CN105712923A - Nintedanib impurity and preparation method and application thereof - Google Patents
Nintedanib impurity and preparation method and application thereof Download PDFInfo
- Publication number
- CN105712923A CN105712923A CN201410729582.7A CN201410729582A CN105712923A CN 105712923 A CN105712923 A CN 105712923A CN 201410729582 A CN201410729582 A CN 201410729582A CN 105712923 A CN105712923 A CN 105712923A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- preparation
- methyl
- nitrobenzophenone
- 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
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000012535 impurity Substances 0.000 title claims abstract description 11
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 title abstract description 4
- 229960004378 nintedanib Drugs 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 47
- XIFJZJPMHNUGRA-UHFFFAOYSA-N n-methyl-4-nitroaniline Chemical compound CNC1=CC=C([N+]([O-])=O)C=C1 XIFJZJPMHNUGRA-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 239000013558 reference substance Substances 0.000 claims abstract description 4
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 8
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical compound CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 4
- VBEGHXKAFSLLGE-UHFFFAOYSA-N n-phenylnitramide Chemical compound [O-][N+](=O)NC1=CC=CC=C1 VBEGHXKAFSLLGE-UHFFFAOYSA-N 0.000 claims 1
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims 1
- 238000006467 substitution reaction Methods 0.000 abstract description 4
- 238000006722 reduction reaction Methods 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 230000010933 acylation Effects 0.000 abstract 2
- 238000005917 acylation reaction Methods 0.000 abstract 2
- 238000001514 detection method Methods 0.000 abstract 1
- 239000000126 substance Substances 0.000 abstract 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 34
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000203 mixture Substances 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 238000001819 mass spectrum Methods 0.000 description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000001291 vacuum drying Methods 0.000 description 6
- 238000001816 cooling Methods 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 4
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- YNNUSGIPVFPVBX-UHFFFAOYSA-N 2-[2-[1-(4-chlorophenyl)-1-phenylethoxy]ethyl]-1-methylpyrrolidine Chemical compound CN1CCCC1CCOC(C)(C=1C=CC(Cl)=CC=1)C1=CC=CC=C1 YNNUSGIPVFPVBX-UHFFFAOYSA-N 0.000 description 3
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 3
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 3
- 229940011051 isopropyl acetate Drugs 0.000 description 3
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- TYMLOMAKGOJONV-UHFFFAOYSA-N 4-nitroaniline Chemical compound NC1=CC=C([N+]([O-])=O)C=C1 TYMLOMAKGOJONV-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- AUALQMFGWLZREY-UHFFFAOYSA-N acetonitrile;methanol Chemical compound OC.CC#N AUALQMFGWLZREY-UHFFFAOYSA-N 0.000 description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 2
- GPWDPLKISXZVIE-UHFFFAOYSA-N cyclo[18]carbon Chemical group C1#CC#CC#CC#CC#CC#CC#CC#CC#C1 GPWDPLKISXZVIE-UHFFFAOYSA-N 0.000 description 2
- UKJLNMAFNRKWGR-UHFFFAOYSA-N cyclohexatrienamine Chemical group NC1=CC=C=C[CH]1 UKJLNMAFNRKWGR-UHFFFAOYSA-N 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 101000983970 Conus catus Alpha-conotoxin CIB Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a nintedanib impurity represented by the formula VI and a preparation method thereof. The preparation method comprises that with N-methyl-4-nitroaniline as a starting material, the compound is obtained through the steps of acylation, substitution, acylation, substitution, reduction, substitution reactions and the like. The compound and an intermediate compound represented by the formula V can be used as reference substances for detection of nintedanib raw materials and preparation related substances.
Description
Technical field
The present invention relates to a kind of Ni Danibu impurity and preparation method thereof and application.
Background technology
Ni Danibu (Nintedanib) is the effective angiogenesis inhibitor of a kind of new oral of Boehringer Ingelheim company exploitation.The structure of Ni Danibu is as follows:
Ni Danibu synthetic method all has been reported that at CN100351235C and CN101883755B, building-up process uses intermediate N (4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) acetamide, wherein, to disclose the synthetic route of this intermediate as follows for CN101883755B description 15 to 16 pages:
Inventors discovered unexpectedly that, when starting material N-methyl-4-nitrophenylamine comprises impurity 4-nitroaniline, through subsequent reactions, intermediate N (4-aminophenyl)-N-methyl-2-(4-methylpiperazine-1-yl) acetamide is likely to contained V structural formula impurity.
Prepare in Ni Danibu process then through subsequent reactions, it is possible to generate Formula IV structural formula impurity.
This impurity at home and abroad there is not yet bibliographical information.The formula V of the present invention or formula VI compound can control the purity of Ni Danibu raw material or preparation as impurity reference substance.
Summary of the invention
It is an aspect of the present invention to provide a kind of noval chemical compound (formula VI compound).
Formula VI compound structure is through nuclear magnetic resoance spectrum and mass spectrum confirmation, and attached data illustrate as follows.
1. mass spectrum (MS) shows [M+H] of this product+The karyoplasmic ratio at peak is 965, it was shown that the molecular weight of this product is 964.
2. high resolution mass spectrum (HRMS) shows this product [M+H]+The measured value of the mass-to-charge ratio at peak is 965.3986, and the molecular composition of its correspondence is C56H53N8O8 +, illustrate that this product molecular composition is C56H52N8O8。
3.1H-NMR and13C-NMR
Hydrogen spectrum measurement result
Carbon spectrum measurement result
The preparation method that another aspect of the present invention is to provide a kind of formula VI compound.
Said method comprising the steps of:
Step (1): N-methyl-4-nitrophenylamine reacts with chloracetyl chloride, generates 2-chloro-n-methyl-N-(4-nitrobenzophenone) acetamide (compounds I).N-methyl-4-nitrophenylamine under existing as reaction dissolvent selected from the organic solvent such as ethyl acetate, isopropyl acetate, can drip chloracetyl chloride, and 30 DEG C, to back flow reaction, obtain compounds I by adding normal heptane etc..
Step (2): compounds I reacts with paranitroanilinum, generates N-methyl-N-(4-nitrobenzophenone)-2-(4-nitrobenzophenone amine) acetamide (compound ii).Compounds I can selected from toluene, dimethylbenzene, N, the organic solvents such as dinethylformamide are as reaction dissolvent, selected from N, under the alkali such as N-diisopropylethylamine, triethylamine, DMAP and potassium iodide exist, with paranitroanilinum under 50 DEG C to reflux temperature, obtain compound ii by substitution reaction.
Step (3): compound ii reacts with chloracetyl chloride, generates the chloro-N-of 2-(2-(methyl (4-nitrobenzophenone) amine)-2-oxoethyl)-N-(4-nitrobenzophenone) acetamide (compound III).Compound ii under existing as reaction dissolvent selected from the organic solvent such as ethyl acetate, isopropyl acetate, can add chloracetyl chloride, and 30 DEG C are obtained by reacting compound III to reflux temperature.
Step (4): compound III is reacted with N methyl piperazine, generates N-methyl-2-(2-(4-methylpiperazine-1-yl)-N-(4-nitrobenzophenone) acetamido)-N-(4-nitrobenzophenone) acetamide (compounds Ⅳ).Compound III under existing as reaction dissolvent selected from the organic solvent such as ethyl acetate, isopropyl acetate, can be obtained by reacting compounds Ⅳ at 30 DEG C to 80 DEG C with N methyl piperazine.
Step (5): compounds Ⅳ carries out catalytic hydrogen reduction reaction, generates N-(4-aminophenyl)-N-(2-((4-aminophenyl) (methyl) amine)-2-oxoethyl)-2-(4-methylpiperazine-1-yl) acetamide (compound V).Compounds Ⅳ under methanol, ethanol equal solvent, under the catalysis of Pd/C or Pd (OH) 2/C, can obtain compound V by hydrogenation with hydrogen under 40 DEG C to reflux temperature.
Step (6): compound V reacts with methyl-3-(methoxyl group (phenyl) methylene)-2-Oxoindole-6-carboxylate methyl ester, production compound (compound VI).Compound V and methyl-3-(methoxyl group (phenyl) methylene)-2-Oxoindole-6-carboxylate methyl ester can selected from methanol, N, the organic solvents such as dinethylformamide are as, under reaction dissolvent, being obtained by reacting compound VI at 40 DEG C to 65 DEG C.
Concrete synthetic route is as follows:
A third aspect of the present invention is to provide the application in the impurity reference substance preparing Ni Danibu raw material or Ni Danibu preparation of described VI or the V compound.
Detailed description of the invention
The present invention will in hereafter by embodiment more detailed description, and these embodiments are exemplarily used for further illustrating, and are not construed as limiting the present invention.
Embodiment 1
Preparation 2-chloro-n-methyl-N-(4-nitrobenzophenone) acetamide
By N-methyl-4-nitrophenylamine (10g, 0.066mol) and ethyl acetate (40mL) mix and blend, heating, to 60 DEG C, drips chloracetyl chloride (9.2g, 0.081mol), back flow reaction 5 hours, cooling, it is added dropwise to normal heptane 30mL, filters, solid vacuum drying.Yield 11.5g (yield 76.6%), HPLC purity 98.6%, MS (m/z): 229 ((M+H)+。
Embodiment 2
Preparation N-methyl-N-(4-nitrobenzophenone)-2-(4-nitrobenzophenone amine) acetamide
By 2-chloro-n-methyl-N-(4-nitrobenzophenone) acetamide (6.9g, 0.0302mol), 4-nitroaniline (4.3g, 0.0311mol), potassium iodide (5.1g, 0.0307mol), N, N-diisopropylethylamine (3.9g, 0.0302mol) with toluene (50mL) mix and blend, heat 100 DEG C and react 3 hours, cooling, add water 50 milliliters, stirring, filters, solid vacuum drying.Yield 6.8g, (yield 68.2%), HPLC purity 99.2%, MS (m/z): 331 (M+H)+。
Embodiment 3
The preparation chloro-N-of 2-(2-(methyl (4-nitrobenzophenone) amine)-2-oxoethyl)-N-(4-nitrobenzophenone) acetamide
By N-methyl-N-(4-nitrobenzophenone)-2-(4-nitrobenzophenone amine) acetamide (6g, 0.018mol), ethyl acetate (60mL) and chloracetyl chloride (2.37g, 0.021mol) mix and blend, heating, to 60 DEG C, is reacted 6 hours.Cooling, filters, solid vacuum drying.Yield 3.9g (yield 53.3%), HPLC purity 98.7%, MS (m/z): 407 (M+H)+。
Embodiment 4
Preparation N-methyl-2-(2-(4-methylpiperazine-1-yl)-N-(4-nitrobenzophenone) acetamido)-N-(4-nitrobenzophenone) acetamide
By chloro-for 2-N-(2-(methyl (4-nitrobenzophenone) amine)-2-oxoethyl)-N-(4-nitrobenzophenone) acetamide (3.7g, 0.0091mol), ethyl acetate (60mL) and N methyl piperazine (2.7g, 0.027mol) mix and blend, heat to 60 DEG C of reactions 6 hours, cooling, filter, solid vacuum drying.Yield 3.1g (yield 72.5%), HPLC purity 99.2%, MS (m/z): 471 (M+H)+。
Embodiment 5
Preparation formula V compound
By N-methyl-2-(2-(4-methylpiperazine-1-yl)-N-(4-nitrobenzophenone) acetamido)-N-(4-nitrobenzophenone) acetamide (2.7g, 0.0057mol), methanol (60mL) and Pd/C1.2 gram of mix and blend, replacing hydrogen reacts, heat to 60 DEG C of reactions 5 hours, filter, filtrate decompression is evaporated, solid vacuum drying.Yield 2.1g (yield 89.5%), HPLC purity 99.1% (chromatographic condition: chromatographic column is carbon 18 bonded silica gel post；Mobile phase A: 10mmol potassium dihydrogen phosphate is containing 0.5% triethylamine, and phosphoric acid adjusts pH8.0；Mobile phase B: acetonitrile-methanol (85:15)；Gradient elution 15～80%B；35 minutes；Flow velocity: 1ml/min).1H-NMR(400MHz,DMSO-d6) δ: 6.96 (d, J=8.4,2H)；6.86 (d, J=8.8,2H)；6.56 (d, J=8.4,2H)；6.51 (d, J=8.8,2H), 5.27 (s, 4H), 3.88 (s, 2H), 3.17 (s, 3H), 2.85 (s, 2H), 2.41 (m, 8H), 2.24 (s, 3H).MS (m/z): 411 (M+H)+。
Embodiment 6
Preparation formula VI compound
By Formula V compound (2g, 0.0049mol), methyl-3-(methoxyl group (phenyl) methylene)-2-Oxoindole-6-carboxylate methyl ester (3.2g, 0.0103mol) with methanol (20mL) mix and blend, heat to 60 DEG C of reactions 12 hours, cooling, filter, solid vacuum drying.Yield 3.8g (yield 79.6%), HPLC purity 99.6% (chromatographic condition: chromatographic column is carbon 18 bonded silica gel post；Mobile phase A: 10mmol potassium dihydrogen phosphate is containing 0.5% triethylamine, and phosphoric acid adjusts pH8.0；Mobile phase B: acetonitrile-methanol (85:15)；Gradient elution 15～80%B；35 minutes；Flow velocity: 1ml/min).
Claims (6)
1. one kind has the compound of structure shown in formula VI:
2. one kind has the compound of structure shown in formula V:
3. the preparation method of formula VI compound described in claim 1, it is characterised in that: the compound of formula VI formula V compound and structure as shown below reacts acquisition:
4. the preparation method of formula V compound described in claim 2, it is characterised in that: the reduction of described formula V formula IV compound obtains:
5. the preparation method of formula VI compound described in claim 4, it is characterised in that: described formula IV compound obtains through the following steps:
A () N-methyl-4-nitrophenylamine reacts with chloracetyl chloride, obtain type I compound
B type I compound is reacted by () with nitroaniline, obtain formula II compound
C formula II compound is reacted by () with chloracetyl chloride, obtain formula III compound
D formula III compound is reacted by () with N methyl piperazine, obtain formula IV compound
6. the application in the impurity reference substance preparing Ni Danibu raw material or Ni Danibu preparation of the compound described in claim 1 or 2.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410729582.7A CN105712923A (en) | 2014-12-03 | 2014-12-03 | Nintedanib impurity and preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410729582.7A CN105712923A (en) | 2014-12-03 | 2014-12-03 | Nintedanib impurity and preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN105712923A true CN105712923A (en) | 2016-06-29 |
Family
ID=56143341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410729582.7A Pending CN105712923A (en) | 2014-12-03 | 2014-12-03 | Nintedanib impurity and preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105712923A (en) |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748961A (en) * | 2016-11-30 | 2017-05-31 | 瑞阳制药有限公司 | The impurity compound of Nintedanib, preparation method, using and its detection method |
| CN106748960A (en) * | 2016-11-30 | 2017-05-31 | 瑞阳制药有限公司 | The potential impurity compound of Nintedanib, preparation method, using and its detection method |
| CN108610308A (en) * | 2016-12-09 | 2018-10-02 | 上海奥博生物医药技术有限公司 | The method that one kettle way prepares Nintedanib intermediate |
| 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 |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1351598A (en) * | 1999-05-25 | 2002-05-29 | 阿斯特拉曾尼卡有限公司 | Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions |
| CN101580473A (en) * | 2009-06-25 | 2009-11-18 | 上海应用技术学院 | Method for preparing N-methyl paranitroaniline |
| CN101883755A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and preparation methods thereof |
-
2014
- 2014-12-03 CN CN201410729582.7A patent/CN105712923A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1351598A (en) * | 1999-05-25 | 2002-05-29 | 阿斯特拉曾尼卡有限公司 | Substituted phenyl compounds with immunosuppressing activity and pharmaceutical compositions |
| CN101883755A (en) * | 2007-12-03 | 2010-11-10 | 贝林格尔.英格海姆国际有限公司 | Indolinone derivatives and preparation methods thereof |
| CN101580473A (en) * | 2009-06-25 | 2009-11-18 | 上海应用技术学院 | Method for preparing N-methyl paranitroaniline |
Non-Patent Citations (1)
| Title |
|---|
| P. Y. PAWAR ET AL.: "Synthesis, Analgesic and Anti-Inflammatory Activity of Some 2-[(4Amino acetyl) amino] Substituted Phenyl Benzimidazole Derivatives", 《JOURNAL OF CURRENT PHARMA RESEARCH》 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106748961A (en) * | 2016-11-30 | 2017-05-31 | 瑞阳制药有限公司 | The impurity compound of Nintedanib, preparation method, using and its detection method |
| CN106748960A (en) * | 2016-11-30 | 2017-05-31 | 瑞阳制药有限公司 | The potential impurity compound of Nintedanib, preparation method, using and its detection method |
| CN108610308A (en) * | 2016-12-09 | 2018-10-02 | 上海奥博生物医药技术有限公司 | The method that one kettle way prepares Nintedanib intermediate |
| US11261158B2 (en) | 2017-11-17 | 2022-03-01 | Fermion Oy | Synthesis of 2-indolinone derivatives |
| 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 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN105712923A (en) | Nintedanib impurity and preparation method and application thereof | |
| CN101585798B (en) | Optical active compound of 1-(3-benzoyloxy-propyl)-5-(2-(1-phenyl ethyl amine) propyl-7-cyano indoline as well as preparation method and application thereof | |
| CN114524701B (en) | A kind of N-N axis chiral pyrrole derivative and its synthesis method | |
| CN103864774B (en) | A kind of preparation method of Lurasidone | |
| WO2016161956A1 (en) | Preparation method of indacaterol or salt thereof | |
| EP3201171B1 (en) | Method of preparing intermediate of salmeterol | |
| CN109678840A (en) | The preparation method of pomalidomide | |
| CN101643431B (en) | New process for synthesizing agomelatine | |
| CN103232380A (en) | Method for preparing pomalidomide key intermediate | |
| US9901913B2 (en) | Catalyst and method for producing optically active anti-1,2-nitroalkanol compound | |
| CN105566225A (en) | Crystal forms of orally-taken mitogen-activated protein kinase inhibitor and preparation method of crystal forms | |
| JP6676146B2 (en) | Novel production method of chromanol derivative | |
| CN104098509B (en) | A kind of method for preparing A type atazanavir sulfate | |
| Maier et al. | Efficient high-performance liquid chromatographic enantioseparation of five-membered aryl-substituted lactones and cyclic carbamates on a (R, R)-diaminodihydroethanoanthracene-derived chiral stationary phase | |
| CN113461561A (en) | Novel dexketoprofen trometamol impurity and preparation method thereof | |
| JP6877100B2 (en) | (1S) -4- [4- (dimethylamino) -1- (4'-fluorophenyl) -1-hydroxybutyl] -3- (hydroxymethyl) -benzonitrile hemi (+)-di- (p-tolu oil) ) Method for producing tartrate, and (1S) -1- [3- (dimethylamino) propyl] -1- (4-fluorophenyl) -1,3-dihydroisobenzofuran-5-carbo using the tartrate. Method for producing nitrile and its salt | |
| CN113200952B (en) | A method for synthesizing 2-amino-3,3-dichlorochromanone or 2-amino-3,3-dibromochromanone by tandem cyclization reaction | |
| JP6284861B2 (en) | Method for producing telmisartan | |
| CN102260224A (en) | Method for synthesizing 2-morpholone derivatives | |
| CN103554074B (en) | Preparation method of 3-trifluoromethyl coumarin derivative | |
| CN101805276B (en) | A method for synthesizing indanone-2-phenylene sulfide derivatives | |
| CN112125958A (en) | Anidulafungin impurity B and preparation method thereof | |
| CN101165054A (en) | Method for synthesizing 1-hydroxy-1,2,4,5-tetrapyridylcyclohexane | |
| CN110041241B (en) | Fullerene aniline derivative and preparation method and application thereof | |
| CN107216277A (en) | A kind of preparation method of LCZ696 impurity of the drug |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20201222 Address after: 570311 No. 2 Yaogu No. 3 Road, Xiuying District, Haikou City, Hainan Province Applicant after: Hainan Simcere Pharmaceutical Co.,Ltd. Applicant after: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. Address before: 210042 699 Xuanwu Road, Xuanwu District, Nanjing, Jiangsu -18 Applicant before: JIANGSU SIMCERE PHARMACEUTICAL Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20160629 |