CN113444052A - Synthesis of gefitinib - Google Patents
Synthesis of gefitinib Download PDFInfo
- Publication number
- CN113444052A CN113444052A CN202110746765.XA CN202110746765A CN113444052A CN 113444052 A CN113444052 A CN 113444052A CN 202110746765 A CN202110746765 A CN 202110746765A CN 113444052 A CN113444052 A CN 113444052A
- Authority
- CN
- China
- Prior art keywords
- oxalyldiamine
- reaction
- bis
- gefitinib
- methoxy
- 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.)
- Pending
Links
- 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 title claims abstract description 24
- 239000005411 L01XE02 - Gefitinib Substances 0.000 title claims abstract description 23
- 229960002584 gefitinib Drugs 0.000 title claims abstract description 22
- 238000003786 synthesis reaction Methods 0.000 title description 5
- 230000015572 biosynthetic process Effects 0.000 title description 4
- 239000010949 copper Substances 0.000 claims abstract description 8
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000000654 additive Substances 0.000 claims abstract description 5
- 230000000996 additive effect Effects 0.000 claims abstract description 5
- 229910052802 copper Inorganic materials 0.000 claims abstract description 5
- 238000000034 method Methods 0.000 claims abstract description 5
- 239000003513 alkali Substances 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 21
- YIKSCQDJHCMVMK-UHFFFAOYSA-N Oxamide Chemical compound NC(=O)C(N)=O YIKSCQDJHCMVMK-UHFFFAOYSA-N 0.000 claims description 19
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- -1 2-phenyl-4-methylphenyl Chemical group 0.000 claims description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 5
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 3
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 3
- 229910000404 tripotassium phosphate Inorganic materials 0.000 claims description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 claims description 2
- 229910021589 Copper(I) bromide Inorganic materials 0.000 claims description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 claims description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 2
- 229930182821 L-proline Natural products 0.000 claims description 2
- 239000002585 base Substances 0.000 claims description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 2
- BERDEBHAJNAUOM-UHFFFAOYSA-N copper(I) oxide Inorganic materials [Cu]O[Cu] BERDEBHAJNAUOM-UHFFFAOYSA-N 0.000 claims description 2
- ZKXWKVVCCTZOLD-FDGPNNRMSA-N copper;(z)-4-hydroxypent-3-en-2-one Chemical compound [Cu].C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O ZKXWKVVCCTZOLD-FDGPNNRMSA-N 0.000 claims description 2
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims description 2
- LPNYRYFBWFDTMA-UHFFFAOYSA-N potassium tert-butoxide Chemical compound [K+].CC(C)(C)[O-] LPNYRYFBWFDTMA-UHFFFAOYSA-N 0.000 claims description 2
- 229960002429 proline Drugs 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 6
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 description 8
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- VWBHHSJRPOSFGG-UHFFFAOYSA-N (4-chloro-7-methoxyquinazolin-6-yl) acetate Chemical compound C1=NC(Cl)=C2C=C(OC(C)=O)C(OC)=CC2=N1 VWBHHSJRPOSFGG-UHFFFAOYSA-N 0.000 description 2
- YSEMCVGMNUUNRK-UHFFFAOYSA-N 3-chloro-4-fluoroaniline Chemical compound NC1=CC=C(F)C(Cl)=C1 YSEMCVGMNUUNRK-UHFFFAOYSA-N 0.000 description 2
- VZKSLWJLGAGPIU-UHFFFAOYSA-N 3-morpholin-4-ylpropan-1-ol Chemical compound OCCCN1CCOCC1 VZKSLWJLGAGPIU-UHFFFAOYSA-N 0.000 description 2
- LMWBTTFRMCPETG-UHFFFAOYSA-N 6-bromo-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine Chemical compound COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1Br LMWBTTFRMCPETG-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical group N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- JLVTVCRXFMLUIF-UHFFFAOYSA-N O-Desmorpholinopropyl Gefitinib Chemical compound C=12C=C(O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 JLVTVCRXFMLUIF-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- ANGPUOTYQQFHKN-UHFFFAOYSA-N [4-(3-chloro-4-fluoroanilino)-7-methoxyquinazolin-6-yl] acetate Chemical compound C=12C=C(OC(C)=O)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 ANGPUOTYQQFHKN-UHFFFAOYSA-N 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- JVTZFYYHCGSXJV-UHFFFAOYSA-N isovanillin Chemical compound COC1=CC=C(C=O)C=C1O JVTZFYYHCGSXJV-UHFFFAOYSA-N 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- MFRIHAYPQRLWNB-UHFFFAOYSA-N sodium tert-butoxide Chemical compound [Na+].CC(C)(C)[O-] MFRIHAYPQRLWNB-UHFFFAOYSA-N 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- ZNBNBTIDJSKEAM-UHFFFAOYSA-N 4-[7-hydroxy-2-[5-[5-[6-hydroxy-6-(hydroxymethyl)-3,5-dimethyloxan-2-yl]-3-methyloxolan-2-yl]-5-methyloxolan-2-yl]-2,8-dimethyl-1,10-dioxaspiro[4.5]decan-9-yl]-2-methyl-3-propanoyloxypentanoic acid Chemical compound C1C(O)C(C)C(C(C)C(OC(=O)CC)C(C)C(O)=O)OC11OC(C)(C2OC(C)(CC2)C2C(CC(O2)C2C(CC(C)C(O)(CO)O2)C)C)CC1 ZNBNBTIDJSKEAM-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 239000004280 Sodium formate Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000005576 amination reaction Methods 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 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
- 235000019253 formic acid Nutrition 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 229910000378 hydroxylammonium sulfate Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940084651 iressa Drugs 0.000 description 1
- 230000001394 metastastic effect Effects 0.000 description 1
- 206010061289 metastatic neoplasm Diseases 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification 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
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 238000006396 nitration reaction Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 1
- 238000011580 nude mouse model Methods 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- HLBBKKJFGFRGMU-UHFFFAOYSA-M sodium formate Chemical compound [Na+].[O-]C=O HLBBKKJFGFRGMU-UHFFFAOYSA-M 0.000 description 1
- 235000019254 sodium formate Nutrition 0.000 description 1
- AKHNMLFCWUSKQB-UHFFFAOYSA-L sodium thiosulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=S AKHNMLFCWUSKQB-UHFFFAOYSA-L 0.000 description 1
- 235000019345 sodium thiosulphate Nutrition 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to preparation of gefitinib. In particular to a method for preparing gefitinib by reacting 3-morpholine propane-1-alcohol (formula I) with 6-halogeno-N- (4-chloro-2-fluorophenyl) -7-methoxyquinazoline-4-amine (formula II) under the conditions of a copper reagent/alkali/additive/solvent.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to gefitinib synthesis.
Background
Gefitinib, a novel antitumor drug developed by eastern astrazen pharmaceutical company, is a small molecule inhibitor against EGFR protein tyrosine kinase and is first marketed in japan in 2002. The drug is approved to be sold in China (trade name: Iressa) formally by the national food and drug administration (NMPA) in 2005 and is used for first-line administration for treating the non-small cell lung cancer which is not suitable for chemotherapy in locally advanced stage or metastatic stage. Research shows that gefitinib can inhibit the growth of human tumor cell transplanted to nude mouse strongly, increase apoptosis of human tumor cell derivative line, and improve antitumor activity of chemotherapy, radiotherapy and hormone therapy.
The chemical name of gefitinib is N- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazoline-4-amine, and the chemical structural formula is as follows:
the synthetic route reported for gefitinib mainly involves the splicing of several fragments. The synthesis of gefitinib is described in the patents EP0566226/WO199633980/WO 199742187. The route takes 6, 7-dimethoxy quinazoline-4 (3H) -ketone as a raw material, and the raw material reacts with methanesulfonic acid to remove methyl to obtain 6-hydroxy-7-methoxy quinazoline-4 (3H) -ketone; the 6-hydroxy-7-methoxy quinazoline-4 (3H) -ketone takes pyridine as a solvent, and when the pyridine reacts with acetic anhydride, 6-hydroxy is protected by acetic anhydride to obtain 7-methoxy-6-acetoxy quinazoline-4 (3H) -ketone; then, in a polar aprotic DMF solvent, reacting 7-methoxy-6-acetoxy quinazoline-4 (3H) -ketone with thionyl chloride, and chlorinating the hydroxyl at the 4 th position to obtain 7-methoxy-6-acetoxy-4-chloroquinazoline; reacting 7-methoxy-6-acetoxyl-4-chloroquinazoline with 3-chloro-4-fluoroaniline to obtain N- (3-chloro-4-fluorophenyl) -7-methoxy-6-acetoxyl quinazoline-4-amine; then, removing the hydroxyl protecting group acetyl from the N- (3-chloro-4-fluorophenyl) -7-methoxyl-6-acetoxy quinazoline-4-amine to obtain N- (3-chloro-4-fluorophenyl) -6-hydroxyl-7-methoxyl quinazoline-4-amine; and finally, carrying out alkoxylation reaction on a 6-site side chain in the N- (3-chloro-4-fluorophenyl) -6-hydroxy-7-methoxyquinazoline-4-amine to obtain the gefitinib. The relevant synthetic route is as follows:
patent W02008125867 describes another synthetic route to gefitinib. The method specifically comprises the following steps: 4-methoxy-3-hydroxybenzaldehyde reacts with 3-morpholine propyl chloride to prepare 4-methoxy-3- (3-morpholine propoxy) benzaldehyde; 4-methoxy-3- (3-morpholine propoxy) benzaldehyde is subjected to mixed acid nitration to prepare 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzaldehyde; 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzaldehyde reacts with formic acid, sodium formate and hydroxylamine sulfate to be condensed to prepare 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzonitrile; reacting 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzonitrile in a dimethyl sulfoxide solvent under the action of alkaline hydrogen peroxide to generate 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzamide; reducing 6-nitro-4-methoxy-3- (3-morpholine propoxy) benzamide into 6-amino-4-methoxy-3- (3-morpholine propoxy) benzamide by using alkaline sodium thiosulfate; condensing 6-amino-4-methoxy-3- (3-morpholine propoxy) benzamide and formamide to form a ring to obtain 7-methoxy-6- (3-morpholine propoxy) quinazoline-4 (3H) -ketone; and finally, carrying out thionyl chloride chlorination and 3-chloro-4-fluoroaniline amination reaction on 7-methoxy-6- (3-morpholinopropoxy) quinazoline-4 (3H) -ketone to prepare the gefitinib. The relevant synthetic route is as follows:
the patents CN1300118, CN101148439, CN101402610, etc. also report the preparation of gefitinib. The strategy of these preparation methods is to install fragments of gefitinib through different stages and in different sequences.
Disclosure of Invention
The invention aims to provide a method for preparing gefitinib, aiming at avoiding the synthetic route reported at present.
The synthetic route of the invention is as follows:
the reaction is specifically that 3-morpholine propane-1-alcohol (formula I) reacts with 6-halogeno-N- (4-chloro-2-fluorophenyl) -7-methoxy quinazoline-4-amine (formula II) under the condition of copper reagent/alkali/additive/solvent to prepare gefitinib.
X in the formula II is Br and I.
The copper reagent used in the reaction is Cu (OAc)2,CuI,CuBr,Cu2O,Cu(acac)2。
The base used in the reaction istBuONa,K3PO4,tBuOK,。
The additive used in the reaction is oxalyl diamine compound, including L-proline, N1,N2Bis (2,4, 6-trimethoxyphenyl) oxalyldiamine, N1,N2Bis (2-phenyl-4-methylphenyl) oxalyldiamine, N1- (1-naphthyl) -N2Alkyl oxalyldiamines, N1-benzyl-N2- (5-methyl- [1,1' -biphenyl)]-2-yl) oxalyldiamine, N1,N2Bis (phenylethyl) oxalyldiamine, N1,N2-bis ([1,1' -biphenyl)]-2-diyl) oxalylDiamine, N1-benzyl-N2- ([1,1' -Biphenyl)]-2-yl) oxalyldiamine, N1,N2Bis (naphthalen-1-ylmethyl) oxalyldiamine, N1,N2Bis (benzyl) oxalyldiamine.
The solvent used in the reaction is tert-butyl alcohol, DMSO, 1, 4-dioxane, acetonitrile and DMF.
The method of the invention can simply and conveniently realize the preparation of gefitinib, and the reaction process does not involve the use of control reagents with high toxicity risks.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
EXAMPLE I preparation of Gefitinib
6-bromo-N- (3-chloro-4-fluorophenyl) -7-methoxyquinazolin-4-amine (38.3g,0.10mol), 3-morpholinopropan-1-ol (17.4g,0.12mol), CuI (955mg,5.0mmol), K3PO4(31.8g,0.15mol) and N1,N2Bis (naphthalen-1-ylmethyl) oxalyldiamine (3.70g,10mmol) was added to a reaction flask, nitrogen gas was replaced three times, anhydrous DMSO (150mL) was added to the reaction flask, and the reaction was heated to 95 ℃ with stirring and reacted for 24 hours. After the reaction is finished, the system is naturally cooled to room temperature. The system was diluted with ethyl acetate (100mL) and filtered through celite. The filtrate was desolventized under reduced pressure to remove the organic solvent. Adding ethanol (1.2L) into the residue, heating to 75-80 deg.C, refluxing, filtering while hot, rapidly cooling the filtrate to 0 deg.C, maintaining the temperature, stirring, crystallizing for 2 hr, filtering, and drying the filter cake in 55 deg.C air-blast drying oven to obtain white crystalline powder (37.9g, 85%).1H NMR(300MHz,DMSO-D6)δ2.00(m,2H),2.39(s,4H),2.48(d,J＝3.0Hz,2H),3.58(t,J＝3.3Hz,4H),3.94(s,3H),4.18(t,J＝3.0Hz,2H),7.20(s,1H),7.44(t,J＝6.9Hz,1H),7.78(m,1H),8.12(dd,J＝1.8,5.1Hz,1H),8.50(s,1H),9.56(s,1H)。Mass:447[M+H]+。
EXAMPLE II preparation of Gefitinib
Coupling 6-bromo-N- (3-chloro-4-fluorophenyl) -7-methoxyquinazolin-4-amine (19.2g,0.05mol), 3-morpholinopropan-1-ol (8.7g,0.06mol), Cu (OAc)2(455mg,2.5mmol), sodium tert-butoxide (7.2g,0.075mol) and N1,N2Bis (phenylethyl) oxalyl diamine (1.48g,5mmol) was added to a reaction flask, nitrogen was replaced three times, anhydrous DMF (100mL) was added to the reaction flask, and the reaction was heated to 100 ℃ with stirring and reacted overnight. After the reaction is finished, the system is naturally cooled to room temperature. The system was diluted with ethyl acetate (100mL) and filtered through celite. The filtrate was desolventized under reduced pressure to remove the organic solvent. Adding ethanol (500mL) into the residue, heating to 75-80 deg.C, refluxing, filtering while hot, rapidly cooling the filtrate to 0 deg.C, maintaining the temperature, stirring, crystallizing, filtering, and drying the filter cake in 55 deg.C air-blast drying oven to obtain white crystalline powder (17.5g, 78.3%).
Claims (6)
1. The method for preparing the gefitinib is characterized in that 3-morpholine propane-1-alcohol (shown in a formula I) reacts with 6-halogenated-N- (4-chloro-2-fluorophenyl) -7-methoxyquinazoline-4-amine (shown in a formula II) under the condition of a copper reagent/alkali/additive/solvent to prepare the gefitinib. The reaction formula is as follows:
2. the reaction of claim 1, wherein the copper reagent used is Cu (OAc)2,CuI,CuBr,Cu2O,Cu(acac)2。
3. The reaction of claim 1, wherein the base used istBuONa,K3PO4,tBuOK。
4. The reaction according to claim 1, wherein the additive used is L-proline, N1,N2Bis (2,4, 6-trimethoxyphenyl) oxalyldiamine, N1,N2Bis (2-phenyl-4-methylphenyl) oxalyldiamine, N1- (1-naphthyl) -N2Alkyl oxalyldiamines, N1-benzyl-N2- (5-methyl- [1,1' -biphenyl)]-2-yl) oxalyldiamine, N1,N2Bis (phenylethyl) oxalyldiamine, N1,N2-bis ([1,1' -biphenyl)]2-diyl) oxalyldiamine, N1-benzyl-N2- ([1,1' -Biphenyl)]-2-yl) oxalyldiamine, N1,N2Bis (naphthalen-1-ylmethyl) oxalyldiamine, N1,N2Bis (benzyl) oxalyldiamine.
5. The reaction according to claim 1, wherein the solvent used in the reaction is selected from the group consisting of t-butanol, DMSO, 1, 4-dioxane, acetonitrile, and DMF.
6. The compound as claimed in claim 1, wherein X is Br, I.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110746765.XA CN113444052A (en) | 2021-07-01 | 2021-07-01 | Synthesis of gefitinib |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110746765.XA CN113444052A (en) | 2021-07-01 | 2021-07-01 | Synthesis of gefitinib |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113444052A true CN113444052A (en) | 2021-09-28 |
Family
ID=77814736
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110746765.XA Pending CN113444052A (en) | 2021-07-01 | 2021-07-01 | Synthesis of gefitinib |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113444052A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535279A (en) * | 2006-09-11 | 2009-09-16 | 柯瑞斯公司 | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
| CN101641338A (en) * | 2006-09-11 | 2010-02-03 | 柯瑞斯公司 | Multi-functional small molecules as anti-proliferative agents |
| CN102153518A (en) * | 2010-02-11 | 2011-08-17 | 江苏德芳医药科研有限公司 | Preparation method of Gefitinib |
| CN111763215A (en) * | 2020-07-21 | 2020-10-13 | 成都海博为药业有限公司 | Compound with nitrogen-containing heterocyclic structure and preparation method and application thereof |
| CN112566906A (en) * | 2018-07-26 | 2021-03-26 | 多曼治疗学公司 | Substituted quinazolinone derivatives and their use as positive allosteric modulators of MGLUR4 |
-
2021
- 2021-07-01 CN CN202110746765.XA patent/CN113444052A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101535279A (en) * | 2006-09-11 | 2009-09-16 | 柯瑞斯公司 | Quinazoline based EGFR inhibitors containing a zinc binding moiety |
| CN101641338A (en) * | 2006-09-11 | 2010-02-03 | 柯瑞斯公司 | Multi-functional small molecules as anti-proliferative agents |
| CN102153518A (en) * | 2010-02-11 | 2011-08-17 | 江苏德芳医药科研有限公司 | Preparation method of Gefitinib |
| CN112566906A (en) * | 2018-07-26 | 2021-03-26 | 多曼治疗学公司 | Substituted quinazolinone derivatives and their use as positive allosteric modulators of MGLUR4 |
| CN111763215A (en) * | 2020-07-21 | 2020-10-13 | 成都海博为药业有限公司 | Compound with nitrogen-containing heterocyclic structure and preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP1511732B9 (en) | Process for the manufacture of quinoline derivatives | |
| JP5478894B2 (en) | Quinazoline derivatives, their preparation and use | |
| CN102356063B (en) | A process for the preparation of 6-(7-((1-aminocyclopropyl)methoxy)-6-methoxyquinolin-4-yloxy)-n-methyl-1-naphthamide and synthetic intermediates thereof | |
| US20050215586A1 (en) | Process for the manufacture of quinoline derivatives | |
| CN104024262B (en) | Methods of preparing icotinib and icotinib hydrochloride, and intermediates thereof | |
| US20040034227A1 (en) | Process for the manufacture of quinoline derivatives | |
| TWI426074B (en) | Process for the preparation of 5-(2-amino-pyrimidin-4-yl)-2-aryl-1h-pyrrole-3-carboxamides | |
| JP2010209071A (en) | Process for preparation of 4-(3'-chloro-4'-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline | |
| JP2009529045A (en) | Process for synthesizing 7-alkynyl-4-aminoquinazolines and related intermediates | |
| CN114369124B (en) | Preparation method of 2' -substituted pyrimidine nucleoside | |
| CN113444052A (en) | Synthesis of gefitinib | |
| TWI541235B (en) | Process of preparing a quinazoline derivative | |
| CN103058936B (en) | The preparation method of 4-[(the chloro-2-pyrimidyl of 4-) is amino] cyanophenyl | |
| CN108191849B (en) | Preparation method of anti-epidermal growth factor receptor drug resistance mutation inhibitor, related intermediate and application | |
| CN106083740B (en) | The 4- anilinoquinazoline derivatives and preparation method of a kind of triazole containing 1,2,3- | |
| CN109206377B (en) | Novel method for preparing N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine | |
| CN109153652A (en) | The preparation process of 1- (aryl methyl) quinazoline -2,4 (1H, 3H)-diketone | |
| CN113336703A (en) | Synthesis of 1,3,4, 5-tetrasubstituted 1H-pyrazole derivatives | |
| CN108947984B (en) | Preparation method of pranlukast | |
| CN112409272A (en) | Preparation method and application of 6-chloro-7-bromo-4 (3H) -quinazolinone | |
| CN107098863B (en) | Preparation method of gefitinib | |
| CN115850240B (en) | Synthesis method of medicine ao Lu Taxi Ni for treating acute myelogenous leukemia | |
| CN114014847B (en) | Benzothiophene pyrimidine derivative, preparation method thereof and application thereof in preparation of antitumor drugs | |
| CN110204490B (en) | Preparation method of disubstituted 4-chloroquinoline-3-carbonitrile derivative and bosutinib | |
| EP1690856A1 (en) | Quinazoline derivative and process for producing the same |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20210928 |
|
| WD01 | Invention patent application deemed withdrawn after publication |