CN106748960A - The potential impurity compound of Nintedanib, preparation method, using and its detection method - Google Patents
The potential impurity compound of Nintedanib, preparation method, using and its detection method Download PDFInfo
- Publication number
- CN106748960A CN106748960A CN201611081117.2A CN201611081117A CN106748960A CN 106748960 A CN106748960 A CN 106748960A CN 201611081117 A CN201611081117 A CN 201611081117A CN 106748960 A CN106748960 A CN 106748960A
- Authority
- CN
- China
- Prior art keywords
- nintedanib
- impurity compound
- mobile phase
- preparation
- potential
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 0 CCCC(CC1)CCN1C(c1ccccc1)=C([C@]1C(*2)=CC(C(C)NC)=CC1)C2=[U] Chemical compound CCCC(CC1)CCN1C(c1ccccc1)=C([C@]1C(*2)=CC(C(C)NC)=CC1)C2=[U] 0.000 description 1
- HOWSSMAGSMKPRK-LLIZZRELSA-N C[I](CC1)CCN1/C(/c1ccccc1)=C(\C1C(N2)=CC(C([U]C)=O)=CC1)/C2=O Chemical compound C[I](CC1)CCN1/C(/c1ccccc1)=C(\C1C(N2)=CC(C([U]C)=O)=CC1)/C2=O HOWSSMAGSMKPRK-LLIZZRELSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/04—Indoles; Hydrogenated indoles
- C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
- C07D209/32—Oxygen atoms
- C07D209/34—Oxygen atoms in position 2
-
- 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
-
- 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
Abstract
Potential impurity compound, preparation method the present invention relates to a kind of Nintedanib, using and its detection method, its structure is as follows：
Description
Technical field
The present invention relates to medicinal chemistry art, and in particular to a kind of potential impurity compound of Nintedanib, preparation method,
Using and its detection method.
Technical background
Nintedanib esilate (NintedanibEsylate) is by Boehringer Ingelheim (BoehringerIngelheim)
Research and development, in Huo FDA (Food and Drug Adminstration)s (FDA) the approval listing of October 15 in 2014, obtained after on November 21st, 2014
European FAD (EMA) approval listing, obtains Japanese Drug with medical instrument management office on July 3rd, 2015 again followed by
(PMDA) approval listing, by Boehringer Ingelheim list marketing.
NintedanibEsylate is a kind of multiple tyrosine kinase inhibitor, by suppression and idiopathic pulmonary fibrosis
(IPF) the related growth factor receptors of pathogenesis and work.Successively granted treatment idiopathic pulmonary fibrosis (IPF) and non-
ED-SCLC (NSCLC).
Not yet listed in China, the Nintedanib soft capsule of the Boehringer Ingelheim of on July 6th, 2016 is by drug evaluation center
(CDE) the new a collection of medicine inventory for intending preferentially evaluating is included.
In Control of drug quality, activity substance content and relevant material are unusual the key links, and its impurity mainly comes
Come from building-up process and degraded.
At present, the open report in domestic and foreign literature without the impurity.
The content of the invention
Potential impurity compound, preparation method it is an object of the invention to provide a kind of Nintedanib, using and its detection
Method, can improve Nintedanib quality standard, for the safe medication of Nintedanib provides guarantee by the miscellaneous Quality Research.
The present invention by synthesis, prepare purer Nintedanib impurity compound, for Nintedanib finished product detection provide it is qualitative and
The reference substance of quantitative analysis.
A kind of potential impurity compound of Nintedanib of the present invention, its structure is as follows：
The preparation method of the potential impurity compound of Nintedanib is as follows：
The impurity compound byReacted with N methyl piperazine, or by
Deprotection generates impurity compound in the basic conditions with after N methyl piperazine reaction, then obtains product by post processing, purifying；
Wherein R is acetyl group or chloracetyl.
Wherein, (1)It is with N methyl piperazine reaction equation：
(2)It is with N methyl piperazine reaction equation：
The compoundWherein
When-R is-H, compound is 3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters；
- R be acetyl group when, compound be N- acetyl group -3- [methoxyl group (phenyl) methylene] -2- oxoindolines -
6- carboxylic acid methyl esters；
During-R chloracetyls, compound is N- chloracetyls -3- [methoxyl group (phenyl) methylene] -2- oxo-dihydros Yin
Diindyl -6- carboxylic acid methyl esters.
The alkalescence condition of deprotection is realized by addition piperidines or KOH.
The reaction dissolvent is one or more mixing in methyl alcohol, ethanol, isopropanol and N,N-dimethylformamide；
The reaction is heated at a temperature of 60 DEG C -80 DEG C；
The post processing is directly to separate out or extracted with dichloromethane, to be separated out in alcohols solvent with after water washing again.
When reaction dissolvent is one or more mixing of methyl alcohol, ethanol and isopropanol, product is directly separated out.Work as reaction dissolvent
For DMF or DMF and alcohols solvent mixing when, product is directly separated out.Or with dichloro
Methane is extracted, and is separated out in alcohols solvent again with after water washing, the alcohols solvent nail alcohol, ethanol or isopropanol.
Way of purification is recrystallization；
Post processing alcohols solvent used is methyl alcohol, ethanol or isopropanol.
The recrystallization is to be purified added with the method that machine poor solvent is crystallized with alcohols solvent or alcohols solvent；
Alcohols solvent used by the recrystallization is methyl alcohol, ethanol or isopropanol；Organic poor solvent is dichloromethane
Or ethyl acetate.
The potential impurity compound of Nintedanib controls described in Nintedanib or ethyl sulfonic acid Nintedanib preparation process
The content of impurity compound is not higher than 0.1%.
The detection method of the potential impurity compound of described Nintedanib, using high performance liquid chromatography, uses octadecane
Base silane bonded silica gel is filler, and mobile phase is potassium dihydrogen phosphate and acetonitrile, carries out gradient elution, and Detection wavelength is
245nm。
Nintedanib is taken, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to 0.4mg/ml
Need testing solution.
Impurity compound is taken, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to 20 μ g/ml
Reference substance solution.
Impurity compound obtained by the present invention, its purity is more than 95%, meets as the requirement of impurity reference substance, is used as
Impurity quantification and quantitative study.Its purity is not less than 99% after recrystallization purifying.
By controlling Nintedanib reaction condition and purifying, Nintedanib is further refined, make impurity content reduction
To test limit, that is, the impurity is not detected, process for purification includes being recrystallized using alcohol, alcohol/water, acetone/water, DMSO/ alcohol
Mode, wherein alcohols are methyl alcohol, ethanol, isopropanol or the tert-butyl alcohol.
The detection method of impurity compound in a kind of Nintedanib of the present invention, specific method is：
Nintedanib is taken, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to 0.4mg/ml
Need testing solution.
Impurity compound is taken, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to 20 μ g/ml
Reference substance solution.
Tested according to high performance liquid chromatography (four general rules 0512 of Chinese Pharmacopoeia version in 2015), chromatographic condition is：
(1) chromatographic column：Octadecylsilane chemically bonded silica.
(2) mobile phase：Mobile phase A is 20mmol/L potassium dihydrogen phosphates (phosphoric acid adjusts pH value to 3.0), and Mobile phase B is
Acetonitrile, carries out gradient elution；0-35min, mobile phase A 45%, Mobile phase B 55%；35-50min, mobile phase A 30%, stream
Dynamic phase B 70%；50min-60, mobile phase A 25%, Mobile phase B 75%；
(3) flow velocity：1ml/min.
(4) Detection wavelength：245nm.
(5) column temperature：30℃.
(6) sample size：20μl.
The content of Nintedanib involved in the present invention and the impurity with purity with high effective liquid chromatography for measuring, by external standard method
Obtained with calculated by peak area.
The present invention is in Nintedanib quality research, it was found that a potential correlation in the building-up process of Nintedanib
Impurity, its residual for deriving from N methyl piperazine in preceding synthesis step is reacted in subsequent step, produces impurity of the present invention
Compound.The Nintedanib of high-purity is obtained by controlling the corresponding limit of impurities, medicinal needs are met.
Compared with prior art, the invention has the advantages that：
The potential impurity compound of Nintedanib of the present invention, preparation method, using and its detection method, by the impurity
Study to improve Nintedanib quality standard, for the safe medication of Nintedanib provides guarantee.The present invention is prepared into by synthesis
To purer Nintedanib impurity compound, the reference substance of Qualitative and quantitative analysis is provided for Nintedanib finished product detection.
Brief description of the drawings
The MS test results of Fig. 1 impurity compounds.
The H-NMR test results of Fig. 2 impurity compounds.
The C-NMR test results of Fig. 3 impurity compounds.
The HPLC test results of Fig. 4 impurity compounds.
Specific embodiment
With reference to embodiment, the present invention will be further described.
Embodiment 1
By 3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters (8.8g, 28mol) and N-
Methyl piperazine (5.6g, 57mmol) is added in methyl alcohol 80mL, and in 60 DEG C of stirring reactions, reaction in 2-5 hours is finished, reaction solution cooling,
Solid is separated out, solid is filtered, methyl alcohol drip washing, obtain the impurity compound 8.9g of pale red solid.
HPLC detections, product purity 96.2%.
HPLC methods are：Impurity compound 5mg is taken, in addition 25mL volumetric flasks, mobile phase A-Mobile phase B (45:55) fit
Amount ultrasound makes to dissolve and be diluted to scale, used as need testing solution.
Chromatographic condition is：
(1) chromatographic column：Octadecylsilane chemically bonded silica.
(2) mobile phase：Mobile phase A is 20mmol/L potassium dihydrogen phosphates (phosphoric acid adjusts pH value to 3.0), Mobile phase B
It is acetonitrile, carries out gradient elution；0-35min, mobile phase A 45%, Mobile phase B 55%；35-50min, mobile phase A 30%, flowing
Phase B70%；50-60min, mobile phase A 25%, Mobile phase B 75%.
(3) flow velocity：1ml/min.
(4) Detection wavelength：245nm.
(5) column temperature：30℃.
Embodiment 2
By N- acetyl group -3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters (10g,
28mmol) and in N methyl piperazine (5.6g, 57mmol) addition methyl alcohol 50mL and DMF 5mL, returned in 68 DEG C
Stream reaction, after reaction in 2-4 hours, adds piperidines (4.8g, 57mmol), continues to react 2 hours.Reaction solution is cooled down, and cooling is separated out
Solid, filtering, residue add methyl alcohol 30mL be beaten, filter pale red solid impurity compound 5.7g.HPLC detections, impurity
Compound purity 97.4%.
Embodiment 3
By N- chloracetyls -3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters (10g,
28mmol) and in N methyl piperazine (5.6g, 57mmol) addition DMF 30mL, in 80 DEG C of reactions, 2 hours anti-
Ying Hou, addition piperidines (4.8g, 57mmol) continues to react 2 hours.Reaction solution is cooled down, and adds water 100mL, dichloromethane 100mL
Extraction, the washing of saturated nacl aqueous solution 50mL × 3.Anhydrous sodium sulfate drying organic phase, filtering, filtrate decompression is distilled off dichloro
Methane, residue adds isopropanol 50mL crystallizations, filtering, obtains the impurity compound 7.4g of pale red solid.HPLC is detected, contaminated
Compound purity 98.5%.
Embodiment 4-6
Embodiment 1,2 or 3 is obtained impurity compound 5.0g respectively, in adding ethanol 80mL, is heated to reflux to complete molten,
The lower slow cooling of stirring separates out solid, and temperature is filtered after being down to room temperature, the impurity compound 3.1g for being purified.HPLC detections,
Purified impurity compound purity is 99.8%.
Raw material in embodiment 1-3 is prepared using following method.
The preparation step of N- acetyl group -3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters
Suddenly：
2- Oxoindole -6- methyl formates 6.9g is added in toluene 15mL and is stirred, add acetic anhydride 15mL, former benzene first
Sour trimethyl 11g, 120-125 DEG C of heating, back flow reaction 5h.Reaction is finished, plus toluene 7mL, cooling；Crystallization, is cooled to 25 DEG C, mistake
Filter.Obtain N- acetyl group -3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters 6.2g.
3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters other step it is as follows：
N- acetyl group -3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters 6.2g is suspended
In 25mL methyl alcohol, stirring is heated to reflux；In in 2min by the methanol solution (0.6g, 5ml) of KOH added in reaction solution.Instead
Answer 10min.Cooling, filtering, obtains 3- [methoxyl group (phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters 4.3g.
The preparation process of Nintedanib is as follows：
By N- (4- aminophenyls)-N, 4- dimethyl -1- piperazineacetamides 17.6g and by N- acetyl group -3- [methoxyl groups
(phenyl) methylene] -2- oxoindoline -6- carboxylic acid methyl esters 19g is added in DMF 15mL and methyl alcohol 75mL, and backflow is anti-
Answer more than 1.5h.N methyl piperazine 9.4g is added in reaction solution, 1h, cooling, to 5 DEG C of filterings is reacted.Obtain product Nintedanib
25.1g.Nintedanib plus methyl alcohol 250mL are recrystallized, Nintedanib HPLC purity 99.58% after purification is obtained.
The content of impurity compound in Nintedanib is detected, HPLC methods are：
Nintedanib 10mg is taken, in addition 25mL volumetric flasks, mobile phase A-Mobile phase B (45:55) appropriate ultrasound makes dissolving
And scale is diluted to, as need testing solution.
Take the impurity compound, mobile phase A-Mobile phase B (45:55) appropriate ultrasound makes to dissolve and be diluted to 20 μ g/ml's
Reference substance solution.
Chromatographic condition is：
(1) chromatographic column：Octadecylsilane chemically bonded silica.
(2) mobile phase：Mobile phase A is 20mmol/L potassium dihydrogen phosphates (phosphoric acid adjusts pH value to 3.0), Mobile phase B
It is acetonitrile, carries out gradient elution；0-35min, mobile phase A 45%, Mobile phase B 55%；35-50min, mobile phase A 30%, flowing
Phase B70%；50-60min, mobile phase A 25%, Mobile phase B 75%.
(3) flow velocity：1ml/min.
(4) Detection wavelength：245nm.
(5) column temperature：30℃.
(6) sample size：20μl.
Impurity compound is not detected in Nintedanib.
Claims (10)
1. the potential impurity compound of a kind of Nintedanib, it is characterized in that, its structure is as follows：
Formulas I：Or Formula II：
2. the preparation method of the potential impurity compound of the Nintedanib described in a kind of claim 1, it is characterized in that, the impurity
Compound byReacted with N methyl piperazine, or byAfter N methyl piperazine reaction
Deprotection generates impurity compound in the basic conditions, then obtains product by post processing, purifying；Wherein R is acetyl group or chlorine
Acetyl group.
3. the preparation method of the potential impurity compound of Nintedanib according to claim 2, it is characterized in that, deprotection
Alkalescence condition is realized by addition piperidines or KOH.
4. the preparation method of the potential impurity compound of Nintedanib according to claim 2, it is characterized in that, the reaction
Solvent is one or more mixing in methyl alcohol, ethanol, isopropanol and N,N-dimethylformamide；
The reaction is heated at a temperature of 60 DEG C -80 DEG C；
The post processing is directly to separate out or extracted with dichloromethane, to be separated out in alcohols solvent with after water washing again；
Way of purification is recrystallization.
5. the preparation method of the potential impurity compound of Nintedanib according to claim 4, it is characterized in that, post-process institute
Alcohols solvent is methyl alcohol, ethanol or isopropanol.
6. the preparation method of the potential impurity compound of Nintedanib according to claim 4, it is characterized in that, the heavy knot
Crystalline substance is to be purified added with the method that machine poor solvent is crystallized with alcohols solvent or alcohols solvent.
7. the preparation method of the potential impurity compound of Nintedanib according to claim 6, it is characterized in that, the heavy knot
Brilliant alcohols solvent used is methyl alcohol, ethanol or isopropanol；Organic poor solvent is dichloromethane or ethyl acetate.
8. the application of the potential impurity compound of the Nintedanib described in a kind of claim 1, it is characterized in that, Nintedanib it is latent
The content of the impurity compound is controlled to be less than in Nintedanib or ethyl sulfonic acid Nintedanib preparation process in impurity compound
0.1%.
9. the detection method of the potential impurity compound of the Nintedanib described in a kind of claim 1, it is characterized in that, using efficient
Liquid chromatography, is filler with octadecylsilane chemically bonded silica, and mobile phase is potassium dihydrogen phosphate and acetonitrile, carries out ladder
Degree wash-out, Detection wavelength is 245nm.
10. the detection method of the potential impurity compound of Nintedanib according to claim 9, it is characterized in that, take Ni Da
Ni Bu, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to the need testing solution of 0.4mg/ml；
Impurity compound is taken, the mass ratio of mobile phase A-Mobile phase B is 45:55, ultrasound makes to dissolve and be diluted to the right of 20 μ g/ml
According to product solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611081117.2A CN106748960A (en) | 2016-11-30 | 2016-11-30 | The potential impurity compound of Nintedanib, preparation method, using and its detection method |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611081117.2A CN106748960A (en) | 2016-11-30 | 2016-11-30 | The potential impurity compound of Nintedanib, preparation method, using and its detection method |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106748960A true CN106748960A (en) | 2017-05-31 |
Family
ID=58901323
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611081117.2A Pending CN106748960A (en) | 2016-11-30 | 2016-11-30 | The potential impurity compound of Nintedanib, preparation method, using and its detection method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106748960A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018165865A1 (en) * | 2017-03-14 | 2018-09-20 | 新源生物科技股份有限公司 | Crystal forms of 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| WO2019097112A1 (en) * | 2017-11-17 | 2019-05-23 | Fermion Oy | Synthesis of a 2-indolinone derivative known as intermediate for preparing nintedanib |
| CN110759848A (en) * | 2018-12-19 | 2020-02-07 | 江苏豪森药业集团有限公司 | Ethanesulfonic acid nintedanib impurity as well as preparation method and application thereof |
| CN111662223A (en) * | 2019-03-08 | 2020-09-15 | 四川科伦药物研究院有限公司 | Process for producing indolinone derivative and intermediate thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| CN105712923A (en) * | 2014-12-03 | 2016-06-29 | 江苏先声药业有限公司 | Nintedanib impurity and preparation method and application thereof |
-
2016
- 2016-11-30 CN CN201611081117.2A patent/CN106748960A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1391557A (en) * | 1999-10-13 | 2003-01-15 | 贝林格尔英格海姆法玛公司 | 6-position substituted indoline, production and use thereof as medicament |
| CN105712923A (en) * | 2014-12-03 | 2016-06-29 | 江苏先声药业有限公司 | Nintedanib impurity and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
|---|
| 杭太俊: "《药物分析》", 31 August 2011, 人民卫生出版社 * |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018165865A1 (en) * | 2017-03-14 | 2018-09-20 | 新源生物科技股份有限公司 | Crystal forms of 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| US10961203B2 (en) | 2017-03-14 | 2021-03-30 | Allgenesis Biotherapeutics Inc. | Crystalline forms of 3-Z-[1-(4-(N-((4-methyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-amino)-phenylamino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone |
| WO2019097112A1 (en) * | 2017-11-17 | 2019-05-23 | Fermion Oy | Synthesis of a 2-indolinone derivative known as intermediate for preparing nintedanib |
| CN111465594A (en) * | 2017-11-17 | 2020-07-28 | 费米有限公司 | Synthesis of 2-indolinones known as intermediates for the preparation of nintedanib |
| JP2021503459A (en) * | 2017-11-17 | 2021-02-12 | フェルミオン オサケ ユキチュア | Synthesis of 2-Indolinone Derivatives Known as Intermediates for Producing Nintedanib |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
| CN111465594B (en) * | 2017-11-17 | 2023-11-07 | 费米有限公司 | Synthesis of 2-indolinones known as intermediates for the preparation of Nidamibu |
| JP7382317B2 (en) | 2017-11-17 | 2023-11-16 | フェルミオン オサケ ユキチュア | Synthesis of 2-indolinone derivatives known as intermediates for producing nintedanib |
| CN110759848A (en) * | 2018-12-19 | 2020-02-07 | 江苏豪森药业集团有限公司 | Ethanesulfonic acid nintedanib impurity as well as preparation method and application thereof |
| CN111662223A (en) * | 2019-03-08 | 2020-09-15 | 四川科伦药物研究院有限公司 | Process for producing indolinone derivative and intermediate thereof |
| CN111662223B (en) * | 2019-03-08 | 2023-07-14 | 四川科伦药物研究院有限公司 | Indolinone derivatives and process for preparing intermediates thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106748960A (en) | The potential impurity compound of Nintedanib, preparation method, using and its detection method | |
| CN106279340B (en) | A method of synthesis momestasone furoate or its monohydrate | |
| CN101863948B (en) | High-purity (2 beta, 3 alpha, 5 alpha, 16 beta, 17 beta)-2-(4-morpholinyl)-16-(1-pyrrolidinyl)-androstane-3,17-diol or composition thereof and preparation method thereof | |
| CN110396080B (en) | Vonoprazan fumarate metabolite and preparation method of deutero metabolite thereof | |
| CN106748961A (en) | The impurity compound of Nintedanib, preparation method, using and its detection method | |
| CN102993205B (en) | High-yield purification method for preparation of high-purity sildenafil freebases | |
| CN101233100A (en) | An impurity of anastrozole intermediate, and uses thereof | |
| CN102070514B (en) | Method for preparing halofuginone intermediate | |
| EA007964B1 (en) | Method for preparing echinocandin compositions | |
| CN106187898A (en) | Carbamate derivatives and preparation method and use thereof | |
| CN111995616A (en) | Tedizolid phosphate impurity and preparation method and application thereof | |
| CN103864646A (en) | Preparation and analysis method of impurity of rasagiline mesylate | |
| CN111825678A (en) | Preparation method of carbamatinib | |
| CN106866625B (en) | Preparation method of ketanserin | |
| CN108033948A (en) | A kind of preparation of De Lasha stars and its intermediate | |
| CN106831742B (en) | A kind of preparation method of Iloperidone intermediate | |
| CN110981771A (en) | Preparation method and application of impurity E of suplatast tosilate process | |
| EP3002286B1 (en) | Preparation method for polymorphic 6-(4-chlorophenoxy)-tetrazolo[5,1-a]phthalazine and use thereof | |
| CN104945398B (en) | A kind of moxifloxacin impurity E preparation method | |
| CN103923142B (en) | Preparation method of roxithromycin intermediate | |
| CN105367487A (en) | Novel synthesis method of clevidipine butyrate important intermediate | |
| JP4265324B2 (en) | Novel nicotinic acid derivatives and synthesis method thereof | |
| CN107353247B (en) | A kind of 2- aryl -3- acylamino- quinoline and preparation method thereof | |
| CN108129537A (en) | A kind of glucocorticoid isomers and its preparation method and application | |
| CN110229078A (en) | A kind of preparation of datro starting material open loop impurity |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20170531 |