CN105693630B - A kind of preparation method of Gefitinib intermediate - Google Patents
A kind of preparation method of Gefitinib intermediate Download PDFInfo
- Publication number
- CN105693630B CN105693630B CN201610136252.6A CN201610136252A CN105693630B CN 105693630 B CN105693630 B CN 105693630B CN 201610136252 A CN201610136252 A CN 201610136252A CN 105693630 B CN105693630 B CN 105693630B
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- CN
- China
- Prior art keywords
- chloro
- preparation
- acetoxyl
- exchange resin
- dosage
- 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.)
- Expired - Fee Related
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- 238000002360 preparation method Methods 0.000 title claims abstract description 34
- QSDWDQNREXOYPH-UHFFFAOYSA-N 2-(1,2,3,4-tetrahydroisoquinolin-4-yl)ethanol Chemical compound C1=CC=C2C(CCO)CNCC2=C1 QSDWDQNREXOYPH-UHFFFAOYSA-N 0.000 title claims abstract description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 30
- 239000003957 anion exchange resin Substances 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 22
- 229910003771 Gold(I) chloride Inorganic materials 0.000 claims abstract description 18
- FDWREHZXQUYJFJ-UHFFFAOYSA-M gold monochloride Chemical compound [Cl-].[Au+] FDWREHZXQUYJFJ-UHFFFAOYSA-M 0.000 claims abstract description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims abstract description 12
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- -1 methoxyl group Chemical group 0.000 claims abstract description 10
- 238000006467 substitution reaction Methods 0.000 claims abstract description 10
- 230000003197 catalytic effect Effects 0.000 claims abstract description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 8
- NTURVSFTOYPGON-UHFFFAOYSA-N Dihydroquinazoline Chemical compound C1=CC=C2C=NCNC2=C1 NTURVSFTOYPGON-UHFFFAOYSA-N 0.000 claims abstract description 3
- QASTYDSBFSWODZ-UHFFFAOYSA-N Cl.ClC1=NC2=CC(=CC=C2C=N1)OC Chemical class Cl.ClC1=NC2=CC(=CC=C2C=N1)OC QASTYDSBFSWODZ-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 7
- 229910052757 nitrogen Inorganic materials 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 239000007789 gas Substances 0.000 claims description 6
- QEZIFBAXJMHDJP-UHFFFAOYSA-N n-chloro-4-fluoroaniline Chemical class FC1=CC=C(NCl)C=C1 QEZIFBAXJMHDJP-UHFFFAOYSA-N 0.000 claims description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 4
- 230000001681 protective effect Effects 0.000 claims description 4
- 229910052786 argon Inorganic materials 0.000 claims description 2
- 239000001307 helium Substances 0.000 claims description 2
- 229910052734 helium Inorganic materials 0.000 claims description 2
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 2
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 claims 1
- QMNUDYFKZYBWQX-UHFFFAOYSA-N 1H-quinazolin-4-one Chemical compound C1=CC=C2C(=O)N=CNC2=C1 QMNUDYFKZYBWQX-UHFFFAOYSA-N 0.000 claims 1
- 150000002118 epoxides Chemical class 0.000 claims 1
- 239000003456 ion exchange resin Substances 0.000 claims 1
- 229920003303 ion-exchange polymer Polymers 0.000 claims 1
- 239000000047 product Substances 0.000 abstract description 6
- 239000000460 chlorine Substances 0.000 abstract description 5
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052801 chlorine Inorganic materials 0.000 abstract description 4
- 239000006227 byproduct Substances 0.000 abstract description 2
- MGNPLIACIXIYJE-UHFFFAOYSA-N n-fluoroaniline Chemical compound FNC1=CC=CC=C1 MGNPLIACIXIYJE-UHFFFAOYSA-N 0.000 abstract description 2
- VRXVUCLJIJWDMH-UHFFFAOYSA-N Cl.C1=CC=CC2=NC(OC)=NC=C21 Chemical compound Cl.C1=CC=CC2=NC(OC)=NC=C21 VRXVUCLJIJWDMH-UHFFFAOYSA-N 0.000 abstract 2
- 239000002027 dichloromethane extract Substances 0.000 abstract 1
- 150000002576 ketones Chemical class 0.000 abstract 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 18
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 18
- 229960002584 gefitinib Drugs 0.000 description 17
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical class NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 6
- 150000003440 styrenes Chemical class 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 5
- 239000003208 petroleum Substances 0.000 description 5
- 150000004982 aromatic amines Chemical class 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 238000005660 chlorination reaction Methods 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 150000002825 nitriles Chemical class 0.000 description 3
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- SYWDWCWQXBUCOP-UHFFFAOYSA-N benzene;ethene Chemical class C=C.C1=CC=CC=C1 SYWDWCWQXBUCOP-UHFFFAOYSA-N 0.000 description 2
- 229960003328 benzoyl peroxide Drugs 0.000 description 2
- 238000010511 deprotection reaction Methods 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- JWVCLYRUEFBMGU-UHFFFAOYSA-N quinazoline Chemical compound N1=CN=CC2=CC=CC=C21 JWVCLYRUEFBMGU-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-Oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 1
- BSCXJHRXVLREBO-UHFFFAOYSA-N 4,5-dihydro-1,3-oxazole;quinoline Chemical group C1CN=CO1.N1=CC=CC2=CC=CC=C21 BSCXJHRXVLREBO-UHFFFAOYSA-N 0.000 description 1
- VWBHHSJRPOSFGG-UHFFFAOYSA-N CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O Chemical compound CC(Oc(c(OC)cc1ncn2)cc1c2Cl)=O VWBHHSJRPOSFGG-UHFFFAOYSA-N 0.000 description 1
- SOLQIFINSOHAQD-UHFFFAOYSA-N CC(Oc(cc(c(N=CN1)c2)C1=O)c2OC)=O Chemical compound CC(Oc(cc(c(N=CN1)c2)C1=O)c2OC)=O SOLQIFINSOHAQD-UHFFFAOYSA-N 0.000 description 1
- ANGPUOTYQQFHKN-UHFFFAOYSA-N CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O Chemical compound CC(Oc1cc2c(Nc(cc3Cl)ccc3F)ncnc2cc1OC)=O ANGPUOTYQQFHKN-UHFFFAOYSA-N 0.000 description 1
- 229910021591 Copper(I) chloride Inorganic materials 0.000 description 1
- 102000001301 EGF receptor Human genes 0.000 description 1
- 108060006698 EGF receptor Proteins 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 229920006397 acrylic thermoplastic Polymers 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000017858 demethylation Effects 0.000 description 1
- 238000010520 demethylation reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000857 drug 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
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- GPRLSGONYQIRFK-UHFFFAOYSA-N hydron Chemical compound [H+] GPRLSGONYQIRFK-UHFFFAOYSA-N 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000005342 ion exchange Methods 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 229940043355 kinase inhibitor Drugs 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012544 monitoring process Methods 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
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- ISXSCDLOGDJUNJ-UHFFFAOYSA-N tert-butyl prop-2-enoate Chemical compound CC(C)(C)OC(=O)C=C ISXSCDLOGDJUNJ-UHFFFAOYSA-N 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 150000005337 veratric acids Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims (5)
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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CN201610136252.6A CN105693630B (en) | 2016-03-10 | 2016-03-10 | A kind of preparation method of Gefitinib intermediate |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610136252.6A CN105693630B (en) | 2016-03-10 | 2016-03-10 | A kind of preparation method of Gefitinib intermediate |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105693630A CN105693630A (en) | 2016-06-22 |
CN105693630B true CN105693630B (en) | 2018-02-16 |
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CN201610136252.6A Expired - Fee Related CN105693630B (en) | 2016-03-10 | 2016-03-10 | A kind of preparation method of Gefitinib intermediate |
Country Status (1)
Country | Link |
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CN (1) | CN105693630B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2008299896B2 (en) * | 2007-09-10 | 2012-02-02 | Curis, Inc. | Tartrate salts or complexes of quinazoline based EGFR inhibitors containing a zinc binding moiety |
CN101367793B (en) * | 2008-09-26 | 2013-09-11 | 中国科学院广州生物医药与健康研究院 | Amino-quinazoline derivative with antineoplastic activity and salts thereof |
-
2016
- 2016-03-10 CN CN201610136252.6A patent/CN105693630B/en not_active Expired - Fee Related
Also Published As
Publication number | Publication date |
---|---|
CN105693630A (en) | 2016-06-22 |
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Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
CB03 | Change of inventor or designer information |
Inventor after: Tian Jing Inventor after: Wu Hailiang Inventor after: Wu Shuqi Inventor before: He Baohong |
|
CB03 | Change of inventor or designer information | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20180115 Address after: 250100 Shandong province Huaiyin District of Ji'nan City tumor hospital building 10, unit 2, No. 101 Applicant after: Tian Jing Address before: Qingdao City, Shandong province 266000 flood ditch cleaning village 106 2 Applicant before: Chen Hong |
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TA01 | Transfer of patent application right | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20180216 Termination date: 20200310 |
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CF01 | Termination of patent right due to non-payment of annual fee |