CN106442831A - Detection method of Rivaroxaban tablet relevant substances - Google Patents

Detection method of Rivaroxaban tablet relevant substances Download PDF

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Publication number
CN106442831A
CN106442831A CN201610667872.2A CN201610667872A CN106442831A CN 106442831 A CN106442831 A CN 106442831A CN 201610667872 A CN201610667872 A CN 201610667872A CN 106442831 A CN106442831 A CN 106442831A
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impurity
detection method
buffered saline
sodium
saline solution
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CN106442831B (en
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胡容
肖玉梅
邓祥林
谭瑶
罗礼平
余佳
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Zhien Biotechnology Co.,Ltd.
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Chongqing Zen Pharmaceutical Co Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • C07D265/32—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings with oxygen atoms directly attached to ring carbon atoms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/04—Preparation or injection of sample to be analysed
    • G01N30/06—Preparation
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N2030/022—Column chromatography characterised by the kind of separation mechanism
    • G01N2030/027—Liquid chromatography
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
    • G01N30/02—Column chromatography
    • G01N30/88—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86
    • G01N2030/8809—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample
    • G01N2030/8872—Integrated analysis systems specially adapted therefor, not covered by a single one of the groups G01N30/04 - G01N30/86 analysis specially adapted for the sample impurities

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Abstract

The invention discloses a method for simultaneously detecting Rivaroxaban tablet relevant substances by high performance liquid chromatography. According to the chromatographic conditions, octadecyl silane is used as a filling agent of a chromatographic column; acetonitrile-buffer salts (containing phosphate and ion-pairing agents) are used as a flowing phase to perform gradient elution; an ultraviolet detector is used as a detector. By using the method provided by the invention, impurities in Rivaroxaban tablets can be effectively detected out; the analysis time is short; the efficiency is high; a simple and reliable method is provided for the Rivaroxaban tablets.

Description

A kind of Rivaroxaban tablets are about the detection method of material
Technical field
The invention belongs to pharmaceutical technology field, relate in particular to the detection method about material for the Rivaroxaban tablets.
Background technology
Razaxaban, Rivaroxaban, its chemical name be the chloro- N- of 5- ((5S) -2- oxygen -3- [4- (3- oxomorpholin - 4- yl) phenyl] -1,3- oxazoline -5- base } methyl) thiophene-2-carboxamide derivatives.
Rivaroxaban tablets structural formula is：
The preparation of razaxaban is a kind of high selectivity, the oral drugs of direct inhibitive factor Xa.Permissible by inhibitive factor Xa Interrupt the endogenouss of blood coagulation waterfall and extrinsic pathway, anticoagulant enzyme generation and thrombosiss, platelet aggregation is not had Direct effect.
The synthesis technique of razaxaban is as follows：
Razaxaban relevant material that may be present be can be inferred that according to synthesis technique, refer to following table：
Impurity sequence number Chemical constitution
Impurity 1.
Impurity 2.
Impurity 3.
Impurity 4.
Impurity 5.
Impurity 6.
Impurity 7.
Impurity 8.
Impurity 9.
Impurity 10.
Impurity 11.
Impurity 12.
Impurity 13.
Impurity 14.
Impurity 15.
Document J. Org. Chem. 1981,46,175-177 reports the side of impurity 1, impurity 15 and its controlled syntheses at present Method；The method that patent CN103896933 reports impurity 2 and its controlled syntheses；Document Chinese Journal of Pharmaceuticals Chinese Journal of Phannaceuticals 2014,45 (4) reports impurity 3, impurity 4, impurity 5, impurity 7, impurity 8, impurity 9 and the method for impurity 13 and its controlled syntheses；Patent WO2012/035057A2 also report impurity 3, impurity 4 and impurity 5 and its The method of controlled syntheses；Patent WO2004/060887 and WO/2013/156936 report the synthetic method of impurity 14.
The difficulty of razaxaban relevant material detection is：Razaxaban relevant material that may be present in building-up process Species is more, in order to preferably control the quality of product, develops new detection method and each relevant material is control effectively, tool There is the significance of reality.Because each relevant substance classes are more, can by all of relevant material once if developing a kind of method Property has detected, will greatly improve efficiency, save energy.But polarity difference is huge between relevant material, impurity 1, impurity 12 are The larger impurity of polarity, retains weaker or almost without reserve in chromatographic system；Impurity 10, impurity 11 polarity are less, in chromatograph Retain extremely strong in system, be difficult to be eluted.
Through retrieval, do not find the detection method about material for the Rivaroxaban tablets.Therefore develop a kind of high performance liquid chromatography, energy Enough efficiently separated each in razaxaban with solvent about material, analysis time is short, it is achieved thereby that to razaxaban About material effective control it is ensured that the quality control of razaxaban, there is realistic meaning, thus efficiently solving above-mentioned asking Topic.
Content of the invention
The invention provides a kind of Rivaroxaban tablets are about the detection method of material, not only achieve each about material and profit Cut down Sha Banjun and reach baseline separation, the larger and less relevant material of polarity all can effectively detect, simple and efficient to handle, analysis Time is short, low cost, can effectively control the relevant material of Rivaroxaban tablets it is ensured that the safety of product and effectiveness.
It is an object of the invention to provide a kind of high performance liquid chromatography detection razaxaban is about the method for material.
Specifically, in embodiments of the invention, the invention provides a kind of high performance liquid chromatography detection profit cuts down sand Class, about the method for material, is the chromatographic column of fixing phase from octadecyl silane, with buffered saline solution and acetonitrile is Mobile phase, with UV-detector as detector；Here, described buffered saline solution comprises phosphate and ion-pairing agent.
In embodiments of the invention, the relevant thing of a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides The method of matter, wherein, in described mobile phase, buffered saline solution and acetonitrile volume ratio are 5～95:5～95, preferably 50～ 90:10～50, more preferably gradient elution is carried out using following volume ratio：
Time（min） Buffer salt（%） Acetonitrile（%）
0 82 18
5 82 18
12 60 40
40 60 40
42 82 18
54 82 18
In embodiments of the invention, the relevant material of a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides Method, wherein, the pH value of described buffered saline solution is 2～3, including 2 and 3；Described phosphate is phosphoric acid alkali metal salt, choosing From sodium salt or the potassium salt of phosphoric acid, more preferably described buffer salt is selected from dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, phosphorus One or more of acid dihydride sodium.Concentration in described buffered saline solution for the described phosphate is 0.01 ~ 0.10mol/L, Preferably 0.02 ~ 0.05mol/L.
In embodiments of the invention, the relevant thing of a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides The method of matter, wherein, described ion-pairing agent is selected from sodium pentanesulfonate, sodium hexanesulfonate, sodium heptanesulfonate, perfluoroetane sulfonic acid One or more of sodium, decane sulfonate.Concentration in described buffered saline solution for the described ion-pairing agent be 0.003 ~ 0.03mol/L, preferably 0.005 ~ 0.03mol/L.
In a preferred embodiment of the invention, a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides have The method closing material, wherein, described buffer salt is preferably dipotassium hydrogen phosphate or sodium dihydrogen phosphate；Ion-pairing agent preferred octane sulphur Sour sodium or decane sulfonate.
In a preferred embodiment of the invention, a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides have The method closing material, wherein said mobile phase, its flow velocity is 0.5～1.5ml/min it is therefore preferable to 1ml/min.
In a preferred embodiment of the invention, a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides have The method closing material, wherein said UV-detector, its Detection wavelength is 240～260nm it is therefore preferable to 250nm.
In a preferred embodiment of the invention, a kind of high performance liquid chromatography detection Rivaroxaban tablets that the present invention provides have The method closing material, the column temperature of wherein said chromatographic column is 20～40 DEG C it is therefore preferable to 30 DEG C.
In embodiments of the invention, the invention provides a kind of relevant thing of high performance liquid chromatography detection Rivaroxaban tablets The method of matter, further includes following operation：
（1）Finely ground Rivaroxaban tablets of learning from else's experience and impurity 1 ~ 15 are appropriate, use 50% acetontrile, are made into every 1ml and contain the mixed of 0.5 μ g Close solution；
（2）Setting flow rate of mobile phase is 0.5～1.5ml/min, preferably 1.0 ml/min；Detection wavelength is 240～260nm, Good Detection wavelength 250nm；Column temperature is 20～40 DEG C, and optimum column temperature is 30 DEG C；Chromatographic column selects C18 post；Buffer salt in mobile phase Aqueous solution and acetonitrile volume ratio are 50～90:10～50, more preferably gradient elution is carried out using above-mentioned volume ratio；
（3）Precision measures（1）Mixed solution 10～50 μ l injects chromatograph of liquid, and the impurity completing in razaxaban cuts down sand with profit The separation of class.
In embodiments of the invention, the invention provides a kind of relevant thing of high performance liquid chromatography detection Rivaroxaban tablets The method of matter, further includes following operation：
（1）Finely ground Rivaroxaban tablets of learning from else's experience and impurity 1 ~ 15 are appropriate, use 50% acetontrile, are made into every 1ml and contain the mixed of 0.5 μ g Close solution；
（2）Setting flow velocity is 1ml/min, and Detection wavelength is 250nm, 30 DEG C of column temperature；Buffered saline solution and acetonitrile in mobile phase Gradient elution is carried out using following volume ratio：
Time（min） Buffer salt（%） Acetonitrile（%）
0 82 18
5 82 18
12 60 40
40 60 40
42 82 18
54 82 18
（3）Precision measures mixed solution 10 μ l injection chromatograph of liquid, completes the relevant material detection of Rivaroxaban tablets.
In embodiments of the invention, unless otherwise specified, described " % " is percent by volume.
It is characteristic of the invention that：Each all reach baseline separation about material and razaxaban, polarity is larger and less miscellaneous Matter all can effectively detect, simple and efficient to handle, and analysis time is short, low cost, can effectively control the relevant of Rivaroxaban tablets Material is it is ensured that the safety of product and effectiveness.
Brief description
What Fig. 1 represented is the high-efficient liquid phase chromatogram of the embodiment of the present invention 1.
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
4.968 Impurity 1 9355 7035 -- 2.172
7.172 Impurity 4 9087 7865 7.864 1.114
9.330 Impurity 2 2341 101310 9.795 1.203
12.186 Impurity 12 13405 72689 19.167 0.821
15.596 Impurity 3 5449 120991 18.936 1.018
15.828 Impurity 5 9129 152020 1.358 1.119
17.258 Impurity 13 8469 222138 9.259 1.159
17.873 Impurity 8 7580 170485 3.851 1.111
18.354 Impurity 7 10924 209920 2.881 1.099
19.605 Impurity 14 13609 169341 7.135 1.105
20.056 Impurity 15 14938 240467 2.548 1.157
22.800 Razaxaban 10186 136088 13.355 1.075
25.808 Impurity 6 4144 99413 10.472 1.052
30.726 Impurity 9 9115 76388 12.738 1.035
42.447 Impurity 10 18881 45778 18.932 1.000
45.042 Impurity 11 24588 41020 3.083 1.044
What Fig. 2 represented is the high-efficient liquid phase chromatogram of the embodiment of the present invention 2.
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
4.870 Impurity 1 9073 7072 -- 1.676
6.552 Impurity 4 9118 8576 6.538 1.070
6.992 Impurity 2 2444 13576 1.683 1.050
10.424 Impurity 12 13619 9789 10.376 1.076
14.602 Impurity 3 5510 82652 13.378 1.064
15.101 Impurity 5 9635 133130 2.706 1.081
16.771 Impurity 13 9855 189887 10.455 --
16.929 Impurity 8 7634 129988 0.921 --
17.665 Impurity 7 10992 204863 4.283 1.071
18.859 Impurity 14 13025 178741 7.139 1.055
19.771 Impurity 15 17272 227974 5.300 1.037
21.945 Razaxaban 9949 162685 11.345 1.054
24.758 Impurity 6 4439 111896 10.951 0.940
29.005 Impurity 9 8577 89560 12.424 1.024
40.676 Impurity 10 17423 56220 21.736 1.057
43.213 Impurity 11 23134 49462 3.468 1.032
What Fig. 3 represented is the high-efficient liquid phase chromatogram of comparative example 1 of the present invention.
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
0.663 Impurity 12 126815 662 -- 1.332
1.577 Impurity 1 23054 335 4.081 0.649
4.006 Impurity 2 25538 1146 5.939 0.567
8.294 Impurity 13 22373 2463 7.511 1.004
13.245 Impurity 15 and 7 32022 2542 5.759 1.241
19.118 Impurity 4 27226 845 3.190 0.702
25.127 Impurity 3 27995 118493 4.111 --
25.585 Impurity 8 31588 80287 1.403 0.941
27.266 Impurity 5 27567 174531 5.403 0.925
28.397 Impurity 14 38645 213399 4.458 1.074
31.288 Razaxaban 29116 289173 12.083 1.092
34.111 Impurity 6 12478 423623 12.762 1.128
35.123 Impurity 9 25252 348209 4.521 1.106
38.850 Impurity 10 27766 455852 15.921 1.154
39.598 Impurity 11 37268 519375 3.324 1.143
Specific embodiment
It is specifically described embodiment of the present invention below by the embodiment of the present invention.
Embodiment 1
Instrument and condition
Shimadzu LC-20A high performance liquid chromatograph, C18 post（4.6 × 250mm, 5 μm）, Detection wavelength is 250nm, flow velocity 1.0ml/ Min, 20 DEG C of column temperature, sample size is 10 μ l, with buffer salt solution（0.01mol/L perfluorooctane sulfonate+0.02mol/L phosphoric acid hydrogen two Sodium, with phosphorus acid for adjusting pH to 2.0）It is performed as follows gradient elution with acetonitrile for mobile phase：
Time（min） Buffer salt（%） Acetonitrile（%）
0 82 18
5 82 18
12 60 40
40 60 40
42 82 18
54 82 18
Experimental procedure：
Finely ground Rivaroxaban tablets of learning from else's experience material relevant with razaxaban is each appropriate, accurately weighed, makes dissolving with 50% acetonitrile is ultrasonic Completely, make every 1ml material relevant with razaxaban containing razaxaban（Impurity 1 ~ 15）The mixed solution of each 0.5 μ g/ml.Take and join Prepared mixed solution, with 0.45 μm of membrane filtration, takes subsequent filtrate, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram, Result is shown in Fig. 1,
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
4.968 Impurity 1 9355 7035 -- 2.172
7.172 Impurity 4 9087 7865 7.864 1.114
9.330 Impurity 2 2341 101310 9.795 1.203
12.186 Impurity 12 13405 72689 19.167 0.821
15.596 Impurity 3 5449 120991 18.936 1.018
15.828 Impurity 5 9129 152020 1.358 1.119
17.258 Impurity 13 8469 222138 9.259 1.159
17.873 Impurity 8 7580 170485 3.851 1.111
18.354 Impurity 7 10924 209920 2.881 1.099
19.605 Impurity 14 13609 169341 7.135 1.105
20.056 Impurity 15 14938 240467 2.548 1.157
22.800 Razaxaban 10186 136088 13.355 1.075
25.808 Impurity 6 4144 99413 10.472 1.052
30.726 Impurity 9 9115 76388 12.738 1.035
42.447 Impurity 10 18881 45778 18.932 1.000
45.042 Impurity 11 24588 41020 3.083 1.044
Under above-mentioned chromatographic condition, between razaxaban and each relevant material, separating degree is good, each relevant matter theory number of plates It is all higher than 3000, and in 54min, terminates entirely relevant material detection, and the relevant material of no matter polarity size all can effectively be examined Go out, analysis time is short, efficiency high, cost-effective, meet the requirement of Chinese Pharmacopoeia.
Embodiment 2
Instrument and condition
Shimadzu LC-20A high performance liquid chromatograph, C18 post（4.6 × 250mm, 5 μm）, Detection wavelength is 250nm, flow velocity 1.0ml/ Min, 20 DEG C of column temperature, sample size is 10 μ l, with buffer salt solution（0.01mol/L perfluorooctane sulfonate+0.02mol/L phosphoric acid hydrogen two Sodium, with phosphorus acid for adjusting pH to 3.0）Carry out eluting with acetonitrile for mobile phase by such as Gradient：
Time（min） Buffer salt（%） Acetonitrile（%）
0 82 18
5 82 18
12 60 40
40 60 40
42 82 18
54 82 18
Experimental procedure：
Finely ground Rivaroxaban tablets of learning from else's experience material relevant with razaxaban is each appropriate, accurately weighed, makes dissolving with 50% acetonitrile is ultrasonic Completely, make every 1ml material relevant with razaxaban containing razaxaban（Impurity 1 ~ 15）The mixed solution of each 0.5 μ g/ml.Take and join Prepared mixed solution, with 0.45 μm of membrane filtration, takes subsequent filtrate, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram, Result is shown in Fig. 2,
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
4.870 Impurity 1 9073 7072 -- 1.676
6.552 Impurity 4 9118 8576 6.538 1.070
6.992 Impurity 2 2444 13576 1.683 1.050
10.424 Impurity 12 13619 9789 10.376 1.076
14.602 Impurity 3 5510 82652 13.378 1.064
15.101 Impurity 5 9635 133130 2.706 1.081
16.771 Impurity 13 9855 189887 10.455 --
16.929 Impurity 8 7634 129988 0.921 --
17.665 Impurity 7 10992 204863 4.283 1.071
18.859 Impurity 14 13025 178741 7.139 1.055
19.771 Impurity 15 17272 227974 5.300 1.037
21.945 Razaxaban 9949 162685 11.345 1.054
24.758 Impurity 6 4439 111896 10.951 0.940
29.005 Impurity 9 8577 89560 12.424 1.024
40.676 Impurity 10 17423 56220 21.736 1.057
43.213 Impurity 11 23134 49462 3.468 1.032
Under above-mentioned chromatographic condition, between razaxaban and each relevant material, separating degree is good, each relevant matter theory number of plates It is all higher than 3000, and in 54min, terminates entirely relevant material detection, and the relevant material of no matter polarity size all can effectively be examined Go out, analysis time is short, efficiency high, cost-effective, meet the requirement of Chinese Pharmacopoeia.
Comparative example 1
Instrument and condition
Shimadzu LC-20A high performance liquid chromatograph, RP-18 post（55mm × 4.0mm, 3 μm）, Detection wavelength is 250nm, flow velocity 1.5ml/min, 45 DEG C of column temperature, sample size is 20 μ l, with the phosphoric acid of 0.01mol/L and acetonitrile as mobile phase, enters by following gradient Row eluting：
Time（min） The phosphoric acid of 0.01mol/L（%） Acetonitrile（%）
0 92 8
15 92 8
42 49 51
42.1 92 8
50 92 8
Experimental procedure：
Finely ground Rivaroxaban tablets of learning from else's experience material relevant with razaxaban is each appropriate, accurately weighed, makes dissolving with 50% acetonitrile is ultrasonic Completely, make every 1ml material relevant with razaxaban containing razaxaban（Impurity 1 ~ 15）The mixed solution of each 0.5 μ g/ml.Take and join Prepared mixed solution, with 0.45 μm of membrane filtration, takes subsequent filtrate, carries out high-efficient liquid phase analysis by above-mentioned condition, records chromatogram, Result is shown in Fig. 3,
Retention time Chemical combination name Peak area The number of plates Separating degree Tailing factor
0.663 Impurity 12 126815 662 -- 1.332
1.577 Impurity 1 23054 335 4.081 0.649
4.006 Impurity 2 25538 1146 5.939 0.567
8.294 Impurity 13 22373 2463 7.511 1.004
13.245 Impurity 15 and 7 32022 2542 5.759 1.241
19.118 Impurity 4 27226 845 3.190 0.702
25.127 Impurity 3 27995 118493 4.111 --
25.585 Impurity 8 31588 80287 1.403 0.941
27.266 Impurity 5 27567 174531 5.403 0.925
28.397 Impurity 14 38645 213399 4.458 1.074
31.288 Razaxaban 29116 289173 12.083 1.092
34.111 Impurity 6 12478 423623 12.762 1.128
35.123 Impurity 9 25252 348209 4.521 1.106
38.850 Impurity 10 27766 455852 15.921 1.154
39.598 Impurity 11 37268 519375 3.324 1.143
By under above-mentioned chromatographic condition, razaxaban is separated with relevant material 1 ~ 15, impurity 1 retention time 0.663min, miscellaneous Matter 12 retention time 0.577min it can be seen that this partly about material in chromatographic system almost without reserve, and impurity 15 He Impurity 7 goes out peak position and overlaps it is impossible to the content of accurate checked for impurities.
The preparation of preparation example 1 razaxaban impurity 6
By 22.6g（111.21mmol） S-（+）-N-（2,3- ethoxycarbonyl propyl）Phthalimide（SM1）、5.34g （27.80mmol）4-（4- aminophenyl）Morpholine -3- ketone（SM2）Sequentially add in 250ml there-necked flask, add dehydrated alcohol 110ml, temperature rising reflux reacts 24h.It is cooled to 50 ~ 55 DEG C with tap water, sucking filtration, remove insoluble matter, collect filtrate, continue cooling To 10 ~ 15 DEG C of crystallizes, filter, obtain yellow solid.This yellow solid is flowed back with dehydrated alcohol 80ml and dissolves, be cooled to 5～10 DEG C, filter, filter cake was in 50～60 DEG C of drying under reduced pressure 5 hours.Obtain product 10.0g, yield 60.0%, purity 96.2%.H1-NMR (600HZ, DMSO-d6):7.86-7.87 (4H, m), 7.82-7.84（4H, m）, 7.08（2H, d）, 6.67（2H, d）, 6.67 （2H, d）, 5.12（2H, d）, 4.14（2H, s）, 4.11（2H, m）, 3.93（2H, t）, 3.57-3.63（8H, m）, 3.39（2H, m）；MS(m/z)：599[M+H]+, 621 [M+Na]+
The preparation of preparation example 2 razaxaban impurity 10
1st, the preparation of compound I
By 243.9g（1.20mol） S-（+）-N-（2,3- ethoxycarbonyl propyl）Phthalimide（SM1）、121.8g （800.30mmol）2- (4- aminophenyiamino) ethanol sequentially adds in 3L there-necked flask, adds dehydrated alcohol 2.0L, heats up 75 ~ 85 DEG C of reaction 24h.It is cooled to 40 ~ 45 DEG C with tap water, sucking filtration, with washing with alcohol, collect filter cake, white solid.In 50～ 60 DEG C of drying under reduced pressure 5 hours.Obtain the 256.0g of compound I, yield 90.0%.
, the preparation of compound II
By 250.0g (0.703mol) compound I, 750ml oxolane adds in 2L there-necked flask, quickly weighs 228.0g (1.406mol) N, N- carbonyl dimidazoles add reaction bulb.In outer 60 ~ 70 DEG C of reaction 10h of temperature.Cooling, adds 228.0g (1.406mol) N, N- carbonyl dimidazoles, continue at 60 ~ 70 DEG C of insulation back flow reaction 10h.Stop heating.It is cooled to interior temperature 20 DEG C, filter, filter cake is washed with oxolane.Filter cake adds in 2L reaction bulb, adds 800ml dehydrated alcohol, in the lower dissolving of backflow. It is cooled to 30 DEG C again；Filter, filter cake absolute ethanol washing.Drain, in 50 ~ 60 DEG C of drying under reduced pressure 5h.Obtain compound II 227.9g, yield 85.6%.
3rd, the preparation of compound III
By 200.0g (0.524mol) compound II, chloracetyl methylamine 230.0g（2.139mol）, acetonitrile 1000ml, potassium carbonate 290.0g（2.101mol）Add in 2L there-necked flask, be warming up to 80 ~ 90 DEG C of reaction 24h.It is cooled to 20 DEG C of interior temperature, filter, filter cake Washed with acetonitrile.Collect filtrate, be evaporated to dry.Add 2L dichloromethane, 1L water stirring and dissolving extracts, and separates organic layer, Wash with water, organic layer is dried with sodium sulfate, filter, filtrate reduced in volume is extremely dry.Residue is tied with 600ml dehydrated alcohol again Crystalline substance, obtains compound III 154.1g, yield 65.0%.
, the preparation of compound IV
In 3L there-necked flask, sequentially add 120g（0.265mol）Compound III, 1.8L dehydrated alcohol and 267.0g （3.445mol）40% methylamine water solution, is warming up to 75 ~ 85 DEG C of reaction 2 ~ 4h, lowers the temperature 0～10 DEG C, Deca concentrated hydrochloric acid 250.0g Adjust PH=2, control 0 ~ 10 DEG C of interior temperature, insulated and stirred crystallizes 30 ~ 40min, filter, with washing with alcohol, filter cake subtracts in 50～60 DEG C Press dry dry 5h, obtain 89.9g compound IV, yield 85.8%
5th, the preparation of razaxaban impurity 10
By 82.1g（0.505mol）The chloro- thiophene -2-carboxylic acid of 5-（SM3）, 320ml N,N-dimethylformamide tri- mouthfuls of 1L of addition Stir in bottle molten clear after, bath on the rocks is cooled to 0 ~ 10 DEG C, adds 98.3g（0.606mol）N, N- carbonyl dimidazoles, in 10 ~ 20 DEG C Stirring reaction 30 ~ 40min, adds 61.2g（0.606mol）Triethylamine.In 10 ~ 20 DEG C of stirring reaction 10 ~ 15min, control interior 10 ~ 20 DEG C of temperature, is slowly added to 80.0g（0.202mol）Compound IV, heat up 30～35 DEG C of reaction 2.0 ~ 3.0h；Reactant liquor is delayed Slowly add in the there-necked flask equipped with 4.0L frozen water, system is changed into milky turbidity liquid, ice bath lower the temperature 0 ~ 10 DEG C of insulated and stirred 30 ~ 40min.Filter, filter cake purification water washing, collect filter cake in 60 ~ 70 DEG C of drying under reduced pressure 12h.Obtain crude product.Thick after being dried Product add 3.0L there-necked flask, add 2L glacial acetic acid recrystallization, obtain 62.0g impurity 10, and yield is 50.2%, purity 100%.H1- NMR (600HZ, DMSO-d6):8.98 (1H, t), 7.63-7.70（3H, m）, 7.55（1H, m）, 7.43（2H, d）, 7.19 （1H, d）, 6.93（1H, d）, 6.52（1H, d）, 4.87（1H, m）, 4.22（1H, t）, 3.90（2H, m）, 3.81（2H, s）, 3.58-3.65（4H, m）, 3.14（1H, m）, 2.59（3H, d）；MS(m/z)：611[M]+.
The preparation of preparation example 3 razaxaban impurity 11
1st, the preparation of compound V
By 243.9g（0.75mol） S-（+）-N-（2,3- ethoxycarbonyl propyl）Phthalimide（SM1）、105.1g （0.500mol）2- (2- (4- aminophenyiamino) ethyoxyl) acetic acid sequentially adds in 3L there-necked flask, adds dehydrated alcohol 1.8L, heat up 75 ~ 85 DEG C of reaction 24h.It is cooled to 40 ~ 45 DEG C with tap water, sucking filtration, with washing with alcohol, collect filter cake, white is solid Body.In 50～60 DEG C of drying under reduced pressure 5 hours.Obtain the 165.4g of compound V, yield 80.0%.
, the preparation of compound VI
By 150.0g (0.363mol) compound V, 400ml oxolane adds in 2L there-necked flask, quickly weighs 118.0g (0.726mol) N, N- carbonyl dimidazoles add reaction bulb.In outer 60 ~ 70 DEG C of reaction 10h of temperature.Cooling, adds 118.0g (0.726mol) N, N- carbonyl dimidazoles, continue at 60 ~ 70 DEG C of insulation back flow reaction 10h.Stop heating.It is cooled to interior temperature 20 DEG C, filter, filter cake is washed with oxolane.Filter cake adds in 1L reaction bulb, adds 400ml dehydrated alcohol, in the lower dissolving of backflow. It is cooled to 30 DEG C again；Filter, filter cake absolute ethanol washing.Drain, in 50 ~ 60 DEG C of drying under reduced pressure 5h.Obtain compound VI 120.9g, yield 75.8%.
, the preparation of compound VII
100.0g (0.228mol) compound VI, 1.5L dehydrated alcohol and 229.7g will be sequentially added in 3L there-necked flask （2.964mol）40% methylamine water solution, is warming up to 75 ~ 85 DEG C of reaction 2 ~ 4h, lowers the temperature 0～10 DEG C, Deca concentrated hydrochloric acid 200.0g Adjust PH=2, control 0 ~ 10 DEG C of interior temperature, insulated and stirred crystallizes 30 ~ 40min, filter, with washing with alcohol, filter cake subtracts in 50～60 DEG C Press dry dry 5h, obtain 78.4g compound VII, yield 90.0%
4th, the preparation of compound VIII
By 79.7g（0.490mol）The chloro- thiophene -2-carboxylic acid of 5-（SM3）, 225ml N,N-dimethylformamide addition 500ml tri- Stir in mouthful bottle molten clear after, bath on the rocks is cooled to 0 ~ 10 DEG C, adds 95.3g（0.588mol）N, N- carbonyl dimidazoles, in 10 ~ 20 DEG C stirring reaction 30 ~ 40min, adds 59.4g（0.588mol）Triethylamine.In 10 ~ 20 DEG C of stirring reaction 10 ~ 15min, control 10 ~ 20 DEG C of interior temperature, is slowly added to 75.0g（0.196mol）Compound IV, heat up 30～35 DEG C of reaction 2.0 ~ 3.0h；By reactant liquor Be slowly added in the there-necked flask equipped with 3.8L frozen water, system is changed into milky turbidity liquid, ice bath lower the temperature 0 ~ 10 DEG C of insulated and stirred 30 ~ 40min.Filter, filter cake purification water washing, collect filter cake in 60 ~ 70 DEG C of drying under reduced pressure 12h.Obtain crude product.Thick after being dried Product add 2L there-necked flask, add 1.2L glacial acetic acid recrystallization, obtain compound VIII60.4g, and yield is 51.5%
5th, the preparation of razaxaban impurity 11
By 50.0g（0.084mol）Compound VIII, 100ml N,N-dimethylformamide adds stirring in 500ml there-necked flask Molten clear after, bath on the rocks is cooled to 0 ~ 10 DEG C, adds 15.9g（0.098mol）N, N- carbonyl dimidazoles, in 10 ~ 20 DEG C of stirring reactions 30 ~ 40min, adds 9.9g（0.098mol）Triethylamine body.In 10 ~ 20 DEG C of stirring reaction 10 ~ 15min, control interior temperature 10 ~ 20 DEG C, it is slowly added to 22.9g（0.070mol）The chloro- N- of 5-（{（5S）- 2- oxo -3- [4-（3- oxo -4- morpholinyl）Phenyl] -1, 3- oxazolidine -5- base } methylamine hydrochloride（Intermediate products C）, heat up 30～35 DEG C of reaction 2.0 ~ 3.0h；Reactant liquor is slowly added to In there-necked flask equipped with 2.0L frozen water, system is changed into milky turbidity liquid, ice bath 0 ~ 10 DEG C of insulated and stirred 30 ~ 40min of cooling.Cross Filter, filter cake purification water washing, collect filter cake in 60 ~ 70 DEG C of drying under reduced pressure 12h.Obtain crude product.After being dried, crude product adds 1L There-necked flask, adds 500ml glacial acetic acid recrystallization, obtains 29.6g impurity 11, and yield is 48.6%, purity 99.9%.H1-NMR (600HZ, DMSO-d6):8.96 (1H, m), 8.05（1H, m）, 7.65-7.68（3H, m）, 7.62（2H, d）, 7.39（4H, t）, 7.17（1H, d）, 6.91（1H, d）, 6.51（1H, d）, 4.82（1H, m）, 4.75（1H, m）, 4.11-4.20（4H, m）, 3.95（2H, t）, 3.87（4H, m）, 3.78（2H, m）, 3.68（2H, t）, 3.55-3.62（4H, m）, 3.45（2H, m）；MS(m/ z)：871[M]+.
The preparation of preparation example 4 razaxaban impurity 12
In 250ml there-necked flask, sequentially add 8.5g（21.50mmol） 2-（（2R）- 2- hydroxyl -3- { [4-（3- oxo -4- Quinoline base）Phenyl] amino } propyl group）- 1H- iso-indoles -1,3（2H）- diketone（A）, 140ml dehydrated alcohol and 21.7g （280.00mmol）40% methylamine water solution, temperature rising reflux reacts 2～4h, lowers the temperature 10～20 DEG C, and Deca concentrated hydrochloric acid 23.1g adjusts Section PH=2, control 10 ~ 15 DEG C of interior temperature, insulated and stirred 30 ~ 40min, be evaporated to dry, with 85ml purify water dissolution concentrate produce Thing, filters out insoluble matter, and filtrate adds 0.05g sodium hydrosulfite, 0.5g activated carbon decolorizing 1h, filters, and filtrate reduced in volume is extremely dry, plus Enter the dissolving of 300ml dichloromethane, filter out insoluble matter, filtrate reduced in volume obtains white solid 7.5g, then use 25ml dichloromethane Pull an oar 0.5h at room temperature, sucking filtration, and filter cake, in 50～60 DEG C of drying under reduced pressure 5h, obtains 2.0g impurity 12, yield 75.0%, purity 99.3%.H1- NMR (600HZ, DMSO-d6):7.02 (2H, t), 6.59（2H, d）, 5.61（1H, s）, 4.13（2H, s）, 3.92（2H, m）, 3.60（3H, m）, 3.08（1H, d）, 2.93（1H, t）, 2.66（1H, m）, 2.53（1H, m）；MS(m/z)：288 [M+Na]+.
Finally illustrate, above example only in order to technical scheme to be described and unrestricted, although by ginseng According to the preferred embodiments of the present invention, invention has been described, it should be appreciated by those of ordinary skill in the art that can Using in the form and details to it as various changes, the present invention's being limited without departing from claims Spirit and scope.

Claims (10)

1. a kind of detection method of the relevant material of Rivaroxaban tablets is it is characterised in that the method is to adopt octadecyl silane For the chromatographic column of fixing phase, the efficient liquid phase with buffered saline solution and acetonitrile as mobile phase, with UV-detector as detector Chromatographic detection method；Here, described buffered saline solution comprises phosphate and ion-pairing agent.
2. detection method according to claim 1, wherein, the volume of buffered saline solution and acetonitrile in described mobile phase Than for 5～95:5～95, carry out gradient elution.
3. detection method according to claim 2, wherein, the volume of buffered saline solution and acetonitrile in described mobile phase Than for 50 ~ 90:10～50, carry out gradient elution.
4. the detection method according to claim 1-3, wherein, described buffer salt is selected from phosphoric acid alkali metal salt, is selected from phosphorus The sodium salt of acid or potassium salt, are preferably chosen from one of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate Or it is several；More preferably dipotassium hydrogen phosphate or sodium dihydrogen phosphate；Concentration in described buffered saline solution for the described phosphate For 0.01 ~ 0.10mol/L, preferably 0.02 ~ 0.05mol/L.
5. the detection method according to claim 1-3, wherein, described ion-pairing agent is sodium pentanesulfonate, hexane sulphur One or more of sour sodium, sodium heptanesulfonate, perfluorooctane sulfonate, decane sulfonate are it is therefore preferable to perfluorooctane sulfonate or decane Sodium sulfonate；Concentration in described buffered saline solution for the described ion-pairing agent is 0.003 ~ 0.03mol/L, preferably 0.005 ~ 0.03mol/L.
6. the detection method according to claim 1-3, wherein, the pH scope of described buffered saline solution is 2～3.
7. the detection method according to claim 1-3, wherein, the flow velocity of described mobile phase is 0.5～1.5ml/min, excellent Selection of land is 1ml/min.
8. the detection method according to claim 1-3, wherein, described UV-detector, its Detection wavelength be 240～ 260nm is it is therefore preferable to 250nm.
9. the detection method according to claim 1-3, wherein, the column temperature of described chromatographic column be 20～40 DEG C it is therefore preferable to 30℃.
10. the detection method according to claim 1-3, further includes following operation：
（1）Finely ground Rivaroxaban tablets of learning from else's experience and razaxaban impurity（Impurity 1 ~ 15）In right amount, use 50% acetontrile, be made into every 1ml contains the mixed solution of 0.5 μ g；
（2）Setting flow rate of mobile phase is 0.5～1.5ml/min, preferably 1.0 ml/min；Detection wavelength is 240～260nm, Good Detection wavelength 250nm；Column temperature is 20～40 DEG C, and optimum column temperature is 30 DEG C；Chromatographic column selects C18 post；Buffer salt in mobile phase Aqueous solution and acetonitrile volume ratio are 50～90:10～50, more preferably carry out gradient elution using following volume ratios：
（3）Precision measures（1）Mixed solution 10～50 μ l injects chromatograph of liquid, completes in Rivaroxaban tablets razaxaban and miscellaneous The separation of matter.
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