WO2012156983A1 - Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide - Google Patents

Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide Download PDF

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WO2012156983A1
WO2012156983A1 PCT/IN2012/000064 IN2012000064W WO2012156983A1 WO 2012156983 A1 WO2012156983 A1 WO 2012156983A1 IN 2012000064 W IN2012000064 W IN 2012000064W WO 2012156983 A1 WO2012156983 A1 WO 2012156983A1
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formula
phenyl
compound
oxo
chloro
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PCT/IN2012/000064
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French (fr)
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Dodda Mohan Rao
Pingili Krishna Reddy
Buthukuri Venkat Reddy
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Symed Labs Limited
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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the present invention relates to processes for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] - 1 ,3 -oxazolidin-5 -yl ⁇ methyl)-2-thiophene-carboxamide.
  • Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is under review in US and approved in several countries of Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe.
  • Rivaroxaban is chemically described as 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl ⁇ methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is r hown below:
  • U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment.
  • the US '860 patent also discloses a process for the preparation of rivaroxaban which
  • the processes of the present invention are simple, eco-friendly, economic, reproducible, robust and are well amenable on industrial scale.
  • the present invention relates to processes for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl ⁇ methyl)-2-thiophene- carboxamide.
  • the present invention provides a process for the preparation of 5-chloro-N- ( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l , 3-oxazolidin-5-yl ⁇ methyl)-2-thiophene- carboxamide of formula (I),
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides an alternate process for the preparation of 5-chloro-N-( ⁇ (5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl ⁇ methyl)- 2-thiophene-carboxamide (I
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula III
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula Ilia
  • Rl is C i.g alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • the present invention provides rivaroxaban (I) having the compound of structural formula II
  • the present invention provides rivaroxaban (I) having the compound of structural formula V
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • Fig. 1 is a schematic representation of the processes of present invention.
  • the present invention is directed to processes for the preparation of 5-chloro-N-( ⁇ (5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl ⁇ methyl)-2-thiophene-carboxamide.
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl; b) reacting the compound of formula (III) with a compound 4- ⁇ 4-[(5S)-5-
  • reaction step (a) comprising the reaction of compound of formula IV with suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like.
  • suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like.
  • suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like
  • the bases that can be used in the reaction steps (a) and (b) are organic bases such as triethylamine, tripropylamine, pyridine, diisopropylamine, diisopropylethylamine, tributylamine;
  • Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and the like; or a mixture thereof, preferably organic base. Most preferably tri ethyl amine is being used.
  • the solvents that can be used in step (a) and (b) include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; aprotic polar solvents such as ⁇ , ⁇ -dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP) and the like; or a mixture thereof.
  • halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like
  • reaction steps (a) and b) are performed separately or can be carried out by single pot.
  • reaction temperature in reaction steps (a) and b) can range from about -10°C to about 30°C, preferably from about -5°C to about 10°C.
  • the time period required for the completion of the reaction step (a) can range from about 30 minutes to about 5 hours, preferably about 30 minutes.
  • the time period required for the completion of the reaction step (b) can range from about 30 minutes to about 20 hours, preferably 10 hours.
  • R is C i -8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
  • the solvent(s) that can be used is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; alkyl ethers such as tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile and the like; N,N-dialkylamides such as ⁇ , ⁇ -dimethylformamide (DMF), ⁇ , ⁇ -dimethylacetamide, sulfoxides and sulfones (e.g. dimethyl sulfoxide and sulfolane); halogenated hydrocarbons such as dichloromethane, chloroform and the like;
  • reaction is performed in the absence of solvents.
  • the reaction temperature can be in the range of about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably about 65°C.
  • the preferred reaction temperature can range from about 100°C to about 150°C, preferably about 120°C.
  • the time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed.
  • the time period required can range from about 30 minutes to about 48 hours, preferably about 10 hours.
  • the bases that can be used optionally include are organic bases or inorganic bases.
  • the organic bases that can be used include, but are not limited to triethylamine, pyridine and the like;
  • Inorganic bases include one or more of alkali metal carbonates, such as sodium carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like or mixtures thereof, preferably organic base.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical
  • saturated hydrocarbon radicals include, but are not limited to groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylme hyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • aryl by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently.
  • Aryl includes, but is not limited to, “heteroaryl” groups.
  • the desired compounds can be obtained from the reaction mixture by conventional means known in the art.
  • the working-up of reaction mixtures, especially in order to isolate desired compounds follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centriiugation and the like.
  • process steps of present invention can be carried out by one pot synthesis.
  • intermediates or their salts used here in the processes of the present invention may exist in either crystalline or amorphous or mixtures thereof.
  • intermediate compound aminomethyloxazolidinone (II) can be used in any salt form and morph.
  • aminomethyloxazolidinone (II) isolated salt form like hydrochloride in pure form or purified form of its free base makes improved reaction management possible in the following reaction with chlorothiophenecarbonyl compound with unwanted side reactions being avoided and a purer product being obtained, so that the elaborate chromatographic purification can be avoided.
  • the compound of formula I obtained by the processes of present invention is optionally purified by making slurry in polar solvents at ambient or mild temperatures or recrystallization using solvents or by acid base or carbon treatment.
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • Rl is C i -8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
  • R is C i.g alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and aryl alkyl, substituted or unsubstituted phenyl;
  • the processes of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.
  • the yield of the intermediates and the final product is about 80%, or more, more preferably, the yield is about 80% to about 90%, most preferably, the yield is about 90% to about 95%, or more, by weight.
  • the product obtained by the processes described above can have high enantiomeric excess.
  • the amount of R-enantiomer is less than about 1% as measured by area percentage by chiral HPLC, more preferably less than about 0.5%, and most preferably less than about 0.15% by chiral HPLC.
  • the processes according to the present invention preferably yields (+)-rivaroxaban or a pharmaceutically acceptable salt thereof in substantially pure enantiomeric form.
  • the ratio of (+) : (-) as obtained by the process of present invention may be at least about 99: 1 , such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1.
  • (+)-rivaroxaban or salt thereof prepared by a processes according to the present invention has an enantiomeric purity of at least about 99.7%, or more preferably at least about 99.9%.
  • (+) rivaroxaban is commonly called as rivaroxaban thus can be referred here in either way.
  • compound of formula (I) can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise within the scope of the invention.
  • the rivaroxaban (I) obtained by the processes of the present invention preferably has an average particle size greater than 300 ⁇ .
  • the term "average particle size” or “particle size” as used herein refers to the volume mean diameter of particles.
  • Rivaroxaban (I) can be further micronized to obtain particles with dc>o >60 ⁇ , more preferably dc>o > 40 ⁇ , and most preferably d%> 30 ⁇ ⁇ .
  • dg 0 > x means that at least 90 % by volume of the particles have a particle size above x.
  • the particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit using purified water as the dilution medium.
  • Micronized rivaroxaban can be obtained for instance by single or multistage micronization in the dry state using dry mills, such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills.
  • rivaroxaban or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 500ppm of N- methylpyrolidine (NMP), less than about 700ppm of tetrahydrofuran, less than about 600ppm of dichloromethane, less than about 400ppm of acetonitrile, ethylene glycol, less than lOOOppm of methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, acetic acid, n-hexane, n-heptane, less than 800ppm of ⁇ , ⁇ -dimethyl formamide (DMF), less tha lOOOppm of dimethyl acetamide (DMA).
  • NMP N- methylpyrolidine
  • DMF dimethyl formamide
  • DMA dimethyl
  • the present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation of rivaroxaban (I) which are well adaptable on a commercial scale.

Abstract

Where R is C 1-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl; in an amount less than or equal to 0.1 area % as determined by HPLC. The present invention is directed to processes for the preparation of 5-chloro-N-( {(5S)-2-oxo-3-[ 4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl methyl)-2-thi6phene-carboxamide. In one embodiment of the present invention, there is provided a process for the preparation of 5-chloro-N-( {(5S)-2-oxo-3-[ 4-(3-oxo-4-morpholinyl) phenyl]-I, 3-oxazolidin-5-yl) methyl)-2-thiophene-carboxamide of formula (I).

Description

PROCESSES FOR THE PREPARATION OF 5-CHLORO-N-({(5S)-2-OXO-3-[4-(3-OXO- 4-MORPHOLINYL) PHENYL]-l,3 0XAZOLIDIN-5-YL}METHYL)-2- THIOPHENECARBOXAMIDE
PRIORITY
This application claims the benefit of Indian Provisional Application with no. 1667/CHE/201 1 filed on 16 May 201 1 the contents of each of which are incorporated by reference herein.
BACKGROUND OF THE INVENTION
1. Technical Field
The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3 - [4-(3 -oxo-4-morpholinyl)phenyl] - 1 ,3 -oxazolidin-5 -yl } methyl)-2-thiophene-carboxamide.
2. Description of the Related Art
Rivaroxaban is a novel anticoagulant used for the prevention of venous thromboembolism in adult patients undergoing elective hip or knee replacement surgery and is under review in US and approved in several countries of Europe. Rivaroxaban is structurally related to the antibacterial compound Linezolid (Zyvox) is enantiomerically pure. Rivaroxaban is available in the market under the brand name Xarelto® as 10 mg tablets in Europe. Rivaroxaban is chemically described as 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl)phenyl] -1,3 -oxazolidin-5 -yl } methyl)-2-thiophene-carboxamide (herein after referred as rivaroxaban) and is r hown below:
Figure imgf000002_0001
U.S. Patent No. US 7,585,860 describes morpholinyl oxazolidinone thiophene carboxamides including rivaroxaban or pharmaceutically acceptable acid addition salts thereof, a pharmaceutical composition and a method of treatment. The US '860 patent also discloses a process for the preparation of rivaroxaban which
illustrated by s
Figure imgf000003_0001
U.S. Publication application US2007/0149522A1 and Drugs of the future 2006, 31(6), 484-493 discloses a e below:
Figure imgf000003_0002
U.S. Patent No. US 7,816,355 Bl describes a process for the preparation of rivaroxaban which is illustrated by below scheme:
Figure imgf000004_0001
Figure imgf000004_0002
The process disclosed in the patent US '860 patent exhibits various disadvantages in the reaction management which has particularly unfavourable effects for preparation of the compound of the formula (I) on the industrial scale.
The alternate process disclosed in the U.S. Publication application US '522A1 involves the usage of toxic solvents or reagents. This is disadvantageous per se, and in addition these toxic substances must be removed from the final product (I) until below the maximum limit permissible in each case in the product for regulatory reasons, may require additional process steps which make the process expensive.
The reported processes aforementioned involves hazardous and expensive reagents, has more scope for the formation of impurities, intricate to handle on commercial scale, requires additional purification steps thus ending up with low yields and purities of the final product thus rendering the process not viable on commercial scale.
Hence there is a need to provide an improved process for the preparation of rivaroxaban, which avoids the use of potentially hazardous, expensive chemicals, the formation of isomeric and other process related impurities, while affording the desired product rivaroxaban or a pharmaceutically acceptable salt resulting in high yield and purity. The reaction steps of the present invention involving the reaction of compound of formula III or V with the compound of formula II of the present invention have not been reported in the literature.
The processes of the present invention are simple, eco-friendly, economic, reproducible, robust and are well amenable on industrial scale.
SUMMARY OF THE INVENTION
The present invention relates to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide.
In one aspect, the present invention provides a process for the preparation of 5-chloro-N- ({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l , 3-oxazolidin-5-yl} methyl)-2-thiophene- carboxamide of formula (I),
Figure imgf000005_0001
comprising:
a) reacting the compound 5-Chloro-thio hene-2-carboxylic acid of formula (IV)
Figure imgf000005_0002
(IV)
with a suitable reagent in the presence of a base to ive the compound of formula (III)
Figure imgf000005_0003
(III)
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
b) reacting the compound of formula (III) with a compound 4-{4-[(5S)-5-(Aminomethyl)-2- oxo-l ,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula II or a salt thereof
Figure imgf000006_0001
(Π)
in the presence of suitable base to give the compound of formula I.
In another aspect, the present invention provides an alternate process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1, 3-oxazolidin-5-yl} methyl)- 2-thiophene-carboxamide (I
Figure imgf000006_0002
(I)
comprising:
reacting the compound substituted 5-Chloro-thiophene-2-carboxylic acid ester of formula (V)
Figure imgf000006_0003
(V)
Where R is C i-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
with a compound 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}- morpholin-3-one of formula II or a salt thereof
Figure imgf000006_0004
optionally in the presence of suitable base to give the compound of formula I. In another aspect, the present invention provides rivaroxaban (I) having the compound of structural formula III
Figure imgf000007_0001
III
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC.
In yet another aspect, the present invention provides rivaroxaban (I) having the compound of structural formula Ilia
Figure imgf000007_0002
Ilia
Where Rl is C i.g alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC.
In yet further aspect, the present invention provides rivaroxaban (I) having the compound of structural formula II
Figure imgf000007_0003
II
in an amount less than or equal to 0.1 area % as determined by HPLC.
In a still further aspect, the present invention provides rivaroxaban (I) having the compound of structural formula V
Figure imgf000007_0004
V Where R is C i-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC.
BRIEF DESCRIPTION OF THE DRAWING
Fig. 1 : is a schematic representation of the processes of present invention.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to processes for the preparation of 5-chloro-N-({(5S)-2- oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene-carboxamide.
In one embodiment of the present invention, there is provided a process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l, 3-oxazolidin-5- yl } methyl)-2-thiophene-carboxamide of formula (I),
Figure imgf000008_0001
(I)
comprising:'
a) reacting the compound 5-chloro-thio hene-2-carboxylic acid of formula (IV)
Figure imgf000008_0002
(IV)
with a suitable reagent in the presence of a base to give the compound of formula (III)
Figure imgf000008_0003
(iii)
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl; b) reacting the compound of formula (III) with a compound 4-{4-[(5S)-5-
(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula II or a salt thereof
Figure imgf000009_0001
in the presence of suitable base to give the compound of formula I.
The reaction step (a) comprising the reaction of compound of formula IV with suitable reagent selected from alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like. Preferably ethyl chloro formate.
The bases that can be used in the reaction steps (a) and (b) are organic bases such as triethylamine, tripropylamine, pyridine, diisopropylamine, diisopropylethylamine, tributylamine;
Inorganic bases such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, and the like; or a mixture thereof, preferably organic base. Most preferably tri ethyl amine is being used.
The solvents that can be used in step (a) and (b) include but are not limited to halogenated solvents such as dichloromethane, ethylene dichloride, chloroform, chlorobenzene and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate, tertiary butyl acetate and the like; ethers such as tetrahydrofuran, 1 ,4-dioxane and the like; hydrocarbons such as toluene, xylene and the like; aprotic polar solvents such as Ν,Ν-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidinone (NMP) and the like; or a mixture thereof. Preferably dichloromethane is being used.
Optionally the reaction steps (a) and b) are performed separately or can be carried out by single pot.
The reaction temperature in reaction steps (a) and b) can range from about -10°C to about 30°C, preferably from about -5°C to about 10°C.
The time period required for the completion of the reaction step (a) can range from about 30 minutes to about 5 hours, preferably about 30 minutes. The time period required for the completion of the reaction step (b) can range from about 30 minutes to about 20 hours, preferably 10 hours.
Optionally the intermediate compound of formula III is being isolated.
In another embodiment of the present invention, there is provided an alternate process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l , 3- oxazolidin-5-yl} methyl)- -thiophene-carboxamide of formula (I),
Figure imgf000010_0001
comprising:
reacting the compound substituted 5-Chlo -thio hene-2-carboxylic acid ester of formula (V)
Figure imgf000010_0002
Where R is C i-8 alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
with a compound 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l ,3-oxazolidin-3-yl]phenyl}-morpholin-3- one of formula II or a salt thereof
Figure imgf000010_0003
in the presence of organic solvent and optionally in the presence of a base to give the compound of formula I.
The solvent(s) that can be used is selected from the group consisting of alcohols such as methanol, ethanol, isopropanol, ethylene glycol and the like; alkyl ethers such as tetrahydrofuran, dioxane and the like; esters such as ethyl acetate, isopropyl acetate and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile and the like; N,N-dialkylamides such as Ν,Ν-dimethylformamide (DMF), Ν,Ν-dimethylacetamide, sulfoxides and sulfones (e.g. dimethyl sulfoxide and sulfolane); halogenated hydrocarbons such as dichloromethane, chloroform and the like; water or a mixture thereof. Preferably ethylene glycol is being used.
Optionally the reaction is performed in the absence of solvents.
The reaction temperature can be in the range of about 25°C to about 150°C or the boiling point of the solvent(s) used, preferably about 65°C.
When the reaction is performed in the absence of solvents the preferred reaction temperature can range from about 100°C to about 150°C, preferably about 120°C.
The time required for the reaction to complete may vary depending on the reaction temperature and the nature of the reagents and solvents employed. The time period required can range from about 30 minutes to about 48 hours, preferably about 10 hours.
The bases that can be used optionally include are organic bases or inorganic bases. The organic bases that can be used include, but are not limited to triethylamine, pyridine and the like; Inorganic bases include one or more of alkali metal carbonates, such as sodium carbonate or potassium carbonate, sodium hydrogen carbonate; and alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide and the like or mixtures thereof, preferably organic base.
As used herein, the term "alkyl" by itself or as part of another substituent, means, unless otherwise stated, a saturated straight or branched chain, or cyclic hydrocarbon radical, Examples of saturated hydrocarbon radicals include, but are not limited to groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylme hyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
As used herein, the term "aryl" by itself or as part of another substituent, means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (often from 1 to 3 rings) which are fused together or linked covalently. "Aryl" includes, but is not limited to, "heteroaryl" groups.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centriiugation and the like.
Optionally the process steps of present invention can be carried out by one pot synthesis.
Advantageously the intermediates or their salts used here in the processes of the present invention may exist in either crystalline or amorphous or mixtures thereof.
Advantageously the intermediate compound aminomethyloxazolidinone (II) can be used in any salt form and morph.
In this way it is possible firstly to avoid the carcinogenic pyridine which is used as solvent and base in the process described in US '860. It is additionally possible according to the invention to avoid the complicated chromatographic purification of the product (I).
The process disclosed in US' 860, in which the aminomethyloxazolidinone (II) crude product obtained after concentration of the reaction mixture is directly employed in the further reaction with chlorothiophenecarbonyl chloride, has by contrast the disadvantage that the secondary components of this reaction, which are present in the aminomethyloxazolidinone (II) crude product, impede the subsequent preparation of the final product (I) and additionally contaminate the product (I). In contrast thereto, the use of aminomethyloxazolidinone (II) isolated salt form like hydrochloride in pure form or purified form of its free base makes improved reaction management possible in the following reaction with chlorothiophenecarbonyl compound with unwanted side reactions being avoided and a purer product being obtained, so that the elaborate chromatographic purification can be avoided.
The compound of formula I obtained by the processes of present invention is optionally purified by making slurry in polar solvents at ambient or mild temperatures or recrystallization using solvents or by acid base or carbon treatment.
Preferably by recrystallization using acetic acid or mixture with water in any proportion without limitation.
In yet another embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula III
Figure imgf000013_0001
III
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC.
In yet further embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula Ilia
Figure imgf000013_0002
Ilia
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC.
In a still further embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structur l formula II
Figure imgf000013_0003
II
in an amount less than or equal to 0.1 area % as determined by HPLC.
In yet another embodiment of the present invention, there is provided rivaroxaban (I) having the compound of structural formula V
Figure imgf000013_0004
V
Where R is C i.g alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and aryl alkyl, substituted or unsubstituted phenyl;
in an amount less than or equal to 0.1 area % as determined by HPLC. The processes of present invention are especially valuable for the following reasons: it makes it possible to obtain the compound of formula (I) on an industrial scale in excellent yields, starting from a simple, low-cost starting materials and reagents.
The processes reported for the preparation of rivaroxaban or its intermediates in the art results in the formation of various impurities and bye products leading to include additional purification steps at several stages thus resulting in very poor yields and purities of the final product.
Advantageously, the processes of present invention does not involve purification steps thus provides the final product rivaroxaban with higher yields and purities.
Preferably, the yield of the intermediates and the final product is about 80%, or more, more preferably, the yield is about 80% to about 90%, most preferably, the yield is about 90% to about 95%, or more, by weight.
The product obtained by the processes described above can have high enantiomeric excess. Preferably, the amount of R-enantiomer is less than about 1% as measured by area percentage by chiral HPLC, more preferably less than about 0.5%, and most preferably less than about 0.15% by chiral HPLC.
The processes according to the present invention preferably yields (+)-rivaroxaban or a pharmaceutically acceptable salt thereof in substantially pure enantiomeric form. Thus the ratio of (+) : (-) as obtained by the process of present invention may be at least about 99: 1 , such as at least about 99.8:0.2, or more preferably at least about 99.9 : 0.1. Preferably (+)-rivaroxaban or salt thereof prepared by a processes according to the present invention has an enantiomeric purity of at least about 99.7%, or more preferably at least about 99.9%.
As referred above (+) rivaroxaban is commonly called as rivaroxaban thus can be referred here in either way.
The intermediate compounds of (II), (IV) and (V) are known per se to the person skilled in the art or can be prepared by customary methods. For ex. US 7,585,860 which is herein incorporated for reference.
Furthermore, compound of formula (I) can be present in tautomeric forms. This is known to the person skilled in the art, and such compounds are likewise within the scope of the invention. The rivaroxaban (I) obtained by the processes of the present invention preferably has an average particle size greater than 300 μιτι. The term "average particle size" or "particle size" as used herein refers to the volume mean diameter of particles.
Rivaroxaban (I) can be further micronized to obtain particles with dc>o >60 μηι, more preferably dc>o > 40 μηι, and most preferably d%> 30 μιη. As used herein dg0 > x means that at least 90 % by volume of the particles have a particle size above x.
The particle size can be determined by laser light scattering for instance using a Malvern Mastersizer Apparatus MS 2000 equipped with a Hydro S dispersion unit using purified water as the dilution medium. Micronized rivaroxaban can be obtained for instance by single or multistage micronization in the dry state using dry mills, such as cutting mills, pin/cage mills, hammer mills, jet mills, fluidized bed jet mills, ball mills and roller mills.
In yet another embodiment, rivaroxaban or its pharmaceutically acceptable salts obtained by the processes described above has residual organic solvents or organic volatile impurities comprises less than the amount recommended for pharmaceutical products, as set forth for example in ICH guidelines and U.S. pharmacopoeia; less than about 500ppm of N- methylpyrolidine (NMP), less than about 700ppm of tetrahydrofuran, less than about 600ppm of dichloromethane, less than about 400ppm of acetonitrile, ethylene glycol, less than lOOOppm of methanol, ethanol, ethyl acetate, isopropyl alcohol, acetone, acetic acid, n-hexane, n-heptane, less than 800ppm of Ν,Ν-dimethyl formamide (DMF), less tha lOOOppm of dimethyl acetamide (DMA).
The present invention provides simple, ecofriendly, inexpensive, reproducible, robust processes for preparation of rivaroxaban (I) which are well adaptable on a commercial scale.
The invention is further defined by reference to the following examples describing in detail the preparation of the composition and methods of use of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES
Example 1: Preparation of Rivaroxaban (I)
16.25 gms of 5-chlorothiophene-2-carboxylic acid and 162.5 ml of dichloromethane were charged into a clean and dry 1 lit. 4 neck R.B. Flask. 12.12 gms of triethyl amine was charged at about 30°C followed by stirring for about 15 mins. to get homogenous solution. The resultant reaction solution was cooled to about -5°C and 11.935 gms of ethyl chloro formate was added at about -5°C over about 15 mins. Then reaction temperature was raised to about 0°C and was stirred for about 30mins. After completion of the reaction, a mixture of 32.75 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin-3-one
hydrochloride, 10.1 gms of triethyl amine and 100ml of dichloromethane was added at about - 5°C over about 30mins. The resultant reaction mixture was stirred at about -5°C for about 1 hr. The reaction temperature was raised to about 30°C and was stirred overnight. After completion of the reaction, the solvent was distilled completely at about 40°C to afford 98 gms of the title compound as solid, the solid obtained was recry stall ized from water to afford of the title compound in pure form.
Yield : 36 gms.; Purity by HPLC: 99.85%.
Purification of Rivaroxaban (I)
35 gms of rivaroxaban obtained from example 1 and 1 6ml of acetic acid were charged into a clean and dry 500ml of R.B. Flask. The reaction suspension was heated to about 1 10°C to get homogenous solution. 2.5 gms of charcoal carbon was charged and was stirred for about 15 mins.The reaction suspension was filtered on celite and the celite was washed with 20ml of acetic acid. The filtrate obtained was cooled to about 309C and further cooled to about 20°C and was stirred for about 1 hr.The solid separated was filtered and the solid obtained was washed with 30ml of acetic acid followed by 60ml of water to afford title compound in pure form.
Yield: 32 gms.: Purity by HPLC: 99.94%.
Example - 2: Alternate process for the preparation of Rivaroxaban (I)
20 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin- 3-one, 25 ml of ethylene glycol and 12.13 gms of methyl-5-chlorothiophene-2-carboxylic acid were charged into a clean and dry 500ml. 4 neck R.B. Flask. The reaction mixture was heated to about 65°C for about 48 hours. After completion of the reaction, the reaction mass was decomposed by addition of 200ml of water. The solid separated was filtered and the solid obtained was dried and recrystallized from acetic acid to afford the title compound in pure form. Yield : 26gms.; Purity by HPLC: 99.8%.
Example - 3: Preparation of Rivaroxaban (I) in neat conditions
20 gms of 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin- 3-one, and 12.13 gms of methyl-5-chlorothiophene-2-carboxylic acid were charged into a clean and dry 500ml. 4 neck R.B. Flask. The reaction mixture was heated to about 120°C for about 48 hours under nitrogen. After completion of the reaction, the reaction mass was cooled to about 30°C, 180ml of acetic acid was added. The resultant reaction suspension was heated to about 110°C, 2.5 gms of charcoal carbon was added. The suspension was filtered and the filtrate was cooled to about 20°C for about 15 mins. The solid separated was filtered and the solid was washed with water afford the title compound in pure form.
Yield : 26gms.; Purity by HPLC: 99.96%.

Claims

We Claim:
1) A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]- 1 , 3-oxazolidin-5-yl} memyl)-2-thiophene-carboxamide of formula (I),
Figure imgf000018_0001
(I)
comprising:
a) reacting the compound 5-Chloro-thiophene-2-carboxylic acid of formula (IV)
HO^ /\ §/ -α
O
(IV)
with a suitable reagent in the presence of a base to ive the compound of formula (III)
Figure imgf000018_0002
(III)
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
b) reacting the compound of formula (III) with a compound 4-{4-[(5S)-5-(aminomethyl)-2- oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula II or a salt thereof
Figure imgf000018_0003
(Π)
in the presence of suitable base to give the compound of formula I.
2) The process of claim 1, wherein the suitable reagent used in step (a) is selected from the group consisting of alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloro formate; aryl alkyl chloro formate like benzyl chloro formate and the like;
preferably ethyl chloro formate.
3) The process of claim 1 , wherein the base used in steps (a) and (b) is selected from the group consisting of organic bases like triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tributylamine; Inorganic bases like sodium carbonate, potassium carbonate, sodium hydrogen carbonate or a mixture thereof, preferably organic base, most preferably triethyl amine.
4) The process of claim 1, wherein the solvents in step (a) and (b) is selected from the group consisting of halogenated solvents like dichloromethane; esters like ethyl acetate; ethers like tetrahydrofuran; hydrocarbons like toluene; aprotic polar solvents like ,N- dimethylformamide (DMF) or mixture thereof, preferably dichloromethane.
5) The process of claim 1 , wherein the reaction steps (a) and (b) can be optionally carried out separately or can be performed in one pot.
6) A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-!, 3-oxazolidin-5-yl} methyl)-2-thiophene-carboxamide of formula (I),
Figure imgf000019_0001
comprising:
reacting the compound of formula (III)
Figure imgf000019_0002
(HI)
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
with a compound 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3- yl]phenyl}morpholin-3-one of formula II or a salt thereof
Figure imgf000020_0001
(Π)
in the presence of suitable base to give the compound of formula I.
A method for the preparation of com ound of formula (III)
Figure imgf000020_0002
(III)
Where Rl is C i-8 alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
comprising,
reacting the compound 5-Chloro-thiophene-2-carbox lic acid of formula (IV)
Figure imgf000020_0003
(IV)
with a suitable reagent to give the compound of formula (III).
8) The process of claim 7, wherein the suitable reagent is selected from the group consisting of alkyl chloro formates like ethyl chloro formate, isobutyl chloro formate; sub. or unsub. phenyl chloroformates like phenyl chloroformate, 4-nitrophenyl chloroformate; aryl alkyl chloroformate like benzyl chloroformate and the like; preferably ethyl chloro formate.
9) An alternate process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4- morpholinyl) phenyl]-! , 3-oxazolidin-5-yl} methyl)-2-thiophene-carboxamide of formula
(I),
Figure imgf000021_0001
(I)
comprising:
reacting the compound substituted 5-Chloro-thiophene-2-carboxylic acid ester of formula (V)
Figure imgf000021_0002
Where R is C i-8 alkyl straight chain or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, aryl alkyl, substituted or unsubstituted phenyl;
with a compound 4-{4-[(5S)-5-(Aminomethyl)-2-oxo-l ,3-oxazolidin-3-yl]phenyl}- morpholin-3-one of formula II or a salt thereof
Figure imgf000021_0003
(II)
optionally in the presence of suitable base to provide the compound of formula I.
10) The process of claim 9, wherein the solvent(s) that can be used optionally is selected from the group consisting of alcohols like methanol, ethanol, ethylene glycol; ethers like tetrahydrofuran; esters like ethyl acetate; hydrocarbons like toluene; aprotic polar solvents like Ν,Ν-dimethylformamide (DMF); halogenated hydrocarbons like dichloromethane or mixture thereof, preferably ethylene glycol.
1 1) . The process of claim 9, wherein the base is being used optionally, is selected from the
group consisting of organic bases like triethyl amine; inorganic bases like sodium carbonate, ammonia, sodium hydroxide or mixture thereof, preferably organic base is being used.
12) . The process of preceding claims, wherein the rivaroxaban (I) has a purity greater than about
99 area % by chiral HPLC and total impurities less than about 0.5 area %, single maximun impurity less than about 0.15 area % by HPLC.
). Rivaroxaban (I) obtained by the processes of preceding claims has the
a) compound of structural formula III
Figure imgf000022_0001
III
Where Rl is C i.g alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
b) compound of structural formula Ilia
Figure imgf000022_0002
Ilia
Where Rl is C \. alkyl straight or branched chain like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, arylalkyl, sub/unsub. phenyl;
c) compound of structural formula II
d) compound of structural fo
Figure imgf000022_0003
Where R is C i.g alkyl straight chain or branched like methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and aryl alkyl, substituted or unsubstituted phenyl;
each in an amount less than or equal to 0.1 area % as determined by HPLC.
PCT/IN2012/000064 2011-05-16 2012-01-30 Processes for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide WO2012156983A1 (en)

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753619A2 (en) 2011-09-08 2014-07-16 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
EP2844654A1 (en) 2012-05-02 2015-03-11 Symed Labs Limited Improved process for preparing rivaroxaban using novel intermediates
CN104422743A (en) * 2013-09-04 2015-03-18 广东东阳光药业有限公司 Separation and detection method for anticoagulant drugs
CN104650057A (en) * 2013-11-22 2015-05-27 重庆医药工业研究院有限责任公司 Rivaroxaban preparation method
WO2015104605A1 (en) 2014-01-08 2015-07-16 Wockhardt Limited A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof
CN104792891A (en) * 2015-04-07 2015-07-22 成都百裕科技制药有限公司 Detection method for R-configuration rivaroxaban intermediate
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN108152412A (en) * 2017-12-20 2018-06-12 乐普药业股份有限公司 A kind of method with liquid chromatography for separating and determining razaxaban and its in relation to substance

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153610A1 (en) * 1999-12-24 2003-08-14 Alexander Straub Substituted oxazolidinones and their in the field of blood coagulation
US20070066611A1 (en) * 2003-09-15 2007-03-22 Bayer Healthcare Ag Method for the production of 4-(4-aminophenyl)-3-morpholinone
US7351823B2 (en) * 2004-01-15 2008-04-01 Bayer Healthcare Ag Preparation process
US20100298293A1 (en) * 2007-06-20 2010-11-25 Bayer Schering Pharma Atiengesellschaft Substituted oxazolidinones and their use
US20110034465A1 (en) * 2009-04-28 2011-02-10 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030153610A1 (en) * 1999-12-24 2003-08-14 Alexander Straub Substituted oxazolidinones and their in the field of blood coagulation
US20070066611A1 (en) * 2003-09-15 2007-03-22 Bayer Healthcare Ag Method for the production of 4-(4-aminophenyl)-3-morpholinone
US7351823B2 (en) * 2004-01-15 2008-04-01 Bayer Healthcare Ag Preparation process
US20100298293A1 (en) * 2007-06-20 2010-11-25 Bayer Schering Pharma Atiengesellschaft Substituted oxazolidinones and their use
US20110034465A1 (en) * 2009-04-28 2011-02-10 Apotex Pharmachem Inc. Processes for the preparation of rivaroxaban and intermediates thereof

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2753619A2 (en) 2011-09-08 2014-07-16 Cadila Healthcare Limited Processes and intermediates for preparing rivaroxaban
EP2844654A1 (en) 2012-05-02 2015-03-11 Symed Labs Limited Improved process for preparing rivaroxaban using novel intermediates
AU2012378913B2 (en) * 2012-05-02 2017-04-13 Symed Labs Limited Improved process for preparing rivaroxaban using novel intermediates
CN104422743A (en) * 2013-09-04 2015-03-18 广东东阳光药业有限公司 Separation and detection method for anticoagulant drugs
CN104650057A (en) * 2013-11-22 2015-05-27 重庆医药工业研究院有限责任公司 Rivaroxaban preparation method
CN104650057B (en) * 2013-11-22 2019-04-23 重庆医药工业研究院有限责任公司 A method of preparing razaxaban
WO2015104605A1 (en) 2014-01-08 2015-07-16 Wockhardt Limited A process for preparing rivaroxaban or a pharmaceutically acceptable salt thereof
US9469628B2 (en) 2014-01-23 2016-10-18 Symed Labs Limited Processes for the preparation of highly pure Rivaroxaban crystal modification I
CN104792891A (en) * 2015-04-07 2015-07-22 成都百裕科技制药有限公司 Detection method for R-configuration rivaroxaban intermediate
CN108152412A (en) * 2017-12-20 2018-06-12 乐普药业股份有限公司 A kind of method with liquid chromatography for separating and determining razaxaban and its in relation to substance

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