aromatic hydrocarbons, chlorinated hydrocarbons, aliphatic acyclic or cyclic hydrocarbons, dimethylformamide and dimethylsulfoxide or any mixtures thereof.

4. The process according to claim 3, wherein the organic solvent is selected from mixture of ethyl acetate and isopropyl ether.

5. The process according to claim 1 and 2, wherein the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) obtained having purity greater than or equal to 99.9% when measured by HPLC.

6. The process according to claim 1 and 2, wherein the isolation 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) comprising the steps of:
a) adding ethyl acetate and isopropyl ether to the residual solid mass containing 1-(4-iodophenyl) piperidine-2-one compound of Formula (II);
b) cooling the reaction mixture below 25°C;
c) filtering and drying the solid material to obtain 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%

7. The process according to claim 6 , wherein the reaction mixture is cooled to temperature of 5-10°C
, Description:Field of Invention

The present invention relates to an improved process for preparing intermediate of Apixaban. The present invention provides an improved process for preparing 1-(4-iodophenyl) piperidine-2-one, which is an intermediate in the synthesis of active substance Apixaban. The product 1-(4-iodophenyl) piperidine-2-one obtained according to the present invention has a HPLC purity of greater than or equal to 99.5%.

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 as a compound of Formula (I).

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.
International (PCT) Publication WO 03/047520 A2 discloses process for the preparation 1-(4-iodophenyl) piperidine-2-one by reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in THF followed by cyclization with potassium tertiary butoxide to obtain 1-(4-iodophenyl) piperidine-2-one.

International (PCT) Publication WO 2010/030983 A2 discloses process for the preparation of 1-(4-iodophenyl) piperidine-2-one starting from 4-iodoaniline and 5-bromopentanoyl chloride.

International (PCT) Publication WO 2014/108919 A2 discloses process for the preparation of 1-(4-iodophenyl) piperidine-2-one by reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in toluene followed by cyclization with sodium tertiary butoxide to obtain 1-(4-iodophenyl) piperidine-2-one.

None of the above cited documents discloses the purity of 1-(4-iodophenyl) piperidine-2-one compound of Formula (II).

Therefore, it is an object of the present invention to provide an improved process for the preparation 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity of greater than or equal to 99.5 %.

Summary of the Invention

The present invention relates to an improved process for preparing intermediate of Apixaban.

In one aspect, the present invention is to provide an improved process for preparing 1-(4-iodophenyl) piperidine-2-one compound of Formula (II)

Formula-II
which is an intermediate in the synthesis of Apixaban, the said process comprising the steps of:
a) reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in tetrahydrofuran;
b) adding potassium hydroxide and then aqueous hydrochloric acid solution to the reaction mixture obtained in step a);
c) extracting the reaction mixture obtained in step b) with dichloromethane;
d) remove the solvent to get 1-(4-iodophenyl) piperidine-2-one compound of Formula (II);
e) optionally purifying the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) using ethyl acetate and isopropyl ether
f) Isolating the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) in an organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

In another aspect of the present invention, the present invention relates to purification of 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) in an organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

Description of the Invention

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

The Apixaban, intermediate 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 one aspect, the present invention is to provide an improved process for preparing 1-(4-iodophenyl) piperidine-2-one compound of Formula (II)

Formula-II
which is an intermediate in the synthesis of Apixaban, the said process comprising the steps of:
a) reacting 4-iodoaniline with 5-bromopentanoyl chloride in presence of triethylamine in tetrahydrofuran;
b) adding potassium hydroxide and then aqueous hydrochloric acid solution to the reaction mixture obtained in step a);
c) extracting the reaction mixture obtained in step b) with dichloromethane;
d) remove the solvent to get 1-(4-iodophenyl) piperidine-2-one compound of Formula (II);
e) optionally purifying the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) using ethyl acetate and isopropyl ether
f) Isolating the 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) in an organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

In another aspect of the present invention, the present invention relates to purification of 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) using organic solvent to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having HPLC purity greater than or equal to 99.5%.

According to the present invention, the organic solvent used for isolating 1-(4-iodophenyl) piperidine-2-one is selected from the group of C1-C4 alcohol, e.g. methanol, ethanol, isopropanol, n-propanol or butanol; a ketone, e.g. acetone, methyl ethyl ketone, methyl isobutyl ketone or methyl isopropyl ketone; a carboxylic ester, e.g. ethylacetate or methyl acetate; an ether, e.g. ethyl ether , isopropyl ether , tetrahydrofuran or dioxane; an aromatic hydrocarbon, e.g. toluene, or xylene; an aliphatic acyclic or cyclic hydrocarbon, e.g. pentane, hexane or cyclohexane ; a chlorinated hydrocarbon, e.g. methylenchloride or chloroform; N,N-dimethylformamide; dimethylsulfoxide or any mixtures thereof.

According to the present invention, the organic solvent used for purification of 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) is selected from a mixture of ethyl acetate and isopropyl ether.

According to the present invention, the isolation of 1-(4-iodophenyl) piperidine-2-one of Formula (II) using mixture of ethylacetate and isopropyl ether is carried out by addition of ethyl acetate followed by isopropyl ether to the residual solid mass containing 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) and cooling the reaction mixture to 5-10°C and maintained for 1 hr. The solid was filtered and dried under vacuum at 45-50°C to get 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having purity greater than or equal to 99.5% when measured by HPLC.

In another aspect, the present invention is schematically represented as follows:

In an aspect, the present invention is to provide 1-(4-iodophenyl) piperidine-2-one compound of Formula (II) having purity greater than 99.5 % when measured by HPLC, more preferably greater than 99.9 % 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 1-(4-iodophenyl) piperidine-2-one compound of Formula (II):
Triethylamine (103.6 gm) was added to a solution of 4-iodoaniline (100 gm) in tetrahydrofuran (700 mL). After cooling the reaction mixture to about 0°C, a solution of 5-bromo-pentanoyl chloride (100 gm) (114.0gm) in tetrahydrofuran (100 mL) was slowly added to the mixture at 0-5° C and maintained the reaction mixture for 2 hrs at 0-5 °C. To the reaction mixture containing 5-bromo-N-(4-iodophenyl) pentanamide, potassium hydroxide pellets (76.8 gm) (86.0 gm) was added at 0-5 °C and maintained for 3 hours at 0-5 °C. After completion of the reaction, the reaction mixture was acidified with 2N HCl (1000 mL) solution and extracted with dichloromethane (500 mL). The organic layer was concentrated in vacuum till the residual volume of solvent obtained. To the residual solid mass, ethyl acetate (100 mL) was added and distilled out. Mixture of ethyl acetate (67 mL) and isopropyl ether (133 mL) was added to the resulting solid mass and cooled to 5-10°C. The reaction mixture was filtered and washed with mixture of ethyl acetate and isopropyl ether. The obtained solid material dried at 45-50°C under vacuum to get the title compound.
Yield: 107 gm
HPLC purity: 99.9 %