CN107216317B - A kind of preparation method of afatinib intermediate - Google Patents
A kind of preparation method of afatinib intermediate Download PDFInfo
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- CN107216317B CN107216317B CN201610158327.0A CN201610158327A CN107216317B CN 107216317 B CN107216317 B CN 107216317B CN 201610158327 A CN201610158327 A CN 201610158327A CN 107216317 B CN107216317 B CN 107216317B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 title description 11
- 229960001686 afatinib Drugs 0.000 title description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 44
- 150000001875 compounds Chemical class 0.000 claims abstract description 23
- XDPCNPCKDGQBAN-BYPYZUCNSA-N (3s)-oxolan-3-ol Chemical compound O[C@H]1CCOC1 XDPCNPCKDGQBAN-BYPYZUCNSA-N 0.000 claims abstract description 18
- LYPGDCWPTHTUDO-UHFFFAOYSA-M sodium;methanesulfinate Chemical compound [Na+].CS([O-])=O LYPGDCWPTHTUDO-UHFFFAOYSA-M 0.000 claims abstract description 15
- 239000003960 organic solvent Substances 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 26
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical group CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 14
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical group [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 239000002585 base Substances 0.000 claims description 5
- 150000001408 amides Chemical class 0.000 claims description 4
- 239000007788 liquid Substances 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- ZRLVQFQTCMUIRM-UHFFFAOYSA-N potassium;2-methylbutan-2-olate Chemical compound [K+].CCC(C)(C)[O-] ZRLVQFQTCMUIRM-UHFFFAOYSA-N 0.000 claims description 4
- 150000003462 sulfoxides Chemical class 0.000 claims description 4
- 238000000926 separation method Methods 0.000 claims description 3
- 238000000967 suction filtration Methods 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 238000001291 vacuum drying Methods 0.000 claims description 3
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 230000000694 effects Effects 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims 2
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000012065 filter cake Substances 0.000 claims 1
- 238000012805 post-processing Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 6
- 238000009776 industrial production Methods 0.000 abstract description 5
- 230000009471 action Effects 0.000 abstract description 3
- 239000007787 solid Substances 0.000 description 12
- ALJPGKSDBZFNBR-UHFFFAOYSA-N 7-chloro-n-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(Cl)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 ALJPGKSDBZFNBR-UHFFFAOYSA-N 0.000 description 10
- 238000010992 reflux Methods 0.000 description 10
- CHLCPTJLUJHDBO-UHFFFAOYSA-M sodium;benzenesulfinate Chemical compound [Na+].[O-]S(=O)C1=CC=CC=C1 CHLCPTJLUJHDBO-UHFFFAOYSA-M 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
- -1 (3-chloro-4-fluorophenyl-amino) -7-chloroquinazoline Chemical compound 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 2
- IBXBOQKFZSMVOL-UHFFFAOYSA-N 7-(benzenesulfonyl)-n-(3-chloro-4-fluorophenyl)-6-nitroquinazolin-4-amine Chemical compound N1=CN=C2C=C(S(=O)(=O)C=3C=CC=CC=3)C([N+](=O)[O-])=CC2=C1NC1=CC=C(F)C(Cl)=C1 IBXBOQKFZSMVOL-UHFFFAOYSA-N 0.000 description 1
- 102000004278 Receptor Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000873 Receptor Protein-Tyrosine Kinases Proteins 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010981 drying operation Methods 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 description 1
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 description 1
- 239000004210 ether based solvent Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses an Afa-FangA preparation method of a tinib intermediate. The method comprises the following steps: in an organic solvent, under the action of alkali, a compound shown as a formula 7, sodium methanesulfinate and (S) -3-hydroxytetrahydrofuran are subjected to the following reaction to prepare a compound shown as a formula 9. The preparation method has the advantages of high yield, simple operation and low cost, and is more suitable for industrial production.
Description
Technical Field
The invention relates to a preparation method of an afatinib intermediate.
Background
Afatinib was developed by bleberg haggarham, germany, approved by FDA in us at 12/7/2013, is an irreversible EGFR-HER-2 dual tyrosine kinase receptor inhibitor and is clinically used for first-line treatment of patients with metastatic non-small cell lung cancer (NSCLC) with exon 19 deletion and exon 21 substitution mutation of EGFR. The chemical name of afatinib is (2E) -N- [4- [ (3-chloro-4-fluorophenyl) amino ] -7- [ [ (3S) -tetrahydro-3-furyl ] oxy ] -6-quinazolinyl ] -4- (dimethylamino) -2-butenamide, and the afatinib is shown in a formula 1.
The method of preparation of intermediate 9 is reported in the original patent WO2007085638 of boliger-berghan: the intermediate 6-nitro-4- [ (3-chloro-4-fluorophenyl-amino) -7-chloroquinazoline 7 reacts with sodium benzene sulfinate in DMF to obtain 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-benzenesulfonylquinazoline 8, and the 8 reacts with (S) -3-hydroxytetrahydrofuran under the action of potassium tert-butoxide to obtain 6-nitro-4- [ (3-chloro-4-fluorophenyl-amino) -7- (S) - (tetrahydrofuran-3-yl) oxy ] quinazoline 9.9, preparing afatinib 1 by hydrogenation reduction and wittig-honner reaction.
Wherein, the process of preparing 9 from 7 needs two steps of reaction: namely, 7 firstly reacts with sodium benzene sulfinate (1.3 equivalent) with reaction amount, 8 is prepared by post-treatment, then 8 reacts with (S) -3-hydroxyl tetrahydrofuran in mixed solvent tetrahydrofuran, tertiary butanol and N, N-dimethylformamide to prepare 9, temperature programming is carried out in the reaction process, and the post-treatment adopts a method of adding water in batches to carry out azeotropic concentration on the solvent. The reaction operation is complicated, and the use of a mixed solvent makes recovery of the solvent difficult, and the yield of the two-step reaction is 86% × 90% ═ 77%. The reaction of a reactive amount of sodium benzene sulfinate (1.3 equivalents) with 7 activates the reaction site and leaves it easily, but the resulting atom waste is not in accordance with the atom economy principle. The reaction mechanism is as follows:
therefore, the preparation method of afatinib intermediate, which has high yield, simple operation and low cost and is more suitable for industrial production, is urgently needed in the field.
Disclosure of Invention
The invention aims to overcome the defects of low yield, complex operation, difficult solvent recovery, high cost, inapplicability to industrial production and the like in the conventional preparation method of the afatinib intermediate, and provides the preparation method of the afatinib intermediate. The preparation method has the advantages of high yield, simple operation and low cost, and is more suitable for industrial production.
The invention provides a preparation method of a compound shown as a formula 9, which comprises the following steps: in an organic solvent, under the action of alkali, carrying out the following reaction on a compound shown as a formula 7, sodium methanesulfinate and (S) -3-hydroxytetrahydrofuran to obtain a compound shown as a formula 9;
the organic solvent may be an organic solvent conventional in such reactions in the art, and preferably one or more of amide solvents, ether solvents and sulfoxide solvents. The amide solvent is preferably N, N-dimethylformamide and/or N, N-dimethylacetamide. The ether solvent is preferably tetrahydrofuran. The sulfoxide solvent is preferably dimethyl sulfoxide. The relationship between the amount of the organic solvent and the compound shown in the formula 7 is not particularly limited as long as the reaction is not affected, and the volume-to-mass ratio of the organic solvent to the compound shown in the formula 7 is preferably 1mL/g to 10mL/g, for example 5 mL/g.
The base may be a base conventional in the art of organic synthesis, such as an organic base and/or an inorganic base. The organic base is preferably potassium tert-butoxide and/or potassium tert-amylate. The inorganic base is preferably potassium carbonate and/or sodium carbonate. The molar ratio of the alkali to the compound shown as the formula 7 is preferably 1:1-3:1, and more preferably 1.5:1-2.5: 1.
The mol ratio of the sodium methanesulfinate to the compound shown as the formula 7 is preferably 0.01:1-1.3:1, and more preferably 0.2:1-0.3: 1.
The molar ratio of the (S) -3-hydroxytetrahydrofuran to the compound shown in the formula 7 is preferably 1:1-5:1, and more preferably 1.1:1-2.5: 1.
The reaction temperature can be the temperature conventional in the reaction in the field of organic synthesis, and is preferably 40-120 ℃, further preferably 40-100 ℃, and most preferably 40-80 ℃.
The progress of the reaction can be monitored by a detection method (such as TLC, HPLC, GC, or HNMR) which is conventional in the field of organic synthesis, and generally, the end point of the reaction is determined as the time when the compound shown in formula 7 disappears or the HPLC content of the compound shown in formula 7 in the reaction solution is less than 0.5%, and the time of the reaction can be the time which is conventional in such a reaction in the field of organic synthesis, preferably 1 to 12 hours, and further preferably 3 to 12 hours.
After the reaction is completed, the reaction preferably further comprises a post-treatment operation. The method and conditions for the post-treatment may be those conventional in the field of organic synthesis, and the present invention preferably comprises the following steps: the reaction mixture after the completion of the above reaction may be mixed with water or the reaction mixture after the completion of the reaction may be concentrated (usually, the organic solvent in the reaction mixture is removed by concentration under reduced pressure), mixed with water, subjected to solid-liquid separation (for example, suction filtration), and then the cake may be washed with water and dried (for example, vacuum drying).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
the preparation method has high yield which can reach 93 percent at most; the dosage of the sodium methanesulfinate is only 0.2 equivalent of the compound 7, the dosage of the raw material is less, and the cost is low; meanwhile, the preparation method provided by the invention adopts a one-pot method, so that the operation is simple, and the preparation method is more suitable for industrial production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the drying operation is generally referred to as vacuum drying.
Example 1
10g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.57g of sodium methanesulfinate, 5.2g of (S) -3-hydroxytetrahydrofuran, 5.9g of potassium carbonate and 50 g of DMF50ml were added into a three-necked flask provided with a thermometer and a reflux condenser tube and reacted at 120 ℃ for 3 hours. The reaction solution was added to 150ml of water, filtered, washed with water and dried to obtain 7.0g of black solid 9 with a yield of 61.2%. mp 243.1-249.9 ℃.
Example 2
In a three-necked flask equipped with a thermometer and a reflux condenser, 20.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 1.27g of sodium methanesulfinate, 10.3g of (S) -3-hydroxytetrahydrofuran, 12.7g of potassium tert-butoxide, 100ml of DMF were added and reacted at 80 ℃ for 3 hours. The reaction solution was added to 300ml of water, filtered, washed with water and dried to obtain 21.3g of a yellow solid 9 with a yield of 93%. mp 245.2-247.9 ℃.
Example 3
In a three-necked flask equipped with a thermometer and a reflux condenser, 20g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 1.27g of sodium methanesulfinate, 10.3g of (S) -3-hydroxytetrahydrofuran, 12.7g of potassium tert-butoxide, 100ml g of DMF, and the reaction is carried out at 60 ℃ for 12 h. Adding the reaction solution into 300ml of water, performing suction filtration, washing with water, and drying to obtain a khaki solid 9 of 18.9g, wherein the yield is 82.7%. mp is 244.5-249.2 ℃.
Example 4
In a three-necked flask equipped with a thermometer and a reflux condenser, 20g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 1.27g of sodium methanesulfinate, 10.3g of (S) -3-hydroxytetrahydrofuran, 12.7g of potassium tert-butoxide, 100ml g of DMF were added, and the reaction was carried out at 100 ℃ for 3 hours. The reaction solution was added to 300ml of water, filtered, washed with water and dried to obtain 18.1g of black solid 9 with a yield of 79.2%. mp 243.6-248.2 ℃.
Example 5
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.43g of sodium methanesulfinate, 1.37g of (S) -3-hydroxytetrahydrofuran, 2.4g of potassium tert-butoxide, and 5ml g of DMF were added into a three-necked flask equipped with a thermometer and a reflux condenser tube, and reacted at 40 ℃ for 10 hours. The reaction solution was added to 70ml of water, filtered, washed with water and dried to give 5.1g of a yellow solid 9 with a yield of 89%. mp 244.7-246.6 ℃.
Example 6
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.36g of sodium methanesulfinate, 3.2g of (S) -3-hydroxytetrahydrofuran, 4.0g of potassium tert-butoxide, 50ml g of DMF, and reacting at 80 ℃ for 6h are added into a three-necked flask provided with a thermometer and a reflux condenser. The reaction solution was added to 70ml of water, filtered, washed with water and dried to give 4.9g of a yellow solid 9 with a yield of 85%. mp 244.3-246.9 ℃.
Example 7
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.36g of sodium methanesulfinate, 1.6g of (S) -3-hydroxytetrahydrofuran, 3.6g of potassium tert-amylate, THF25ml and reaction at 80 ℃ for 3h were added into a three-necked flask equipped with a thermometer and a reflux condenser. The reaction solution is concentrated and then added with 50ml of water to be stirred, filtered, washed and dried to obtain 5.1g of yellow solid 9 with the yield of 90 percent. mp 245.6-247.8 ℃.
Example 8
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.36g of sodium methanesulfinate, 1.6g of (S) -3-hydroxytetrahydrofuran, 3.6g of potassium tert-amylate, and DMSO25ml were put into a three-necked flask equipped with a thermometer and a reflux condenser and reacted at 80 ℃ for 3 hours. The reaction solution was added to 70ml of water, filtered, washed with water and dried to give 5.0g of a yellow solid 9 with a yield of 87%. mp is 244.6-247.1 ℃.
Comparative example 1
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 0.47g of sodium benzenesulfinate, 1.6g of (S) -3-hydroxytetrahydrofuran, 3.2g of potassium tert-butoxide, DMF25ml were added to a three-necked flask equipped with a thermometer and a reflux condenser and reacted at 80 ℃ for 20 hours, indicating the remaining 50% of starting material by HPLC. The reaction solution was added to 70ml of water, filtered, washed with water and dried to obtain a solid 9 as a yellowish solid in an amount of 4.3g with a yield of 75%. mp is 240.1-249.9 ℃.
Comparative example 2
5.0g of 6-nitro-4- [ (3-chloro-4-fluoro-phenyl) amino ] -7-chloroquinazoline, 3.0g of sodium benzene sulfinate, 1.6g of (S) -3-hydroxytetrahydrofuran, 3.2g of potassium tert-butoxide, DMF25ml were added to a three-necked flask equipped with a thermometer and a reflux condenser, and reacted at 80 ℃ for 20 hours, indicating 10% remaining starting material by HPLC. The reaction solution was added to 70ml of water, filtered, washed with water and dried to obtain a solid 9 as a yellowish solid in an amount of 4.3g with a yield of 70%. mp 242.3-248.9 ℃.
Claims (8)
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007085638A1 (en) * | 2006-01-26 | 2007-08-02 | Boehringer Ingelheim International Gmbh | Process for preparing aminocrotonylamino-substituted quinazoline derivatives |
| WO2013178575A1 (en) * | 2012-05-30 | 2013-12-05 | Boehringer Ingelheim International Gmbh | New indanyloxyphenylcyclopropanecarb oxylic acids |
| CN104774184A (en) * | 2015-04-17 | 2015-07-15 | 中国药科大学 | Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof |
| CN104910140A (en) * | 2014-03-14 | 2015-09-16 | 齐鲁制药有限公司 | Quinazoline compound, preparation method and application thereof |
| CN104926798A (en) * | 2014-03-21 | 2015-09-23 | 江苏豪森药业股份有限公司 | High purity preparation method of Afatinib intermediate |
| CN105037333A (en) * | 2009-12-21 | 2015-11-11 | 张强 | Novel quinazoline derivatives |
-
2016
- 2016-03-21 CN CN201610158327.0A patent/CN107216317B/en active Active
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007085638A1 (en) * | 2006-01-26 | 2007-08-02 | Boehringer Ingelheim International Gmbh | Process for preparing aminocrotonylamino-substituted quinazoline derivatives |
| CN105037333A (en) * | 2009-12-21 | 2015-11-11 | 张强 | Novel quinazoline derivatives |
| WO2013178575A1 (en) * | 2012-05-30 | 2013-12-05 | Boehringer Ingelheim International Gmbh | New indanyloxyphenylcyclopropanecarb oxylic acids |
| CN104910140A (en) * | 2014-03-14 | 2015-09-16 | 齐鲁制药有限公司 | Quinazoline compound, preparation method and application thereof |
| CN104926798A (en) * | 2014-03-21 | 2015-09-23 | 江苏豪森药业股份有限公司 | High purity preparation method of Afatinib intermediate |
| CN104774184A (en) * | 2015-04-17 | 2015-07-15 | 中国药科大学 | Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof |
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