cas 446292-10-0, 3-MORPHOLINONE, 4-[4-[(5S)-5-(AMINOMETHYL)-2-OXO-3-OXAZOLIDINYL]PHENYL]-

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Oxazolidinone derivative and preparation method thereof
The invention relates to a preparation method of an oxazolidinone compound impurity 5-chloro-nitrogen-[[(5S)-2-oxo-3-[4-acetamidophenyl]-1, 3- oxazolidine-5-yl]methyl] thiophene-2-methanamide (formulaI) in rivaroxaban. According to a preparation method, 4-aminoacetanilide (formula II) and (S)-N-epoxypropyl phthalimide (formula III) are used as raw materials, and the impurity is obtained through ring opening coupling, ring closing, protecting group removal and condensation reaction. The compound represented by formula I can be applied to rivaroxaban bulk drug quality control and qualitative and quantitative research and detection of impurities.
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Paragraph 0018; 0020

(2020/03/05)

Synthesis method of rivaroxaban
The invention discloses a synthetic method of rivaroxaban. According to the method, rivaroxaban is prepared by adopting a one-pot method; 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-5-oxazolidinyl]methyl]-1H-isoindol-1,3(2H)-one in an alcohol solvent is subjected to an ammonolysis reaction in the presence of an alkali to remove a protective group, then to evaporation to remove the alcohol solvent, and finally to condensation with 5-chlorothiophene-2-formyl chloride under the action of an acid-binding agent, wherein the reaction alcohol solvent is alcohol with a carbon number of 4 or below, the alkali is an organic alkali or inorganic alkali, a condensation reaction solvent is water, and the acid-binding agent is potassium carbonate or sodium carbonate. The method has the advantages ofmild reaction conditions, simple post-treatment, conservation of a large amount of manpower and material resources, and applicability to large-scale industrial production.
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Paragraph 0012; 0034-0049

(2020/07/02)

A [...] synthesis process
The invention relates to the technical field of heterocyclic chemistry, specifically to the technical field of nitrogen-oxygen heterocyclic chemistry. Specifically speaking, the invention discloses a novel synthetic process for rivaroxaban. According to the process, the R group of a compound with a structure as shown in a formula (I) is removed so as to obtain a compound with a structure as shown in a formula (II) or an acid salt thereof, and the compound with the structure as shown in the formula (II) or the acid salt thereof reacts with a compound with a structure as shown in a formula (III) under the action of alkali so as to prepare rivaroxaban, wherein the formulas are described in the specification, and R in the formulas is a C1-20 aliphatic/aromatic hydrocarbon group.
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(2019/01/16)

Synthesis preparation method of rivaroxaban key intermediate
The invention discloses a synthesis preparation method of a key intermediate for synthesizing rivaroxaban as shown in formula I. The preparation method comprises the following steps: using compounds as shown in formulae II and III as the initial raw materials, performing condensation and cyclization, hydrolysis, oxidation and reductive amination to obtain the key intermediate for synthesizing rivaroxaban as shown in the formula I. The preparation method has the characteristics of being mild in reaction conditions, simple and convenient in process operation, high in stability and controllability, high in atom utilization ratio, environment-friendly, and low in production cost, is suitable for industrial mass production.
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Paragraph 0076-0079

(2020/01/03)

Rivaroxaban intermediate preparation method
The invention provides a preparation method of a Rivaroxaban intermediate compound in a formula I. The method includes dissolving a compound in a formula II in an organic solvent; and carrying out ammonolysis reaction by taking C3-4 alkyl primary ammonia as an ammonia source to obtain the compound in the formula I. The preparation method is safer, economical, simple and convenient, environment-friendly and suitable for industrialization.
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Paragraph 0028-0034; 0037-0038

(2019/08/07)

A method for preparing [...]
The invention discloses a preparation method of rivaroxaban, which includes the steps of 1) performing a one-step cyclization reaction to an intermediate, N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide, to prepare a key intermediate, 4-(4-aminophenyl)-3-morpholinone, of the rivaroxaban; 2) performing a series reactions comprising ring opening with an epoxide, a substitution reaction, a ring formation reaction and the like to the 4-(4-aminophenyl)-3-morpholinone to obtain an intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one; and 3) performing a substitution reaction to the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one with 2-chloroformyl-5-chlorothiophene to obtain the rivaroxaban. The whole preparation process is short in route, is high in yield, is less in pollution, can avoid usage of expensive metal palladium for nitroreduction and is suitable for industrial production.
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Paragraph 0074; 0075; 0078; 0081; 0084

(2018/05/16)

Identification and Synthesis of Impurities During a Novel Process Development of Rivaroxaban
During the development of rivaroxaban, seven process-related impurities have been identified and synthesized. These structures are confirmed by nuclear magnetic resonance spectroscopy and high-resolution mass spectrometry. The impurities (S)-2-(2-((4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)amino)ethoxy)acetohydrazide (A) and (S)-4-(4-(((2-oxooxazolidin-5-yl)methyl)amino)phenyl)morpholin-3-one (F) are confirmed and distinguished from their isomers by single-crystal diffraction. This work proves to be valuable in regard to complying with regulatory norms and assessing the quality of rivaroxaban.
Yu, Jun,Qiu, Peng-Cheng,Ke, Bin,Chen, Hui,Zhao, Chuan-Meng,Zhang, Fu-Li
p. 2852 - 2858
(2018/10/26)

A related substance [...] F, G synthetic method
The invention provides synthetic methods of related substances F and G of rivaroxaban. With the adoption of the synthetic methods of the related substances F and G of the rivaroxaban, the yield is high, and industrial production and technology transformation are realized easily.
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Paragraph 0059; 0061; 0065; 0067

(2018/03/01)

Synthetic method for rivaroxaban
The invention relates to a synthetic method for rivaroxaban. In the process of synthesizing a compound of a formula 3, the method provided by the invention adopts a sulfide for a deprotection reaction, and the process conditions are mild, safe and environmentally friendly; in the process of synthesizing the rivaroxaban, a method of performing acylation firstly and then performing chlorination is used, so that an expensive reagent 5-chlorothiophene-2-carbonyl chloride is avoided, and the production costs are greatly reduced; and the method provided by the invention has high operability, does not need to adopt a column chromatography method with complicated operation and higher costs to purify the product or other special equipment, has a mild and safe process as well as simple reaction operation, and is beneficial for industrialized production.
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Paragraph 0011; 0032-0034; 0037-0039; 0042-0044

(2018/06/15)

Preparation process for rivaroxaban
The invention provides a preparation process for rivaroxaban, and particularly relates to the technical field of pharmaceutical chemistry. The preparation process comprises the following steps: (S)-4-chloro-3-hydroxylbutyronitrile reacts with phthalimide potassium salt, (S)-4-(1,3-dioxoisoindol-2-yl)-3-hydroxybutyramide is obtained by nitrile group hydrolysis, (S)-2-[[2-oxo-1,3-oxazolidine-5-yl]methyl]-1H-isoindol-1,3(2H)-diketone is obtained by rearrangement under the action of iodobenzene, and carries out Ullmann coupling with 4-(4-bromophenyl)morpholine-3-ketone, so that 2-[[(S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidine-5-yl]methyl]-1H-isoindol-1,3(2H)-diketone is obtained, and by hydrazinolysis and amidation, rivaroxaban is obtained. The preparation process has the advantages of easiness in operation, moderate reaction conditions and higher yield.
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Paragraph 0026; 0032; 0034; 0040; 0042; 0048

(2018/11/04)

Synthesis of 4 - {4 - [(5 S) - 5 - (aminomethyl) - 2 - oxo - 1, 3 - oxazolidine - 3 - yl] phenyl} morpholine - 3 - one method
The invention provides a method of synthesizing 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, wherein the method includes the steps of (1) performing a one-step cyclization reaction to an intermediate N-(4-aminophenyl)-2-(2-haloethyoxyl)acetamide to prepare 4-(4-aminophenyl)-3-morpholinone; and (2) carrying out a ring-opening reaction with an epoxy compound, a substitution reaction, a cyclization reaction and like to the 4-(4-aminophenyl)-3-morpholinone to obtain the key intermediate, 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl}morpholine-3-one, of rivaroxaban. The method is high in yield, is less in pollution, is free of an expensive metal palladium for performing nitro-reduction during the process and is suitable for industrial production.
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Paragraph 0074; 0077; 0078; 0080; 0083; 0084

(2018/03/13)

A key intermediate for synthesizing [...] method
The present invention discloses a method for synthesizing a rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione, wherein 4-(4-methylamino alkenyl phenyl)-3-morpholinone and (S)-{1-(chloroformate)-2-[2-(1,3-dioxo-isoindol)yl]ethyl}halogenation salt are subjected to a ring-closing reaction to prepare the key intermediate. According to the present invention, the operation is simple, the raw materials are easy to obtain, the yield can be up to about 90%, the prepared (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione has good purity, the purity can be up to more than or equal to 98%, and the method is suitable for industrial large-scale production.
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(2018/01/05)

A method for preparing the advantage cuts down Sha Ban
The invention provides a preparation method of rivaroxaban. The preparation method comprises the following steps: coupling and performing ring-closing on a compound as shown in formula II described in the specification and a compound as shown in formula III described in the specification in the presence of an organic solvent and lithium tert-butoxide to generate a compound as shown in formula IV; (2) directly adding the reactants which are not subjected to after-treatment and obtained in the last-step reaction into hydrochloric acid to hydrolyze to generate a compound as shown in formula V; after the hydrolysis is completed, extracting the reactants by an organic solvent, removing an organic phase and keeping a water phase for later use; and (3) adding inorganic alkali and the compound as shown in formula VI into the water phase, and reacting to obtain the compound rivaroxaban as shown in formula I. The preparation method of the rivaroxaban disclosed by the invention can be used for greatly reducing the technological operation steps, and is simple in after-treatment; only one organic solvent is used in the reaction and the after-treatment thereof, so that the environmental pollution is reduced and the production cost is lowered, and therefore, the preparation method is suitable for large-scale industrial production and has a great application value.
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Paragraph 0039; 0040; 0041; 0042; 0043; 0044; 0045; 0046

(2017/08/25)

A process for preparing 4 - (4 - aminophenyl) - 3 - morpholinon method (by machine translation)
The invention discloses a process for preparing 4 - (4 - aminophenyl) - 3 - morpholone (type IV) method, which belongs to the field of chemical synthesis. The specific method comprises: intermediate N - (4 - aminophenyl) - 2 - (2 - halo ethoxy) acetamide (type III) by the one-step cyclization reaction systems benefit cuts down Sha Ban key intermediate 4 - (4 - aminophenyl) - 3 - morpholone (type IV), wherein X represents halogen. The prepared 4 - (4 - aminophenyl) - 3 - morpholinon purity is good, the reaction yield is high, can be as high as 87% of the left and right, and the preparation process avoids the use of expensive metal palladium on nitro reduction, the operation is simple, and is suitable for industrial production. (by machine translation)
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(2017/08/24)

A method for preparing the advantage cuts down Sha Ban
The invention discloses a preparation method for rivaroxaban. A target product, namely rivaroxaban is obtained by a five-step reaction of amino-substitution, chloro-substitution, cyclization, elimination and substitution. The preparation method for rivaroxaban, which is disclosed by the invention, is cheap and easily-available in raw materials, stable in reaction condition, simple to operate, high in productivity, and simple in aftertreatment, and the reaction cost is reduced; a crude product obtained after reaction is high in purity, so that the high-purity rivaroxaban can be easily obtained by purification, and is more suitable for industrialized production.
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(2017/08/26)

Preparation method of Rivaroxaban intermediate
The invention provides a preparation method of a Rivaroxaban intermediate. The method includes: a compound with a structure as shown in formula (I) is allowed to have mixed reaction with phosgene in the presence of a catalyst and a solvent so as to prepare the Rivaroxaban intermediate. The preparation method has the advantages that the method is high in reaction yield, the prepared Rivaroxaban intermediate contains few impurities, and the Rivaroxaban intermediate high in purity can be obtained through beating only.
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(2017/08/28)

Rivaroxaban intermediate preparation method
The invention discloses a rivaroxaban intermediate preparation method. 4-(4-aminophenyl)morpholinyl-3-one and S-glycidol as staring raw materials are synthesized into a compound shown in the structural formula (IV), wherein in the formula (IV), R represents methyl, p-methylphenyl, phenyl or trifluoromethyl. The rivaroxaban intermediate preparation method has the advantages of mild reaction conditions, operation simpleness, high yield and industrialization easiness.
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Paragraph 0033

(2016/10/10)

A the advantage cuts down Sha Ban method for the preparation of intermediates thereof, and intermediate compound
The present invention discloses a preparation method for a rivaroxaban intermediate compound represented by a formula 5, wherein the preparation method comprises the following steps: carrying out a benzyl group removing reaction of a compound 4 in a solvent to prepare a compound 5. The present invention further discloses a rivaroxaban preparation method and intermediate compounds. According to the preparation method, chiral raw materials are easy to obtain, and have cheap price, the process is simple, the post treatment is simple, the intermediate and the final product are easy to purify, the total yield is high, the purity is high, and industrial production is easily achieved.
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(2016/10/09)

PROCESS FOR THE PREPARATION OF RIVAROXABAN
The present invention relates to an environmentally friendly process for preparing rivaroxaban. The present invention provides a process for preparing rivaroxaban of formula I, the process comprising: reacting a compound of formula VI with a base in the presence of a solvent to form a compound of formula VII; and condensing the compound of formula VII with a compound of formula VIII or a compound of formula IX in the presence of a solvent to prepare rivaroxaban of formula I, wherein the solvent used in both steps comprises water.
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(2016/03/22)

AN IMPROVED PROCESS FOR PREPARATION OF RIVAROXABAN
The present invention relates to an improved process for the preparation of Rivaroxaban of formula (I) in high yield and purity. More particularly, the present invention is directed to an improved and greener process for preparation of Rivaroxaban employing isolated compound of formula (II) in high yield which substantially eliminates potential impurities.
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(2016/12/26)

Method for synthesizing Rivaroxaban intermediate and application of method
The invention belongs to the technical field of pharmaceutical synthesis and discloses a method for synthesizing a Rivaroxaban intermediate B. The method comprises the steps of removing a phthalimide protective group from a raw material A in the presence of a deprotection reagent, i.e., ethanolamine in a reaction solvent, i.e., toluene, and carrying out aftertreatment, thereby obtaining the intermediate B. Simultaneously, the invention also discloses an application of the method for synthesizing the Rivaroxaban intermediate B in the preparation of Rivaroxaban. Compared with the existing routes for synthesizing the Rivaroxaban, the method has the advantages that 4-(4-iodophenyl)-3-morpholone is subjected to condensation cyclization with N-(3-amino-2-hydroxylisopropyl)phthalimide, and the phthalimide protective group is removed by using an ethanolamine solution, so that the consumption of a methylamine solution and hydrazine is avoided, thus, toxic or side effects caused by the consumption of the methylamine solution or hydrazine are avoided; and the method is environment-friendly and is relatively high in yield.
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Paragraph 0042; 0043

(2016/10/10)

Preparation method of rivaroxaban
The invention discloses a preparation method of rivaroxaban. With (S)-4-chloro-3-hydroxybutyronitrile (compound 1) as a raw material, the rivaroxaban is obtained through phthalimide potassium salt substitution, cyano hydrolysis, Hofmann rearranging cyclization, Ullmann coupling, hydrazinolysis and amidation. The rivaroxaban is introduced into a chiral center instead of (S)-epoxy chloropropane which is volatile, high in toxicity and unstable; the safety is relatively high; precious catalyst, raw materials and reagent with large environmental pollution are avoided in the total process in the total synthetic route; the overall synthesis process is small in pollution and easy to treat; the yield and the purity of various steps are high; the preparation method is environmentally friendly, low in production cost and suitable for industrial production.
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Paragraph 0077; 0078

(2016/11/02)

PROCESS FOR PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
An improved process for the preparation of Rivaroxaban wherein the process substantially eliminates the potential impurities. process for preparation of Rivaroxaban which uses a novel intermediate. A process for preparing the novel intermediate which is used for the preparation of Rivaroxaban.
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Paragraph 0128; 0129; 0130

(2015/02/18)

PROCESS FOR OBTAINING RIVAROXABAN AND INTERMEDIATE THEREOF
This invention relates to a procedure for obtaining a thiophene-2-carboxamide compound, specifically rivaroxaban, which comprises the (i) fragmentation of the N═C bond of a compound of formula 23 where R1 is selected among hydrogen, halogen, and (C1-C6)alkyl; and (ii) acylation of the resulting intermediate with 5-chloro-tiofen-2-carbonyl chloride in a solvent medium, in the presence of a base. The invention also relates to the compounds of formula 23 and their use in the obtention of rivaroxaban.
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(2014/05/20)

PROCESS FOR PREPARATION OF OXAZOLIDINONE DERIVATIVES
A process for preparation of oxazolidinone derivatives such as Linezolid and Rivaroxaban using (S)-Epichlorohydrin.
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Page/Page column 36

(2014/11/11)

NOVEL METHOD FOR SYNTHESIZING RIVAROXABAN INTERMEDIATE, 4-MORPHOLIN-3-ONE
The present invention discloses novel methods for synthesizing Rivaroxaban intermediate, i.e., 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3 -oxazolidin-3 -yl]phenyl}morpholin-3-one. The novel methods provided in the present invention involve mild reaction conditions, convenient operations, easy purification, and low production costs, and thus the process is environmental-friendly and suitable for industrial production.
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Paragraph 0074-0075

(2014/05/07)

NOVEL METHOD FOR SYNTHESIZING RIVAROXABAN INTERMEDIATE, 4-{4-[(5S)-5-(AMINOMETHYL)-2-OXO-1,3-OXAZOLIGDIN-3-YL]PHENYL}MORPHOLIN-3-ONE
The present invention discloses novel methods for synthesizing Rivaroxaban intermediate, i.e., 4- {4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl} morpholin-3-one. The novel methods provided in the present invention involve mild reaction conditions, convenient operations, easy purification, and low production costs, and thus the process is environmental-friendly and suitable for industrial production.
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Paragraph 0036

(2014/05/07)

A PROCESS FOR THE PREPARATION OF RIVAROXABAN BASED ON THE USE OF (S)-EPICHLOROHYDRIN
The invention relates to the stereoisomers of 4-{4-[(S/R)-5-[(((aryl)methylene)- amino)methyl]-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-ones described by the chemical formulae (S)-(9) and (R)-(9). The optical isomer of compound (9) with the (S)- configuration is industrially applicable for the manufacture of the antithrombotic drug rivaroxaban (1). The new preparation process of rivaroxaban comprises a reaction of (S)-1- chloro-3-(((aryl)methylene)amino)propan-2-ols (S)-(14) with alkyl 4-(3-oxomorpholine-4- yl)phenylcarbamates (15) providing the key intermediate (S)-(9), which is further subjected to hydrolytic deprotection and subsequent acylation, producing rivaroxaban. The commercially available (S)-epichlorohydrin has been conveniently used as the chiral building block for the production of the key intermediate.
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Page/Page column 36; 37

(2013/08/28)

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 AND INTERMEDIATES THEREOF
The present invention relates to processes for the preparation of oxazolidinone derivatives. More particularly the present invention provides processes for the preparation of 5-chloro-N-( {(5S)-2-oxo-3-[4-(3-oxo-4-moφholinyl)phenyl]-1,3-oxazolidin-5-yl methyl)-2-thiophene-carboxamide and intennediates thereof. Where L is a leaving group like halogen atom (F, CI, Br, I) or -OS02R where R = C'-4 alkyl straight chain or branched chain, sub or unsubstituted aryl, sub or unsub aryl alkyl; with a suitable reagent to provide the compound of formula (II). The reaction step is performed by reacting the compound of formula (IV) with amine source which may be dissolved in solvent like water or alcohol. For example ammonium hydroxide.
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(2013/07/25)

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 AND INTERMEDIATES THEREOF
TThe present invention provides 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 (I) and intermediates thereof. Also provides novel intermediates and their use in the synthesis of oxazolidine derivatives.
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(2013/04/13)

PROCESSES FOR THE PREPARATION OF 4-{4-[5(S)-(AMINOMETHYL)-2-OXO-1,3-OXAZOLIDIN-3-YL]PHENYL} MORPHOLIN-3-ONE
The present invention provides simple, eco-friendly, cost-effective, reproducible, robust and industrial processes for the preparation of intermediate compound 4-{4-[5(S)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one (II). The present invention also provides novel intermediates and their use in the synthesis of morpholinone oxazolidine derivatives.
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Page/Page column 18; 19

(2013/03/26)

A PROCESS FOR PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
An improved process for the preparation of Rivaroxaban; wherein the said process substantially eliminates the potential impurities. The present invention also relates to process for preparation of Rivaroxaban using a novel intermediate. The present invention also relates to a process for preparing the novel intermediate, used for preparation of Rivaroxaban.
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Page/Page column 29

(2013/08/28)

PROCESS FOR OBTAINING RIVAROXABAN AND INTERMEDIATE THEREOF
This invention relates to a procedure for obtaining a thiophene-2-carboxamide compound, specifically rivaroxaban, which comprises the (i) fragmentation of the N=C bond of a compound of formula 23 where R1 is selected among hydrogen, halogen, and (C1-C6)alkyl; and (ii) acylation of the resulting intermediate with 5-chloro-tiofen-2-carbonyl chloride in a solvent medium, in the presence of a base. The invention also relates to the compounds of formula 23 and their use in the obtention of rivaroxaban.
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(2012/12/13)

PROCESSES FOR THE PREPARATION OF 4-{4-[5(S)-(AMINOMETHYL)-2-OXO-1,3-OXAZOLIDIN-3-YL]PHENYL} MORPHOLIN-3-ONE
The present invention provides processes for the preparation of 4-{4-[5(S)-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one which are simple, eco-friendly, cost-effective, reproducible, robust and are well amenable on industrial scale.
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(2012/03/27)

An approach to the anticoagulant agent rivaroxaban via an isocyanate-oxirane cycloaddition promoted by MgI2.etherate
A convergent and efficient synthesis of anticoagulant rivaroxaban was developed using the cycloaddition of commercially available (R)-epichlorohydrin with 4-(morpholin-3-one)phenyl isocyanate catalysed by MgI2 etherate as the key step, in 22% overall yield.
Li, Chao,Liu, Yingshuai,Zhang, Yongjun,Zhang, Xingxian
p. 400 - 401
(2011/10/08)

PROCESSES FOR CRYSTALLIZATION OF RIVAROXABAN
The invention relates to rivaroxaban, more particularly to a process for preparation of rivaroxaban or a pharmaceutically acceptable salt or solvate thereof and its crystallization in order to obtain product having desired quality properties.
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(2011/02/24)

Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3-[4- (3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide (BAY 59-7939): An oral, direct factor Xa inhibitor
Despite recent progress in antithrombotic therapy, there is still an unmet medical need for safe and orally available anticoagulants. The coagulation enzyme Factor Xa (FXa) is a particularly promising target, and recent efforts in this field have focused on the identification of small-molecule inhibitors with good oral bioavailability. We identified oxazolidinone derivatives as a new class of potent FXa inhibitors. Lead optimization led to the discovery of BAY 59-7939 (5), a highly potent and selective, direct FXa inhibitor with excellent in vivo antithrombotic activity. The X-ray crystal structure of 5 in complex with human FXa clarified the binding mode and the stringent requirements for high affinity. The interaction of the neutral ligand chlorothiophene in the S1 subsite allows for the combination of good oral bioavailability and high potency for nonbasic 5. Compound 5 is currently under clinical development for the prevention and treatment of thromboembolic diseases.
Roehrig, Susanne,Straub, Alexander,Pohlmann, Jens,Lampe, Thomas,Pernerstorfer, Josef,Schlemmer, Karl-Heinz,Reinemer, Peter,Perzborn, Elisabeth
p. 5900 - 5908
(2007/10/03)

Preparation process
The present invention relates to a process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide starting from 2-[(2S)-2-oxiranylmethyl]-1H-isoindole-1,3(2H)-dione, 4-(4-aminophenyl)-3-morpholinone and 5-chlorothiophene-2-carbonyl chloride.
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Page/Page column 1; 3-4

(2008/06/13)

PRODUCTION METHOD
The invention relates to a method for producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidine-5-yl}-methyl)-2-thiophene carboxamide from 2-[(2S)-2-oxiranylmethyl]-1H-isoindol-1,3(2H)-dione, 4-(4-aminophenyl)-3-morpholinone, and 5-chlorothiophene-2-carbonyl chloride.
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Page/Page column 7-8

(2008/06/13)