CN104109158A - Rivaroxaban purification method - Google Patents
Rivaroxaban purification method Download PDFInfo
- Publication number
- CN104109158A CN104109158A CN201310132071.2A CN201310132071A CN104109158A CN 104109158 A CN104109158 A CN 104109158A CN 201310132071 A CN201310132071 A CN 201310132071A CN 104109158 A CN104109158 A CN 104109158A
- Authority
- CN
- China
- Prior art keywords
- razaxaban
- thick product
- ethylene glycol
- glycol monomethyl
- monomethyl ether
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- 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
Abstract
The invention provides a rivaroxaban purification method. The method comprises the following steps: dissolving a rivaroxaban coarse product in ethylene glycol monomethyl ether or n-butanol under a heating condition, adding active carbon after clarification, carrying out suction filtration when the solution is still hot, crystallizing and cooling the mother liquor, and filtering so as to obtain the crystallization product rivaroxaban. The rivaroxaban purification method has the following advantages: (1) ethylene glycol monomethyl ether or n-butanol is used to carry out recrystallization to avoid the complicated chromatogram purification; (2) compared to the acetate, ethylene glycol monomethyl ether or n-butanol will not corrode the reaction equipment and is convenient for industrial production.
Description
Technical field
The present invention relates to pharmaceutical chemistry field, relate to particularly a kind of method of purifying razaxaban.
Background technology
Razaxaban (Rivaroxaban, trade(brand)name: Xarelto) chemistry by name: the chloro-N-of 5-((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidine-5-yl } methyl)-2-thenoyl amine, it is corresponding to general formula (I), and molecular formula is: C
19h
18n
3o
5sCl, molecular weight is: 435.88g/mol.
Razaxaban is the direct inhibitor of oral Xa factor by Bayer and Johson & Johnson's cooperative research and development.In September And October, 2008 obtains listing in Canada and European Union respectively and ratifies, and is clinically mainly used in preventing hip or knee replacements Venous Blood bolt embolism.Within 2011, U.S. FDA is ratified it for deep venous thrombosis.Compared with other anticoagulants, razaxaban has predictable pharmacokinetics and pharmacodynamic properties, and onset is rapid, low with the possibility of food and drug interaction in addition, therefore do not need conventional coagulation function to detect, makes anti-freezing become easy, safe, effective.Along with the increase of aging population, cardiovascular disease incidence rate, the demand of anticoagulant is constantly increased, the direct inhibitor of Xa factor is the development trend of anticoagulation.
The synthetic method report of razaxaban is more, such as patent documentation WO01/47919, US7351823, DE10300111.5 etc.As everyone knows, recrystallization is refining the most frequently used method, but less about the method report of razaxaban recrystallization.In document WO2005/068456, there is the method for purifying of description, be suspended in by the thick product of razaxaban that in acetic acid, to add thermosol clear, then cooling precipitation, suction filtration, water, acetic acid washing are then dry.But because acetic acid acidity is stronger, perishable conversion unit, is not suitable for suitability for industrialized production.Also the method that has report to refine razaxaban with DMSO and acetonitrile mixed solvent in document WO2012035057, but acetonitrile toxicity is not suitable for more greatly industrialization.Therefore, finding a kind of economical and practical recrystallization method is necessary.
Summary of the invention
A first aspect of the present invention provides a kind of method of purifying razaxaban, comprise the following steps: under heating condition, thick razaxaban product is dissolved in ethylene glycol monomethyl ether or propyl carbinol, moltenly adds gac, suction filtration while hot after clear, mother liquor crystallisation by cooling, filters and obtains crystallized product razaxaban.
More specifically, the inventive method comprises the steps: thick razaxaban product to be suspended in ethylene glycol monomethyl ether or propyl carbinol, adds thermosol clear, adds proper amount of active carbon, suction filtration while hot, mother liquor crystallisation by cooling, suction filtration, ethylene glycol monomethyl ether or propyl carbinol are washed, and dry, and obtain the recrystallized product of razaxaban.
According to of the present invention one preferred embodiment, the mass volume ratio of the thick product of described razaxaban and ethylene glycol monomethyl ether or propyl carbinol is 1: 5-20, is preferably 1: 5-15.
Mass volume ratio of the present invention refers to the ratio of the quality of the thick product of razaxaban and the volume of ethylene glycol monomethyl ether or propyl carbinol.For example: the thick product of 1g razaxaban is dissolved in 15ml ethylene glycol monomethyl ether, mass volume ratio is 1: 15.
According to of the present invention one preferred embodiment, the mass volume ratio of the thick product of described razaxaban and gac is 1: 0.05-0.3, is preferably 1: 0.1-0.2.
According to of the present invention another preferred embodiment, the temperature of the thick product of razaxaban is 60-140 DEG C described in heating for dissolving, preferably 100-125 DEG C.
According to of the present invention another preferred embodiment, described mother liquor crystallisation by cooling is 0-60 DEG C, is preferably 0-30 DEG C.
It is 99.7% that the refining razaxaban that the method for the invention obtains is measured purity through HPLC, is determined as crystal formation I through X-powdery diffractometry method.
A second aspect of the present invention provides the application at the thick product of purifying razaxaban of ethylene glycol monomethyl ether or propyl carbinol.
The preparation method of preparation method's reference (J.Med.Chem.48:5900-5908,2005) of the thick product of razaxaban of the present invention.Concrete steps are as follows:
By 2-[(2S)-oxyethane-2-ylmethyl]-1H-isoindole-1, 3 (2H)-diketone (II) and 4-(4-aminophenyl)-3-morpholone mai (III) are suspended in alcohol-water (9: 1) solution, (raw material is molten clear gradually for back flow reaction 14h, after for some time, form again precipitation), filter out this precipitation, ether washing is also dry under vacuum, the mother liquor that concentrating under reduced pressure merges also adds second part of 2-[(2S)-oxyethane-2-ylmethyl]-1H-isoindole-1, in alcohol-water (9: the 1) suspension of 3 (2H)-diketone (II), back flow reaction 13h, filter, ether washing, dry under vacuum, obtaining white solid is compound IV.
By N, N '-carbonyl dimidazoles with Dimethylamino pyridine (catalytic amount) is added to 2-((2R)-2-hydroxyl-3-{[4-(3-oxo morpholine-4-yl) phenyl] amino } propyl group)-1H-isoindole-1, in the tetrahydrofuran (THF) suspension of 3 (2H)-diketone (IV), (raw material is molten clear gradually to stir this suspension 12h at 60 DEG C, after for some time, form again precipitation), add second part of N, N '-carbonyl dimidazoles also continues to stir 12h at 60 DEG C, filter out this precipitation, tetrahydrofuran (THF) washing, it is compound V that vacuum-drying obtains white solid
By aqueous methylamine solution (40% the aqueous solution) be added drop-wise to 2-((5S)-2-oxo-3-[4-(3 oxo morpholine-4-yl) phenyl]-1,3-oxazolidine-5-yl } methyl)-1H-isoindoline-1, in the ethanolic soln of 3 (2H)-diketone (V), this reaction mixture 1h refluxes, concentrating under reduced pressure reaction solution, obtain the thick product of compound VI, be directly used in next step.
At 0 DEG C, chloro-5-2-thiophene chloride is added dropwise to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazoles alkane-3-yl]-phenyl } in the pyridine solution of morpholone mai (VI), be warming up to room temperature, after stirred reaction mixture 1h, mix with water, add after methylene dichloride phase-splitting, water layer dichloromethane extraction, merges organic layer, add anhydrous sodium sulfate drying, filter, decompression is spin-dried for, and obtaining white solid is the thick product of razaxaban.
The invention has the advantages that spent glycol methyl ether or propyl carbinol carry out recrystallization, can avoid using complicated chromatography purity; And ethylene glycol monomethyl ether or propyl carbinol be compared with acetic acid, can corrosion reaction equipment, be convenient to suitability for industrialized production.
Brief description of the drawings
Fig. 1 is the X-powder diagram of the razaxaban that makes of embodiment 1;
Fig. 2 is the DSC figure of the razaxaban that makes of embodiment 1.
Embodiment
Below by specific embodiment, technical scheme of the present invention is described further; But protection scope of the present invention is not limited in these embodiment.Unless otherwise stated, all data is based on weight percentage.
Be below part chemical feedstocks related in experiment and purchase company and the product batch number of reagent:
Embodiment 1: the preparation of the thick product of razaxaban
The preparation method of reference (J.Med.Chem.48:5900-5908,2005).
The first step: 2-((2R)-2-hydroxyl-3-{[4-(3-oxo morpholine-4-yl) phenyl] amino } propyl group)-1H-isoindole-1, the preparation of 3 (2H)-diketone (IV)
By 2-[(2S)-oxyethane-2-ylmethyl]-1H-isoindole-1, 3 (2H)-diketone (II) (5.68g, 27.9mmol) and 4-(4-aminophenyl)-3-morpholone mai (III) (5.37g, 27.9mmol) be suspended in alcohol-water (9: 1, 140ml) in solution, (raw material is molten clear gradually for back flow reaction 14h, after for some time, form again precipitation), filter out this precipitation, ether washing is also dry under vacuum, the mother liquor that concentrating under reduced pressure merges also adds second part of 2-[(2S)-oxyethane-2-ylmethyl]-1H-isoindole-1, 3 (2H)-diketone (II) (2.84g, alcohol-water 14.0mmol) (9: 1, 70ml) in suspension, back flow reaction 13h, filter, ether washing, dry under vacuum, obtaining white solid 10.14g is compound IV, yield is 92%.
Second step: 2-((5S)-2-oxo-3-[4-(3 oxo morpholine-4-yl) phenyl] and-1,3-oxazoles alkane-5-yl } methyl)-1H-isoindoline-1, the preparation of 3 (2H)-diketone (V)
By N, N '-carbonyl dimidazoles (2.94g, 18.1mmol) with Dimethylamino pyridine (catalytic amount) is added to 2-((2R)-2-hydroxyl-3-{[4-(3-oxo morpholine-4-yl) phenyl] amino } propyl group)-1H-isoindole-1, 3 (2H)-diketone (IV) (3.58g, in tetrahydrofuran (THF) suspension 9.05mmol), (raw material is molten clear gradually to stir this suspension 12h at 60 DEG C, after for some time, form again precipitation), add second part of N, N '-carbonyl dimidazoles (2.94g, 18.1mmol) also continue to stir 12h at 60 DEG C, filter out this precipitation, tetrahydrofuran (THF) washing, it is compound V that vacuum-drying obtains white solid 3.32g, yield 87%.
The 3rd step: 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazoles alkane-3-yl]-phenyl } preparation of morpholone mai (VI)
By aqueous methylamine solution (40% the aqueous solution, 10.2ml, 0.142mmol) be added drop-wise to 2-((5S)-2-oxo-3-[4-(3 oxo morpholine-4-yl) phenyl]-1,3-oxazolidine-5-yl } methyl)-1H-isoindoline-1,3 (2H)-diketone (V) (4.45g, in ethanol (102ml) solution 10.6mmol), this reaction mixture 1h refluxes, concentrating under reduced pressure reaction solution, obtain the thick product of compound VI, be directly used in next step.
The 4th step: the preparation of the chloro-N-of (S)-5-((2-oxo-3-(4-(3-oxo-morpholinyl) phenyl) oxazolidine-5-yl) methyl) thiophene-2-carboxamide derivatives (I)
At 0 DEG C, by chloro-5-2-thiophene chloride (2.29g, 12.7mmol) be added dropwise to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1, 3-oxazolidine-3-yl]-phenyl } morpholone mai (VI) (3.08g, in pyridine (90ml) solution 10.6mmol), be warming up to room temperature, after stirred reaction mixture 1h, mix with water, add after methylene dichloride phase-splitting, water layer dichloromethane extraction, merge organic layer, add anhydrous sodium sulfate drying, filter, decompression is spin-dried for, obtain white solid 3.92g, for the thick product of razaxaban, yield: 86%.
Embodiment 2: the thick product of razaxaban refining
The thick product of 4g razaxaban be suspended in 60ml ethylene glycol monomethyl ether and be heated to 125 DEG C, add gac 0.4g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to room temperature by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 3.46g white solid, recrystallization yield: 86.5%.HPLC purity 99.74%, ee%:99.96%.DSC solvent temperature: 230 DEG C.
1hNMR (400MHz, d
6-DMSO): 9.00-8.93 (t, J=5.6Hz, 6Hz, 1H), 7.70 (d, J=4Hz, 1H), 7.60-7.53 (d, J=8.8Hz, 2H), 7.44-7.37 (d, J=8.2Hz, 2H), 7.21-7.17 (d, J=4Hz, 1H), 4.80-4.89 (m, 1H), 4.24-4.15 (m, 3H), 4.00-3.94 (m, 2H), 3.89-3.82 (m, 1H), 3.75-3.68 (m, 2H), 3.64-3.58 (t, J=5.6Hz, 2H); 2 θ angles of powdery diffractometry are: 8.960 °, and 16.481 °, 25.582 °, 26.608 °, 19.483 °, 19.877 °, 21.654 °, 22.481 °, 23.291 °.
Embodiment 3: the thick product of razaxaban refining
The thick product of 5g razaxaban be suspended in 50ml ethylene glycol monomethyl ether and be heated to 140 DEG C, add gac 1.5g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 60 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 4.3g white solid; Recrystallization yield: 86.0%.HPLC purity 99.67%.
Embodiment 4: the thick product of razaxaban refining
The thick product of 5g razaxaban be suspended in 100ml ethylene glycol monomethyl ether and be heated to 60 DEG C, add gac 0.25g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 0 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 3.70g white solid, recrystallization yield: 74.0%.HPLC purity 99.62%.
Embodiment 5: the thick product of razaxaban refining
The thick product of 1g razaxaban be suspended in 5ml ethylene glycol monomethyl ether and be heated to 110 DEG C, add gac 0.2g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 30 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 0.80g white solid, recrystallization yield: 80.0%.HPLC purity 99.52%.
Embodiment 6: the thick product of razaxaban refining
The thick product of 3g razaxaban be suspended in 45ml ethylene glycol monomethyl ether and be heated to 100 DEG C, add gac 0.45g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 0 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 2.49g white solid, recrystallization yield: 83.0%.HPLC purity 99.55%.
Embodiment 7: the thick product of razaxaban refining
The thick product of 5g razaxaban be suspended in 75ml propyl carbinol and be heated to 125 DEG C, add gac 0.5g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to room temperature by mother liquor.Suction filtration, leaches the product of precipitation, with propyl carbinol washing, dry, obtains 4.20g white solid, recrystallization yield: 84.0%.HPLC purity 99.7%.
Embodiment 8: the thick product of razaxaban refining
The thick product of 3g razaxaban be suspended in 30ml propyl carbinol and be heated to 140 DEG C, add gac 0.9g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 60 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, with propyl carbinol washing, dry, obtains 2.58g white solid; Recrystallization yield: 86.0%.HPLC purity 99.64%.
Embodiment 9: the thick product of razaxaban refining
The thick product of 4g razaxaban be suspended in 80ml propyl carbinol and be heated to 60 DEG C, add gac 0.20g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 0 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, with propyl carbinol washing, dry, obtains 3.4g white solid, recrystallization yield: 85.0%.HPLC purity 99.63%.
Embodiment 10: the thick product of razaxaban refining
The thick product of 1g razaxaban be suspended in 5ml propyl carbinol and be heated to 110 DEG C, add gac 0.2g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 30 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 0.81g white solid, recrystallization yield: 81.0%.HPLC purity 99.52%.
Embodiment 11: the thick product of razaxaban refining
The thick product of 3g razaxaban be suspended in 45ml propyl carbinol and be heated to 100 DEG C, add gac 0.45g, stirring gained solution 10 minutes in this temperature, then filtered while hot, is cooled to 0 DEG C by mother liquor.Suction filtration, leaches the product of precipitation, and the washing of spent glycol methyl ether is dry, obtains 2.49g white solid, recrystallization yield: 83.0%.HPLC purity 99.54%.
Claims (10)
1. the method for a purifying razaxaban, described method comprises the steps: under heating condition, thick razaxaban product to be dissolved in ethylene glycol monomethyl ether or propyl carbinol, moltenly adds gac, suction filtration while hot after clear, mother liquor crystallisation by cooling, filters and obtains crystallized product razaxaban.
2. according to the method for claim 1, it is characterized in that, the mass volume ratio of the thick product of described razaxaban and ethylene glycol monomethyl ether or propyl carbinol is 1: 5-1: 20.
3. according to the method for claim 2, it is characterized in that, the mass volume ratio of the thick product of described razaxaban and ethylene glycol monomethyl ether or propyl carbinol is 1: 5-1: 15.
4. according to the method for claim 1, it is characterized in that, the mass volume ratio of the thick product of described razaxaban and gac is 1: 0.05-0.3.
5. according to the method for claim 4, it is characterized in that, the mass volume ratio of the thick product of described razaxaban and gac is 1: 0.1-0.2.
6. according to the method for claim 1, it is characterized in that, the temperature of the thick product of razaxaban is 60-140 DEG C described in heating for dissolving.
7. according to the method for claim 6, it is characterized in that, the temperature of the thick product of razaxaban is 100-125 DEG C described in heating for dissolving.
8. according to the method for claim 1, it is characterized in that, the temperature of described mother liquor crystallisation by cooling is 0-60 DEG C.
9. method according to Claim 8, is characterized in that, the temperature of described mother liquor crystallisation by cooling is 0-30 DEG C.
10. ethylene glycol monomethyl ether or propyl carbinol are in the application of the thick product of purifying razaxaban.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310132071.2A CN104109158A (en) | 2013-04-16 | 2013-04-16 | Rivaroxaban purification method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310132071.2A CN104109158A (en) | 2013-04-16 | 2013-04-16 | Rivaroxaban purification method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN104109158A true CN104109158A (en) | 2014-10-22 |
Family
ID=51706164
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310132071.2A Pending CN104109158A (en) | 2013-04-16 | 2013-04-16 | Rivaroxaban purification method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104109158A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
| CN108546265A (en) * | 2018-06-22 | 2018-09-18 | 苏州中联化学制药有限公司 | A kind of synthetic method of Rivaroxaban intermediate |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
| CN114163395A (en) * | 2021-12-07 | 2022-03-11 | 中国人民解放军空军军医大学 | Chiral oxazolinone derivatives, synthesis method and application thereof in preparation of linezolid and rivaroxaban |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1906191A (en) * | 2004-01-15 | 2007-01-31 | 拜耳医药保健股份公司 | Preparation method |
| WO2009080226A2 (en) * | 2007-12-26 | 2009-07-02 | Sanofis-Aventis | Heterocyclic pyrazole-carboxamides as p2y12 antagonists |
| CN101663293A (en) * | 2007-04-23 | 2010-03-03 | 塞诺菲-安万特股份有限公司 | Quinoline-carboxamide derivatives as p2y12 antagonists |
| WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
| WO2012035057A2 (en) * | 2010-09-14 | 2012-03-22 | Medichem S.A. | Process for determining the suitability for distribution of a batch of a thiophene-2-carboxamide derivative |
| CN102584738A (en) * | 2011-01-07 | 2012-07-18 | 浙江九洲药业股份有限公司 | New technology for synthesizing rivaroxaban intermediate |
| CN102753537A (en) * | 2010-02-10 | 2012-10-24 | 桑多斯股份公司 | Method for the preparation of rivaroxaban |
-
2013
- 2013-04-16 CN CN201310132071.2A patent/CN104109158A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1906191A (en) * | 2004-01-15 | 2007-01-31 | 拜耳医药保健股份公司 | Preparation method |
| CN101663293A (en) * | 2007-04-23 | 2010-03-03 | 塞诺菲-安万特股份有限公司 | Quinoline-carboxamide derivatives as p2y12 antagonists |
| WO2009080226A2 (en) * | 2007-12-26 | 2009-07-02 | Sanofis-Aventis | Heterocyclic pyrazole-carboxamides as p2y12 antagonists |
| WO2011012321A1 (en) * | 2009-07-31 | 2011-02-03 | Krka, D.D., Novo Mesto | Processes for crystallization of rivaroxaban |
| CN102753537A (en) * | 2010-02-10 | 2012-10-24 | 桑多斯股份公司 | Method for the preparation of rivaroxaban |
| WO2012035057A2 (en) * | 2010-09-14 | 2012-03-22 | Medichem S.A. | Process for determining the suitability for distribution of a batch of a thiophene-2-carboxamide derivative |
| CN102584738A (en) * | 2011-01-07 | 2012-07-18 | 浙江九洲药业股份有限公司 | New technology for synthesizing rivaroxaban intermediate |
Non-Patent Citations (1)
| Title |
|---|
| 王海燕，等: "利伐沙班合成路线图解", 《中国药物化学杂志》, vol. 22, no. 3, 30 June 2012 (2012-06-30) * |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105777738A (en) * | 2014-12-16 | 2016-07-20 | 南京生命能科技开发有限公司 | Rivaroxaban bulk drug and preparation method thereof |
| CN105440028A (en) * | 2015-12-07 | 2016-03-30 | 石家庄康贺威药业有限公司 | Rivaroxaban compound and preparing method thereof |
| CN106008490A (en) * | 2016-01-11 | 2016-10-12 | 南京生命能科技开发有限公司 | New crystal of rivaroxaban and preparation method thereof |
| CN106008490B (en) * | 2016-01-11 | 2019-01-04 | 南京生命能科技开发有限公司 | A kind of new crystal of razaxaban and preparation method thereof |
| CN108546265A (en) * | 2018-06-22 | 2018-09-18 | 苏州中联化学制药有限公司 | A kind of synthetic method of Rivaroxaban intermediate |
| CN110172060A (en) * | 2018-12-27 | 2019-08-27 | 苏州二叶制药有限公司 | Razaxaban, synthesis and refining methd |
| CN114163395A (en) * | 2021-12-07 | 2022-03-11 | 中国人民解放军空军军医大学 | Chiral oxazolinone derivatives, synthesis method and application thereof in preparation of linezolid and rivaroxaban |
| CN114163395B (en) * | 2021-12-07 | 2023-10-10 | 中国人民解放军空军军医大学 | Chiral oxazolinone derivative, synthesis method and application thereof in preparation of linezolid and rivaroxaban |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104109158A (en) | Rivaroxaban purification method | |
| CN101967145B (en) | Method for preparing antithrombotic medicament apixaban | |
| EP3168220B1 (en) | Novel method for synthesizing rivaroxaban intermediate, 4-{4-[(5s)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholin-3-one | |
| CN103724336B (en) | A kind of synthetic method of novel anticoagulation medicine | |
| CN103864772A (en) | Preparation method for rivaroxaban and intermediate thereof | |
| CN106496201A (en) | A kind of preparation method of avanaphil crude drug | |
| EP0412899B1 (en) | Oxazolo pyridine derivatives, process for their preparation and pharmaceutical compositions containing them | |
| CN106967057A (en) | A kind of efficient preparation technology of Aprepitant | |
| CN104974149A (en) | Preparation method of rivaroxaban | |
| JP2009280521A (en) | Production method of 2,4-disubstituted pyridine | |
| CN104844588B (en) | A kind of synthetic method of razaxaban related substances diamines | |
| CN104926807B (en) | A kind of razaxaban related substances " diamines " and its synthetic method | |
| CN104530002A (en) | Bilastine compound and preparation method thereof | |
| CN107382897A (en) | A kind of intermediate of betrixaban and its preparation method and application | |
| CN111039860B (en) | Synthetic method and application of 2-hydroxy-N- (4' -chlorobiphenyl-2-yl) nicotinamide | |
| CN104974059B (en) | A kind of Rivaroxaban intermediate and preparation method thereof | |
| CN105622357B (en) | A kind of synthetic method of Dapagliflozin impurity | |
| CN113563319A (en) | Indazole heterocycles having phosphodiesterase 4B inhibitory activity | |
| CN104961736A (en) | Related substance of rivaroxaban--triamine and synthetic methods thereof | |
| CN105481831B (en) | A kind of method for preparing dabigatran etexilate intermediate | |
| CN102086147B (en) | Preparation method of substituted phenol | |
| CN101450946B (en) | Synthetic method of ziprasidone | |
| CN103951661B (en) | A kind of preparation method of razaxaban | |
| CN103570698A (en) | Compound for preparing vilazodone as well as intermediate and application thereof | |
| CN103864771A (en) | Rivaroxaban preparation method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20141022 |
|
| RJ01 | Rejection of invention patent application after publication |