446292-10-0Relevant articles and documents
Oxazolidinone derivative and preparation method thereof
-
Paragraph 0018; 0020, (2020/03/05)
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.
Synthesis method of rivaroxaban
-
Paragraph 0012; 0034-0049, (2020/07/02)
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.
Synthesis preparation method of rivaroxaban key intermediate
-
Paragraph 0076-0079, (2020/01/03)
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.
A [...] synthesis process
-
Paragraph 0092-0094, (2019/01/16)
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.
Rivaroxaban intermediate preparation method
-
Paragraph 0028-0034; 0037-0038, (2019/08/07)
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.
A method for preparing [...]
-
, (2018/05/16)
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.
Identification and Synthesis of Impurities During a Novel Process Development of Rivaroxaban
Yu, Jun,Qiu, Peng-Cheng,Ke, Bin,Chen, Hui,Zhao, Chuan-Meng,Zhang, Fu-Li
, p. 2852 - 2858 (2018/10/26)
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.
A related substance [...] F, G synthetic method
-
Paragraph 0059; 0061; 0065; 0067, (2018/03/01)
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.
Synthetic method for rivaroxaban
-
Paragraph 0011; 0032-0034; 0037-0039; 0042-0044, (2018/06/15)
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.
Preparation process for rivaroxaban
-
Paragraph 0026; 0032; 0034; 0040; 0042; 0048, (2018/11/04)
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.
