CN103242244A - Canertinib preparation method - Google Patents
Canertinib preparation method Download PDFInfo
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- CN103242244A CN103242244A CN2013101806472A CN201310180647A CN103242244A CN 103242244 A CN103242244 A CN 103242244A CN 2013101806472 A CN2013101806472 A CN 2013101806472A CN 201310180647 A CN201310180647 A CN 201310180647A CN 103242244 A CN103242244 A CN 103242244A
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- morpholinyl
- preparation
- dihydroquinazoline
- buddhist nun
- propoxy
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- OMZCMEYTWSXEPZ-UHFFFAOYSA-N C=CC(Nc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OCCCN1CCOCC1)=O Chemical compound C=CC(Nc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OCCCN1CCOCC1)=O OMZCMEYTWSXEPZ-UHFFFAOYSA-N 0.000 description 2
- JQNPQLKZPZFJCN-UHFFFAOYSA-N C=CC(Nc(cc(c(N=CN1)c2)C1=O)c2OCCCN1CCOCC1)=O Chemical compound C=CC(Nc(cc(c(N=CN1)c2)C1=O)c2OCCCN1CCOCC1)=O JQNPQLKZPZFJCN-UHFFFAOYSA-N 0.000 description 1
- LEBIECDJOWFFPT-UHFFFAOYSA-N CCCN(C=Nc(c1c2)cc(O)c2N)C1=O Chemical compound CCCN(C=Nc(c1c2)cc(O)c2N)C1=O LEBIECDJOWFFPT-UHFFFAOYSA-N 0.000 description 1
- HZPUQEDBAYDSJH-UHFFFAOYSA-N Nc(cc(c(N=CN1)c2)C1=O)c2OCCCN1CCOCC1 Chemical compound Nc(cc(c(N=CN1)c2)C1=O)c2OCCCN1CCOCC1 HZPUQEDBAYDSJH-UHFFFAOYSA-N 0.000 description 1
Abstract
The invention discloses a Canertinib (I) preparation method which comprises the following steps: performing etherification reaction on 6-amino-7-hydroxy-3,4-dihydroquinazoline-4-one (II) and 3-(4-morpholinyl)-1-propanol to generate 6-amino-7-[3-(4-morpholinyl)propoxy]-3,4-dihydroquinazoline-4-one (III); performing acylation reaction on the compound (III) and propenoic acid or acryloyl chloride to generate 7-[3-(4-morpholinyl)propoxy]-6-acrylamido-3,4-dihydroquinazoline-4-one (IV); and performing condensation on the compound (IV) and 4-fluoro-3-chloroaniline to obtain Canertinib (I). The preparation method is simple, economic and environment-friendly in process, and meets the requirements for large-scale industrialization.
Description
But patent REFERENCE TO RELATED people of the present invention submits on the same day other one its be called the application for a patent for invention of " 6-amino-7-hydroxyl-3,4-dihydroquinazoline-4-ketone ".
Technical field
The invention belongs to organic synthesis highway route design and bulk drug thereof and intermediate preparation technical field, particularly how a kind of card replaces Buddhist nun's preparation method.
Background technology
How card is for Buddhist nun (Canertinib, I), chemistry 4-(3-chloro-4-fluoroanilino) by name-7-[3-(4-morpholinyl) propoxy-]-6-acrylamido quinazoline, it is a kind of irreversible EGF-R ELISA (pan-ErbB) selective depressant by Pfizer Inc. and Warner Lambert AG Safnern cooperative research and development, it can be attached to the Triphosaden binding site of all member's surface of cell membrane of ErbB family, thereby suppresses activation and the downstream mitotic division signal transduction pathway thereof of these acceptors.Clinical study shows that this product has good tolerability, can effectively treat kinds of tumors such as relapse and metastasis mammary cancer, ovarian cancer, cervical cancer, all can show synergy with multiple antitumour drug coupling.
Chinese patent CN1160338C number, CN1438994A number and reported that card is how for Buddhist nun's preparation method for CN1745073A number: with parent nucleus 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-fluquinconazole quinoline (VIII) is starting raw material, with 3-(4-morpholinyl)-1-propyl alcohol 7-position substitution reaction taking place under the alkaline condition, generates 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[3-(4-morpholinyl)-1-propoxy-] quinazoline (IX); Intermediate (IX) obtains corresponding aminocompound (X) through the nitroreduction of 6-position; How aminocompound (X) obtains card for Buddhist nun (I) with vinylformic acid or acrylate chloride generation acylation reaction.
In addition, the 404th page of the 559th page of " Shandong medicine thing " 2011 30 the 10th phase of volume and " Chinese Journal of Pharmaceuticals " 2010 41 the 6th phase of volume also reported the improving one's methods of above-mentioned preparation, and studied from the method for 7-fluquinconazole quinoline-3-ketone (V) through prepared in reaction intermediates (VIII) such as nitrated, chloro and condensations.
Find out that thus at present how card mainly is to be converted by the sense that intermediate (VII) carries out 4-position, 6-position and 7-position respectively to realize for Buddhist nun's preparation.Because intermediate (VII) be fluorochemicals, raw material is difficult for acquisition, and step is more, and many steps need separate and purifying by column chromatography, thereby is not suitable for industrialization demands.
Summary of the invention
The objective of the invention is to seek new preparation approach, according to the synthetic theory of the Atom economy of Green Chemistry, provide a kind of improved card how to replace Buddhist nun's preparation method, its raw material is easy to get, technology is succinct, economic environmental protection is conducive to the suitability for industrialized production of this medicine, promotes the development of the economic technology of this bulk drug.
To achieve these goals, main technical schemes provided by the present invention is as follows: a kind of card how for the Buddhist nun (4-(3-chloro-4-fluoroanilino)-7-[3-(4-morpholinyl) propoxy-]-6-acrylamido quinazoline, preparation method I),
It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxy-]-3; 4-dihydroquinazoline-4-ketone (III); this compound (III) carries out acylation reaction with vinylformic acid or acrylate chloride and generates 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3; 4-dihydroquinazoline-4-ketone (IV), this compound (IV) carry out condensation reaction with 4-fluoro-3-chloroaniline and how make card for Buddhist nun (I).
In addition, the present invention also provides following attached technical scheme:
The raw material 7-[3-of described condensation reaction (4-morpholinyl) propoxy-]-6-acrylamido-3, the molar ratio of 4-dihydroquinazoline-4-ketone (IV) and 4-fluoro-3-chloroaniline is 1: 1-2, preferred 1: 1.1-1.4.
The condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide (DCC), carbonyl dimidazoles (CDI), N, N '-DIC (DIC), 1-hydroxyl-benzotriazole (HOBt), O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HATU), benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP), preferred benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).
The alkali promotor of described condensation reaction is triethylamine (TEA), pyridine, 2, the 6-lutidine, 4-Dimethylamino pyridine (DMAP), N-methylmorpholine (NMM), N-ethylmorpholine (NEM), diisopropylethylamine (DIEA), 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN), 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,4-diazabicylo [2.2.2] octane (DABCO), preferred 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU) or 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene (DBN) or 1,4-diazabicylo [2.2.2] octane (DABCO).
The solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, N, dinethylformamide or acetonitrile, preferred acetonitrile.
Described condensation reaction, the temperature that it is characterized in that described reaction is 0-120 ℃, preferred 50-60 ℃.
Than prior art; how card involved in the present invention replaces Buddhist nun's preparation method; it is by 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxy-]-3; 4-dihydroquinazoline-4-ketone (III); this compound (III) can make target product by acidylate and condensation reaction again; so mainly being raw material, advantage of the present invention is easy to get; technology is succinct; economic environmental protection; the suitability for industrialized production that is conducive to this medicine promotes the development of the economic technology of this bulk drug.
Embodiment
Below in conjunction with several preferred embodiments technical solution of the present invention is done further nonrestrictive detailed description.
Embodiment one:
Under the room temperature, (3mL, 15mmol) with tetrahydrofuran (THF) 5mL, (4.0g, tetrahydrofuran (THF) 25mL solution 15mmol) kept room temperature reaction 2 hours to drip triphenylphosphine under the room temperature to add the diisopropyl azo-2-carboxylic acid in there-necked flask.Under nitrogen protection; with 3-(4-morpholinyl)-1-propyl alcohol (0.49g; 3.4mmol) tetrahydrofuran (THF) 5mL solution dropwise join in the above-mentioned reaction system; drip complete after; add 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) (0.53g, 3.0mmol), stirring at room reaction 4 hours.(0.38g, tetrahydrofuran (THF) 5mL solution 2.6mmol) continued room temperature reaction 2 hours, and the TLC monitoring reaction finishes to drip 3-(4-morpholinyl)-1-propyl alcohol.Vacuum distillation recovered solvent, resistates is transferred pH=5-6 with dilute hydrochloric acid, uses ethyl acetate extraction, and organic phase is transferred pH=10-11 with saturated sodium carbonate.Tell water, vacuum freezedrying gets off-white color solid 6-amino-7-[3-(4-morpholinyl) propoxy-]-3,4-dihydroquinazoline-4-ketone (III) 0.80g, yield is 87.7%.
Embodiment two:
In there-necked flask, add 6-amino-7-[3-(4-morpholinyl) propoxy-]-3,4-dihydroquinazoline-4-ketone (III) (0.76g, 2.5mmol), (0.25g 2.5mmol) and methylene dichloride 20mL, is warming up to 40-45 ℃ to triethylamine, is stirred to system dissolving homogeneous.Be down to below 10 ℃, (0.25g, methylene dichloride 10mL solution 2.8mmol) drip off the back room temperature and continue reaction 6 hours, and the TLC detection reaction finishes slowly to drip acrylate chloride.Reaction solution is used 10% sodium hydrogen carbonate solution and water washing, anhydrous sodium sulfate drying respectively.Decompression and solvent recovery, the residuum re-crystallizing in ethyl acetate obtains white solid 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) 0.81g, yield 90.5%.
Embodiment three:
Under the nitrogen protection; in there-necked flask, add 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), (6.63g is 15mmol) with acetonitrile 100mL for benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 60 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates is with the dissolving of 100mL tetrahydrofuran (THF), add 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g 13mmol), is warming up to 50 ℃, stirring reaction 5 hours, the end of TLC monitoring reaction.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets pale solid.How get off-white color solid card for Buddhist nun (I) 4.05g with ethyl alcohol recrystallization, yield is 83.5%.
Embodiment four:
Under the nitrogen protection; in there-necked flask, add 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), (6.63g is 15mmol) with acetonitrile 100mL for benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP).Stir down, dropping 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-(1.86g 15mmol), drips and finishes room temperature reaction 12 hours 5-alkene (DBN).Be warming up to 60 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.Resistates is with the dissolving of 100mL tetrahydrofuran (THF), add 4-chloro-3-fluoroaniline (1.89g, 13mmol) and sodium hydride (0.32g 13mmol), is warming up to 50 ℃, stirring reaction 5 hours, the end of TLC monitoring reaction.With saturated aqueous common salt cancellation reaction, tell organic phase, drying, vacuum distillation recovered solvent gets pale solid.How get off-white color solid card for Buddhist nun (I) 3.85g with ethyl alcohol recrystallization, yield is 79.4%.
Embodiment five:
Under the nitrogen protection; in there-necked flask, add 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3; 4-dihydroquinazoline-4-ketone (IV) (3.58g; 10mmol), benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate (BOP) (6.63g; 15mmol), 4-chloro-3-fluoroaniline (1.89g; 13mmol) and N, dinethylformamide 100mL.Stir down, (2.28g 15mmol), drips and finishes room temperature reaction 12 hours to drip 1,8-diazabicyclo [5.4.0]-11-7-alkene (DBU).Be warming up to 60 ℃, continue reaction 12 hours.The underpressure distillation desolventizing adds ethyl acetate 100mL dissolving, and washs with 2M sodium hydroxide 20mL.Tell organic phase, drying, concentrating under reduced pressure.How resistates gets off-white color solid card for Buddhist nun (I) 2.32g with ethyl alcohol recrystallization, and yield is 47.8%.
It is pointed out that above-described embodiment only is explanation technical conceive of the present invention and characteristics, its purpose is to allow the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.
Claims (6)
- A card how for Buddhist nun's preparation method, how described card is for Buddhist nun's chemistry 4-(3-chloro-4-fluoroanilino) by name-7-[3-(4-morpholinyl) propoxy-]-6-acrylamido quinazoline (I)It is characterized in that described preparation method comprises the steps: 6-amino-7-hydroxyl-3; 4-dihydroquinazoline-4-ketone (II) and 3-(4-morpholinyl)-1-propyl alcohol generation etherification reaction generates 6-amino-7-[3-(4-morpholinyl) propoxy-]-3; 4-dihydroquinazoline-4-ketone (III); described 6-amino-7-[3-(4-morpholinyl) propoxy-]-3; 4-dihydroquinazoline-4-ketone (III) carries out acylation reaction with vinylformic acid or acrylate chloride and generates 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3; 4-dihydroquinazoline-4-ketone (IV); described 7-[3-(4-morpholinyl) propoxy-]-6-acrylamido-3,4-dihydroquinazoline-4-ketone (IV) carries out condensation reaction with 4-fluoro-3-chloroaniline and how makes described card for Buddhist nun (I).
- 2. how to replace Buddhist nun's preparation method according to the described card of claim 1, it is characterized in that: the raw material 7-[3-of described condensation reaction (4-morpholinyl) propoxy-]-6-acrylamido-3, the molar ratio of 4-dihydroquinazoline-4-ketone (IV) and 4-fluoro-3-chloroaniline is 1: 1-2.
- 3. how to replace Buddhist nun's preparation method according to the described card of claim 1, it is characterized in that: the condensing agent of described condensation reaction is N, N,-dicyclohexylcarbodiimide, carbonyl dimidazoles, N, N '-DIC, 1-hydroxyl-benzotriazole, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester, O-(7-azo benzotriazole)-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester, benzotriazole-N, N, N ', N '-tetramethyl-urea phosphofluoric acid ester or benzotriazole-1-base oxygen base three (dimethylamino) phosphorus hexafluorophosphate.
- 4. how to replace Buddhist nun's preparation method according to the described card of claim 1, it is characterized in that: the alkali promotor of described condensation reaction is triethylamine, pyridine, 2,6-lutidine, 4-Dimethylamino pyridine, N-methylmorpholine, N-ethylmorpholine, diisopropylethylamine, 1,5-diazabicylo [4.3.0]-ninth of the ten Heavenly Stems-5-alkene, 1,8-diazabicyclo [5.4.0]-11-7-alkene or 1,4-diazabicylo [2.2.2] octane.
- 5. how to replace Buddhist nun's preparation method according to the described card of claim 1, it is characterized in that: the solvent of described condensation reaction is toluene, dimethylbenzene, ethyl acetate, isopropyl acetate, butylacetate, chloroform, methyl-sulphoxide, N, dinethylformamide or acetonitrile.
- 6. how to replace Buddhist nun's preparation method according to the described card of claim 1, it is characterized in that: the temperature of described condensation reaction is 0-120 ℃.
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| CN201310180647.2A CN103242244B (en) | 2013-05-16 | 2013-05-16 | Canertinib preparation method |
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| CN201310180647.2A CN103242244B (en) | 2013-05-16 | 2013-05-16 | Canertinib preparation method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183560A1 (en) * | 2013-05-16 | 2014-11-20 | 苏州明锐医药科技有限公司 | Afatinib and preparation method of intermediate thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330642A (en) * | 1998-11-19 | 2002-01-09 | 沃尼尔·朗伯公司 | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, irreversible inihibotr of tyrosine kinases |
| WO2004069791A2 (en) * | 2003-02-05 | 2004-08-19 | Warner-Lambert Company Llc | Preparation of substituted quinazolines |
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
-
2013
- 2013-05-16 CN CN201310180647.2A patent/CN103242244B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1330642A (en) * | 1998-11-19 | 2002-01-09 | 沃尼尔·朗伯公司 | N-[4-(3-chloro-4-fluoro-phenylamino)-7-(3-morpholin-4-yl-propoxy)-quinazolin-6-yl]-acrylamide, irreversible inihibotr of tyrosine kinases |
| WO2004069791A2 (en) * | 2003-02-05 | 2004-08-19 | Warner-Lambert Company Llc | Preparation of substituted quinazolines |
| CN102153519A (en) * | 2011-02-18 | 2011-08-17 | 上海长林化学科技有限公司 | Preparation method of quinazoline derivative |
Non-Patent Citations (2)
| Title |
|---|
| PATRICK A. PLE,等: "Discovery of a New Class of Anilinoquinazoline Inhibitors with High Affinity and Specificity for the Tyrosine Kinase Domain of c-Src", 《JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 刘剑峰,等: "卡奈替尼的合成工艺改进", 《齐鲁药事》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014183560A1 (en) * | 2013-05-16 | 2014-11-20 | 苏州明锐医药科技有限公司 | Afatinib and preparation method of intermediate thereof |
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