WO2015104605A1 - A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof - Google Patents

A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof Download PDF

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Publication number
WO2015104605A1
WO2015104605A1 PCT/IB2014/067072 IB2014067072W WO2015104605A1 WO 2015104605 A1 WO2015104605 A1 WO 2015104605A1 IB 2014067072 W IB2014067072 W IB 2014067072W WO 2015104605 A1 WO2015104605 A1 WO 2015104605A1
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WO
WIPO (PCT)
Prior art keywords
formula
pharmaceutically acceptable
rivaroxaban
acceptable salt
reaction
Prior art date
Application number
PCT/IB2014/067072
Other languages
English (en)
French (fr)
Inventor
Jagdish Dattopant Shukla
Ramprasad Yadav
Arvind Yekanathsa Merwade
Keshav Deo
Original Assignee
Wockhardt Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Wockhardt Limited filed Critical Wockhardt Limited
Publication of WO2015104605A1 publication Critical patent/WO2015104605A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to a process for the preparation of Rivaroxaban and its novel intermediates, or pharmaceutically acceptable salts thereof.
  • the present invention provides novel intermediates, which may be useful for the preparation of Rivaroxaban or its pharmaceutically acceptable salts thereof.
  • the process of preparation by using novel intermediate is very simple cost effective and may be employed at commercial scale.
  • the product obtained by using novel intermediate yield the Rivaroxaban of purity 99% or more, when measured by HPLC.
  • the drug compound having the adopted name "Rivaroxaban” has chemical name, 5- chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5- yljmethyl)- 2-thiophenecarboxamide; and has the structural formula I,
  • Rivaroxaban is a factor Xa inhibitor useful as oral anticoagulant. Rivaroxaban can be used for the prevention and treatment of various thromboembolic diseases, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
  • DVT deep vein thrombosis
  • PE pulmonary embolism
  • myocardial infract myocardial infract
  • angina pectoris and restenoses after angioplasty or aortocoronary bypass
  • cerebral stroke CAD
  • transitory ischemic attacks and peripheral arterial occlusive diseases.
  • U.S. Patent No. 7, 157,456 describes Rivaroxaban and process for the preparation thereof.
  • the process of US '456 for rivaroxaban involves reaction of 2-[(2S)-2-oxiranylmethyl]- lH-isoindole-l,3(2H)-dione with 4-(4-aminophenyl)-3-morpholinone to provide 2-((2R)- 2-hydroxy-3- ⁇ [4-(3-oxo-4-morpholiny)phenyl]amino Jpropyl)- lH-isoindole- 1 ,3(2H)- dione, which on cyclization using ⁇ , ⁇ -carbonyl diimidazole to afford 2-( ⁇ 5S)-2-Oxo-3- [4-(3-oxo-4-morpholiny)phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-lH-isoindole-l,3(2H)
  • the present invention provides a process for the preparation of Rivaroxaban intermediates, or pharmaceutically acceptable salt thereof.
  • the present invention is to provide thioester of Formula II,
  • R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole.
  • the present invention is to provide thioester of Formula IIA,
  • the present invention is to provide a process for the preparation of Rivaroxaban o
  • R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, , benzimidazole, benzisoxazole, with the 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3- oxazolidin-3-yl]phenyl ⁇ morpholine-3-one of formula III,
  • Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
  • the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
  • the process includes the step of, reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
  • Rivaroxaban pharmaceutically acceptable salt thereof isolating the Rivaroxaban pharmaceutically acceptable salt thereof.
  • alkyl refers to methyl, ethyl, n- propyl, isopropyl and butyl.
  • aryl refers to phenyl, naphthyl or substituted phenyl and naphthyl.
  • the substitution can be with alkyl, halo, nitro, amine and the like.
  • the intermediates and starting materials of the present invention may be used as free bases or its salts.
  • Inorganic salt may include hydrochloride, hydrobromide and the like; organic slat may include acetate, mesylate, tosylate and the like.
  • the present invention is to provide thioesters of Formula II,
  • R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole and benzisoxazole.
  • the compound of formula II of the present invention is selected from the compounds of,
  • the process for the preparation of compound of Formula II which includes the step of reacting 5-chlorothiophene-2-carboxylic acid with the sulfide compound (R'-S-R or R'- S-S-R), wherein R' is benzothiazolyl, acetyl, substituted or unsubstituted benzoyl or benzopyridyl.
  • the reaction may be performed in presence of a tri-(lower alkyl)- or tri(aryl) phosphine or phosphite, such as triphenylphosphine.
  • a base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide.
  • the reaction may be performed at the temperature range of between -30°C to 100°C, such as the temperature range of between -30°C to 60°C, or -5 °C to 5°C.
  • the reaction may be performed in an inert, non-hydroxy-containing, organic solvent, for example a chlorinated hydrocarbon, such as methylene chloride; an ester solvent, such as ethyl acetate and optionally in the presence of water.
  • a chlorinated hydrocarbon such as methylene chloride
  • an ester solvent such as ethyl acetate
  • the present invention is to provides, thioester of Formula IIA,
  • the process includes the step of, esterifyin chlorothiophene-2-carboxylic acid of formula IV,
  • the esterification reaction is performed in presence of solvent and base.
  • the solvent includes but are not limited to a chlorinated solvent such as dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester such as ethyl acetate, and the like; a nitrile such as acetonitrile, propionitrile, and the like.
  • the reaction is performed in presence of base includes but are not limited to organic base such as dimethylamine, diethylamine or triethylamine and inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably triethylamine.
  • organic base such as dimethylamine, diethylamine or triethylamine
  • inorganic base such as ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide preferably triethylamine.
  • the temperature for performing the esterification is in between -30°C to 40°C more preferably at -5°C to 5°C.
  • the reaction may be maintained for a period of 30 minutes to 2 hours to complete at -5°C to 5°C for the completion.
  • Isolation of compound of formula IIA carried out by means of filtration and washed with methylene chloride.
  • the compound dried under vacuum at temperature range between 50°C to 60°C.
  • the present invention is to provide a process for the preparation of Rivaroxaban o
  • the process includes the step of , reacting thioester of formula II or pharmaceutically acceptable salt thereof
  • R is leaving group selected from the alkyl, aryl, 2-pyridyl, pyrimidinyl, triazolyl or thiazolyl, 2-benzothiazolyl, benzimidazole, benzisoxazole, or a pharmaceutically acceptable salt thereof with the 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl ⁇ morpholine- -one of formula III,
  • Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof
  • the reaction may be carried out in the presence of an organic solvent and a base and optionally in the presence of water.
  • the reaction may be carried out at a temperature ranging from -5°C to about ambient temperature.
  • the organic solvent used is selected from tetrahydrofuran, N,N- dimethylacetamide, N,N-dimethylformamide (DMF), chlorinated hydrocarbons, ketones, esters or a mixture thereof.
  • the reaction is carried out in the presence of bases such as inorganic base or organic base.
  • the organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof; inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
  • the compound of formula III may be prepared from the known processes, for example, US 7,157,456.
  • the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
  • the process includes the step of , reacting thioester of formula IIA or pharmaceutically acceptable salt thereof
  • Rivaroxaban or a pharmaceutically acceptable salt thereof and isolating the Rivaroxaban and pharmaceutically acceptable salt thereof.
  • reaction may be carried out in the presence of an organic solvent and a base as herein described and optionally in the presence of water.
  • the reaction may be carried out at a temperature ranging from -5°C to about ambient temperature for about 2 to 12 hours.
  • the organic solvent used is selected from tetrahydrofuran, N,N-dimethylacetamide, N,N- dimethylformamide, chlorinated hydrocarbons, ketones, esters or a mixture thereof.
  • the reaction is carried out in the presence of bases such as inorganic base or organic base.
  • the organic base is selected from group of triethylamine, methyl amine, diisopropyl amine, N-methylpiperidine, pyridine, 1,8-diazabicycloundecene, 4-dimethylamino pyridine, or a mixture thereof;
  • inorganic base is selected from group of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or mixtures thereof.
  • the present invention is to provide a process for the preparation of Rivaroxaban of Formula I,
  • the process includes the steps of , a) esterification of 5-chlorothiophene-2-carboxylic acid with l,2-bis(2- benzothiazolyl) disulfide in the presence of triphenylphosphine to obtain the S- benzo[d]thiazol-2-yl 5-chlorothiophene-2-carbothioate in the solvent
  • Rivaroxaban carried out by means of quenching of reaction after completion with water, followed by repeated extraction in methylene chloride.
  • the pH of methylene chloride layer is adjusted in the range of 6 to 7 with 2N hydrochloric acid. Finally distillation of solvent yields Rivaroxaban.
  • the present invention provides a Rivaroxaban, has purity more than 99.9 %.
  • the solvent is selected from the group of one or more chlorinated solvent, ester solvent, and nitrile solvent.
  • the chlorinated solvent is selected from the group of one or more dichloromethane, dichloroethane, chloroform, chlorobenzene and the like; an ester is selected from the group of one or more ethyl acetate, and the like; a nitrile is selected from the group of one or more acetonitrile, propionitrile.
  • Rivaroxaban or a pharmaceutically acceptable salt thereof obtained from the present invention is useful for pharmaceutical composition.
  • the present invention relates to pharmaceutical composition
  • pharmaceutical composition comprising rivaroxaban or a pharmaceutically acceptable salt obtained from the present invention and pharmaceutically acceptable carriers and/or diluents thereof, and if desired, other active ingredients, which may be administered orally, intravascularly, subcutaneously, intramuscularly or topically for the use as anticoagulant in a mammal in need thereof.
  • EXAMPLE 2 A process for the preparation of rivaroxaban Exemplified procedure in example 1 with the replacement thioester of compound IIA with S-methyl 5-chlorothiophene-2-carbothioate in N,N-dimethylacetamide and water with potassium carbonate were used in place of triethylamine, during workup methylene chloride was used in mixture of N,N dimethyl acetamide and water to extract the Rivaroxaban.
  • triphenylphosphine (11.5g) and mercaptobenzothiazole disulphide (15.31g) were taken in methylene chloride and reaction mixture was stirred at 28°C -30°C for 1 hr.
  • the 5-chlorothiophene-2-carboxylic acid (7.2g) and triethylamine (3.8 g) were added to the above reaction mixture.
  • the reaction mixture is stirred at 0°C -25 °C for 1 hr. after 1 hr 4- ⁇ 4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl ⁇ morpholine-3-one (lOg) and triethylamine (3.8g) were added.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Cephalosporin Compounds (AREA)
PCT/IB2014/067072 2014-01-08 2014-12-18 A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof WO2015104605A1 (en)

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IN72MU2014 IN2014MU00072A (zh) 2014-01-08 2014-12-18

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WO2016133935A1 (en) * 2015-02-17 2016-08-25 Neupharma, Inc. Certain chemical entities, compositions, and methods

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