CN110172060A - Razaxaban, synthesis and refining methd - Google Patents
Razaxaban, synthesis and refining methd Download PDFInfo
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- CN110172060A CN110172060A CN201910546769.6A CN201910546769A CN110172060A CN 110172060 A CN110172060 A CN 110172060A CN 201910546769 A CN201910546769 A CN 201910546769A CN 110172060 A CN110172060 A CN 110172060A
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- razaxaban
- synthetic method
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The present invention relates to field of medicinal chemistry, provide the synthesis and refining methd of razaxaban, synthetic method includes: 1) under alkaline system, 4- { 4- [(5S) -5- (amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } condensation reaction occurs for morpholine -3- ketone (LF-II) and 5- chlorothiophene -2- formic acid (SMI), razaxaban crude product is made；Refining methd further comprises that crystallization 2) is stirred at room temperature in razaxaban crude product and alcoholic solution, obtains the highly finished product of high-purity, and is conformed to crystal form requirement, and whole preparation process is easy to operate, high income, pollutes small, is suitble to large-scale industrial production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the synthesis and refining methd of razaxaban.
Background technique
Razaxaban (I), English name: Rivaroxaban.Its chemical name is: the chloro- N- of 5- ({ (5S) -2- oxo -3-
[4- (3- oxo -4- morpholinyl) phenyl] -1,3-oxazoles alkane -5- base } methyl) -2- thenoyl amine, molecular formula are as follows:
C19H18ClN3O5S。
Razaxaban is a kind of efficient selective Xa factor inhibitor researched and developed jointly by Beyer Co., Ltd and Johson & Johnson,
It gets the Green Light listing in Canada and European Union within 2008, trade name Xarelto.In June, 2009 in Chinese official listing, 2011
July in year is approved listing by U.S. FDA.Razaxaban is global first oral direct Xa factor inhibitor, it can height
Selectively directly inhibit the Xa factor in free or bonding state, generate anticoagulation, with bioavilability height, treatment
Spectrum of disease is wide, and dose-effect relationship is stablized, convenient oral, the low feature of bleeding risk.Razaxaban is also the medicine for preventing and treating phlebothrombosis
Object.Clinically it is mainly used for preventing hip joint and knee prosthesis postoperative patient person deep vein thrombosis (DVT) and pulmonary embolism (PE)
It is formed.It can also be used for prevention non-valve artrial fibrillation patient cerebral apoplexy and non-central nervous system embolism, reduce coronal dynamic
The risk etc. of arteries and veins syndrome recurrence.
The synthesis of razaxaban is often with 4- { 4 [(5S) -5- (amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl }
Morpholine -3- ketone or its hydrochloride (LF-II) and the chloro- 2- acyl chlorides thiophene of 5- or derivatives thereof, which react, to be prepared.
It is specific as follows:
Patent CN102786516B is using toluene and water as solvent, by the chloro- 2- acyl chlorides thiophene of 5- and compound in alkaline condition
Lower reaction, razaxaban is obtained with Recrystallisation from acetic acid, acetic acid has toxicity and corrosivity.
Patent WO2012035057A synthetic method is that the sulfate of compound is dissolved in mixed liquor (acetone and water), then
The toluene solution of the chloro- 2- acyl chlorides thiophene of 5- is added dropwise.The solid of precipitation is filtered after reaction, acetone washing 2 times, through dry
To white solid.
For patent WO2012159992A by the hydrochloride salt of compound in tetrahydrofuran, triethylamine does acid binding agent, is added dropwise
The chloro- 2- acyl chlorides thiophene of 5- (30% toluene) solution.
The chloro- 2- acyl chlorides thiophene of raw material 5- used in above-mentioned patent contains acid chloride groups, as hydrazine class compound, by
It confirms that there is potential genetoxic and carcinogenicity, and has very strong corrosivity to equipment.Patent WO3013118130 is with boric acid
Or derivatives thereof be catalyst, compound and the chloro- thiophene -2-carboxylic acid of 5- carry out condensation reaction.But the reaction time is long, and yield is low,
And boric acid and its derivative price are higher, cost free advantage.
For patent CN104650057A using CDMT or TCT as condensing agent, NMM is acid binding agent, and compound and 5- are chloro- in DMF
Thiophene -2-carboxylic acid carries out condensation reaction.Reaction solution is added in water and is beaten, but needs ice bath crystallization, increases temperature control cost,
And solvent DMF with dissolve each other, be beaten in water, DMF easily caused to remain, increase trouble to subsequent dry removal of impurities.
Patent CN102250076A is refined using column chromatography, and high production cost is cumbersome.Patent
CN200480040552 post-processing purification condition is relatively high, needs to be heated to 100 DEG C or more, increases energy consumption, and safety is low, and needs
To repeat purification can just obtain qualified samples.CN1906191B recrystallization using acetic acid makees solvent, in the use in the workshop GMP by
To larger limitation, equipment and operator are all adversely affected.DMF and DMSO is remained in finished product should not also remove, and poison
Property is big, and environment is unfriendly.
In order to solve the problem above-mentioned, the present invention provides a kind of synthesis of razaxaban and refining methds.Of the invention
Method is easy to operate, and raw material low toxicity is easy to get, and post-processing is simple, avoids dissolvent residual, yield and purity is high, is suitble to large-scale industry
Metaplasia produces.
Summary of the invention
To achieve the above object, the following technical solution is employed by the present invention:
A kind of synthetic method of razaxaban: in the system containing condensing agent, acid binding agent and reaction dissolvent, 4- { 4-
[(5S) -5- (amino methyl) -2- oxo -1,3-oxazoles alkane -3- base] phenyl } morpholine -3- keto hydrochloride (LF-II), it is chloro- with 5-
Thiophene -2-carboxylic acid (SMI), which reacts, is made razaxaban (I).
Wherein:
The molar ratio of the compound L F-II and compound SMI is 1:1.0~1.2；Preferably 1:1.0-1.1.
The molar ratio of the compound L F-II and condensing agent is 1:1.1~1.5；Preferably 1:1.1~1.2.
The molar ratio of the compound L F-II and acid binding agent is 1:1.5~5.0；Preferably 1:2~3.
The condensing agent is selected from: N, N- carbonyl dimidazoles (CDI), 1- (3- dimethylamino-propyl) -3- ethyl carbodiimide
Hydrochloride (EDCI), N, N'- dicyclohexylcarbodiimide (DCC), 2- (7- azepine benzotriazole)-N, N, N', N'- tetramethyl
Urea tetrafluoroborate (TATU) or 2- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid ester (TBTU)；Preferably N,
N- carbonyl dimidazoles (CDI)；
The acid binding agent is selected from organic base or inorganic base；Preferably organic base；More preferably trimethylamine, tri-n-butylamine, three second
The group of amine, diisopropylethylamine and its mixture composition；Most preferably trimethylamine.
The organic solvent be selected from N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, methanol,
One or more of ethyl alcohol, isopropanol, n-butanol；Preferably N,N-dimethylformamide (DMF) or N, N- dimethylacetamide
Amine；The mass ratio of organic solvent and compound L F-II are 5-20:1, preferably 5-10:1.
The synthetic method of above-mentioned razaxaban, specifically: raw material compound LF- is sequentially added at 0 DEG C into organic solvent
II, SMI, condensing agent obtain suspension (or suspension)；0-5 DEG C of temperature control, acid binding agent is added dropwise；Drop finishes, and 0-5 DEG C of heat preservation is stirred to react
It is warmed to room temperature after a period of time and continues stirring to end of reaction；Reaction solution is filtered to and is used organic solvent washing, filtrate water is dilute
It releases, crystallization is sufficiently stirred at room temperature, centrifugal exsolution obtains razaxaban crude product；The razaxaban is refined to get razaxaban
Sterling.
In the synthetic method of above-mentioned razaxaban, centrifugal exsolution processing at least needs to be centrifuged with centrifuge to cutout；It will
Reaction flask purifying water washing, and close cleaning solution and carry out the centrifugal exsolution, product loss can be reduced.
In the synthetic method of above-mentioned razaxaban, it is preferably 30-60 minutes that 0-5 DEG C of heat preservation, which is stirred to react the time,；Room temperature
Being stirred to react the time is preferably 1-3 hours；The dosage for diluting filtrate is used with react and is washed with the mass ratio of organic solvent total amount
Are as follows: 1~3:1；The time being sufficiently stirred at room temperature after filtrate water dilution is preferably 1-3h, is more preferably 1.5~2h.
Invention further provides the refining methds of razaxaban, including by razaxaban crude product in alcoholic solution room temperature
Lower stirring and crystallizing.
The refining methd of above-mentioned razaxaban, including by razaxaban crude product in alcoholic solution stirring and crystallizing at room temperature, from
Heart precipitation；Filter cake after precipitation is mixed with alcohol solution, continues stirring and crystallizing, and centrifugal exsolution is dry, obtains razaxaban sterling.
The refining methd of above-mentioned razaxaban, may also include, and after centrifugal exsolution, gained filter cake is eluted with alcohol solution,
Continue centrifugal exsolution, then dries.
The refining methd of above-mentioned razaxaban, may also include, after dry, with air-flow crushing razaxaban sterling；It is described dry
Dry is preferably to be dried in vacuo to be dried under reduced pressure.
The refining methd of above-mentioned razaxaban, the alcoholic solution be methanol, ethyl alcohol, isopropanol, n-butanol, propylene glycol one
Kind or several aqueous solutions；Preferably ethanol water；The ethanol water concentration is 60~90%, preferably 75%；Institute
The mass ratio for stating alcoholic solution and compound L F-II is 2~12:1, preferably 6-12:1, more preferably 8-10:1.
The refining methd of above-mentioned razaxaban, specifically: at room temperature, razaxaban crude product is mixed with alcohol solution, is filled
Divide stirring and crystallizing, is centrifuged by gained slurry centrifugal exsolution, such as with centrifuge to cutout, obtains filter cake；By gained filter cake and alcohol
Aqueous solution mixing, continues that crystallization is sufficiently stirred, obtains slurry, centrifugal exsolution, such as be centrifuged to cutout with centrifuge, get profit and cut down
Husky class's wet product, it is dry that white powder, i.e. razaxaban sterling, the sterling can be handled through air-flow crushing.
In the refining methd of above-mentioned razaxaban, what razaxaban crude product was mixed with alcohol solution is sufficiently stirred the time,
And the filter cake mixed with alcohol solution be sufficiently stirred the time, respectively can be 1-5 hours, it is preferably 2-4 hours, more excellent
It is selected as 3 hours；It is above-mentioned twice using in alcohol solution mixing, each time the mass ratio of alcohol solution and compound L F-II be 1~
6:1, preferably 3~6:1；More preferably 4~5:1；The drying can be to be dried under reduced pressure, and be preferably vacuum drying.
The present invention is using condensing agents such as CDI, DCC in the synthesis of razaxaban, and cheap and easy to get, condensation efficiency is high；Using
The chloro- thiophene -2-carboxylic acid of 5- (SMI) is avoided using toxicity, carcinogenicity and the chloro- 2- acyl chlorides thiophene of corrosive 5-；Triethylamine etc. is tied up
Sour agent is cheap and easy to get, and reaction effect is good；All kinds of raw material dosage proportions are economical, at low cost, reaction effect is good.
The present invention is in the subtractive process of razaxaban, using alcohol solution, especially ethanol water as refining solvent,
It on the one hand can be to avoid the use of the toxic solvents such as acetic acid, safety and environmental protection；On the other hand, it is at room temperature in entire subtractive process
It can carry out, controllability is strong, without heating or low temperature control, reduces temperature control cost, improves the safety of production technology
With the stability of product, it is more advantageous to industrialized production；Process for refining is easy to operate high-efficient, high income, purity is high.
Using synthesis and refining methd of the invention, the yield of razaxaban is up to 93% or more, 99.5% or more purity.
The razaxaban product of purification identifies that grind medicinal crystal-form with original identical through X-ray powder diffraction, and crystal form and granularity meet medicinal
It is required that.
Detailed description of the invention
Attached drawing shows illustrative embodiments disclosed by the invention, and it is bright be used to explain the present invention together disclosure
Mechanism or result characterization, which includes these attached drawings to be further understood with providing to disclosed by the invention, and attached drawing packet
It includes in the present specification and forms part of this specification.
Fig. 1 present invention gained razaxaban (API) X-ray powder X-ray RPD diffraction pattern.
The electron-microscope scanning figure of Fig. 2 reference razaxaban piece.
Fig. 3 present invention gained does not crush the electron-microscope scanning figure of razaxaban (API).
Specific embodiment
The present invention is disclosed with embodiment with reference to the accompanying drawing and is described in further detail.It is understood that this
Locate described specific embodiment to be only used for explaining related content, rather than to restriction disclosed by the invention.It further needs exist for
It is bright, it illustrates only disclose relevant part to the present invention for ease of description, in attached drawing.
It should be noted that in the absence of conflict, the present invention disclose in embodiment and embodiment in spy
Sign can be combined with each other.It is open to come that the present invention will be described in detail below with reference to the accompanying drawings and in conjunction with embodiment.In order to of the invention easy
In understanding, the present invention is further described combined with specific embodiments below, to help the contents of the present invention are understood, but should not be with this
It limits the scope of the invention.
Embodiment 1
(1) preparation of razaxaban crude product
At room temperature, 650g n,N-Dimethylformamide (DMF) is added into reaction flask, opens stirring, is cooled to 0 DEG C, with
40g compound (LF-II), 73g compound (SMI), 39.7g CDI are successively put into afterwards, and reaction solution is in suspension；Temperature control 0-5
DEG C, 67.6g triethylamine is added dropwise in reaction solution, 0-5 DEG C of temperature, drop finish in control reaction solution when dropwise addition, and insulated and stirred 30 minutes,
It is warming up to room temperature (20-25 DEG C), insulated and stirred is reacted 2 hours.It filters, filter cake is washed with 80g DMF, and filtrate is added to 1200g
In water, stirring and crystallizing 2 hours at room temperature.Paste mixture is centrifuged with centrifuge to cutout, with 500g purified water washing reaction
Bottle merges cleaning solution and is centrifuged to cutout, obtains razaxaban crude product.
(2) purification of razaxaban crude product
At room temperature, 75% ethanol solution of 350g is added in reaction flask, is mixed with razaxaban crude product, stirring and crystallizing 2~
3 hours, slurry is obtained, is centrifuged with centrifuge to cutout, filter cake (or filter residue) is obtained；75% ethyl alcohol of 350g is added again and is reacted
In bottle, stirring and crystallizing 2~3 hours, slurry is also obtained, is centrifuged with centrifuge to cutout, with 75% ethanol rinse filter cake of 30g
(or filter residue), centrifugation obtain razaxaban wet product, decompression or vacuum drying, obtain white powder, quality 89.7g, purity to stopping
For 99.7% (HPLC), yield 92.5%.
Embodiment 2
(1) at room temperature, 600g n,N-Dimethylformamide (DMF) is added into reaction flask in the preparation of razaxaban crude product,
Stirring is opened, is cooled to 0 DEG C, then successively puts into 36g compound (LF-II), 65.5g compound (SMI), 39g CDI, reaction
Liquid be in suspension, 0-5 DEG C of temperature control.60g triethylamine is added dropwise in reaction solution, 0-5 DEG C of temperature, drop in control reaction solution when dropwise addition
Finish, insulated and stirred 30 minutes, be warming up to room temperature (20-25 DEG C), insulated and stirred is reacted 1.5 hours.It filters, filter cake 50g DMF
Washing, filtrate are added in 1000g water, at room temperature stirring and crystallizing 1.5h.Paste mixture is centrifuged with centrifuge to cutout,
300g purified water washing reaction bottle merges cleaning solution and is centrifuged to cutout, obtains razaxaban crude product.
(2) purification of razaxaban crude product
At room temperature, 75% ethanol solution of 330g is added in reaction flask, stirs lower razaxaban crude product, room temperature (20~25
DEG C) stirring and crystallizing 2 hours, slurry is obtained, is centrifuged with centrifuge to cutout, obtains filter cake.350g is added into reaction flask again
75% ethyl alcohol, room temperature (20~25 DEG C) stirring and crystallizing 2 hours, obtains slurry, is centrifuged with centrifuge to cutout, uses 20g75%
Ethanol rinse filter cake, centrifugation obtain wet product to stopping.It is dried under reduced pressure, obtains white powder, quality 82.6g, yield 94.% is pure
Degree is 99.8% (HPLC).
Comparative example 1
Refining solvent in 2 step of above-described embodiment (2) is replaced with into purified water by 75% ethyl alcohol, other conditions are constant,
According to the operation, final product is white powder, quality 81.3g, yield 93.3%, purity 88.2% (HPLC).Show
At room temperature, 75% ethyl alcohol is substituted as refining solvent by water, refining effect is obviously deteriorated.
Comparative example 2
Gained slurry centrifugal exsolution in 2 step of above-described embodiment (2) (being centrifuged with centrifuge to cutout) is replaced with and is subtracted
Pressure filters precipitation, and products obtained therefrom humidity is big, it is difficult to filter completely, extension is dried under reduced pressure time and air-flow grinding time, gained powder
Last color is deeper compared with embodiment 2, product quality 77.9g, yield 89.4%, purity 89.1% (precipitation HPLC).Show that centrifugation is de-
It is molten to be better than decompression suction filtration precipitation.
Testing example 1
Fig. 1 is the X-ray powder diffraction collection of razaxaban sterling obtained by the embodiment of the present invention.
Measuring unit: Institute of Analysis, University Of Suzhou
Instrument: X, Pert Pro MPD type powder x-ray diffraction
Test condition: 40kv 40Ma slit: 1.0/1.0/Ni/0.1 step-length: 0.02 ° of target type: Cu Range:3.00-
40.00Deg scan Rate:10.00Deg/min
The X-ray diffraction measurement result of 1 razaxaban sample of table
The result shows that present invention gained razaxaban product is crystal, and crystal form (I type) is ground unanimously with original.
Testing example 2
Fig. 2 is razaxaban piece (lot number: BXHRC71, producer: Beyer Co., Ltd) the Electronic Speculum detection and analysis figure for reference.
Razaxaban (API) is distributed relatively uniform inside tablet in reference preparation, and crystal habit is in particle or tip-like, and granularity is about 5 μm,
It is distributed relatively uniform.
Fig. 3 is that the razaxaban crystal form Electronic Speculum that do not crush after present invention purification tests and analyzes, razaxaban grain of the invention
Degree≤20 μm, have about 10%≤7 μm, the crystal habit of granularity≤7 μm is in granular form, granularity close to 20 μm crystal habit in the form of sheets.
Homemade crystal habit (≤7 μm) character not crushed in reference preparation API it is almost the same, in conjunction with X-RPD data,
It proves that homemade crystal form is I brilliant, and is medicinal crystal-form.
In order to obtain the razaxaban of high quality, the stability study of influence factor and Acceleration study is carried out, specific knot
Fruit is shown in Table 2,3:
The Stability Determination result of 2 razaxaban sample of table
The influence factor measuring result of 3 razaxaban sample of table
As can be seen from the above data, bulk pharmaceutical chemicals product provided by the invention, (adds in high temperature, high humidity, illumination and stability
Speed is placed 6 months) under the conditions of, each component has no significant change, and can satisfy safe and effective, the quality controllable feature of drug.
The synthesis of razaxaban of the present invention and refining methd are tested by lab scale craft, process certification, stability
It just obtains, can be directly obtained not by preparation teaching material or other references, by screening test, work after research
Skill verifying, stability study confirm condensation product of the present invention with when refining methd, and stable preparation process, finished product is stable, meets medicine
With requiring.
Claims (10)
1. a kind of synthetic method of razaxaban, comprising: in the system containing condensing agent, acid binding agent and reaction dissolvent, 4- { 4-
[(5S) -5- (amino methyl) -2- oxo -1,3- oxazolidine -3- base] phenyl } morpholine -3- keto hydrochloride (LF-II) and 5- it is chloro-
Thiophene -2-carboxylic acid (SMI), which reacts, is made razaxaban (I)；Reaction equation is as follows:
2. the molar ratio of synthetic method according to claim 1, compound L F-II and compound SMI are 1:1.0~1.2.
3. the molar ratio of synthetic method according to claim 1 or 2, compound L F-II and condensing agent is 1:1.1~1.5.
4. the molar ratio of synthetic method according to claim 1 or 2, compound L F-II and acid binding agent is 1:1.5~5.0.
5. synthetic method according to claim 1 or 2, the condensing agent is selected from: N, N- carbonyl dimidazoles (CDI), 1- (3-
Dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), N, N'- dicyclohexylcarbodiimide (DCC), 2- (7- azepine
Benzotriazole)-N, N, N', N'- tetramethylurea tetrafluoroborate (TATU) or 2- benzotriazole-N, N, N', N'- tetramethyl
Urea tetrafluoro boric acid ester (TBTU).
6. synthetic method according to claim 1 or 2, the acid binding agent is selected from organic base or inorganic base.
7. synthetic method according to claim 1 or 2, wherein the reaction dissolvent is selected from n,N-Dimethylformamide, N,
One or more of N- dimethyl acetamide, dimethyl sulfoxide, methanol, ethyl alcohol, isopropanol, n-butanol.
8. a kind of refining methd of razaxaban: by razaxaban crude product in alcoholic solution stirring and crystallizing at room temperature.
9. refining methd according to claim 8, the razaxaban crude product is described in any item according to claim 1-7
Method preparation.
10. method according to claim 8 or claim 9, it is characterised in that: the alcoholic solution is methanol, ethyl alcohol, isopropanol, just
The aqueous solution of one or more of butanol, propylene glycol, the methanol, ethyl alcohol, isopropanol, n-butanol propylene glycol.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811610663X | 2018-12-27 | ||
| CN201811610663 | 2018-12-27 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105970A (en) * | 2022-01-05 | 2022-03-01 | 安徽悦康凯悦制药有限公司 | Preparation method of rivaroxaban |
| CN114989159A (en) * | 2022-07-11 | 2022-09-02 | 天津力生制药股份有限公司 | Synthetic method of rivaroxaban |
Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008052671A2 (en) * | 2006-11-02 | 2008-05-08 | Bayer Schering Pharma Aktiengesellschaft | Combination therapy of substituted oxazolidinones |
| US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
| CN103864773A (en) * | 2012-12-13 | 2014-06-18 | 北京京卫信康医药科技发展有限公司 | Preparation method for rivaroxaban and intermediate thereof |
| CN104086539A (en) * | 2014-07-17 | 2014-10-08 | 天津炜捷制药有限公司 | Preparation method of rivaroxaban |
| CN104109158A (en) * | 2013-04-16 | 2014-10-22 | 上海医药工业研究院 | Rivaroxaban purification method |
| CN104650057A (en) * | 2013-11-22 | 2015-05-27 | 重庆医药工业研究院有限责任公司 | Rivaroxaban preparation method |
| CN107778303A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | The process for purification of razaxaban |
-
2019
- 2019-06-24 CN CN201910546769.6A patent/CN110172060A/en active Pending
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008052671A2 (en) * | 2006-11-02 | 2008-05-08 | Bayer Schering Pharma Aktiengesellschaft | Combination therapy of substituted oxazolidinones |
| US20110288294A1 (en) * | 2010-05-21 | 2011-11-24 | Michael Nonnenmacher | Preparation process for an inhibitor of a blood clotting factor |
| CN103864773A (en) * | 2012-12-13 | 2014-06-18 | 北京京卫信康医药科技发展有限公司 | Preparation method for rivaroxaban and intermediate thereof |
| CN104109158A (en) * | 2013-04-16 | 2014-10-22 | 上海医药工业研究院 | Rivaroxaban purification method |
| CN104650057A (en) * | 2013-11-22 | 2015-05-27 | 重庆医药工业研究院有限责任公司 | Rivaroxaban preparation method |
| CN104086539A (en) * | 2014-07-17 | 2014-10-08 | 天津炜捷制药有限公司 | Preparation method of rivaroxaban |
| CN107778303A (en) * | 2016-08-27 | 2018-03-09 | 鲁南制药集团股份有限公司 | The process for purification of razaxaban |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114105970A (en) * | 2022-01-05 | 2022-03-01 | 安徽悦康凯悦制药有限公司 | Preparation method of rivaroxaban |
| CN114989159A (en) * | 2022-07-11 | 2022-09-02 | 天津力生制药股份有限公司 | Synthetic method of rivaroxaban |
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Application publication date: 20190827 |