CN105693630B - A kind of preparation method of Gefitinib intermediate - Google Patents
A kind of preparation method of Gefitinib intermediate Download PDFInfo
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- 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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- 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
The invention discloses a kind of preparation method of Gefitinib intermediate, the preparation method comprises the following steps：1) in the presence of anion exchange resin, by the methoxyl group 3 of 6 acetoxyl group 7, the ketone of 4 dihydroquinazoline 4 carries out haptoreaction with sulfonic acid chloride in acetonitrile, reaction terminates rear frozen water and is quenched, dichloromethane extracts, it is concentrated under reduced pressure, obtains the methoxyquinazoline hydrochloride of 6 acetoxyl group, 4 chlorine 7, wherein catalytic temperature is 65 75 DEG C；2) in the presence of AuCl, Gefitinib intermediate is obtained by substitution reaction is carried out at the methoxyquinazoline hydrochloride of 6 acetoxyl group of thing, 4 chlorine 7 and the Fluoroaniline of 3 chlorine 4 that step 1) obtains in methyl alcohol 55 65 DEG C.The method of the present invention can greatly improve product yield, mild condition, less side products.
Description
Technical field
The invention belongs to field of medicine and chemical technology, in particular it relates to a kind of preparation method of Gefitinib intermediate.
Background technology
Gefitinib, the entitled Gefitinib of English, it is a kind of oral epidermal growth factor receptor that Astrazeneca AB develops
Body (EGFR) TYR kinase inhibitor, listed in Japan within 2002, for treating advanced Non-small cell lung (NSCLC).
It is 2005 non-small thin in Discussion on Chinese Listed, the Locally Advanced or metastatic previously received chemotherapy for treatment with trade name Iressa
Born of the same parents' lung cancer.
The chemical name of Gefitinib is 4- (the chloro- 4- fluoroanilinos of 3-) -7- methoxyl groups -6- (morpholinyl propoxyl group) quinoline
Oxazoline, concrete structure are as follows：
Research at present on the preparation of Gefitinib is more, and CN1182421A discloses a kind of preparation side of Gefitinib
Method, specific synthetic route are as follows：
This method with 3,4- dihydros -6,7- dimethoxy-4 '-oxoquinazolin for initiation material, through deprotection, hydroxyl again
Protection, halo and then Gefitinib is obtained with steps such as aromatic amine necleophilic reactions, wherein only having from chlorination to Gefitinib yield
50% or so, further, since not controlled with aromatic amine necleophilic reaction without selectivity, cause 2 ', 6 ', 5,8 to have virtue
Fragrant amine nucleophilic product, because accessory substance is similar with target product structure, cause to be difficult to separate, target product purity, which is difficult to reach, to be wanted
Standard.
CN1300118C discloses a kind of preparation method of Gefitinib, and specific synthetic route is as follows：
This method with 3,4- dimethoxybenzoic acids for raw material, by nitrification, selective demethylation, reduction, cyclisation, chlorine
In generation and aromatic amine necleophilic reaction etc., obtain Gefitinib.This method yield is extremely low, and raw material availability deficiency, accessory substance is more, studies carefully it
Reason is due to that the hydroxyl of deprotection is not protected again, and as active group, the step such as reduction, cyclisation, chloro all receives influence
Side reaction is more, low yield.
In view of the good drug effect and huge prospect of Gefitinib, therefore, it is few and purify that this area needs high income, accessory substance badly
The preparation method of simple Gefitinib and its intermediate.
The content of the invention
Reaction yield is low, secondary in preparation method it is an object of the invention to overcome above-mentioned existing Gefitinib intermediate
A kind of the defects of product is more, there is provided preparation method of Gefitinib intermediate.
To achieve these goals, the present invention provides a kind of preparation method of Gefitinib intermediate, comprises the following steps：
1) in the presence of anion exchange resin, by compound 6- acetoxyl group -7- methoxyl groups -3,4- shown in Formulas I
Dihydroquinazoline -4- ketone carries out haptoreaction with sulfonic acid chloride in acetonitrile, and reaction terminates rear frozen water and is quenched, dichloromethane extraction,
It is concentrated under reduced pressure, the chloro- 7- methoxyquinazoline hydrochlorides of the acetoxyl group of compound 6- shown in Formula II -4- is obtained, wherein catalytic temperature
For 65-75 DEG C；
2) in the presence of AuCl, the chloro- 7- methoxyl groups quinolines of compound 6- acetoxyl groups -4- shown in Formula II that step 1) is obtained
Oxazoline and the chloro- 4- Fluoroanilines of 3- carry out substitution reaction at 55-65 DEG C in methyl alcohol and obtained among the Gefitinib shown in formula III
Body；
In the present invention, in order to further improve the yield of reaction, under preferable case, in step 1), 6- acetoxyl groups-
The mol ratio of the dosage of 7- methoxyl group -3,4- dihydroquinazoline -4- ketone and sulfonic acid chloride is 1：1.3-1.8；Anion exchange resin
Dosage be 6- acetoxyl group -7- methoxyl group -3,4- dihydroquinazoline -4- ketone weight 50-65%；Further preferred situation
Under, the mol ratio of the dosage of 6- acetoxyl groups -7- methoxyl groups -3,4- dihydroquinazoline -4- ketone and sulfonic acid chloride is 1：1.4-1.6；
The dosage of anion exchange resin is the 60-65% of 6- acetoxyl group -7- methoxyl group -3,4- dihydroquinazoline -4- ketone weight.
In the present invention, the property of the anion exchange resin can not only influence the progress of chlorination reaction, can also influence
The stability of azacyclo- in quinazoline, under preferable case, the anion exchange resin is weak base type anion exchange resin.Make
For commercially available product, the weak base type anion exchange resin can be 303 alkalescent epoxy type anion exchange resins, D301 macropores
Weakly basic styrene type anion exchange resin or D311 macroporous acrylics system weak-base anion-exchange resin etc..
In the prior art, the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4- 4- Fluoroanilines reaction chloro- with 3- needs
Under highly basic or specific condition such as microwave etc., methoxyl group can occur that methyl comes off or with amine amine occurs for methoxyl group on such phenyl ring
Solution generation accessory substance.In the present invention, it has been found surprisingly that AuCl can promote substitution reaction and other groups will not be produced
It is raw to influence, under preferable case, in step 2), the chloro- 4- Fluoroanilines of described AuCl, 3- and the chloro- 7- methoxies of 6- acetoxyl groups -4-
The mol ratio of the dosage of base quinazoline is 0.15-0.45：1.5-2.5：1.In the case of further preferably, the chloro- 4- of AuCl, 3-
The mol ratio of Fluoroaniline and the dosage of the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4- is 0.35：1.7：1.
In the present invention, the haptoreaction of the step 1) is carried out preferably in the presence of protective gas, the protective gas
For the one or more in helium, argon gas and nitrogen.
In the present invention, step 1) and the amount of solvent used in step 2) are not particularly limited, such as step 1)
The usage amount of middle acetonitrile can be 2-10 times of volume of 6- acetoxyl group -7- methoxyl group -3,4- dihydroquinazoline -4- ketone weight,
2-10ml acetonitriles are used per 1g6- acetoxyl group -7- methoxyl group -3,4- dihydroquinazoline -4- ketone；Methanol in step 2) makes
Dosage can be 2-10 times of the weight of the mixture of the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4-, i.e., per 1g6- acetyl oxygen
The mixture of the chloro- 7- methoxyquinazoline hydrochlorides of base -4- uses 2-10ml methanol.
In the present invention, the various reactions in preparation method can be carried out in container commonly used in the art, example
Such as flask, reactor, the size of container can be according to selection be actually needed, and all reactions are preferably carried out under agitation, are reacted
The monitoring of process can use method commonly used in the art, such as TLC, GCMS or LCMS etc..
The synthetic route of the present invention is as follows：
Compared with prior art, the advantage of the invention is that：1. the preparation of the Gefitinib intermediate of the present invention is particularly
Chlorination and aromatic amine substitution yield significantly improve；2. the method for the present invention is more stable, more traditional extreme condition is destroyed to female ring
Smaller, the less side products of property.
For beneficial effect caused by the present invention, step 1) have adjusted the soda acid of system using anion exchange resin
Property so that each group can keep stable, and caused hydrogen ion exchanges in time so that react and carried out to positive reaction direction；Step
2) combined using monovalence gold, specificity with Cl so that N is easier attack carbon atom, and so as to complete to substitute, and other groups are then not
It is impacted, thus complete the present invention.
Other features and advantages of the present invention will be described in detail in subsequent specific embodiment part.
Embodiment
The embodiment of the present invention is described in detail below.It is it should be appreciated that described herein specific
Embodiment is merely to illustrate and explain the present invention, and is not intended to limit the invention.
The present invention will be described in detail by way of examples below.
Embodiment 1
A kind of preparation method of Gefitinib intermediate, the preparation method comprise the following steps：
1) nitrogen protection under, will D301 macroreticular weakly base styrene series anion exchange resin 14g, 6- acetoxyl group-
7- methoxyl group -3,4- dihydroquinazoline -4- ketone (23.4g, 100mol), sulfonic acid chloride (20.3g, 150mmol) are in 100ml acetonitriles
Haptoreaction is carried out, catalytic temperature is 65 DEG C, and reaction terminates rear frozen water and is quenched, and dichloromethane extraction, is concentrated under reduced pressure, obtains
To the chloro- 7- methoxyquinazoline hydrochlorides 24.3g of 6- acetoxyl groups -4-, yield 96.3%, purity 98.81%.
2) by the chloro- 7- methoxyquinazoline hydrochlorides (12.6g, 50mmol) of AuCl (4.2g, 18mmol), 6- acetoxyl groups -4-, 3-
Chloro- 4- Fluoroanilines (12.3g, 85mmol) 65 DEG C of progress substitution reactions, reaction in 50ml methanol terminate, and filter, filtrate is dense
Contracting, petroleum ether obtain Gefitinib intermediate 16.9g, yield 93.4%, purity 99.91%.
Embodiment 2
A kind of preparation method of Gefitinib intermediate, the preparation method comprise the following steps：
1), will be in D301 macroreticular weakly bases styrene series anion exchange resin (15.2g), 6- acetyl oxygen under nitrogen protection
Base -7- methoxyl group -3,4- dihydroquinazoline -4- ketone (23.4g, 100mol), sulfonic acid chloride (21.6g, 160mmol) are in 120ml second
Haptoreaction is carried out in nitrile, catalytic temperature is 70 DEG C, and reaction terminates rear frozen water and is quenched, dichloromethane extraction, and decompression is dense
Contracting, obtains the chloro- 7- methoxyquinazoline hydrochlorides 24.2g of 6- acetoxyl groups -4-, yield 95.63%, purity 98.10%,.
2) by the chloro- 7- methoxyquinazoline hydrochlorides (12.6g, 50mmol) of AuCl (3.5g, 15mmol), 6- acetoxyl groups -4-, 3-
Chloro- 4- Fluoroanilines (10.9g, 75mmol) 60 DEG C of progress substitution reactions, reaction in 50ml methanol terminate, and filter, filtrate is dense
Contracting, petroleum ether obtain Gefitinib intermediate 16.4g, yield 90.7%, purity 99.85%.
Embodiment 3
A kind of preparation method of Gefitinib intermediate, the preparation method comprise the following steps：
1), will be in D301 macroreticular weakly bases styrene series anion exchange resin (14.5g), 6- acetyl oxygen under nitrogen protection
Base -7- methoxyl group -3,4- dihydroquinazoline -4- ketone (23.4g, 100mol), sulfonic acid chloride (18.9g, 140mmol) are in 90ml acetonitriles
Middle carry out haptoreaction, catalytic temperature are 75 DEG C, and reaction terminates rear frozen water and is quenched, and dichloromethane extraction, are concentrated under reduced pressure,
Obtain the chloro- 7- methoxyquinazoline hydrochlorides 24.1g of 6- acetoxyl groups -4-, yield 95.47%, purity 96.95%,.
2) by the chloro- 7- methoxyquinazoline hydrochlorides (12.6g, 50mmol) of AuCl (4.7g, 20mmol), 6- acetoxyl groups -4-, 3-
Chloro- 4- Fluoroanilines (14.6g, 100mmol) 65 DEG C of progress substitution reactions, reaction in 30ml methanol terminate, and filter, filtrate is dense
Contracting, petroleum ether obtain Gefitinib intermediate 16.8g, yield 92.7%, purity 99.76%.
Embodiment 4
A kind of preparation method of Gefitinib intermediate, the preparation method comprise the following steps：
1), will be in D301 macroreticular weakly bases styrene series anion exchange resin (11.7g), 6- acetyl oxygen under nitrogen protection
Base -7- methoxyl group -3,4- dihydroquinazoline -4- ketone (23.4g, 100mol), sulfonic acid chloride (17.5g, 130mmol) are in 100ml second
Haptoreaction is carried out in nitrile, catalytic temperature is 65 DEG C, and reaction terminates rear frozen water and is quenched, dichloromethane extraction, and decompression is dense
Contracting, obtains the chloro- 7- methoxyquinazoline hydrochlorides 23.5g of 6- acetoxyl groups -4-, yield 93.20%, purity 97.91%.
2) by the chloro- 7- methoxyquinazoline hydrochlorides (12.6g, 50mmol) of AuCl (5.3g, 23mmol), 6- acetoxyl groups -4-, 3-
Chloro- 4- Fluoroanilines (12.3g, 85mmol) 55 DEG C of progress substitution reactions, reaction in 50ml methanol terminate, and filter, filtrate is dense
Contracting, petroleum ether obtain Gefitinib intermediate 15.9g, yield 87.8%, purity 99.78%.
Embodiment 5
A kind of preparation method of Gefitinib intermediate, the preparation method comprise the following steps：
1), will be in D301 macroreticular weakly bases styrene series anion exchange resin (12.9g), 6- acetyl oxygen under nitrogen protection
Base -7- methoxyl group -3,4- dihydroquinazoline -4- ketone (23.4g, 100mol), sulfonic acid chloride (24.3g, 180mmol) are in 100ml second
Haptoreaction is carried out in nitrile, catalytic temperature is 65 DEG C, and reaction terminates rear frozen water and is quenched, dichloromethane extraction, and decompression is dense
Contracting, obtains the chloro- 7- methoxyquinazoline hydrochlorides 23.2g of 6- acetoxyl groups -4-, yield 91.72%, purity 97.81%.
2) by the chloro- 7- methoxyquinazoline hydrochlorides (12.6g, 50mmol) of AuCl (1.9g, 8mmol), 6- acetoxyl groups -4-, 3-
Chloro- 4- Fluoroanilines (18.2g, 125mmol) 60 DEG C of progress substitution reactions, reaction in 60ml methanol terminate, and filter, filtrate is dense
Contracting, petroleum ether obtain Gefitinib intermediate 15.2g, yield 84.2%, purity 99.81%.
Embodiment 6
Such as the preparation method of the Gefitinib intermediate in embodiment 1, except that, the D301 macroreticular weakly bases benzene
Ethene series anion exchange resin usage amount is 4.7g, obtains the chloro- 7- methoxyquinazoline hydrochlorides 19g of 6- acetoxyl groups -4-, yield
75.3%, purity 96.20%.
Embodiment 7
Such as the preparation method of the Gefitinib intermediate in embodiment 1, except that, the D301 macroreticular weakly bases benzene
Ethene series anion exchange resin usage amount is 20g, obtains the chloro- 7- methoxyquinazoline hydrochlorides 24.1g of 6- acetoxyl groups -4-, yield
75.3%, purity 97.45%.
Embodiment 8
Such as the preparation method carried among the Gefitinib in embodiment 1, except that, AuCl usage amounts are 0.6g, are obtained
To Gefitinib intermediate 11.8g, yield 65.7%, purity 90.78%.
Comparative example 1
Such as the preparation method carried among the Gefitinib in embodiment 1, except that, without using D301 macroreticular weakly bases
Styrene series anion exchange resin, obtains the chloro- 7- methoxyquinazoline hydrochlorides 11.1g of 6- acetoxyl groups -4-, and yield 41.7% is pure
Degree 80.53%.
Comparative example 2
Such as the preparation method carried among the Gefitinib in embodiment 1, except that, without using AuCl, obtained
Gefitinib intermediate 6.7g, yield 37.2%, purity 84.33%.
Comparative example 3
Such as the preparation method carried among the Gefitinib in embodiment 1, except that, use the AuCl of same mole3
Replacement uses AuCl, obtains Gefitinib intermediate 7.5g, yield 41.5%, purity 87.52%.
Comparative example 4
Such as the preparation method carried among the Gefitinib in embodiment 1, except that, use the CuCl of same mole2
Replacement uses AuCl, obtains Gefitinib intermediate 7.3g, yield 40.6%, purity 74.69%.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of simple variants can be carried out to technical scheme, this
A little simple variants belong to protection scope of the present invention.
It is further to note that each particular technique feature described in above-mentioned embodiment, in not lance
In the case of shield, can be combined by any suitable means, in order to avoid unnecessary repetition, the present invention to it is various can
The combination of energy no longer separately illustrates.In addition, any group can also be carried out between a variety of embodiments of the present invention
Close, as long as it without prejudice to the thought of the present invention, it should equally be considered as content disclosed in this invention.
Claims (5)
1. a kind of preparation method of Gefitinib intermediate, it is characterised in that the preparation method comprises the following steps：
1) in the presence of anion exchange resin, by compound 6- acetoxyl group -7- methoxyl group -3,4- dihydros shown in Formulas I
Quinazoline-4-one carries out haptoreaction with sulfonic acid chloride in acetonitrile, and reaction terminates rear frozen water and is quenched, dichloromethane extraction, decompression
Concentration, obtains the chloro- 7- methoxyquinazoline hydrochlorides of the acetoxyl group of compound 6- shown in Formula II -4-, wherein catalytic temperature is 65-
75℃；
2) in the presence of AuCl, the chloro- 7- methoxyquinazoline hydrochlorides of compound 6- acetoxyl groups -4- shown in Formula II that step 1) is obtained
The Gefitinib intermediate shown in formula III is obtained with carrying out substitution reaction at the chloro- 4- Fluoroanilines of 3- in methyl alcohol 55-65 DEG C；
In step 1), the mol ratio of the dosage of 6- acetoxyl groups -7- methoxyl groups -3,4- dihydroquinazoline -4- ketone and sulfonic acid chloride is 1：
1.3-1.8；The dosage of anion exchange resin is 6- acetoxyl group -7- methoxyl group -3,4- dihydroquinazoline -4- ketone weight
50-65%；In step 2), the chloro- 4- Fluoroanilines of AuCl, 3- and the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4-
The mol ratio of dosage is 0.15-0.45：1.5-2.5：1；
2. according to the method for claim 1, it is characterised in that in step 1), 6- acetoxyl group -7- methoxyl groups -3,4-
The mol ratio of the dosage of dihydroquinazoline -4- ketone and sulfonic acid chloride is 1：1.4-1.6；The dosage of anion exchange resin is 6- acetyl
The 60-65% of epoxide -7- methoxyl group -3,4- dihydroquinazoline -4- ketone weight.
3. preparation method according to claim 1 or 2, it is characterised in that the anion exchange resin is that weak base type is cloudy
Ion exchange resin.
4. according to the method for claim 1, it is characterised in that in step 2), the chloro- 4- Fluoroanilines of AuCl, 3-
Mol ratio with the dosage of the chloro- 7- methoxyquinazoline hydrochlorides of 6- acetoxyl groups -4- is 0.35：1.7：1.
5. according to the method for claim 1, it is characterised in that the step 1) is carried out in the presence of protective gas, described
Protective gas is the one or more in helium, argon gas and nitrogen.
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