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IMPURITIES OF RIVAROXABAN AND PROCESSES FOR THEIR PREPARATION

IP.com Disclosure Number: IPCOM000238888D
Publication Date: 2014-Sep-23

Publishing Venue

The IP.com Prior Art Database

Abstract

We have identified Compounds II-VIII as impurities during the manufacture of rivaroxaban. The present disclosure provides identification of the Compounds II-VIII and processes for the preparation thereof. These compounds after being synthesized individually are used as reference standards in determining the level of impurity of each of these in a given rivaroxaban batch. This further helps us controlling the impurity and thus the quality in a given rivaroxaban batch.

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IMPURITIES OF RIVAROXABAN AND PROCESSES FOR THEIR PREPARATION

Abstract

We have identified Compounds II-VIII as impurities during the manufacture of rivaroxaban.  The present disclosure provides identification of the Compounds II-VIII and processes for the preparation thereof.  These compounds after being synthesized individually are used as reference standards in determining the level of impurity of each of these in a given rivaroxaban batch.  This further helps us controlling the impurity and thus the quality in a given rivaroxaban batch.

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Rivaroxaban chemically is 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide, represented by Formula I.

Formula I

We have identified Compounds II-VIII as impurities during the manufacture of rivaroxaban.  Impurities, even in trace amounts, may influence the efficacy and safety of a pharmaceutical product.  Therefore, identification and quantification of known impurities present in an active pharmaceutical ingredient, is necessary step during the manufacture of dosage forms in order to meet the required regulatory standards.  In order to quantify the level at which each of these impurities are present in the active pharmaceutical ingredient, each impurity needs to be synthesized separately, thereby creating a “reference standard”.  We also report herein the processes for synthesizing these impurities.

The structures of these impurities (Compounds II-VIII) are given below,

Formula II,

Formula II

Formula III,

Formula III

Formula IV,

Formula IV

Formula V,

Formula V

Formula VI,

Formula VI

Formula VII, and

Formula VII

Formula VIII.

Formula VIII

Process for preparation of a compound of Formula II

A process for the preparation of a compound of Formula II,

Formula II

comprises reacting a compound of Formula IX

Formula IX

with phosgene or a phosgene equivalent.

The compound of Formula IX is treated with phosgene or the phosgene equivalent in a solvent, in the optional presence of a base, to obtain the compound of Formula II.

The phosgene equivalent is selected from the group consisting of diphosgene, triphosgene, and a carbon monoxide equivalent selected from the group consisting of carbonyldiimidazole and disuccinimidyl carbonate.

The base is an organic or an inorganic base.  Examples of organic bases include triethylamine, pyridine, N,N’-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 1,4-diazabicyclo[2.2.2]octane.  Examples of inorganic bases include sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, potassium carbonate, and calcium bicarbonate.

The solvent is selected from the group consisting of water, halogenated hydrocarbons, ethers, esters, amides, nitriles, and mixtures thereof.  Examples of halogenated hydrocarbon solvents include dichloromethane, dichloroethane, chloroform, and carbon tetrachloride.  Examples of ether solvents i...