CN104628724A - Method for preparing apixaban - Google Patents
Method for preparing apixaban Download PDFInfo
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- CN104628724A CN104628724A CN201510076614.2A CN201510076614A CN104628724A CN 104628724 A CN104628724 A CN 104628724A CN 201510076614 A CN201510076614 A CN 201510076614A CN 104628724 A CN104628724 A CN 104628724A
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- Prior art keywords
- refining
- eliquis
- ethanol
- virahol
- compound
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- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 title claims abstract description 36
- 238000000034 method Methods 0.000 title claims abstract description 23
- 229960003886 apixaban Drugs 0.000 title abstract description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 74
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 238000007670 refining Methods 0.000 claims abstract description 22
- 238000010189 synthetic method Methods 0.000 claims abstract description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 30
- 229940047562 eliquis Drugs 0.000 claims description 29
- 239000007787 solid Substances 0.000 claims description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 18
- 238000005406 washing Methods 0.000 claims description 18
- 238000002425 crystallisation Methods 0.000 claims description 17
- 230000008025 crystallization Effects 0.000 claims description 17
- 229910021529 ammonia Inorganic materials 0.000 claims description 15
- 235000011114 ammonium hydroxide Nutrition 0.000 claims description 13
- 238000003756 stirring Methods 0.000 claims description 13
- 238000000967 suction filtration Methods 0.000 claims description 13
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 11
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 claims description 11
- 238000000746 purification Methods 0.000 claims description 10
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 239000003960 organic solvent Substances 0.000 claims description 7
- 229910001220 stainless steel Inorganic materials 0.000 claims description 7
- 239000010935 stainless steel Substances 0.000 claims description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 5
- -1 Eliquis compound Chemical class 0.000 claims description 3
- 238000009413 insulation Methods 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims 1
- 239000006227 byproduct Substances 0.000 abstract description 4
- 239000000126 substance Substances 0.000 abstract description 4
- 239000002904 solvent Substances 0.000 abstract description 2
- 230000001988 toxicity Effects 0.000 abstract description 2
- 231100000419 toxicity Toxicity 0.000 abstract description 2
- 238000005915 ammonolysis reaction Methods 0.000 abstract 2
- 239000012043 crude product Substances 0.000 abstract 1
- 235000019441 ethanol Nutrition 0.000 abstract 1
- 239000012535 impurity Substances 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 13
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 9
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 6
- 239000003153 chemical reaction reagent Substances 0.000 description 5
- 238000001035 drying Methods 0.000 description 5
- 239000012065 filter cake Substances 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002360 explosive Substances 0.000 description 2
- XBLVHTDFJBKJLG-UHFFFAOYSA-N nicotinic acid ethyl ester Natural products CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention relates to the field of chemical pharmacy and particularly relates to a method for preparing apixaban. The method comprises the following steps: (1) synthetic method of apixaban crude product: performing ammonolysis by an ammonia-accessing method; (2) refining method of apixaban: the refining method includes ethyl alcohol refining and isopropanol refining. The purity of the compounded apixaban is more than 97%, the byproducts are few, the operation method is simple and the reaction process is easy to control, at the same time, the yield of the ammonolysis is more than 91%; after two refining processes, the purity of the apixaban is greatly increased to more than 99.6%, and the single impurity is less than 0.1% and the yield is more than 90%. The solvent used in the refining process is low in toxicity, high in safety, cheap and easy to obtain. The refining process is simple in operation, mild in reaction condition, low in cost and is suitable for industrial production.
Description
Technical field
The present invention relates to chemical pharmacy field, be specifically related to a kind of Eliquis preparation method.
Background technology
Eliquis (apixaban, commodity are called Eliquis), chemical name: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide; Molecular formula: C25H25N5O4; Molecular weight: 459.50; CAS registration number: 503612-47-3, chemical structure is:
Synthesis for Eliquis obtains mainly with 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester ammonia solution.
Carry out ammonia solution with the ethylene glycol solution of ammonia in document [pinto D.J.P.et.J.Med.Chem.2007,50 (22): 5339-5356] and patent WO2010030983.WO2010030983 but total recovery also only has 1.3%.
In patent WO2003049681, compound (2) generates compound (1) with the formamide of 10 times of equivalents under excessive sodium methylate exists.Yield also only has 5.2%.
In patent CN102675314A, 2 is generate compound (1) with the formamide of 10 times of equivalents in the methanol solution of the sodium methylate of 1 times of equivalent
Be carry out ammonia solution with the methanol solution of ammoniacal liquor in patent CN101967145A, be Material synthesis Eliquis with p-Nitroaniline, but use the inflammable and explosive reagent such as sodium hydride in reaction process, severe reaction conditions, and reaction process is complicated.
Carry out ammonia solution with the ethylene glycol solution of ammonia in these methods, the solubleness of ammonia in ethylene glycol solution is smaller, and reaction is complete not.Using methane amide as ammonia solution reagent under the existence of sodium methylate, operation is loaded down with trivial details, and by product is more, and yield is low.Using the methanol solution of ammoniacal liquor as ammonia solution reagent, because the existence of water in system, make reaction incomplete, and by product is many.
By analyze above-mentioned document report the synthetic route of Eliquis, there is lower column defects in the preparation process of Eliquis: use the expensive organic compound containing iodine, auxiliary reagent large usage quantity and price are costly.Reagent used is inflammable and explosive, severe reaction conditions, and aftertreatment is more loaded down with trivial details, and yield is low, and purity is low.
Above problem have impact on purity and the yield of Eliquis all greatly.Document up to now also not in refining.
Summary of the invention
For overcoming the problem that in above-mentioned prior art, ubiquity yield is low, purity is low, the present invention's first object is the synthetic method providing a kind of Eliquis, and it specifically comprises the steps:
A kind of synthetic method of Eliquis, by 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxylic acid ethyl ester and compound (2), carry out ammonia solution in the mode passing into ammonia and obtain compound (1), i.e. Eliquis.
Preferably, compound (2), organic solvent are joined in stainless steel cauldron successively, pass into ammonia, reaction pressure is made to remain on 0.2-0.4MPa, insulation, reactor cool to room temperature after reaction stops, opening reactor, filter, obtain white solid and compound (1).
Preferably, described organic solvent is selected from methyl alcohol, ethanol, Virahol, DMF, acetonitrile polar solvent, is preferably ethanol.
Preferably, the quality of described compound (2): organic solvent volume=1G:20-50mL, more preferably, the quality of compound (2): organic solvent volume=1G:30-40mL.
Preferably, temperature when passing into ammonia is 30-120 DEG C, is more preferably 60-80 DEG C.
Preferably, described reaction pressure remains on 0.3-0.4MPa.
Preferably, described soaking time is 4-12h, is more preferably 8-9h.
The present invention's second object is to provide a kind of Eliquis process for purification, and described process for purification comprises refining two steps refining with Virahol of ethanol, specifically comprises the steps:
Ethanol purification step: add ethanol in Eliquis, is heated with stirring to backflow, and system is clarified, filtered while hot insolubles, left at room temperature crystallization, suction filtration, and washing with alcohol, obtains white solid, dries.
Preferably, during ethanol is refining, ethanol contend: Eliquis quality=15-60ML:1G; More preferably, ethanol contend: Eliquis quality=30ML:1G; Leave standstill crystallization time 10-16h.
Virahol purification step: add Virahol in Eliquis, is heated with stirring to backflow, and system is clarified, filtered while hot insolubles, left at room temperature crystallization, suction filtration, and washing with alcohol, obtains white solid, dries.
Preferably, during Virahol is refining, Virahol volume: Eliquis quality=20-80ML:1G, more preferably, Virahol volume: Eliquis quality=50ML:1G; Leave standstill crystallization 10-16h.
Compared to prior art, technical solution of the present invention can reach following technique effect:
Carry out ammonia solution with ammonia, purity is greater than 97%, and by product is few, and working method is easy, and reaction process is easy to control, and the yield of ammonia solution is greater than 91% simultaneously.After twice refining, the purity of Eliquis has had the raising of large step, and purity reaches more than 99.6%, and single mixing is less than 0.1%, and yield is more than 90%.Solvent toxicity used in treating process is little, and security is high, cheap and easy to get.Process for refining is simple to operate, and reaction conditions is gentle, and cost is low, is applicable to suitability for industrialized production.
Embodiment
Illustrate the present invention and beneficial effect thereof by the following examples, the apparent change that those of ordinary skill in the art do the present invention and modification are also contained within the present invention.
Embodiment 1
Compound (2) (4.9g), 150mL ethanol are joined in stainless steel pressure still successively, airtight, start to pass into ammonia, be heated to 60 DEG C, keep pressure at 0.3MPa, react 8 hours, stopped reaction.Reactor is opened after being cooled to room temperature, filters, filter cake washing with alcohol, obtains 4.32g white solid mp236-239 DEG C, yield 94.02%, HPLC purity 98.31% after drying.
Ethanol is refined: ethanol contend: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=30ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 92.04%, purity 99.23%.
Virahol is refined: Virahol volume: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=50ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 94.03%, purity 99.81%.
Embodiment 2
Compound (2) (4.9g), 100mL Virahol are joined in stainless steel pressure still successively, airtight, start to pass into ammonia, be heated to 60 DEG C, keep pressure at 0.4MPa, react 12 hours, stopped reaction.Reactor is opened after being cooled to room temperature, filters, filter cake washing with alcohol, obtains 4.23g white solid mp236-239 DEG C, yield 92.06%, HPLC purity 97.15% after drying.
Ethanol is refined: ethanol contend: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=15ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 93.24%, purity 98.92%.
Virahol is refined: Virahol volume: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=50ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 94.13%, purity 99.62%.
Embodiment 3
Compound (2) (4.9g), 200mL methyl alcohol are joined in stainless steel pressure still successively, airtight, start to pass into ammonia, be heated to 80 DEG C, keep pressure at 0.2MPa, react 4 hours, stopped reaction.Reactor is opened after being cooled to room temperature, filters, filter cake washing with alcohol, obtains 4.27g white solid mp236-239 DEG C, yield 92.93%, HPLC purity 97.51% after drying.
Ethanol is refined: ethanol contend: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=60ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 90.23%, purity 99.54%.
Virahol is refined: Virahol volume: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=80ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 91.28%, purity 99.73%.
Embodiment 4
The DMF of compound (2) (4.9g), 240Ml is joined in stainless steel pressure still successively, airtight, start to pass into ammonia, be heated to 30 DEG C, keep pressure at 0.3MPa, react 8 hours, stopped reaction.Reactor is opened after being cooled to room temperature, filters, filter cake washing with alcohol, obtains 4.18g white solid mp236-239 DEG C, yield 90.97%, HPLC purity 97.05% after drying.
Ethanol is refined: ethanol contend: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=20ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 93.82%, purity 98.91%.
Virahol is refined: Virahol volume: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=20ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 95.43%, purity 99.62%.
Embodiment 5
The acetonitrile of compound (2) (4.9g), 170Ml is joined in stainless steel pressure still successively, airtight, start to pass into ammonia, be heated to 120 DEG C, keep pressure at 0.3MPa, react 9 hours, stopped reaction.Reactor is opened after being cooled to room temperature, filters, filter cake washing with alcohol, obtains 4.37g white solid mp236-239 DEG C, yield 95.10%, HPLC purity 97.85% after drying.
Ethanol is refined: ethanol contend: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=20ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 93.72%, purity 98.91%.
Virahol is refined: Virahol volume: 1-(4-p-methoxy-phenyl)-7-oxo-6-[4-(2-oxo-piperidino) phenyl]-4,5,6,7-tetrahydrochysene-1H-pyrazolo [3,4-C] pyridine-3-carboxamide quality=20ML:1G, be heated with stirring to backflow, system is clarified, filtered while hot insolubles, crystallization 12h is left standstill, suction filtration, washing with alcohol at 25 DEG C, obtain white solid, dry.Yield 95.13%, purity 99.62%.
Claims (10)
1. an Eliquis synthetic method, obtains Eliquis compound (1) with compound (2) ammonia solution, it is characterized in that, carries out ammonia solution in the mode passing into ammonia.
2. Eliquis synthetic method according to claim 1, it is characterized in that, compound (2), organic solvent is comprised the steps: to join successively in stainless steel cauldron, pass into ammonia, make reaction pressure remain on 0.2-0.4MPa, insulation reaction, reactor cool to room temperature after reaction stops, open reactor, filter, obtain white solid and compound (1).
3. Eliquis synthetic method according to claim 2, it is characterized in that, described organic solvent is selected from methyl alcohol, ethanol, Virahol, DMF, acetonitrile, is preferably ethanol.
4. Eliquis synthetic method according to claim 2, it is characterized in that, the quality of described compound (2): organic solvent volume=1G: 20-50mL, temperature when passing into ammonia is 30-120 DEG C, described reaction pressure remains on 0.3-0.4MPa, and the described insulation reaction time is 4-12h.
5. the process for purification of an Eliquis: comprise refining two steps refining with Virahol of ethanol.
6. process for purification as claimed in claim 5, it is characterized in that, described ethanol is refining or Virahol is refining comprises the steps: to add ethanol in Eliquis, and be heated with stirring to backflow, system is clarified, filtered while hot insolubles, left at room temperature crystallization, suction filtration, washing with alcohol, obtain white solid, dry.
7. process for purification as claimed in claim 6, is characterized in that, during described ethanol is refining, and ethanol contend: Eliquis quality=15-60ML: 1G.
8. as right wants process for purification as described in 6, it is characterized in that, during described ethanol is refining, leaving standstill the crystallization time is 10-16h.
9. process for purification as claimed in claim 6, is characterized in that, during described Virahol is refining, and Virahol volume: Eliquis quality=20-80ML: 1G.
10. process for purification as claimed in claim 6, is characterized in that, during described Virahol is refining, leaves standstill crystallization 10-16h.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117201A (en) * | 2016-06-27 | 2016-11-16 | 青岛云天生物技术有限公司 | A kind of preparation method of antithrombotic reagent Eliquis |
| CN106518867A (en) * | 2016-10-14 | 2017-03-22 | 乐普药业股份有限公司 | Refining method for apixaban |
| CN114085222A (en) * | 2021-12-30 | 2022-02-25 | 杭州煌森生物科技有限公司 | Preparation method of apixaban |
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| WO2023218470A1 (en) * | 2022-05-12 | 2023-11-16 | Iol Chemicals And Pharmaceuticals Limited | Efficient process for preparation of apixaban having crystalline particles with d90 greater than 89 micron |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106117201A (en) * | 2016-06-27 | 2016-11-16 | 青岛云天生物技术有限公司 | A kind of preparation method of antithrombotic reagent Eliquis |
| CN106518867A (en) * | 2016-10-14 | 2017-03-22 | 乐普药业股份有限公司 | Refining method for apixaban |
| CN106518867B (en) * | 2016-10-14 | 2017-11-28 | 乐普药业股份有限公司 | A kind of process for purification of Eliquis |
| CN114085222A (en) * | 2021-12-30 | 2022-02-25 | 杭州煌森生物科技有限公司 | Preparation method of apixaban |
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