CN1300118C - Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline - Google Patents
Preparation method of 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl)quinazoline Download PDFInfo
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Abstract
The present invention relates to a method for preparing 4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl) quinazoline (gefitinib, I), which is characterized in that 3, 4-dimethoxybenzoic acid (II) is used as raw material for synthesis to obtain the precursor (-2-amino-4-methoxy-5-hydroxybenzoic acid ((V))of an intermediate body (6-hydroxy-7-methoxy-3, 4-dihydro quinazoline-4-ketone (VI)) for preparing the quinazoline derivative (4-(3-chlor-4-fluorobenzeneamidocyanogen)-7-methoxy-6-(3-morpholine oxypropyl) quinazoline (gefitinib, I)); after cyclization, 6-hydroxy-7-methoxy-3, 4-dihydro quinazoline-4-ketone (VI) is obtained, wherein the intermediate body (6-hydroxy-7-methoxy-3, 4-dihydro quinazoline-4-ketone (VI))is directly chloridized to obtain 4-chlorine-6-hydroxy-7-methoxy-quinazoline (VII), and is directly reacted with 3-chlorine-4-fluoroaniline to obtain 4-(3-chlorine-4-fluoroanilino)-6-hydroxy-7-methoxy-quinazoline (VIII) by amination; finally the 4-(3-chlorine-4-fluoroanilino)-6-hydroxy-7-methoxy-quinazoline (VIII) is reacted with morpholinyl chloropropane to obtain the gefitinib (I).
Description
Technical field
The present invention relates to 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, preparation method I).
Background technology
4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib) (structural formula I, trade(brand)name: Iressa, Iressa) be the selective depressant of EGF-R ELISA (EGFR) Tyrosylprotein kinase, the clinical treatment that is mainly used in nonsmall-cell lung cancer at present.
The synthetic route of the KH Ji Busen report of Zeneca Limited (WO9633980, CN96193526) as follows:
This route is with 6; 7-dimethoxy-3; 4-dihydroquinazoline-4-ketone is raw material; with methylsulfonic acid and L-methionine(Met) selectivity demethylation; obtain 6-hydroxyl-7-methoxyl group-3; 4-dihydroquinazoline-4-ketone, through acetylize protection 6-position hydroxyl, chlorination, the amination of 3-chloro-4-fluoroaniline, deacetylation, last morpholine propyl group etherificate obtains Gefitinib (I) then.This method needs embodiment 5 will use a large amount of methylsulfonic acids and L-methionine(Met) demethylation, and methylsulfonic acid and L-methionine(Met) reclaim difficulty, and environmental pollution is big, and reaction yield lower (＜50%).
(China Medicine University's journal, 2005,36 (1): 92-94) adopt the method for Ji Busen described in Chinese patent to prepare Gefitinib (I) substantially such as the Jin Bo of China Medicine University.
The JP gill Mount Tai of Astrazenca AB and D not flute improve the former synthetic method of company, and it is as follows to have designed a suitable industrialized synthetic route (WO2004024703):
This route is a starting raw material from 3-hydroxyl-4-methoxybenzaldehyde, at first prepares 3-hydroxyl-4-anisole nitrile, passes through etherificate, nitrated, reduction, hydrolysis, cyclization and chlorination again, and last amination obtains Gefitinib (I).Though this method has overcome the shortcoming that former route uses a large amount of methylsulfonic acids and L-methionine(Met) demethylation,, the costing an arm and a leg of starting raw material 3-hydroxyl-4-methoxybenzaldehyde, be former route use 3, more than 20 times of 4-dimethoxy benzaldehyde.
(Chinese pharmaceutical chemistry magazines such as the Yuan Li of Shenyang Pharmaceutical University, 2005,15 (1): though 39-41) reported method is slightly different with the method for JP gill Mount Tai etc.,, the starting raw material that uses is 3-hydroxyl-4-methoxyl methyl benzoate, and the method for its deficiency and JP gill Mount Tai etc. is similar.
Summary of the invention
The present invention seeks to provides a kind of 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, preparation method I) at above-mentioned weak point.The present invention uses 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V) cyclization directly to prepare 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), avoided the present conventional first cyclization preparation of adopting 6,7-dimethoxy-3,4-dihydroquinazoline-4-ketone, prepare 6-hydroxyl-7-methoxyl group-3 with methylsulfonic acid and L-methionine(Met) demethylation then, the method for 4-dihydroquinazoline-4-ketone (VI) has reduced environmental pollution and production cost.
The present invention takes following scheme to realize: 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, I) preparation method, it is characterized in that using 3,4-dimethoxybenzoic acid (II) is a raw material, synthesize and obtain producing quinazoline derivant 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, I) intermediate 6-hydroxyl-7-methoxyl group-3, the precursor of 4-dihydroquinazoline-4-ketone (VI)---2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), cyclization obtains 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI).And KH Ji Busen etc. use 3 per capita, 4-dimethoxybenzoic acid (II) is a raw material, through nitrated, the reduction and cyclization obtain 6,7-dimethoxy-3,4-dihydroquinazoline-4-ketone uses methylsulfonic acid and L-methionine(Met) demethylation to prepare 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI) then, last demethylating reaction not only needs a large amount of methylsulfonic acids and L-methionine(Met), and yield lower (＜50%).
4-of the present invention (3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, I) another feature of preparation method is employed intermediate 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), direct chlorination obtains 4-chloro-6-hydroxyl-7-methoxyl group-quinazoline (VII), and direct and 3-chloro-4-fluoroaniline reaction, amination obtains 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII), then with morpholinyl chloropropane reaction obtain 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, I).Need not through acetylize protection and deprotection reaction program, it is continuous to have reduced the reaction step, has improved reaction efficiency.
4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, I) preparation method, it is characterized in that from 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), directly cyclization obtains 6-hydroxyl-7-methoxyl group-3, the employed cyclization reagent of preparation method of 4-dihydroquinazoline-4-ketone (VI) is selected the salt of methane amide or carbonamidine for use, and the salt of carbonamidine can be selected acetate, hydrochloride, vitriol or nitrate for use; Temperature of reaction is 60～210 ℃.
The preparation method of 2-amino of the present invention-4-methoxyl group-5-hydroxy-benzoic acid (V), it is characterized in that by 3,4-dimethoxy-6-nitrobenzoic acid (III) is in alkaline aqueous solution, demethylation and reduction simultaneously once are generated as 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), the route that we are designed is more succinct, more convenient operation.Employed alkali is selected sodium hydroxide or potassium hydroxide for use, and the reductive agent of use is selected iron powder, zinc powder, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium sulphite, ammonium bisulfite and V-Brite B for use; Temperature of reaction is 20～100 ℃.
6-hydroxyl of the present invention-7-methoxyl group-3, the chlorination of 4-dihydroquinazoline-4-ketone (VI), the chlorination reagent of use is selected sulfur oxychloride, phosphorus oxychloride or phosphorus pentachloride for use; The chlorination reaction solvent is selected inert solvent benzene,toluene,xylene, methylene dichloride, ethylene dichloride, normal hexane, hexanaphthene or sherwood oil for use, and temperature of reaction is 50-150 ℃.
Direct and the 3-chloro-4-fluoroaniline reaction of 4-chloro-6-hydroxyl of the present invention-7-methoxyl group-quinazoline (VII), react used solvent and select the ether or the dimethyl formamide of methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, butyl alcohol-tert, amylalcohol, primary isoamyl alcohol, tert-pentanol, ethylene glycol, ethylene glycol for use, temperature of reaction is 30-150 ℃.
The present invention relates to 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (Gefitinib, synthetic route I) is as follows:
The invention has the advantages that the raw material 3 that uses market to be easy to get, 4-dimethoxybenzoic acid (II), obtain 3 through nitrated, 4-dimethoxy-6-nitrobenzoic acid (III), utilize nitro to the neighbour, the activation of contraposition, behind the selectivity demethylation, and do not separate demethylation product IV, directly add reductive agent, simultaneously nitroreduction is become amino, demethylation and reduction are once finished, 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V) that one step obtained, reaction conditions is to carry out in alkaline aqueous solution, and employed alkali is sodium hydroxide or potassium hydroxide, and the reductive agent of use is an iron powder, zinc powder, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium sulphite, ammonium bisulfite and V-Brite B; Temperature of reaction is 20～100 ℃; Preferably 50～60 ℃;
The present invention be advantageous in that and use 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V) cyclization directly to prepare 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), avoided the present conventional first cyclization preparation of adopting 6,7-dimethoxy-3,4-dihydroquinazoline-4-ketone, prepare 6-hydroxyl-7-methoxyl group-3 with methylsulfonic acid and L-methionine(Met) demethylation then, the method for 4-dihydroquinazoline-4-ketone (VI) has reduced environmental pollution and production cost.Employed cyclization reagent is the salt of methane amide or carbonamidine, as acetate, hydrochloride, vitriol or nitrate; Temperature of reaction is 60～210 ℃; Preferably at 170～180 ℃.
Another advantage of the present invention is that also cyclization obtains the key intermediate 6-hydroxyl-7-methoxyl group-3 of synthetic Gefitinib; 4-dihydroquinazoline-4-ketone (VI) does not need to carry out the protection to hydroxyl; directly carry out chlorination; 4-chloro-6-hydroxyl-7-methoxyl group-quinazoline (VII) that this reaction generates does not need purifying; direct and 3-chloro-4-fluoroaniline carries out amination reaction, obtains 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII).Therefore, reduced protection and two step of deprotection base reactions steps, made reaction scheme more succinct, more practical.The chlorination reagent that chlorination is used is sulfur oxychloride, phosphorus oxychloride or phosphorus pentachloride; The solvent of reaction is that excess chlorination reagent or inert solvent such as benzene,toluene,xylene, methylene dichloride, ethylene dichloride, normal hexane, hexanaphthene or sherwood oil are made reaction solvent, and temperature of reaction is 50-150 ℃; The all solvents of aminating reaction are the ether or the dimethyl formamide of methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, butyl alcohol-tert, amylalcohol, primary isoamyl alcohol, tert-pentanol, ethylene glycol, ethylene glycol, and temperature of reaction is 30-150 ℃.
The invention has the advantages that in a word; all reagent that use more are easy to get; more economical; promptly do not need to use a large amount of methylsulfonic acids and L-methionine(Met) demethylation; also do not need the complicated process through hydroxyl protection and deprotection base, whole synthetic route only needs the operation of 5 steps, and is simpler and more direct; more practical, the present invention is more suitable for industrialized production.
Concrete real mode
Embodiment:
Embodiment 1,3, the preparation of 4-dimethoxy-6-nitrobenzoic acid (III):
3 of 182g, 4-dimethoxybenzoic acid (II) gradation in 1 hour is added in the concentrated nitric acid (d, 1.42) of 0～5 ℃ of 1000mL, finishes, continue reaction 0.5 hour, pour in the trash ice of high degree of agitation, yellow solid filters, water washing, ethyl alcohol recrystallization, obtain yellow needle 185g, mp190～1 ℃, yield 81.5%.
Embodiment 2, the preparation of 3-hydroxyl-4-methoxyl group-6-benzaminic acid (V):
3 of 185g, 4-dimethoxy-6-nitrobenzoic acid (III) is added in 10% potassium hydroxide aqueous solution of 1250mL, 20-100 ℃ heated and stirred 2-4 hour, then, gradation adds the 460g vat powder in 1 hour, 40～70 ℃ keep reaction 1 hour, use the concentrated hydrochloric acid acidifying under the ice bath cooling, separate white precipitate, the Diluted Alcohol crystallization, obtain 3-hydroxyl-4-methoxyl group-6-benzaminic acid (V), colourless needle, 122.5g, mp214～5 ℃, yield 82%.
Embodiment 3,6-hydroxyl-7-methoxyl group-3, the preparation of 4-dihydroquinazoline-4-ketone (VI)
122.5g 3-hydroxyl-4-methoxyl group-6-benzaminic acid (V), mix with the methane amide of 380mL, be heated to 60～210 ℃, stirring reaction 12 hours, cooling, pour in the frozen water, filter water washing, obtain 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI) needle crystal 116.7g, mp＞200 ℃, yield 90.8%.
Embodiment 4,
122.5g 3-hydroxyl-4-methoxyl group-6-benzaminic acid (V), with or 122g FORMAMIDINE ACETATE mixture, be heated to 170～180 ℃, stirring reaction 12 hours, aftertreatment is with embodiment 3, yield 92%
Embodiment 5, the preparation of 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII):
116.7g 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), the mixture of the DMF of 800mL sulfur oxychloride and 16mL, 50-150 ℃ of reacting by heating 8 hours, the excess chlorination sulfoxide is removed in distillation, adds 100 dry-out benzene, boil off solvent, the 3-chloro-4-fluoroaniline and the 1000mL Virahol that add 57.5g, 30-150 ℃ of stirring heating 10 hours, cooling, add strong aqua, stirred 12 hours, ice-cold freezing 4 hours filtered, methanol wash, obtain 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII) 97.8g, mp＞270 ℃, yield 50%.
Embodiment 6,116.7g 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), the mixture of the dimethylbenzene of 200mL sulfur oxychloride and 600mL, also can select benzene for use, toluene, dimethylbenzene, methylene dichloride, ethylene dichloride, normal hexane, hexanaphthene or sherwood oil are made reaction solvent, 50-150 ℃ of reacting by heating 8 hours, the excess chlorination sulfoxide is removed in distillation, the 3-chloro-4-fluoroaniline and the 1000mL Virahol that add 57.5g, also can select methyl alcohol for use, ethanol, propyl alcohol, Virahol, butanols, butyl alcohol-tert, amylalcohol, primary isoamyl alcohol, tert-pentanol, ethylene glycol, the ether or the dimethyl formamide of ethylene glycol are made reaction solvent, 30-150 ℃ of stirring heating 10 hours, aftertreatment obtains 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII) with embodiment 5.
Embodiment 7, the preparation of 4-(3-chloro-4-fluoroanilino)-6 (3-morpholine propoxy-)-7-methoxyl group-quinazolines (I):
97.8g 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII) and 138g salt of wormwood, the mixture of the DMF of 1500mL, be heated to about 80 ℃, stir the DMF solution of the 140mL of the morpholinyl chloropropane that drips 39g down, finish, continue reaction 3-4 hour, cooling, pour in the water, product separates, toluene-recrystallizing methanol, get 4-(3-chloro-4-fluoroanilino)-6 (3-morpholine propoxy-)-7-methoxyl group-quinazoline (I) 66.7g, white crystals, mp192～194 ℃, yield 48.8%.
Claims (5)
1, the preparation method of a kind of 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline, it is characterized in that using 3,4-dimethoxybenzoic acid (II) is a raw material, the synthetic intermediate 6-hydroxyl-7-methoxyl group-3 that obtains producing quinazoline derivant 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I), the precursor of 4-dihydroquinazoline-4-ketone (VI)---2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), cyclization obtains 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI); Intermediate 6-hydroxyl-7-methoxyl group-3,4-dihydroquinazoline-4-ketone (VI), direct chlorination obtains 4-chloro-6-hydroxyl-7-methoxyl group-quinazoline (VII), and direct and 3-chloro-4-fluoroaniline reaction, amination obtains 4-(3-chloro-4-fluoroanilino)-6-hydroxyl-7-methoxyl group-quinazoline (VIII), obtains 4-(3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I) with the reaction of morpholinyl chloropropane then.
2, the preparation method of 4-according to claim 1 (3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I), it is characterized in that from 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), directly cyclization obtains 6-hydroxyl-7-methoxyl group-3, the salt that the employed cyclization reagent of preparation method of 4-dihydroquinazoline-4-ketone (VI) is methane amide or carbonamidine, the salt of carbonamidine can be selected acetate, hydrochloride, vitriol or nitrate for use; Temperature of reaction is 60～210 ℃.
3, the preparation method of 4-according to claim 1 (3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I), the preparation method who it is characterized in that 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), be by 3,4-dimethoxy-6-nitrobenzoic acid (III) is in alkaline aqueous solution, demethylation and reduction simultaneously once are generated as 2-amino-4-methoxyl group-5-hydroxy-benzoic acid (V), employed alkali is selected sodium hydroxide or potassium hydroxide for use, and the reductive agent of use is selected iron powder for use, zinc powder, sodium sulphite, sodium disulfide, S-WAT, sodium bisulfite, ammonium sulphite, ammonium bisulfite and V-Brite B; Temperature of reaction is 20～100 ℃.
4, the preparation method of 4-according to claim 1 (3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I), it is characterized in that 6-hydroxyl-7-methoxyl group-3, the chlorination of 4-dihydroquinazoline-4-ketone (VI), the chlorination reagent of use is selected sulfur oxychloride, phosphorus oxychloride or phosphorus pentachloride for use; Chlorination reaction is selected inert solvent benzene,toluene,xylene, methylene dichloride, ethylene dichloride, normal hexane, hexanaphthene or sherwood oil for use with solvent, and temperature of reaction is 50-150 ℃.
5, the preparation method of 4-according to claim 1 (3-chloro-4-fluorophenyl amido)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline (I), it is characterized in that the direct and 3-chloro-4-fluoroaniline reaction of 4-chloro-6-hydroxyl-7-methoxyl group-quinazoline (VII), react used solvent and select the ether or the dimethyl formamide of methyl alcohol, ethanol, propyl alcohol, Virahol, butanols, butyl alcohol-tert, amylalcohol, primary isoamyl alcohol, tert-pentanol, ethylene glycol, ethylene glycol for use, temperature of reaction is 30-150 ℃.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101570516B (en) * | 2009-04-14 | 2011-01-05 | 重庆威尔德·浩瑞医药化工有限公司 | Method for preparing 4-(3-chlorine-4-fluorophenylalanine)-7-methoxy-6-[3-(4-morpholinyl) propoxy] quinazoline |
| CN102146060B (en) * | 2010-02-09 | 2013-07-03 | 陕西师范大学 | Method for preparing gefitinib and intermediate thereof |
| CN102153518B (en) * | 2010-02-11 | 2012-10-10 | 江苏德芳医药科研有限公司 | Preparation method of Gefitinib |
| CN103012290B (en) * | 2011-09-28 | 2015-05-13 | 齐鲁制药有限公司 | Preparation method of high-purity gefitinib |
| CN103130729B (en) * | 2011-12-05 | 2015-07-15 | 齐鲁制药有限公司 | Preparation method of 4-chloro-7-methoxyl quinazoline-6-alchol acetate |
| CN103570633B (en) * | 2012-07-27 | 2015-08-05 | 中国科学院广州生物医药与健康研究院 | The preparation method of Gefitinib |
| CN103910690A (en) * | 2013-01-06 | 2014-07-09 | 上海科胜药物研发有限公司 | New iressa crystal form and preparation methods thereof |
| CN103304491A (en) * | 2013-06-17 | 2013-09-18 | 连云港盛和生物科技有限公司 | Preparation method of gefitinib |
| CN104693127B (en) * | 2015-02-14 | 2016-06-15 | 齐鲁制药有限公司 | Gefitinib ethylene glycol solvent compound and its production and use |
| CN105153065B (en) * | 2015-09-29 | 2017-03-15 | 上海天慈国际药业有限公司 | The preparation method of 4 (3 chlorine, 4 fluorophenylamino) 7 methoxyl group 6 (3 morpholine propoxyl group) quinazoline |
| CN105399688A (en) * | 2015-12-02 | 2016-03-16 | 西南科技大学 | Gefitinib preparation method |
| CN106083740B (en) * | 2016-06-03 | 2018-05-15 | 江苏开放大学 | The 4- anilinoquinazoline derivatives and preparation method of a kind of triazole containing 1,2,3- |
| CN108503597B (en) * | 2018-05-16 | 2019-05-07 | 济南爱思医药科技有限公司 | A kind of high efficiency preparation method of Gefitinib |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2005023783A1 (en) * | 2003-09-05 | 2005-03-17 | Astrazeneca Ab | Process for the manufacture of gefitinib |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1182421A (en) * | 1995-04-27 | 1998-05-20 | 曾尼卡有限公司 | Quinazoline derivatives |
| WO2005023783A1 (en) * | 2003-09-05 | 2005-03-17 | Astrazeneca Ab | Process for the manufacture of gefitinib |
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