CN105001143A - Method for preparing high-purity ethanesulfonic acid nintedanib - Google Patents
Method for preparing high-purity ethanesulfonic acid nintedanib Download PDFInfo
- Publication number
- CN105001143A CN105001143A CN201510442659.7A CN201510442659A CN105001143A CN 105001143 A CN105001143 A CN 105001143A CN 201510442659 A CN201510442659 A CN 201510442659A CN 105001143 A CN105001143 A CN 105001143A
- Authority
- CN
- China
- Prior art keywords
- danibu
- sulfonic acid
- ethyl sulfonic
- solid
- reflux
- 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
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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a refining method for preparing ethanesulfonic acid nintedanib. Through a refining mode of combining recrystallization and backflow washing, the impurity content in a finished product is reduced remarkably, so that the medication safety of medicine is guaranteed, and the refining method is simple in process and suitable for industrialized batch production.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a kind of method can preparing high purity ethyl sulfonic acid Ni Danibu.
Background technology
Idiopathic pulmonary fibrosis (idiopathic pulmonary fibrosis, IPF) is a kind of disease that is agnogenio, progressive, that be feature with two interstitial pulmonary fibrosis companion Honeycomb changes.Idiopathic pulmonary fibrosis (IPF) case of about 15% is acute, often finds because upper respiratory tract infection is medical that Progressive symmetric erythrokeratodermia expiratory dyspnea increases the weight of, in 6 months, dies from respiratory and circulatory failure.Large absolutely number IPF is chronic type (still may have subacute type between), but the chronic mean survival time also only has 3.2 years.Chronic type seems not to be that acute develops, and definite relation is not still understood.
Lung cancer is one of modal malignant tumour in the world, has become the 1st of China's urban population Death Cause for Malignant Tumors.Non-small cell type lung cancer comprises squamous cell carcinoma (squama cancer), gland cancer, large cell carcinoma, and the division of its growth of cancer cells is comparatively slow compared with small cell carcinoma, and diffusion transfer is relatively late.Nonsmall-cell lung cancer accounts for 80% of all lung cancer, and be in middle and advanced stage during the Finding case of about 75%, within 5 years, survival rate is very low.
Ethyl sulfonic acid Ni Danibu (formula I) is the effective angiogenesis inhibitor of a kind of new oral developed by Boehringer Ingelheim company, 3 kinds of key receptor families that can simultaneously relate in vasoactive generative process: vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and fibroblast growth factor acceptor (FGFR).In October, 2014 and in January, 2015, Ni Danibu (taking esilate as salt form) is respectively by FDA and EMA approval listing, and be used for the treatment of idiopathic pulmonary fibrosis (IPF), commodity are called
specification is 100 and 150mg.EMA ratifies Ni Danibu listing in November, 2014, treats Local advancement, transitivity or local recurrence nonsmall-cell lung cancer (NSCLC) adult patients with docetaxel coupling, and commodity are called
Chinese patent CN101883755 and CN101883756A discloses the preparation method of ethyl sulfonic acid Ni Danibu.Although these methods disclose the preparation technology of ethyl sulfonic acid Ni Danibu, the not openly ethyl sulfonic acid Ni Danibu purity result of gained under preparation technology.
Obtain high purity, particularly to obtain and meet the ethyl sulfonic acid Ni Danibu of ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) to (single maximum contaminant must not be greater than 0.1%) within the scope of the impurity reporting limit in bulk drug, still need to carry out further refinement treatment, such refinement treatment mode is there are no report.
Summary of the invention
By groping multiple solvent and operating process, we are surprised to find, use methanol solvate to carry out recrystallization+methyl tert-butyl ether solvent to ethyl sulfonic acid Ni Danibu and the refining mode of washing that refluxes is carried out to ethyl sulfonic acid Ni Danibu, single maximum contaminant content can be reduced to less than 0.1%, make final finished meet medicinal standard.
The object of the present invention is to provide a kind of method preparing high purity ethyl sulfonic acid Ni Danibu.It is characterized in that, comprise the steps:
Step 1: be dissolved in methyl alcohol by ethyl sulfonic acid Ni Danibu crude product, stir and be warming up to reflux state, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten;
This steps characteristic is: the weight ratio of ethyl sulfonic acid Ni Danibu crude product and methyl alcohol is selected from 1:2.5 ~ 4.0, and preferred weight ratio is 1:3.0 ~ 3.5; Reflux temperature is 60 DEG C ~ 65 DEG C, preferably 63 DEG C ~ 65 DEG C.
Step 2: ethyl sulfonic acid Ni Danibu whole molten clear after, start cooling under stirring, after being cooled to target temperature, direct filtration;
This steps characteristic is: start the target temperature after lowering the temperature and be selected from 25 DEG C ~ 35 DEG C, preferably 28 DEG C ~ 33 DEG C.
Step 3: step 2 gained work in-process are dissolved in methyl tertiary butyl ether, stir and be warming up to reflux state;
This steps characteristic is: the weight ratio of ethyl sulfonic acid Ni Danibu work in-process and methyl tertiary butyl ether is selected from 1:45 ~ 105, and preferred weight ratio is 1:60 ~ 105; Reflux temperature is 55 DEG C ~ 60 DEG C, preferably 55 DEG C ~ 57 DEG C.
Step 4: after the system stirred at reflux specified time, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, and the sampling of solid suction filtration removing methyl tertiary butyl ether detects.
This steps characteristic is: the stirred at reflux time is 2 ~ 4 hours, and preferred churning time is 2 hours.
Accompanying drawing explanation
The HPLC collection of illustrative plates of the ethyl sulfonic acid Ni Danibu finished product of accompanying drawing 1 embodiment 7.
Embodiment
Content of the present invention is illustrated below by embodiment.In the present invention, the example of the following stated is to better set forth the present invention, is not for limiting the scope of the invention.
Liquid phase detection method: be weighting agent with octadecylsilane chemically bonded silica; With 0.1% trifluoroacetic acid for mobile phase A, acetonitrile is Mobile phase B, and according to the form below carries out gradient elution, and flow velocity is per minute 1.0ml; Determined wavelength is 387nm, column temperature 35 DEG C.
Embodiment 1
Investigate different solvents (conventional recrystallization solvent) refining effect under identical purification operations process.
Ethyl sulfonic acid Ni Danibu (preparation method is with reference to Chinese patent CN101883755 (license notification number)) crude product is dissolved in different solvents, stirs and be warming up to reflux state, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, after being cooled to 29 DEG C to 31 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, and solid suction filtration detects except sampling after desolventizing.
Investigation item and result please see the following form:
Conclusion: under identical purification operations process, the refining effect of methyl alcohol is best, the effect removing maximum single impurity is the strongest, and other solvents do not have removal of impurities effect substantially, and maximum list content of mixing does not have considerable change before refining afterwards.
Embodiment 2
Investigate the impact of different methyl alcohol usage quantity on refining effect under identical purification operations process.
Ethyl sulfonic acid Ni Danibu (preparation method is with reference to Chinese patent CN101883755 (license notification number)) crude product is dissolved in the methyl alcohol of different ratios, stir and be warming up to reflux state, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, after being cooled to 25 DEG C to 35 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, and solid suction filtration detects except sampling after desolventizing.
Investigation item and result please see the following form:
Conclusion: under identical purification operations process, crude product: when methanol ratio is lower than 1:2.5, does not have removal of impurities effect substantially; Crude product: the effect that methanol ratio removes maximum single impurity at 1:2.5 to 1:4.0 is obvious, and product yield is also more than 60%; When crude product: when methanol ratio is greater than 1:4.0, although can reduce the assorted content of maximum list, treating process product loss is comparatively large, and yield significantly reduces, only less than 50%.
Embodiment 3
Investigate the impact on refining effect of filtration temperature under identical purification operations process after different cooling.
Ethyl sulfonic acid Ni Danibu (preparation method is with reference to Chinese patent CN101883755 (license notification number)) crude product is dissolved in the methyl alcohol of same ratio, stir and be warming up to reflux state, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, after being cooled to differing temps, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, and solid suction filtration detects except sampling after desolventizing.
Investigation item and result please see the following form:
Conclusion: under identical purification operations process, different filtration temperatures has a significant impact refining effect.When filtration temperature is lower than 25 DEG C, before and after refining, maximum list is assorted does not change substantially; When filtration temperature is greater than 25 DEG C, the effect removing maximum single impurity starts to manifest, and within 35 DEG C, product yield is also more than 60%; When filtration temperature is greater than 35 DEG C, although people can reduce the assorted content of maximum list, yield significantly reduces, and treating process product loss is comparatively large, and yield is only less than 50%.
Embodiment 4
Ethyl sulfonic acid Ni Danibu crude product (single maximum contaminant 0.22%) 0.953kg is dissolved in 3.050kg methyl alcohol, stirs and be warming up to 65 DEG C of reflux states, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, cooling is started under stirring, when being cooled to 34 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, after solid suction filtration removing methyl alcohol, sampling detects, and liquid phase result display main peak purity is 98.8%, and single maximum contaminant is 0.12%, the faint yellow solid 0.612kg weighed after finished product drying, yield 64.2%.
Embodiment 5
Investigate the refining effect of methyl tert-butyl ether solvent under identical purification operations process of different amounts.
Be dissolved in the methyl tertiary butyl ether of different ratios by embodiment 4 gained work in-process, stir and be warming up to reflux state, stir direct filtration after 2 hours and obtain ethyl sulfonic acid Ni Danibu finished solid, solid sampling detects.
Investigation item and result please see the following form:
Conclusion: under identical purification operations process, crude product: when methyl tertiary butyl ether ratio is lower than 1:45, although have removal of impurities effect impurity-eliminating effect and not obvious; Crude product: the effect that methyl tertiary butyl ether ratio removes maximum single impurity at 1:45 to 1:105 is obvious, and product yield is also more than 60%; When crude product: when methanol ratio is greater than 1:105, although can reduce the assorted content of maximum list, treating process product loss is comparatively large, and yield significantly reduces, only less than 50%.
Embodiment 6
Investigate the refining effect of different churning time under identical purification operations process.
Be dissolved in the methyl tertiary butyl ether of fixed proportion by embodiment 4 gained work in-process, stir and be warming up to reflux state, after stirring different time, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, and solid sampling detects.
Investigation item and result please see the following form:
Conclusion: using the methyl tertiary butyl ether of fixed proportion with under identical purification operations process, under different churning time, the yield of finished product is close.Churning time is at present little 1, have impurity-eliminating effect but purity promote amplitude little; Along with the prolongation of churning time, after churning time is greater than 2 hours, compared to the situation that stirring is filtered for 2 hours, impurity-eliminating effect does not obviously promote.
Embodiment 7
Ethyl sulfonic acid Ni Danibu crude product (single maximum contaminant 0.22%) 0.953kg is dissolved in 3.050kg methyl alcohol, stirs and is warming up to 65 DEG C of reflux states, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, when being cooled to 33 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, solid suction filtration removing methyl alcohol, the faint yellow solid 0.612kg weighed after finished product drying, yield 64.2%.
Above-mentioned finished product is dissolved in 55.08kg methyl tertiary butyl ether, stirs and be warming up to 56 DEG C of reflux states, stir 2 hours under keeping reflux state.Direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, after solid suction filtration removing methyl tertiary butyl ether, sampling detects, liquid phase result display main peak purity is 99.8%, single maximum contaminant is 0.04% (referring to accompanying drawing 1), the faint yellow solid 0.441kg weighed after finished product drying, yield 72.1%.
Embodiment 8
Ethyl sulfonic acid Ni Danibu crude product (single maximum contaminant 0.19%) 1kg is dissolved in 3.5kg methyl alcohol, stirs and is warming up to 63 DEG C of reflux states, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, when being cooled to 28 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, solid suction filtration removing methyl alcohol, the faint yellow solid 0.742kg weighed after finished product drying, yield 74.2%.
Above-mentioned finished product is dissolved in 66.78kg methyl tertiary butyl ether, stirs and be warming up to 56 DEG C of reflux states, stir 2 hours under keeping reflux state.Direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, after solid suction filtration removing methyl tertiary butyl ether, sampling detects, liquid phase result display main peak purity is 99.6%, single maximum contaminant is 0.05% (referring to accompanying drawing 1), the faint yellow solid 0.528kg weighed after finished product drying, yield 71.1%.
Embodiment 9
Ethyl sulfonic acid Ni Danibu crude product (single maximum contaminant 0.21%) 0.953kg is dissolved in 3.050kg methyl alcohol, stirs and is warming up to 65 DEG C of reflux states, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, when being cooled to 33 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, solid suction filtration removing methyl alcohol, the faint yellow solid 0.612kg weighed after finished product drying, yield 64.2%.
Above-mentioned finished product is dissolved in 36.72kg methyl tertiary butyl ether, stirs and be warming up to 57 DEG C of reflux states, stir 2 hours under keeping reflux state.Direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, after solid suction filtration removing methyl tertiary butyl ether, sampling detects, liquid phase result display main peak purity is 99.6%, single maximum contaminant is 0.05% (referring to accompanying drawing 1), the faint yellow solid 0.428kg weighed after finished product drying, yield 70.1%.
Embodiment 10
Ethyl sulfonic acid Ni Danibu crude product (single maximum contaminant 0.21%) 0.953kg is dissolved in 3.050kg methyl alcohol, stirs and is warming up to 65 DEG C of reflux states, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten.Solid molten clear after, start cooling under stirring, when being cooled to 33 DEG C, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, solid suction filtration removing methyl alcohol, the faint yellow solid 0.612kg weighed after finished product drying, yield 64.2%.
Above-mentioned finished product is dissolved in 64.26kg methyl tertiary butyl ether, stirs and be warming up to 55 DEG C of reflux states, stir 2 hours under keeping reflux state.Direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, after solid suction filtration removing methyl tertiary butyl ether, sampling detects, liquid phase result display main peak purity is 99.7%, single maximum contaminant is 0.04% (referring to accompanying drawing 1), the faint yellow solid 0.398kg weighed after finished product drying, yield 65.1%.
Claims (5)
1. prepare a method of high purity ethyl sulfonic acid Ni Danibu, it is characterized in that comprising the following steps:
A) ethyl sulfonic acid Ni Danibu crude product is dissolved in methyl alcohol, stirs and be warming up to reflux state, until the ethyl sulfonic acid Ni Danibu in system is whole clearly molten;
B) ethyl sulfonic acid Ni Danibu whole molten clear after, start cooling under stirring, after being cooled to target temperature, direct filtration obtains ethyl sulfonic acid Ni Danibu work in-process, solid suction filtration removing methyl alcohol;
C) by step b) gained finished product is dissolved in methyl tertiary butyl ether, and stir and be warming up to reflux state;
D) after the system stirred at reflux specified time, direct filtration obtains ethyl sulfonic acid Ni Danibu finished solid, solid suction filtration removing methyl tertiary butyl ether;
Wherein, the weight ratio of step a) described ethyl sulfonic acid Ni Danibu crude product and methyl alcohol is 1:2.5 ~ 4.0, and reflux temperature is 60 DEG C ~ 65 DEG C; Step b) described target temperature is 25 DEG C ~ 35 DEG C; Step c) weight ratio of described finished product and methyl tertiary butyl ether is 1:45 ~ 105, reflux temperature is 55 DEG C ~ 60 DEG C; Steps d) the described stirring specified time is 2 ~ 4 hours.
2. a kind of method preparing high purity Ni Danibu according to claim 1, is characterized in that, step a) described in ethyl sulfonic acid Ni Danibu crude product and the weight ratio of methyl alcohol be 1:3.0 ~ 3.5, reflux temperature is 63 DEG C ~ 65 DEG C.
3. a kind of method preparing high purity Ni Danibu according to claim 1, is characterized in that, step b) described in target temperature be 28 DEG C ~ 33 DEG C.
4. a kind of method preparing high purity Ni Danibu according to claim 1, is characterized in that, step c) weight ratio of described finished product and methyl tertiary butyl ether is 1:60 ~ 105, reflux temperature is 55 DEG C ~ 57 DEG C.
5. a kind of method preparing high purity Ni Danibu according to claim 1, is characterized in that, steps d) the described stirring specified time is 2 hours.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510442659.7A CN105001143A (en) | 2015-07-24 | 2015-07-24 | Method for preparing high-purity ethanesulfonic acid nintedanib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510442659.7A CN105001143A (en) | 2015-07-24 | 2015-07-24 | Method for preparing high-purity ethanesulfonic acid nintedanib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105001143A true CN105001143A (en) | 2015-10-28 |
Family
ID=54374056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510442659.7A Pending CN105001143A (en) | 2015-07-24 | 2015-07-24 | Method for preparing high-purity ethanesulfonic acid nintedanib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105001143A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105902507A (en) * | 2016-06-12 | 2016-08-31 | 佛山市腾瑞医药科技有限公司 | Ethanesulfonic acid nintedanib preparation and application thereof |
| CN105963268A (en) * | 2016-06-12 | 2016-09-28 | 佛山市腾瑞医药科技有限公司 | Ethanesulfonic acid nintedanib dispersible tablet and preparation method thereof |
| CN106841495A (en) * | 2017-04-21 | 2017-06-13 | 常州佳德医药科技有限公司 | The high-sensitivity analysis method of genotoxicity impurity in ethyl sulfonic acid Nintedanib |
| CN107011241A (en) * | 2017-04-24 | 2017-08-04 | 常州佳德医药科技有限公司 | A kind of preparation method of Nintedanib esilate |
| WO2017198202A1 (en) * | 2016-05-19 | 2017-11-23 | 上海诚妙医药科技有限公司 | Novel crystal form of nintedanib, manufacturing method thereof, and application of same |
| CN108295072A (en) * | 2015-12-09 | 2018-07-20 | 瑞阳(苏州)生物科技有限公司 | Nintedanib prevents the purposes of eye disease |
| CN111848490A (en) * | 2020-08-24 | 2020-10-30 | 江西国药有限责任公司 | Preparation method of high-purity ethanesulfonic acid nintedanib |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671660A (en) * | 2002-07-24 | 2005-09-21 | 贝林格尔英格海姆法玛两合公司 | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composi |
| WO2007057397A1 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| CN101883755B (en) * | 2007-12-03 | 2013-06-26 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and process for their manufacture |
-
2015
- 2015-07-24 CN CN201510442659.7A patent/CN105001143A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1671660A (en) * | 2002-07-24 | 2005-09-21 | 贝林格尔英格海姆法玛两合公司 | 3-z-[1-(4-(n-((4-methyl-piperazin-1-yl)-methylcarbonyl)-n-methyl-amino)-anilino)-1-phenyl-methylene]-6-methoxycarbonyl-2-indolinone-monoethanesulphonate and the use thereof as a pharmaceutical composi |
| WO2007057397A1 (en) * | 2005-11-15 | 2007-05-24 | Boehringer Ingelheim International Gmbh | Treatment of cancer |
| CN101883756A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Process for the manufacture of an indolinone derivative |
| CN101883755B (en) * | 2007-12-03 | 2013-06-26 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and process for their manufacture |
Non-Patent Citations (2)
| Title |
|---|
| 理化基本技能训练: "《理化基本技能训练》", 31 August 2014, 中国医药科技出版社 * |
| 赵红双: "尼达尼布", 《中国药物化学杂志》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108295072A (en) * | 2015-12-09 | 2018-07-20 | 瑞阳(苏州)生物科技有限公司 | Nintedanib prevents the purposes of eye disease |
| WO2017198202A1 (en) * | 2016-05-19 | 2017-11-23 | 上海诚妙医药科技有限公司 | Novel crystal form of nintedanib, manufacturing method thereof, and application of same |
| CN109415314A (en) * | 2016-05-19 | 2019-03-01 | 上海诚妙医药科技有限公司 | Novel crystal forms of Nintedanib and preparation method thereof and application thereof |
| CN105902507A (en) * | 2016-06-12 | 2016-08-31 | 佛山市腾瑞医药科技有限公司 | Ethanesulfonic acid nintedanib preparation and application thereof |
| CN105963268A (en) * | 2016-06-12 | 2016-09-28 | 佛山市腾瑞医药科技有限公司 | Ethanesulfonic acid nintedanib dispersible tablet and preparation method thereof |
| CN106841495A (en) * | 2017-04-21 | 2017-06-13 | 常州佳德医药科技有限公司 | The high-sensitivity analysis method of genotoxicity impurity in ethyl sulfonic acid Nintedanib |
| CN107011241A (en) * | 2017-04-24 | 2017-08-04 | 常州佳德医药科技有限公司 | A kind of preparation method of Nintedanib esilate |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
| CN111848490A (en) * | 2020-08-24 | 2020-10-30 | 江西国药有限责任公司 | Preparation method of high-purity ethanesulfonic acid nintedanib |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105001143A (en) | Method for preparing high-purity ethanesulfonic acid nintedanib | |
| CN105622525B (en) | The method for being used to prepare antiviral compound | |
| CN105968093B (en) | The preparation method of amber love song Ge Lieting | |
| CN102329325B (en) | Pyrrolopyrimidone dipeptidyl peptidase-IV (DPP-IV) inhibitors | |
| CN105418603A (en) | Method for preparing high-purity palbociclib and reaction intermediate of palbociclib | |
| TWI706951B (en) | Isethionate and crystalline form of cyclin-dependent kinase inhibitor and preparation methods thereof | |
| CN106046004A (en) | Total synthesis method for theacrine | |
| CN106117148B (en) | A kind of preparation and purification technique of Lopinavir | |
| CN104592195A (en) | A preparing process of alogliptin benzoate | |
| EP2956439B1 (en) | Process for preparing atazanavir sulphate | |
| CN106795159A (en) | A kind of crystal form of cyclin dependent kinase inhibitor and preparation method thereof | |
| CN106916142A (en) | A kind of method for preparing high-purity De Lasha stars | |
| CN102304116A (en) | Fluorescein compound and preparation method thereof | |
| CN107337684B (en) | A kind of preparation method of Faropenem sodium | |
| CN106749226A (en) | A kind of preparation method of avatrombopag maleates crystal formation C | |
| CN106518867B (en) | A kind of process for purification of Eliquis | |
| CN112457311B (en) | Preparation method of compound containing chloro-bromo-pyrrole-pyrimidone structure | |
| CN110467600A (en) | A kind of De Lasha star meglumine salt crystal form L and preparation method thereof | |
| CN111995588B (en) | Synthesis method of 6- (dibromomethyl) -2-methyl quinazoline-4 (3H) -ketone | |
| CN103910685A (en) | Method used for purifying sulfadimoxine | |
| CN115466248A (en) | Diterpenoid compound and extraction method and application thereof | |
| CN114031560A (en) | Preparation method of letermovir sodium salt | |
| CN104016930B (en) | A kind of process for purification of Gefitinib | |
| CN118290436A (en) | Method for improving stability of gambogic acid | |
| CN102850206A (en) | Refinement method for ibuprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20151028 |
|
| RJ01 | Rejection of invention patent application after publication |