CN104356111B - A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity - Google Patents
A kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity Download PDFInfo
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- CN104356111B CN104356111B CN201410541901.1A CN201410541901A CN104356111B CN 104356111 B CN104356111 B CN 104356111B CN 201410541901 A CN201410541901 A CN 201410541901A CN 104356111 B CN104356111 B CN 104356111B
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
The invention provides the method for preparing dabigatran etcxilate mesylate hydrolysis impurity A, comprise the following steps:(1) using dabigatran etcxilate or dabigatran etcxilate mesylate as raw material, reaction is hydrolyzed in the blending agent for being dissolved in organic solvent and alkaline aqueous solution composition;(2) mixed liquor obtained by step (1) is adjusted to acidity, separates out grease;(3) organic solvent is added in gained grease, crystal is separated out, produces impurity A.Present invention also offers the method for preparing dabigatran etcxilate mesylate hydrolysis impurity B, comprise the following steps:(1) using dabigatran etcxilate mesylate hydrolysis impurity A as raw material, the blending agent of organic solvent and acidic aqueous solution composition is dissolved in, reaction is hydrolyzed;(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, extracted with dichloromethane;(3) gained extract is purified using medium pressure preparative chromatography, removes solvent and obtain grease;(4) crystal is separated out after adding ethyl acetate dissolving, produces impurity B.
Description
Technical field
The present invention relates to the quality control of dabigatran etcxilate, and in particular to a kind of dabigatran etcxilate mesylate hydrolysis impurity for preparing
Method.
Background technology
Dabigatran etcxilate mesylate is a kind of oral thrombin inhibitor, and its chemical constitution is:
Its preparation dabigatran etcxilate capsule obtains listing license in Europe in March, 2008, turns into after warfarin,
The new category oral anticoagulant thing of five first listings during the last ten years.Dabigatran etcxilate can be converted into dabigatran in vivo, after
Person can suppress thrombin activity so as to reach blood coagulation resisting function, and the medicine is mainly used in Postoperative Intravenous thromboembolism and specific trouble
Person crowd.The listing of the medicine, it is a major progress in anticoagulant therapy field and potential lethal thrombus prevention field, is
The another big rising star in cardiovascular treatment field.
At present, the study of pharmacy to dabigatran etcxilate mesylate focuses primarily upon the synthesis work of patent medicine and its intermediate
Skill, patent document US2010/0099882A1, US2011/0295018A1, CN102633713A and CN102911160A are reported respectively
The road wherein synthesis of mesosome and purification process, WO98/37075 report the synthesis technique of bulk drug, CN1845917B reports
The crystalline structure of dabigatran etcxilate mesylate.
Because dabigatran etcxilate contains two amido links and two ester bonds, therefore, the medicine is in preparation, storage and production process
In easily hydrolyze, the impurity that most probable contains in the product is hydrolysis impurity, thus in quality control to hydrolyze it is miscellaneous
The standard items of matter are in great demand, and have no the report to the research of such impurity at present.As WO2012/152855A1 only refers to this
The preparation technology of impurity, analysis method and the dabigatran etcxilate that may contain in medicine, but the synthetic method of hydrolysis impurity is not provided.
CN102964307A disclose a kind of relevant material 2- of dabigatran etcxilate [4- (amino-n-hexane epoxide acid imide-methylene)-
Benzene imines]-methylene } -1- methyl isophthalic acids hydrogen-benzimidazole -5- Ethyl formates and its synthetic method, but the impurity is non-hydrolytic miscellaneous
Matter.
Dabigatran etcxilate can produce a series of hydrolysis impurities in building-up process, wherein main hydrolysis impurity and its change
It is as follows to learn structure:
The Study on Preparation of three kinds of described hydrolysis impurities, the quality control for the medicine have highly important meaning
Justice.At present, the method for preparing high-purity impurity A or B has no report.
The content of the invention
It is an object of the invention to provide the method for preparing dabigatran etcxilate mesylate hydrolysis impurity A and B, methods described is simple, easily grasps
Make, mild condition, the hydrolysis impurity reference of high-purity can be provided for the quality control of dabigatran etcxilate medicine.
Dabigatran etcxilate A of the present invention structural formula is:
Dabigatran etcxilate B of the present invention structural formula is:
To achieve these goals, the invention provides a kind of method for preparing dabigatran etcxilate mesylate hydrolysis impurity A, the side
Method comprises the following steps:
(1) using dabigatran etcxilate or dabigatran etcxilate mesylate as raw material, organic solvent and alkaline water are completely dissolved in
The blending agent of solution composition;Reaction is hydrolyzed at 10-50 DEG C, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is adjusted to acidity, separates out grease, after removing solvent, with distillation water washing oil
Shape thing;
(3) organic solvent is added in grease obtained by step (2), is sufficiently stirred dissolving, stood and separate out crystal, suction filtration removes
Solvent is removed, is dried in vacuo, produces dabigatran etcxilate mesylate hydrolysis impurity A.
In above-mentioned steps (1):
The raw material is preferably dabigatran etcxilate;
Organic solvent in the blending agent is selected from ethanol, methanol, acetonitrile, acetone, isopropanol or tetrahydrofuran, preferably
For acetonitrile;
It is water-soluble that alkaline aqueous solution in the blending agent is selected from sodium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide
Liquid, preferably sodium hydrate aqueous solution;
The concentration of alkaline aqueous solution is 0.02-2mol/L, preferably 0.05-0.5mol/L, more preferably 0.1mol/
L;
The volume ratio of organic solvent and alkaline aqueous solution is 0.5-1.5:1, preferably 1:1;
Raw material should be completely dissolved in the blending agent, and the weight of preferred feedstock and blending agent is than 1:5-100, enter
One step is preferably 1:30;
The temperature of the hydrolysis is preferably 20 DEG C.
In above-mentioned steps (2):
Reagent used in adjusting mixed liquor pH value is preferably acetic acid;The acid ph value is preferably 3.5-4.5, further
Preferably pH4.0.
In above-mentioned steps (3):
The organic solvent added is selected from ethanol, methanol, acetone or isopropanol, preferably acetone;The organic solvent should
Grease is fully dissolved, the w/v of preferable grease and organic solvent is 1:5-1:30, more preferably 1:10.
Preferably, the method for the present invention for preparing dabigatran etcxilate mesylate hydrolysis impurity A comprises the following steps:
(1) using dabigatran etcxilate as raw material, acetonitrile and 0.1mol/L sodium hydrate aqueous solutions are dissolved in volume ratio 1:1 group
Into blending agent, the weight ratio of the raw material and blending agent is 1:Reaction is hydrolyzed at 30,20 DEG C, after reaction completely,
Obtain mixed liquor;
(2) mixed liquor obtained by step (1) is adjusted to pH4.0 with acetic acid, separates out grease, discard solvent, use distilled water
Wash grease;
(3) acetone of 10 times of volumes will be added in grease obtained by step (2), dissolving is sufficiently stirred, stands and separate out crystal,
Filter and remove solvent, be dried in vacuo at 40 DEG C, produce dabigatran etcxilate mesylate hydrolysis impurity A.
Present invention also offers the method for preparing dabigatran etcxilate mesylate hydrolysis impurity B, this method are miscellaneous with dabigatran ester hydrolysis
Matter A is raw material;The raw material can be commercially available sterling, can also be by preparation dabigatran etcxilate mesylate hydrolysis impurity A's of the present invention
Method is prepared.
The method that the present invention provides preparation dabigatran etcxilate mesylate hydrolysis impurity B comprises the following steps:
(1) using dabigatran etcxilate mesylate hydrolysis impurity A as raw material, the mixing for being dissolved in organic solvent and acidic aqueous solution composition is situated between
Matter;Reaction is hydrolyzed at 10-50 DEG C, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, removes solvent, added in grease
Dichloromethane is extracted, and collects extract;
(3) alkyl silica gel, mobile phase are selected using extract obtained by medium pressure preparative chromatography purification step (2), stationary phase
From organic solvent and pH 4.0~5.0 aqueous solution;Solvent is removed after vacuum distillation, obtains grease, with distillation water washing oil
Shape thing;
(4) ethyl acetate is added in grease obtained by step (3), is heated to dissolving completely, crystal is separated out after cooling, is taken out
Filter, vacuum drying, produces dabigatran etcxilate mesylate hydrolysis impurity B.
In above-mentioned steps (1):
Organic solvent in the blending agent is selected from ethanol, methanol, acetonitrile, acetone, isopropanol or tetrahydrofuran, preferably
For acetonitrile;
It is water-soluble that acidic aqueous solution in the blending agent is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or p-methyl benzenesulfonic acid
Liquid, preferably aqueous hydrochloric acid solution;The concentration of acidic aqueous solution is 0.02-2mol/L, preferably 0.1-1mol/L, further preferably
For 0.5mol/L;
In the blending agent, the volume ratio of organic solvent and acidic aqueous solution is 0.5-1.5:1, preferably 1:1;
Raw material should be completely dissolved in the blending agent, and the weight of preferred feedstock and blending agent is than 1:5-100, enter
One step is preferably 1:30;
The temperature of the hydrolysis is preferably 40 DEG C.
In above-mentioned steps (2):
In order to realize the purpose of extraction, grease should be completely dissolved in dichloromethane, and preferable grease is with adding dichloro
The w/v of methane is 1:10-100, more preferably 1:50.
In above-mentioned steps (3):
The stationary phase is selected from eight -18 alkyl silica gel, preferably 18 alkyl silica gel;
Organic solvent in the mobile phase is selected from ethanol, methanol, acetonitrile, preferably isopropanol, acetonitrile;
The ammonium acetate aqueous solution for concentration 0.1~0.3% of the aqueous solution in the mobile phase, its pH value is adjusted with acetic acid
To 4.0~5.0;The aqueous solution is preferably the ammonium acetate aqueous solution of concentration 0.1~0.3%, with acetic acid by its pH value reconcile to
4.4;
The volume ratio of the organic solvent and the aqueous solution is 55-65:40, preferably 60:40;
The Detection wavelength of medium pressure preparative chromatography is 310nm;The retention time of target components is preferably 13~
14min。
In above-mentioned steps (4):
Grease should be dissolved completely in ethyl acetate, the w/v of preferable grease and the ethyl acetate added
For 1:4-10, more preferably 1:8;It is preferred that the temperature dissolved is 55-77 DEG C, more preferably 60 DEG C;
The crystallization should be abundant, and preferably recrystallization temperature is 0-4 DEG C, more preferably 0 DEG C.
Preferably, the method for the present invention for preparing dabigatran etcxilate mesylate hydrolysis impurity B comprises the following steps:
(1) as raw material, be dissolved in volume ratio is the dabigatran etcxilate mesylate hydrolysis impurity A being prepared using the method for the invention
1:The weight ratio of the blending agent of 1 anhydrous acetonitrile and 0.5mol/L hydrochloric acid composition, raw material and blending agent is 1:At 30,40 DEG C
Reaction is hydrolyzed, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, removes solvent, using w/v as
1:50 addition dichloromethane are extracted, and collect extract;
(3) extract obtained by medium pressure preparative chromatography separation and purification step (2), stationary phase is 18 alkyl silica gel,
Mobile phase is volume ratio 60:40 acetonitrile and pH 4.4 aqueous solution, the aqueous solution are the ammonium acetate of concentration 0.1~0.3%
The aqueous solution, its pH value is adjusted to 4.4 with acetic acid, the group that retention time is 13.5min is collected under the conditions of Detection wavelength is 310nm
Point, it is evaporated under reduced pressure, obtains grease;
(4) grease obtained by step (3) is washed twice with distilled water, using w/v as 1:8 add ethyl acetate,
60 DEG C of fully dissolvings are heated to, 0 DEG C is naturally cooling to, separates out crystal, filter, vacuum drying, it is miscellaneous to produce dabigatran ester hydrolysis
Matter B.
The dabigatran etcxilate mesylate hydrolysis impurity A and/or B that further protection methods described of the invention is prepared are in dabigatran
Application in ester quality control.Dabigatran etcxilate mesylate hydrolysis impurity A and B that the method for the invention is prepared purity are high, can
It is used for purity detecting and the quality control of dabigatran etcxilate as standard items.
Embodiment
Following examples are used to illustrate the present invention, but are not limited to the scope of the present invention.
Embodiment 1
Impurity A is prepared according to following steps:
(1) 2g dabigatran etcxilates are taken, are dissolved in the sodium hydrate aqueous solution of 30mL acetonitriles and 30mL concentration for 0.1mol/L,
Reaction is hydrolyzed at 20 DEG C, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is adjusted to pH4.0 with acetic acid, separates out grease, discard solvent, use distilled water
Wash grease twice;
(3) 20ml acetone will be added in grease obtained by step (2), is sufficiently stirred dissolving, stood and separate out crystal, suction filtration removes
Solvent is removed, is dried in vacuo, obtains yellow solid powder 1.04g, weight yield 52%.
Product detection:Through ESI (+)-MS Mass Spectrometer Methods, [M+H] of the present embodiment products therefrom+For 600.7, [M+Na]+Peak
For 622.7, with dabigatran etcxilate impurity A (C32H37N7O5) molecular weight be consistent;Through proton nmr spectra parsing and nuclear magnetic resonance
Carbon spectrum parsing, the present embodiment products therefrom are consistent with the structure of dabigatran etcxilate impurity A;Outsourcing standard items are used as standard items pair
According to the liquid chromatogram appearance time of products therefrom of the present invention is consistent with standard items.Above characterization information is proved obtained by the present embodiment
Product is dabigatran etcxilate impurity A, uses its purity of HPLC area normalization methods detection gained as 99.2%.
Embodiment 2
Impurity A is prepared according to following steps:
(1) 2g dabigatran etcxilates are taken, are dissolved in the aqueous sodium carbonate that 45mL acetonitriles and 30mL concentration are 2mol/L, 50 DEG C
Under be hydrolyzed reaction, after reaction completely, obtain mixed liquor;
(2) mixed liquor obtained by step (1) is adjusted to pH3.5 with acetic acid, separates out grease, discard solvent, use distilled water
Wash grease twice;
(3) 20ml isopropanols will be added in grease obtained by step (2), is sufficiently stirred dissolving, stood and separate out crystal, filtered
Solvent is removed, vacuum drying, obtains faint yellow solid powder 0.74g, weight yield 37%;After testing, gained powder is impurity
A, purity 98.5%.
Embodiment 3
Impurity A is prepared according to following steps:
(1) 2g dabigatran etcxilates are taken, are dissolved in the aqueous sodium carbonate of 20mL ethanol and 40mL concentration for 0.02mol/L,
Reaction is hydrolyzed at 10 DEG C, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is adjusted to pH4.5 with acetic acid, separates out grease, discard solvent, use distilled water
Wash grease twice;
(3) 40ml acetone will be added in grease obtained by step (2), is sufficiently stirred dissolving, stood and separate out crystal, suction filtration removes
Solvent is removed, is dried in vacuo, obtains faint yellow solid powder 0.83g, weight yield 41.5%;After testing, gained powder is impurity
A, purity 97.8%.
Embodiment 4
Using the gained of embodiment 1 than adding group's ester impurity A to prepare impurity B according to following steps as raw material:
(1) 1g raw materials are taken, the aqueous hydrochloric acid solution of 15ml acetonitriles and 15ml concentration for 0.5mol/L is dissolved in, is carried out at 40 DEG C
Hydrolysis, after reaction completely, obtain mixed liquor;
(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, removes solvent, add 50ml dichloromethanes
Alkane is extracted, and collects extract;
(3) extract obtained by medium pressure preparative chromatography separation and purification step (2), stationary phase is 18 alkyl silica gel,
Mobile phase is volume ratio 60:40 acetonitrile and pH 4.4 aqueous solution, the aqueous solution are water-soluble for the ammonium acetate of concentration 0.2%
Liquid, its pH value is adjusted to 4.4 with acetic acid, the component that retention time is 13.5min is collected under the conditions of Detection wavelength is 310nm,
It is evaporated under reduced pressure, obtains grease;
(4) grease obtained by step (3) is washed twice with distilled water, adds ethyl acetate 6ml, be heated to 60 DEG C fully
Dissolving, 0 DEG C is naturally cooling to, separates out crystal, filtered, vacuum drying, obtain faint yellow solid powder 215mg, weight yield is about
21.5%.
Product detection:Through ESI (+)-MS Mass Spectrometer Methods, [M+H] of the present embodiment products therefrom+For 601.2, [M+Na]+Peak
For 623.2, with dabigatran etcxilate impurity B (C32H36N6O6) molecular weight be consistent;Through proton nmr spectra parsing and nuclear magnetic resonance
Carbon spectrum parsing, the present embodiment products therefrom are consistent with the structure of dabigatran etcxilate impurity B;Outsourcing standard items are used as standard items pair
According to the liquid chromatogram appearance time of products therefrom of the present invention is consistent with standard items.Above characterization information is proved obtained by the present embodiment
Product is dabigatran etcxilate impurity B, uses its purity of HPLC area normalization methods detection gained as 99.3%.
Embodiment 5
Using the gained of embodiment 1 than adding group's ester impurity A to prepare impurity B according to following steps as raw material:
(1) 1g raw materials are taken, the aqueous sulfuric acid of 20ml acetonitriles and 15ml concentration for 2mol/L is dissolved in, enters water-filling at 50 DEG C
Solution reaction, after reaction completely, obtains mixed liquor;
(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, removes solvent, add 40ml dichloromethanes
Alkane is extracted, and collects extract;
(3) extract obtained by medium pressure preparative chromatography separation and purification step (2), stationary phase is 18 alkyl silica gel,
Mobile phase is volume ratio 65:40 acetonitrile and pH 5.0 aqueous solution, the aqueous solution are water-soluble for the ammonium acetate of concentration 0.1%
Liquid, its pH value is adjusted to 5.0 with acetic acid, the component that retention time is 13min is collected under the conditions of Detection wavelength is 310nm, is subtracted
Pressure distillation, obtains grease;
(4) grease obtained by step (3) is washed twice with distilled water, adds ethyl acetate 4ml, be heated to 65 DEG C fully
Dissolving, 4 DEG C are naturally cooling to, separate out crystal, filtered, vacuum drying, obtain faint yellow solid powder 193mg, weight yield is about
19.3%;After testing, gained powder is impurity B, purity 98.6%.
Embodiment 6
Using the gained of embodiment 1 than adding group's ester impurity A to prepare impurity B according to following steps as raw material:
(1) 1g raw materials are taken, the aqueous hydrochloric acid solution of 50ml acetone and 50ml concentration for 0.02mol/L is dissolved in, enters at 10 DEG C
Row hydrolysis, after reaction completely, obtain mixed liquor;
(2) mixed liquor obtained by step (1) is evaporated under reduced pressure to there is grease generation, removes solvent, add 60ml dichloromethanes
Alkane is extracted, and collects extract;
(3) extract obtained by medium pressure preparative chromatography separation and purification step (2), stationary phase is 18 alkyl silica gel,
Mobile phase is volume ratio 55:40 acetonitrile and pH 4.0 aqueous solution, the aqueous solution are water-soluble for the ammonium acetate of concentration 0.3%
Liquid, its pH value is adjusted to 4.0 with acetic acid, the component that retention time is 14min is collected under the conditions of Detection wavelength is 310nm, is subtracted
Pressure distillation, obtains grease;
(4) grease obtained by step (3) is washed twice with distilled water, adds ethyl acetate 10ml, be heated to 55 DEG C and fill
Divide dissolving, be naturally cooling to 0 DEG C, separate out crystal, filter, vacuum drying, obtain faint yellow solid powder 204mg, weight yield is about
20.4%;After testing, gained powder is impurity B, purity 98.5%.
Embodiment 7
Using commercially available dabigatran etcxilate impurity A as raw material, impurity B is prepared according to step and parameter described in embodiment 4;Obtain
Faint yellow solid powder 145mg, weight yield about 14.5%;After testing, gained powder is impurity B, and purity 97.1%, its is pure
The dabigatran etcxilate mesylate hydrolysis impurity B's that degree is slightly below prepared using the impurity A that the method for the invention is prepared as raw material
Purity.
Although above the present invention is made to retouch in detail with general explanation, embodiment and experiment
State, but on the basis of the present invention, it can be made some modifications or improvements, this is apparent to those skilled in the art
's.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, are belonged to claimed
Scope.
Claims (1)
- A kind of 1. method for preparing dabigatran etcxilate mesylate hydrolysis impurity B, it is characterised in that comprise the following steps:(1) using dabigatran etcxilate as raw material, ethanol and 0.05-0.5mol/L sodium hydrate aqueous solutions are dissolved in volume ratio 0.5- 1.5:The blending agent of 1 composition, the weight ratio of the raw material and blending agent is 1:5-100;It is hydrolyzed at 10-50 DEG C anti- Should, after reaction completely, obtain mixed liquor;(2) mixed liquor obtained by step (1) is adjusted to pH 3.5-4.5 with acetic acid, separates out grease, discard solvent, use distilled water Wash grease;(3) acetone is added in grease obtained by step (2), is sufficiently stirred dissolving, stood and separate out crystal, filtered and remove solvent, Vacuum drying, produces dabigatran etcxilate mesylate hydrolysis impurity A;(4) using the dabigatran etcxilate mesylate hydrolysis impurity A as raw material, acetonitrile and 0.02-2mol/L aqueous hydrochloric acid solutions are dissolved in body Product compares 0.5-1.5:The blending agent of 1 composition, the weight ratio of the raw material and blending agent is 1:5-100;Carried out at 10-50 DEG C Hydrolysis, after reaction completely, obtain mixed liquor;(5) mixed liquor obtained by step (4) is evaporated under reduced pressure to there is grease generation, removes solvent, added dichloromethane and extracted Take, collect extract;(6) extract obtained by medium pressure preparative chromatography separation and purification step (5), stationary phase is 18 alkyl silica gel, flowing It is mutually volume ratio 60:40 acetonitrile and pH 4.4 aqueous solution, the aqueous solution are water-soluble for the ammonium acetate of concentration 0.1~0.3% Liquid, its pH value is adjusted to 4.4 with acetic acid;The group that retention time is 13~14min is collected under the conditions of Detection wavelength is 310nm Point, solvent is removed after vacuum distillation, obtains grease, with distillation water washing grease;(7) ethyl acetate is added in grease obtained by step (6), is heated to dissolving completely, crystal is separated out after cooling, filter, Vacuum drying, produces dabigatran etcxilate mesylate hydrolysis impurity B;The structure of the dabigatran etcxilate mesylate hydrolysis impurity A is:The structure of the dabigatran etcxilate mesylate hydrolysis impurity B is:
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CN105566296A (en) * | 2015-12-16 | 2016-05-11 | 蚌埠丰原医药科技发展有限公司 | Method for preparing dabigatran amidated impurities |
CN105859686B (en) | 2016-05-24 | 2021-10-08 | 浙江华海药业股份有限公司 | Refining method of dabigatran etexilate free alkali |
CN109975448B (en) * | 2017-12-28 | 2022-05-20 | 成都倍特药业股份有限公司 | Method for detecting related substances or/and content of dabigatran etexilate mesylate or preparation thereof |
CN108373465B (en) * | 2018-04-13 | 2020-04-07 | 成都倍特药业股份有限公司 | Dabigatran etexilate impurity and preparation and detection methods thereof |
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WO2012152855A1 (en) * | 2011-05-11 | 2012-11-15 | Medichem S.A. | Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers |
CN102838588A (en) * | 2011-06-24 | 2012-12-26 | 中国药科大学 | Oral thrombin inhibitors, preparation methods and medical uses thereof |
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CN102838588A (en) * | 2011-06-24 | 2012-12-26 | 中国药科大学 | Oral thrombin inhibitors, preparation methods and medical uses thereof |
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