- New synthetic strategy for preparation of the anticoagulant drug Rivaroxaban via an asymmetric Henry reaction
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A new synthetic approach towards the anticoagulant drug (S)-Rivaroxaban was described. This reaction sequence involved six steps overall, starting from commercially available and inexpensive N-(4-aminophenyl)morpholin-3-one. The stereogenic centre was introduced by an asymmetric Henry reaction catalysed by the complex of copper(II) acetate and (2R,5S)-2-(pyridine-2-yl)imidazolidine-4-one with 87% ee. The individual reaction steps proceeded with high yields and did not require any unusual or expensive reagents.
- Drabina, Pavel,Feixová, Viola,Sedlák, Milo?
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Read Online
- Preparation method of rivaroxaban
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The invention relates to a preparation method of rivaroxaban, belongs to the field of medicines, particularly relates to a preparation method for efficiently synthesizing rivaroxaban by taking 5-chlorothiophene-2-amide as a raw material through four steps of Boc protection, substitution reaction, cyclization reaction and deprotection reaction. The preparation method has few steps, less three wastes and good product purity.
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- Preparation method of rivaroxaban
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The invention provides a preparation method of a drug as shown in formula I, namely a preparation method of (S)-5-chloro-N-(((5S)-2-oxo-3-(4-(3-oxo-morpholine-4-yl) phenyl)-1, 3-oxazoline-5-yl) methyl)-thiophene-2-formamide. According to the method, the reaction steps are few, the solvent reagent consumption in the reaction process and the product loss caused by excessive operation are reduced, the yield is high, the product quality is stable, and industrial production is facilitated; and a solvent reagent is selected as a solvent reagent, so that the method is pollution-free to the environment, safe and environment-friendly, and a new method is provided for the preparation of rivaroxaban.
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Paragraph 0013; 0017
(2021/03/24)
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- Preparation method of rivaroxaban
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The invention relates to a preparation method of rivaroxaban, in particular to a method for efficiently synthesizing rivaroxaban by taking p-nitroaniline and (S)-N-glycidol phthalimide as raw materials through seven steps: an addition reaction, a cyclization reaction, a hydrolysis reaction, an amidation reaction, a reduction reaction, an addition reaction and a cyclization reaction. The provided rivaroxaban preparation method has the advantages of high yield, low cost, few three wastes, and high product purity and is suitable for industrialization.
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- Preparation method of rivaroxaban intermediate
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The invention belongs to the field of drug synthesis, and relates to a preparation method of a rivaroxaban intermediate. The rivaroxaban intermediate is further used for preparing rivaroxaban, and thesynthesis method has the advantages of simple operation, high product yield and high purity, and can meet the requirements of industrial production.
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Paragraph 0029; 0030
(2020/04/17)
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- Method for preparing rivaroxaban intermediate and method for preparing rivaroxaban from rivaroxaban intermediate
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The invention provides a method for preparing a rivaroxaban intermediate shown as a formula (VI) and a method for preparing rivaroxaban. The preparation method of the intermediate has the advantages of simple steps, easily controlled conditions, good selectivity, high yield, few impurities and the like, and green synthesis of rivaroxaban can be realized.
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- Preparation of intermediates (by machine translation)
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In the method of manufacturing a method of manufacturing problems [to] [ribarokisaban[ribarokisaban][ribarokisaban[ribarokisaban] which, in particular, intermediate compounds on an industrial scale manufacturing method is excellent in operability. [Solution] water-miscible organic solvent other than alcohols in, 2 - ({(5S) -2 - [4 - (3 - oxo--4 - morpholinyl) - phenyl] - 1, 3 - oxazolidine -3 - oxo -5 - yl} methyl) - 1, 3 (2H) dione is reacted with methylamine - 1H - isoindole, 2 layers separated from the solution 4 - {4 - [(aminomethyl) - 1, 3 - oxazolidine -3 - oxo (5S) -5 - -2 - yl] - phenyl} morpholine hydrochloride is precipitated on the production of -3 -, and method of manufacturing the compound [ribarokisaban[ribarokisaban]. Figure 4 [drawing] (by machine translation)
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Paragraph 0004; 0046-0051
(2020/10/19)
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- Oxazolidinone derivative and preparation method thereof
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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; 0021
(2020/03/05)
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- Synthesis method of rivaroxaban
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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)
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- A [...] synthesis process
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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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- Synthesis preparation method of rivaroxaban key intermediate
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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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- A process for preparing [...] method
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The invention relates to a rivaroxaban preparation method. The method is characterized in that 4-{4-[(4S)-5-(aminomethyl)-2-oxo-1,3-oxazolidinyl-3-yl]pheny}morpholine-3-one represented by formula II or its salt reacts with 5-chloro-thiophene-2-formic acid in an organic alkali-containing system in the presence of a condensing agent selected from 2,4,6-trichloro-1,3,5-triazine (TCT), 4,6-dimethoxy-2-chloro-1,3,5-triazine, 2-methoxy-4,6-dichloro-1,3,5-triazine, 4,6-dibenzyloxy-2-chloro-1,3,5-triazine and 4,6-diphenoxyl-2-chloro-1,3,5-triazine to prepare rivaroxaban. The method has the advantages of simple and practical operation, low cost, high yield, environmental protection, easily available raw materials, extremely great increase of the yield and the purity, and suitableness for large-scale industrial production.
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Paragraph 0035; 0036; 0037; 0038; 0039; 0040-0046
(2019/05/04)
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- Preparation method and use of rivaroxaban intermediate
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The present invention relates to a preparation method of a rivaroxaban intermediate I. The method provided by the invention has the advantages of greatly shortening the reaction time, easy preparationby scale, simple operation, good stability, high purity, low environmental pollution and suitable for industrial production.
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Paragraph 0028; 0031
(2019/04/26)
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- Rivaroxaban, synthesis and refining method (by machine translation)
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The invention relates to the field, in particular to the field of pharmaceutical chemistry. The synthesis method comprises 1) under basic system, 4 - {4 - [(5S) -5 - oxo -2 -1 oxazoli 3 -yl] phenyl} morpholine -3 - ketone (LF-II) and -3 - chlorothiophene 5 - formic acid (SMI) to obtain rivaroxaban crude; and the refining method further comprises -2 2 -) stirring crystallization, and obtaining high-purity refined product, wherein the crude product is obtained from rivaroxaban. The method meets the requirement of crystal form requirements, is simple to operate, high in yield, small in pollution, and suitable for large-scale industrial production. (by machine translation)
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Paragraph 0044-0046; 0049-0050; 0052
(2019/09/05)
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- Identification and Synthesis of Impurities During a Novel Process Development of Rivaroxaban
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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
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p. 2852 - 2858
(2018/10/26)
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- The preparation method of the [...] (by machine translation)
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The invention provides a method for preparing [...], using 4 - (4 - aminophenyl) - 3 - morpholone and 5 - chloro - N - (2 - ethylene oxide-based methyl) - 2 - thiophene carboxamide reaction to obtain 5 - [...] - 2 - {(R)- 2 - hydroxy - 3 - [4 - (3 - oxo - 4 - morpholinyl) phenyl amino] - propyl} amide, then adding N, N' - carbonyl di-imidazole, 4 - dimethylamino pyridine, begins to stir, heating reaction to obtain the - 5 - chloro - N - (( (5 S) - 2 - oxo - 3 - (4 - (3 - oxo-morpholine - 4 - yl) phenyl) - 1, 3 - Oxacillin - 5 - yl) methyl) thiophene - 2 - carboxamide. The technique of the invention route after the condition is optimized, mild reaction, high yield. (by machine translation)
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- One-pot process rivaroxaban preparation method
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The invention discloses a one-pot process rivaroxaban preparation method. The method takes 2-[[(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-5-oxazolidinyl]methyl]-1H-isobenzazole-1,3(2H)-diketone asthe raw material, ammonolysis reaction is conducted to remove a protecting group and generate an intermediate 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidine-3-radical]phenyl]morpholine-3-ketone, andthe rivaroxaban is generated through the amidation of the intermediate and the 5-chlorothiophene-2-formic acid under the action of a condensating agent. The method adopts the one-pot process, the DMTMM is taken as the condensating agent, the rivaroxaban is obtained through the condensation reaction in an alcohol and/or water system, the reaction is simplified, the reaction time is shortened, theyield of the rivaroxaban is high, the purity is high; moreover, the post-processing is simple, no extra purifying is needed, and the chemical waste is reduced.
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Paragraph 0033; 0034; 0036; 0038; 0040; 0042; 0044
(2018/07/30)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF RIVAROXABAN INVOLVING NOVEL INTERMEDIATE
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The present invention relates to the novel key intermediate, 4-{4-[(5S)-(Aminomethyl)-2- oxo-l,3-oxazolidin-3-yl]-phenyl}-morpholin-3-one perchlorate, in the synthesis of rivaroxaban. The invention further relates to the crystalline form of novel intermediate, the process to prepare the novel intermediate and method of preparing rivaroxaban using this novel intermediate. The invention provides an improved and efficient process for preparation of Rivaroxaban.
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Page/Page column 14
(2018/07/31)
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- Synthetic method for rivaroxaban
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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 0015; 0032; 0036-0037; 0041-0042; 0046
(2018/06/15)
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- A method for preparing [...]
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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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- ONE POT SYNTHESIS FOR THE PREPARATION OF SUBSTITUTED PHTHALIMIDO OXAZOLIDINONE ANTIBACTERIALS AND OXAZOLIDINONE ANTIHAROMBOTICS COMPOUNDS BY USING RECYCLABLE HETEROGENEOUS CATALYST
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A novel one pot and high yield process for the preparation of substituted phthalimidooxazolidinone compounds by using recyclable heterogeneous catalyst and preparation of oxazolidinoneantibacterials and oxazolidinoneantithrombotics thereof.
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Page/Page column 12
(2018/04/20)
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- Preparation process for rivaroxaban
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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; 0033; 0034; 0041; 0042; 0049
(2018/11/04)
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- Rivaroxaban synthesis and refining method
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The invention discloses a novel rivaroxaban synthesis and refining method. The novel rivaroxaban synthesis and refining method is characterized by adopting new initial raw materials and a refining method thereof. The method disclosed by the invention is simple to operate, stable and reliable in the process, high in product yield and high in optical purity (ee% value), thereby being very suitable for large-scale industrialized rivaroxaban production.
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- NOVEL MORPHOLINE DIPHOSPHATE SALT, AND METHOD FOR MANUFACTURING HIGH PURITY RIVAROXABAN USING SAME
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The present invention relates to a method of producing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-2-thiophene carboxamide (hereinafter, andPrime;rivaroxabanandPrime;, chemical formula 1) with high purity in an economical and mass-producible manner by using novel 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one disphosphate salts (hereinafter, andPrime;morpholine disphosphate saltsandPrime;, chemical formula 2).COPYRIGHT KIPO 2017
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Paragraph 0088-0093; 0118-0120
(2017/12/15)
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- Rivaroxaban preparation method
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The invention discloses a rivaroxaban preparation method and belongs to the field of medical chemistry. The method comprises the steps: firstly reacting N-(4-aminophenyl)-3-morpholinone with Boc anhydride or benzylcarbonyl chloride or other ester to generate N-(4-alkoxycarbonyl aminophenyl)-3-morpholinone intermediate I; reacting 5-chlorothiophene-2-methanamide with epoxy chloropropane to generate N-(1,2-glycidyl)-5-chlorothiophene-2-methanamide intermediate II. The intermediate I and the intermediate II are open loop-cyclization condensed under alkali condition to be directly prepared into rivaroxaban. The method has short synthesizing path, moderate condition, convenience to operate, high yield, stable product quality and easiness in achieving industrial production. The structural formula is shown in the specification.
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Paragraph 0029; 0045
(2017/09/26)
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- A method for preparing the advantage cuts down Sha Ban
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The invention discloses a preparation method of rivaroxaban, belonging to the field of chemical synthesis of medicine. The preparation method of rivaroxaban comprises the following steps: reacting 5-chlorothiophene-2-carboxylic acid-[(s)-2,3-dyhydroxy propyl]-amide with iodine under the catalytic action of triphenylphosphine and imidazole to produce 5-chlorothiophene-2-carboxylic acid-[(s)-3-iodo-2-hydroxy propyl]-amide; then reacting 5-chlorothiophene-2-carboxylic acid-[(s)-3-iodo-2-hydroxy propyl]-amide with 4-(4-aminophenyl)-3-morpholinone to produce 5-chlorothiophene-2-carboxylic acid{(R)-2-hydroxy-3-[4-(3-oxomorpholine-4-yl) phenyl amino]-propyl} amide; and finally introducing CO2 to react to produce rivaroxaban. The preparation method provided by the invention has the advantages that expensive and poisonous raw materials are not used, the production cost is low, the production safety is high, the environment pollution is hardly caused. Therefore, the preparation method is suitable for industrial production.
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Paragraph 0051
(2017/08/25)
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- A process for preparing 4 - (4 - aminophenyl) - 3 - morpholinon method (by machine translation)
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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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- Synthesis of 4 - {4 - [(5 S) - 5 - (aminomethyl) - 2 - oxo - 1, 3 - oxazolidine - 3 - yl] phenyl} morpholine - 3 - one method
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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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- (S)- 1 - halo - 2 - [2 - (1, 3 - two oxygen different indole) yl] ethyl formate and its preparation method
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The present invention discloses a compound (S)-1-halo-2-[2-(1,3-dioxo-isoindol)yl]ethyl chloroformate represented by a formula V, and a preparation method thereof, wherein X represents a halogen. According to the present invention, the compound is used for preparing the rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban intermediate, and the obtained product is firstly obtained through the method in the present invention; and the preparation method is safe and simple, the yield can be up to about 85%, and the purity of the obtained product is high and can achieve more than or equal to 97%. The formula V is defined in the specification.
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- A key intermediate for synthesizing [...] method
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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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- 4 - (4 - a ammonia alkenyl phenyl) - 3 - morpholone and its preparation method
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The present invention discloses a compound 4-(4-methylamino alkenyl phenyl)-3-morpholinone represented by a formula III, and a preparation method thereof. According to the present invention, the compound is used for preparing the rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban intermediate, and the obtained product is firstly obtained through the method in the present invention; and the operation of the preparation method is simple, the yield is up to about 90%, and the product purity is good. The formula III is defined in the specification.
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- A method for synthesizing [...] (by machine translation)
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The invention discloses a method for synthesizing [...], from 4 - (4 - a ammonia alkenyl phenyl) - 3 - morpholone with (S)- {1 - (chloromethane ester) - 2 - [2 - (1, 3 - two oxygen different indole) yl] ethyl} halide salt to ring-closure reaction, to make the key intermediate (S)- 2 - {[2 - oxo - 3 - (4 - (3 - oxo-morpholine) phenyl) oxazolidine - 5 - yl] methyl} isoindole - 1, 3 - dione, then the key intermediate to remove the amino protecting base 4 - {4 - [(5 S) - 5 - (aminomethyl) - 2 - oxo - 1, 3 - oxazolidine - 3 - yl] phenyl} morpholine - 3 - one hydrochloride, with 2 - chloro formyl - 5 - [...][...] further reaction. This invention prepares mild condition, the process is simple, low cost, high yield, is suitable for industrial production. (by machine translation)
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- the advantage cuts down Sha Ban and intermediate preparation method
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The present invention discloses a new method for preparing rivaroxaban through an intermediate represented by a formula (5), wherein the method comprises that: S-1-amino-3-chloro-2-propanol represented by a formula (2) is subjected to acylation modification to obtain a compound represented by a formula (3), the compound represented by the formula (3) reacts with 4-(3-oxomorpholineone)phenylamine formyl benzyl ester represented by a formula (4) under alkali catalysis so as to provide a structure represented by a formula (5) in a high yield manner, the intermediate is subjected to acid hydrolysis to prepare 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl-morpholin-3-one represented by a formula (6), and the 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl-morpholin-3-one reacts with 5-chlorothiophene-2-carbonyl chloride represented by a formula (c) to prepare the rivaroxaban. The rivaroxaban preparation method has advantages of high reaction yield, easy purification, mild reaction conditions, simple operation and the like, wherein the yield is significantly increased although acylation modification is required during the synthesis process, the purification process can be simplified, and the preparation method is suitable for industrial production.
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Paragraph 0038; 0074; 0110; 0111; 0112; 0113
(2017/07/31)
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- The preparation method of the the advantage cuts down Sha Ban
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The invention provides a preparation method of rivaroxaban, which uses 4-(4-iodophenyl)-3-morpholone and (S)-(+)-N-(3-amino-2-hydroxyisopropyl)phthalimide as initial raw materials. The synthesis route is simple, the reaction conditions in each reaction are mild, and the product is easy to separate; and thus, the reaction yield is high, the product purity is high, and the method can be used for industrial production.
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- A method for preparing the advantage cuts down Sha Ban
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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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- A method for preparing the advantage cuts down Sha Ban
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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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- Preparation method of Rivaroxaban intermediate
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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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Paragraph 0044; 0051
(2017/08/28)
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- A oxazolidinone compounds of preparation method
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The invention discloses a method for preparing an oxazolidinone compound. The method comprises the following steps of carrying out ammonolysis reaction on a racemic or optically active 3-chloro-2-hydroxypropyl aniline compound (2) as a starting material and ammonia in a proper solvent and under alkaline condition to obtain a 3-amino-2-hydroxypropyl aniline compound (3); carrying out acylation reaction on the compound (3) to obtain 3-acylamino-2-hydroxypropyl aniline compound (4); and carrying out cyclization reaction on the compound (4) and a corresponding acylating reagent to obtain the racemic or optically active oxazolidinone compound (II) as shown in the description, wherein R1 represents morpholinyl or 3-oxo-4-morpholinyl; R2 represents H or F; and R3 represents C1-12 alkyl, 5-chloro-thiophen-2-yl, thiophen-2-yl or 4,5-dichloro-2-yl; and the compound is a racemate and (S)- or (R)- optical isomers.
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Paragraph 0081; 0082; 0083; 0090; 0091; 0092
(2017/08/25)
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- (S)- {1 - (chloromethane ester) - 2 - [2 - (1, 3 - two oxygen different indole) yl] ethyl} halide salt and its preparation method
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The present invention discloses a compound (S)-{1-(chloroformate)-2-[2-(1,3-dioxo-isoindol)yl]ethyl}halogenation salt represented by a formula VI, and a preparation method thereof, wherein X represents a halogen. According to the present invention, the compound is used for preparing the rivaroxaban key intermediate (S)-2-{[2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidine-5-yl]methyl}isoindole-1,3-dione and/or rivaroxaban intermediate, and the obtained product is firstly obtained through the method in the present invention; and the preparation method is mature and reliable, and can be suitable for industrial large-scale production. The formula VI is defined in the specification.
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Paragraph 0113; 0114
(2017/08/25)
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- S-epihydric a phthalic acid imide preparation method
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The invention relates to a preparation method of S-glycidylphthalimide. The preparation method is characterized in that in a reaction of potassium phthalimide or phthalimide and (S) epichlorohydrin, a phase transfer catalyst and potassium iodide are used so that S-glycidylphthalimide synthesis is realized. Compared with the prior art, the preparation method greatly improves an S-glycidylphthalimide yield, has simple and safe processes, produces high-purity products, has a low cost and is suitable for industrial production of S-glycidylphthalimide.
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Paragraph 0076; 0077
(2017/03/08)
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- A process for the preparation of intermediates the advantage cuts down Sha Ban
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The invention discloses a synthetic method of rivaroxabanintermediate4-(4-nitrosobenzene)-3-morpholine. The method comprises steps as follows: (1), halogenated benzene (I) and ethanolamine react under the condition of a catalyst and alkali to generate N-ethoxylaniline (II), N-ethoxylaniline (II) and nitrous acid or nitrite react to generate 4-nitroso-N-ethoxylaniline (III), and 4-nitroso-N-ethoxylaniline (III) and chloroacetyl chloride react to generate 4-(4-nitrosobenzene)-3-morpholine (IV). According to the synthetic method of 4-(4-nitrosobenzene)-3-morpholine, required raw materials and reagents are cheap and are easy to obtain, the yield is high, and the cost is low; the reaction condition is mild; fewer three wastes are produced; and the product quality is reliable and stable, and the whole process is very suitable for industrial production.
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- Rivaroxaban intermediate preparation method
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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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- Rivaroxaban bulk drug and preparation method thereof
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The invention discloses a rivaroxaban bulk drug and a preparation method thereof. The rivaroxaban bulk drug is characterized in that the purity of rivaroxaban is not smaller than 99.5%, and the content of impurities represented by formula 1 is not greater than 0.1%. The preparation method of the rivaroxaban comprises the following steps: reacting hydrochloride of the compound represented by formula 1 with a toluene solution of 5-chlorothiophene-2-carbonyl chloride in an acetone and water mixed solution in the presence of triethylamine, and carrying out routine solid-liquid separation and drying to obtain crude rivaroxaban; and re-crystallizing the crude rivaroxaban by using a water and acetic acid mixed solvent to obtain purified rivaroxaban. The rivaroxaban prepared through using the preparation method has the advantages of high purity, low content of impurities, and suitableness for large scale production.
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Paragraph 0006; 0060; 0061; 0062
(2016/10/10)
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- A the advantage cuts down Sha Ban method for the preparation of intermediates thereof, and intermediate compound
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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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- PROCESS FOR THE PREPARATION OF RIVAROXABAN
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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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Page/Page column 30; 31
(2016/03/22)
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- N-epoxy propyl-N-acyl aniline compounds, process for their preparation and use
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The present invention discloses a class of N-epoxypropyl-N-acylaniline compounds represented by a formula (I), and further discloses a preparation method of the N-epoxypropyl-N-acylaniline compounds, and applications of the N-epoxypropyl-N-acylaniline compounds in preparation of oxazolidinone treating drugs including but being not limited to linezolid and rivaroxaban racemate or optical isomers, wherein R1 represents morpholinyl or 3-O-4-morpholinyl, R2 represents H or F, R3 represents C1-12 alkyl, thien-2-yl or 5-chlorothiophen-2-yl, and the compounds are racemates, (S)-optical isomers, or (R)-optical isomers.
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Paragraph 0122; 0123; 0124; 0131; 0132; 0133
(2016/10/10)
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- AN IMPROVED PROCESS FOR PREPARATION OF RIVAROXABAN
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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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- Preparation method of rivaroxaban
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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 0081; 0082
(2016/11/02)
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