CN102827086A - Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline - Google Patents
Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline Download PDFInfo
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- CN102827086A CN102827086A CN2012102762299A CN201210276229A CN102827086A CN 102827086 A CN102827086 A CN 102827086A CN 2012102762299 A CN2012102762299 A CN 2012102762299A CN 201210276229 A CN201210276229 A CN 201210276229A CN 102827086 A CN102827086 A CN 102827086A
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- methoxy ethoxy
- acid
- quinazoline
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- ZPJLDMNVDPGZIU-UHFFFAOYSA-N 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline Chemical compound C1=NC(Cl)=C2C=C(OCCOC)C(OCCOC)=CC2=N1 ZPJLDMNVDPGZIU-UHFFFAOYSA-N 0.000 title abstract description 5
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 13
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims description 81
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 32
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- 239000003960 organic solvent Substances 0.000 claims description 27
- 235000019441 ethanol Nutrition 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 23
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 23
- 239000003153 chemical reaction reagent Substances 0.000 claims description 19
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 18
- 238000001035 drying Methods 0.000 claims description 18
- 230000002829 reductive effect Effects 0.000 claims description 18
- 238000000967 suction filtration Methods 0.000 claims description 18
- 239000000243 solution Substances 0.000 claims description 17
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical class O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 16
- AVRPFRMDMNDIDH-UHFFFAOYSA-N 1h-quinazolin-2-one Chemical class C1=CC=CC2=NC(O)=NC=C21 AVRPFRMDMNDIDH-UHFFFAOYSA-N 0.000 claims description 15
- 238000005406 washing Methods 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 14
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 13
- 239000012141 concentrate Substances 0.000 claims description 13
- 229910017604 nitric acid Inorganic materials 0.000 claims description 13
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 claims description 12
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 239000012286 potassium permanganate Substances 0.000 claims description 12
- 235000017550 sodium carbonate Nutrition 0.000 claims description 11
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 11
- 239000003795 chemical substances by application Substances 0.000 claims description 10
- WVDDGKGOMKODPV-UHFFFAOYSA-N Benzyl alcohol Chemical compound OCC1=CC=CC=C1 WVDDGKGOMKODPV-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 8
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 8
- 238000001953 recrystallisation Methods 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 6
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- 238000004090 dissolution Methods 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 6
- -1 methane amide Chemical class 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims description 6
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims description 6
- 239000000843 powder Substances 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- 235000019260 propionic acid Nutrition 0.000 claims description 4
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 4
- FGUUSXIOTUKUDN-IBGZPJMESA-N C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 Chemical compound C1(=CC=CC=C1)N1C2=C(NC([C@H](C1)NC=1OC(=NN=1)C1=CC=CC=C1)=O)C=CC=C2 FGUUSXIOTUKUDN-IBGZPJMESA-N 0.000 claims description 3
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical class CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- 229910019213 POCl3 Inorganic materials 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 239000002253 acid Substances 0.000 claims description 3
- 239000003513 alkali Substances 0.000 claims description 3
- 239000012670 alkaline solution Substances 0.000 claims description 3
- VZTDIZULWFCMLS-UHFFFAOYSA-N ammonium formate Chemical compound [NH4+].[O-]C=O VZTDIZULWFCMLS-UHFFFAOYSA-N 0.000 claims description 3
- 239000002585 base Substances 0.000 claims description 3
- 235000019445 benzyl alcohol Nutrition 0.000 claims description 3
- 229960004217 benzyl alcohol Drugs 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 3
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 claims description 3
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 claims description 3
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 3
- 235000015320 potassium carbonate Nutrition 0.000 claims description 3
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 3
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 238000000034 method Methods 0.000 abstract description 13
- 230000008569 process Effects 0.000 abstract description 5
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- 230000003647 oxidation Effects 0.000 abstract description 3
- 238000007254 oxidation reaction Methods 0.000 abstract description 3
- GPEGMQBVLGNIMY-UHFFFAOYSA-N 3,4-bis(2-methoxyethoxy)benzaldehyde Chemical compound COCCOC1=CC=C(C=O)C=C1OCCOC GPEGMQBVLGNIMY-UHFFFAOYSA-N 0.000 abstract description 2
- DDCGTKAPQABUQM-UHFFFAOYSA-N 4,5-bis(2-methoxyethoxy)-2-nitrobenzaldehyde Chemical compound COCCOC1=CC(C=O)=C([N+]([O-])=O)C=C1OCCOC DDCGTKAPQABUQM-UHFFFAOYSA-N 0.000 abstract description 2
- PMQWTUWLIGJTQD-UHFFFAOYSA-N 6,7-bis(2-methoxyethoxy)-1h-quinazolin-4-one Chemical compound N1C=NC(=O)C2=C1C=C(OCCOC)C(OCCOC)=C2 PMQWTUWLIGJTQD-UHFFFAOYSA-N 0.000 abstract description 2
- BVZLOXBXCDSRNS-UHFFFAOYSA-N 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid Chemical compound COCCOC1=CC(C(O)=O)=C([N+]([O-])=O)C=C1OCCOC BVZLOXBXCDSRNS-UHFFFAOYSA-N 0.000 abstract 2
- HUJDMSWRGMPHJD-UHFFFAOYSA-N 2-amino-4,5-bis(2-methoxyethoxy)benzoic acid Chemical compound COCCOC1=CC(N)=C(C(O)=O)C=C1OCCOC HUJDMSWRGMPHJD-UHFFFAOYSA-N 0.000 abstract 1
- 230000032050 esterification Effects 0.000 abstract 1
- 238000005886 esterification reaction Methods 0.000 abstract 1
- 238000006396 nitration reaction Methods 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 238000010792 warming Methods 0.000 description 12
- 238000010438 heat treatment Methods 0.000 description 10
- 229940102398 methyl anthranilate Drugs 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 8
- 238000010992 reflux Methods 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 7
- 239000013078 crystal Substances 0.000 description 6
- GTTBEUCJPZQMDZ-UHFFFAOYSA-N erlotinib hydrochloride Chemical compound [H+].[Cl-].C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 GTTBEUCJPZQMDZ-UHFFFAOYSA-N 0.000 description 6
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- 238000001514 detection method Methods 0.000 description 5
- 229960005073 erlotinib hydrochloride Drugs 0.000 description 5
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229960000583 acetic acid Drugs 0.000 description 4
- MTZQAGJQAFMTAQ-UHFFFAOYSA-N ethyl benzoate Chemical compound CCOC(=O)C1=CC=CC=C1 MTZQAGJQAFMTAQ-UHFFFAOYSA-N 0.000 description 4
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
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- 150000002923 oximes Chemical class 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 1
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- YKIOKAURTKXMSB-UHFFFAOYSA-N adams's catalyst Chemical compound O=[Pt]=O YKIOKAURTKXMSB-UHFFFAOYSA-N 0.000 description 1
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- 230000010534 mechanism of action Effects 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. The process flow of the method is as follows: A, 3,4-bis(2-methoxyethoxy)benzaldehyde undergoes nitration to produce 4,5-bis(2-methoxyethoxy)-2-nitrobenzaldehyde; B, oxidation is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzoic acid; C, esterification is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-nitrobenzoate; D, reduction is carried out so as to obtain 4,5-bis(2-methoxyethoxy)-2-aminobenzoate; E, cyclization is carried out so as to obtain 6,7-bis(2-methoxyethoxy)-4(3H)-quinazolinone; and F, chlorination is carried out so as to obtain 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline. The preparation method provided in the invention has the advantages of a concise and practical synthetic route, high yield and a good industrial application prospect.
Description
Technical field
The present invention relates to 4-chloro-6, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline belongs to the technical field of medication preparation.
Background technology
4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline is the key intermediate of anti-cancer agent Erlotinib hydrochloride, its structural formula is suc as formula 1:
Formula 1
Erlotinib hydrochloride (erlotinib hydrochloride); Chemical name is N-(3-Phenylacetylene)-6; 7-two (the own oxygen of methoxy)-4-quinazoline amine hydrochlorate, its structural formula is seen formula 2, is by Luo Shi (Roche), the treatment nonsmall-cell lung cancer of the common research and development of west (OSI) biopharmaceutical company difficult to understand and Genentech (Genentech) drugmaker and the new drug of advanced pancreatic cancer; Obtained FDA approval in 2004, went on the market in the U.S. in 2005.
Formula 2
The mechanism of action of Erlotinib hydrochloride is to combine with Triphosaden (ATP) site on the TK structural domain in the cell is competitive; Reversibility, selectivity suppress EGFR relevant TK activity and endocellular phosphorus acidization; Thereby suppress downstream signal transduction path; Antagonizing vessel generation, cellular invasion and proliferation function, blocking-up tumor tissue growth.
As the key intermediate of Erlotinib hydrochloride, 4-chloro-6, the compound method of 7-two-(2-methoxy ethoxy)-quinazoline bibliographical information mainly contains following three kinds:
(1) Schnur etc. has reported 4-chloro-6 at US547498; The synthetic route of 7-two-(2-methoxy ethoxy)-quinazoline, promptly with 3, the 4-dihydric ethyl benzoate is a raw material; Elder generation and bromo-ethyl-methyl ether reaction; Obtain 4-chloro-6 through alkoxylate, nitrated, reduction, Cheng Huan, chlorination again, 7-two-(2-methoxy ethoxy)-quinazoline, its synthetic route is as follows:
The weak point of this route is raw material 3, and 4-dihydric ethyl benzoate valency is high rare, uses expensive platinum dioxide during the reduction nitro, and production cost is higher.
(2) Chandregowda etc. is in [Heterocycles, 2007,71 (1); 39-48] reported another kind of compound method, this method is with 3, and the 4-Dihydroxy benzaldehyde is a raw material; Elder generation and bromo-ethyl-methyl ether reaction; Pass through again into oxime, dehydration, nitrated, cyclisation, chlorination and obtain 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline, its synthetic route is as follows:
In this route, become the oxime process to use pyridine, because the pyridine stench, environment is abominable in the generating run process, and environmental protection pressure is bigger; And it is nitrated, and under heating condition with the concentrated nitric acid to be that medium carries out nitrated, comparatively seriously the taking place of this step side reaction, and yield is lower; In addition, Hydrazine Hydrate 80 has been used in the reduction of nitro in this route, and toxicity is bigger.
(3) Adriana Chilin etc. is in [Tetrahedron, 2010,66 (4); 962-968] reported 4-chloro-6; Another synthetic route of 7-two-(2-methoxy ethoxy)-quinazoline, promptly 3,4-dihydroxyl oil of mirbane etherificate, reduction, formylation, cyclisation, oxidation, chlorination and get.
The employed raw material 3 of this route, 4-dihydroxyl oil of mirbane is to get through the nitrated of pyrocatechol in preparation, this technology is dangerous big, so raw material is difficult for obtaining; Secondly, it is under the microwave radiation condition, to accomplish that this route becomes the ring process, in suitability for industrialized production, is difficult to utilization; This route has used ceric ammonium nitrate to the oxidation of quinazoline at last, is easy to generate a large amount of waste water in synthesizing, and causes environmental pollution.
Summary of the invention
For overcoming the weak point of aforesaid method, the purpose of this invention is to provide the 4-chloro-6 that a kind of cost is low, security good, productive rate is high, be easy to amplify, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline.4-chloro-6, the preparing method's of 7-two-(2-methoxy ethoxy)-quinazoline step is following:
A. with 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde is dissolved in the organic solvent, and dripping mass percentage concentration down at 0 ℃～20 ℃ is 40～90% concentrated nitric acids; In 20～80 ℃ of reactions 3～10 hours, reaction added water after accomplishing, and uses extracted in toluene then; Washing, drying, concentrate 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde, concentrated nitric acid and 3, the mol ratio 1～10:1 of 4-two-(2-methoxy ethoxy)-phenyl aldehyde;
B.4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde is dissolved in the organic solvent, is that 10～50% potassium permanganate solution reacted 2～10 hours with mass percentage concentration down at 20～80 ℃; Reaction finishes, and filters acidifying; Suction filtration obtains 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, potassium permanganate and 3, the mol ratio of 4-two-(2-methoxy ethoxy)-6-nitrobenzaldehyde is 1～5:1;
C.4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid reacted 6～48 hours in the condition refluxed of catalyzer with alcohol, and reaction is finished; Concentrate away alcohol; Residue is used weakly alkaline solution washing, drying with organic solvent dissolution; Steam to desolventize again and obtain 4,5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate; Alcohol and 3, the envelope-bulk to weight ratio 1～5ml/g of 4-two-(2-methoxy ethoxy)-6-nitrobenzoic acid
D. with 4; 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate is dissolved in the organic solvent and reductive agent reacted suction filtration 2～8 hours in 20～100 ℃; Concentrate and obtain 4; 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate, 4, the mol ratio of 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate and reductive agent is 1:1～10;
E.4,5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate and cyclization reagent
In 50～200 ℃ of reactions 2～20 hours, cooling, suction filtration; Washing, recrystallization makes 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; Cyclization reagent and 4, the envelope-bulk to weight ratio of 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate is 2～10ml/g;
F. with 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones are dissolved in organic solvent and chlorination reagent reacted 2～20 hours at 0～150 ℃, and alkali lye is poured in cooling into, and separatory concentrates and obtains 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline; 6, the mol ratio of 7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones and chlorination reagent is 1:1～10.
In step a, the mass percentage concentration of said concentrated nitric acid is 50～70%; Said organic solvent is one or more in formic acid, acetate, propionic acid or the butyric acid.
In step b, said organic solvent is acetone, methyl alcohol, ethanol, butanols or dioxane; The used acid of said acidifying is sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid; The mass percentage concentration of said potassium permanganate solution is 20%.
In step c, described alcohol is the alcohol or the benzylalcohol of carbon atom 1～6; Described catalyzer is the vitriol oil, phosphoric acid, methylsulfonic acid or tosic acid; Described weak base is yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus.
In steps d, described organic solvent solvent is that carbonatoms is 1～4 alcohol, acetic acid or ETHYLE ACETATE; Reductive agent is hydrogen, iron powder, zinc powder, vat powder or ammonium formiate.
In step e, described cyclization reagent is formic acid or methane amide.
In step f, described organic solvent is benzene,toluene,xylene, methylene dichloride, chloroform, ethylene dichloride or DMSO 99.8MIN.; Described chlorination reagent is sulfur oxychloride, oxalyl chloride, POCl3, phosphorus pentachloride or phosphorus trichloride.
The present invention compares the beneficial effect that has with background technology:
(1) the invention has the advantages that raw material used in the building-up process and reagent cheaply are easy to get, whole route yield is higher, and manufacturing cost is low.
(2) whole technology aftertreatment can use ordinary method as filter, concentrate, extraction, crystallization, recrystallization separates and purifying, operation is very easy, and respectively goes on foot the reaction conditions gentleness, and is simple to equipment requirements, is easy to suitability for industrialized production.
In a word, whole synthetic route is more succinct practical, and yield is high, has good industrialized application prospect.
Description of drawings
Accompanying drawing be Erlotinib hydrochloride proton nmr spectra (1H-NMR, CDCl3).
Embodiment
The present invention prepares 4-chloro-6, and the operational path of 7-two-(2-methoxy ethoxy)-quinazoline is as follows:
The raw material 3 that the present invention is used, 4-two-(2-methoxy ethoxy)-phenyl aldehyde can by 3, the 4-Dihydroxy benzaldehyde conveniently makes by document [Heterocyces, 2007,71 (1), 39-48].4-chloro-6, the preparing method's of 7-two-(2-methoxy ethoxy)-quinazoline step is following:
A. with 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde is dissolved in the organic solvent, and dripping mass percentage concentration down at 0 ℃～20 ℃ is 40～90% concentrated nitric acids; In 20～80 ℃ of reactions 3～10 hours, reaction added water after accomplishing, and uses extracted in toluene then; Washing, drying, concentrate 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde, concentrated nitric acid and 3, the mol ratio 1～10:1 of 4-two-(2-methoxy ethoxy)-phenyl aldehyde;
B.4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde is dissolved in the organic solvent, is that 10～50% potassium permanganate solution reacted 2～10 hours with mass percentage concentration down at 20～80 ℃; Reaction finishes, and filters acidifying; Suction filtration obtains 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, potassium permanganate and 3, the mol ratio of 4-two-(2-methoxy ethoxy)-6-nitrobenzaldehyde is 1～5:1;
C.4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid reacted 6～48 hours in the condition refluxed of catalyzer with alcohol, and reaction is finished; Concentrate away alcohol; Residue is used weakly alkaline solution washing, drying with organic solvent dissolution; Steam to desolventize again and obtain 4,5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate; Alcohol and 3, the envelope-bulk to weight ratio 1～5ml/g of 4-two-(2-methoxy ethoxy)-6-nitrobenzoic acid;
D. with 4; 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate is dissolved in the organic solvent and reductive agent reacted suction filtration 2～8 hours in 20～100 ℃; Concentrate and obtain 4; 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate, 4, the mol ratio of 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate and reductive agent is 1:1～10;
E.4,5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate and cyclization reagent are in 50～200 ℃ of reactions 2～20 hours, cooling; Suction filtration; Washing, recrystallization makes 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; Cyclization reagent and 4, the envelope-bulk to weight ratio of 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate is 2～10ml/g;
F. with 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones are dissolved in organic solvent and chlorination reagent reacted 2～20 hours at 0～150 ℃, and alkali lye is poured in cooling into, and separatory concentrates and obtains 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline; 6, the mol ratio of 7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones and chlorination reagent is 1:1～10.
In step a, the mass percentage concentration of said concentrated nitric acid is 50～70%; Said organic solvent is one or more in formic acid, acetate, propionic acid or the butyric acid.
In step b, said organic solvent is acetone, methyl alcohol, ethanol, butanols or dioxane; The used acid of said acidifying is sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid; The mass percentage concentration of said potassium permanganate solution is 20%.
In step c, described alcohol is the alcohol or the benzylalcohol of carbon atom 1～6; Described catalyzer is the vitriol oil, phosphoric acid, methylsulfonic acid or tosic acid; Described weak base is yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus.
In steps d, described organic solvent solvent is that carbonatoms is 1～4 alcohol, acetic acid or ETHYLE ACETATE; Reductive agent is hydrogen, iron powder, zinc powder, vat powder or ammonium formiate.
In step e, described cyclization reagent is formic acid or methane amide.
In step f, described organic solvent is benzene,toluene,xylene, methylene dichloride, chloroform, ethylene dichloride or DMSO 99.8MIN.; Described chlorination reagent is sulfur oxychloride, oxalyl chloride, POCl3, phosphorus pentachloride or phosphorus trichloride.
Further set forth the present invention below in conjunction with specific embodiment, what should explain is that these embodiment only are used to technology of the present invention is described and are not used in restriction protection scope of the present invention.
Embodiment 1
The preparation of (1) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde
In the 2000ml reaction flask, add 180g (0.708mol) 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde, 200ml glacial acetic acid; 15 ℃ drip 206ml (2.975mol) 65% concentrated nitric acid down, are warming up to 50 ℃ of reactions 6 hours after dripping off gradually, and reaction finishes; Be cooled to room temperature, add 500ml water in the reaction flask, with 500ml methylbenzene extraction 2 times; Isolating toluene layer washs 2 times with the 1mol/L aqueous sodium carbonate, anhydrous sodium sulfate drying, and steaming desolventizes; Residue obtains the glassy yellow crystal 4 with 1:1 methanol-water recrystallization, 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 180g, yield 85%.
The preparation of (2) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid
In the 2000ml reaction flask, add 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 180g (0.6mol), 200ml acetone, dissolving back adding 1000g massfraction are 23.7% potassium permanganate solution; Stir and be warming up to 60 ℃ of reactions 3 hours down gradually, reaction removes by filter Manganse Dioxide after finishing; The first concentrating under reduced pressure of filtrating steams and removes most of acetone, and it is 1～2 that concentrated hydrochloric acid accent PH is used in back ice bath cooling down; Separate out a large amount of solids, suction filtration washs after drying with frozen water; Obtain 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid 174g, yield 92%.
The preparation of (3) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters
In the 500ml reaction flask, add 170g (0.54mol) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, 340ml anhydrous methanol, the 4g vitriol oil; Heating reflux reaction 12 hours, the TLC detection reaction finishes, and steams earlier and removes methyl alcohol; Resistates is used the 200ml acetic acid ethyl dissolution, with aqueous sodium carbonate washing 3 times, anhydrous sodium sulfate drying; Remove solvent under reduced pressure and obtain weak yellow liquid 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 167g, yield 94%.
The preparation of (4) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate
In the 1000ml reaction flask, add 136g (2.43mol) reduced iron powder, 150ml water; The 3ml concentrated hydrochloric acid stirred 10 minutes, with 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 160g (0.486mol) is dissolved in disposable joining in the reaction flask behind the 500ml absolute ethyl alcohol, heating reflux reaction 4 hours, and the TLC detection reaction finishes; Suction filtration while hot, iron mud is with washing with alcohol 2 times, and filtrating is concentrated into dried; Obtain 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate 123.6g, yield 85%.
The preparation of (5) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones
In the 1000ml reaction flask, add 120g (0.4mol) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate; The 720ml methane amide is warming up to 180 ℃ of reactions gradually, and 5 reactions as a child finish; The ice bath cooling; Suction filtration, filter cake gets white crystal 103.49g with re-crystallizing in ethyl acetate, yield 88%.
(6) the 4-chloro-6, the preparation of 7-two-(2-methoxy ethoxy)-quinazoline
In the 1000ml reaction flask, add 90g (0.3058mol) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; The 400ml chloroform after the heating for dissolving, adds 45ml sulfur oxychloride and 5mlDMF more successively; Be warming up to back flow reaction 5 hours, reaction finishes, and reaction solution is poured in 500ml 30% sodium carbonate solution; Stir standing demix after 0.5 hour, tell organic layer, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, residue obtains white solid 83.2g with sherwood oil and re-crystallizing in ethyl acetate, yield 87%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (CDCl3) δ 3.49-3.51 (d, 6H), 3.88-3.90 (t, 4H), 4.33-4.35 (t, 4H), 7.39 (s, 1H), 7.45 (1H), 8.87 (s, 1H).
Embodiment 2
The preparation of (1) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde
In the 2000ml reaction flask, add 180g (0.708mol) 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde, 200ml propionic acid; 15 ℃ drip 49ml (0.708mol) 65% concentrated nitric acid down, are warming up to 50 ℃ of reactions 6 hours after dripping off gradually, and reaction finishes; Be cooled to room temperature, add 500ml water in the reaction flask, with 500ml methylbenzene extraction 2 times; Isolating toluene layer washs 2 times with the 1mol/L sodium carbonate solution, anhydrous sodium sulfate drying, and steaming desolventizes; Residue obtains the glassy yellow crystal 4 with 1:1 methanol-water recrystallization, 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 105.8g, yield 50%.
The preparation of (2) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid
In the 2000ml reaction flask, add 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 105g (0.35mol), the 200ml dioxane, the dissolving back adds 276ml 20% potassium permanganate solution; Stir and be warming up to 60 ℃ of reactions 3 hours down gradually, reaction removes by filter Manganse Dioxide after finishing; The first concentrating under reduced pressure of filtrating steams and removes most of acetone, and back ice bath cooling uses concentrated hydrochloric acid accent PH to be 1-2 down; Separate out a large amount of solids, suction filtration washs after drying with frozen water; Obtain 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid 53g, yield 48%.
The preparation of (3) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters
In the 500ml reaction flask of being furnished with water trap and reflux condensing tube, add 53g (0.168mol) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, 53ml anhydrous methanol, the 4g vitriol oil; Behind the heating reflux reaction 12 hours, steam earlier and remove methyl alcohol, resistates is used the 200ml acetic acid ethyl dissolution; With aqueous sodium carbonate washing 3 times, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains weak yellow liquid 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 46g, yield 80%.
The preparation of (4) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate
In the 1000ml reaction flask, add 7.5g (0.134mol) reduced iron powder, 50ml water; The 3ml concentrated hydrochloric acid stirred 10 minutes, with 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 46g (0.134mol) is dissolved in disposable joining in the reaction flask behind the 100ml absolute ethyl alcohol, heating reflux reaction 4 hours, and the TLC detection reaction finishes; Suction filtration while hot, iron mud is with washing with alcohol 2 times, and filtrating is concentrated into dried; Obtain 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate 23.5g, yield 56%.
The preparation of (5) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones
In the 1000ml reaction flask, add 23.5g (0.075mol) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate; The 47ml methane amide is warming up to 180 ℃ of reactions gradually, and 5 reactions as a child finish; The ice bath cooling; Suction filtration, filter cake gets white crystal 17.2g with re-crystallizing in ethyl acetate, yield 78%.
(6) the 4-chloro-6, the preparation of 7-two-(2-methoxy ethoxy)-quinazoline
In the 1000ml reaction flask, add 17g (0.0577mol) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; The 400ml ethylene dichloride after the heating for dissolving, adds 4.18ml sulfur oxychloride and 0.465mlDMF again; Be warming up to back flow reaction 5 hours, reaction finishes, and reaction solution is poured in 500ml 30% sodium carbonate solution; Stir standing demix after 0.5 hour, tell organic layer, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, residue obtains white solid 14.63g with sherwood oil and re-crystallizing in ethyl acetate, yield 81%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (CDCl3) δ 3.49-3.51 (d, 6H), 3.88-3.90 (t, 4H), 4.33-4.35 (t, 4H), 7.39 (s, 1H), 7.45 (1H), 8.87 (s, 1H).
Embodiment 3
The preparation of (1) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde
In the 2000ml reaction flask, add 180g (0.708mol) 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde, 200ml glacial acetic acid; 15 ℃ add 490ml (7.08mol) 65% concentrated nitric acid down, are warming up to 50 ℃ of reactions 4 hours gradually, and reaction finishes; Be cooled to room temperature, add 500ml water in the reaction flask, with 500ml methylbenzene extraction 2 times; Isolating toluene layer washs 2 times with the 1mol/L sodium carbonate solution, anhydrous sodium sulfate drying, and steaming desolventizes; Residue obtains the glassy yellow crystal 4 with 1:1 methanol-water recrystallization, 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 160g, yield 76%.
The preparation of (2) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid
In the 2000ml reaction flask, add 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde 160g (0.535mol), 200ml acetone, it is 40.94% potassium permanganate solution that the dissolving back adds the 1000ml massfraction; Stir and be warming up to 60 ℃ of reactions 3 hours down gradually, reaction removes by filter Manganse Dioxide after finishing; The first concentrating under reduced pressure of filtrating steams and removes most of acetone, and it is 1～2 that concentrated hydrochloric acid accent PH is used in back ice bath cooling down; Separate out a large amount of solids, suction filtration washs after drying with frozen water; Obtain 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid 140g, yield 83%.
The preparation of (3) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters
In the 500ml reaction flask of being furnished with water trap and reflux condensing tube, add 140g (0.444mol) 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, 700ml anhydrous methanol, the 4g vitriol oil; Heating reflux reaction 12 hours, the TLC detection reaction finishes, and steams earlier and removes methyl alcohol; Resistates is used the 200ml acetic acid ethyl dissolution; With aqueous sodium carbonate washing 3 times, anhydrous sodium sulfate drying removes solvent under reduced pressure and obtains weak yellow liquid 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 134g, yield 88%.
The preparation of (4) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate
In the 1000ml reaction flask, add 212.8g (3.8mol) reduced iron powder, 200ml water; The 5ml concentrated hydrochloric acid stirred 10 minutes, with 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid methyl esters 130g (0.38mol) is dissolved in disposable joining in the reaction flask behind the 500ml absolute ethyl alcohol, heating reflux reaction 4 hours, and the TLC detection reaction finishes; Suction filtration while hot, iron mud is with washing with alcohol 2 times, and filtrating is concentrated into dried; Obtain 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate 95.25g, yield 80%.
The preparation of (5) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones
In the 1000ml reaction flask, add 95g (0.3mol) 4,5-two-(2-methoxy ethoxy)-2-Methyl anthranilate; The 950ml methane amide is warming up to 180 ℃ of reactions gradually, and 5 reactions as a child finish; The ice bath cooling; Suction filtration, filter cake gets white crystal 53.53g with re-crystallizing in ethyl acetate, yield 60%.
(6) the 4-chloro-6, the preparation of 7-two-(2-methoxy ethoxy)-quinazoline
In the 1000ml reaction flask, add 50g (0.17mol) 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; The 200ml methylene dichloride after the heating for dissolving, adds 202ml sulfur oxychloride and 20mlDMF again; Be warming up to back flow reaction 5 hours, reaction finishes, and reaction solution is poured in the 500ml30% sodium carbonate solution; Stir standing demix after 0.5 hour, tell organic layer, anhydrous sodium sulfate drying; Remove solvent under reduced pressure, residue obtains white solid 44.66 with sherwood oil and re-crystallizing in ethyl acetate, yield 84%.Confirm that through nuclear-magnetism H spectrum its nuclear magnetic data is: 1H-NMR (CDCl3) δ 3.49-3.51 (d, 6H), 3.88-3.90 (t, 4H), 4.33-4.35 (t, 4H), 7.39 (s, 1H), 7.45 (1H), 8.87 (s, 1H).
Claims (7)
1. 4-chloro-6, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline is characterized in that its step is following:
A. with 3,4-two-(2-methoxy ethoxy)-phenyl aldehyde is dissolved in the organic solvent, and dripping mass percentage concentration down at 0 ℃～20 ℃ is 40～90% concentrated nitric acids; In 20～80 ℃ of reactions 3～10 hours, reaction added water after accomplishing, and uses extracted in toluene then; Washing, drying, concentrate 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde, concentrated nitric acid and 3, the mol ratio 1～10:1 of 4-two-(2-methoxy ethoxy)-phenyl aldehyde;
B. 4,5-two-(2-methoxy ethoxy)-2-nitrobenzaldehyde is dissolved in the organic solvent, is that 10～50% potassium permanganate solution reacted 2～10 hours with mass percentage concentration down at 20～80 ℃; Reaction finishes, and filters acidifying; Suction filtration obtains 4; 5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid, potassium permanganate and 3, the mol ratio of 4-two-(2-methoxy ethoxy)-6-nitrobenzaldehyde is 1～5:1;
C. 4,5-two-(2-methoxy ethoxy)-2-nitrobenzoic acid and alcohol were the condition refluxed reaction of catalyzer 6～48 hours, and reaction is finished; Concentrate and remove alcohol; Residue is used weakly alkaline solution washing, drying with organic solvent dissolution; Steam to desolventize again and obtain 4,5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate; Alcohol and 3, envelope-bulk to weight ratio 1～5 ml/g of 4-two-(2-methoxy ethoxy)-6-nitrobenzoic acid
D. with 4; 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate is dissolved in the organic solvent and reductive agent reacted suction filtration 2～8 hours in 20～100 ℃; Concentrate and obtain 4; 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate, 4, the mol ratio of 5-two-(2-methoxy ethoxy)-2-ethyl nitrobenzoate and reductive agent is 1:1～10;
E.4,5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate and cyclization reagent are in 50～200 ℃ of reactions 2～20 hours, cooling; Suction filtration; Washing, recrystallization makes 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones; Cyclization reagent and 4, the envelope-bulk to weight ratio of 5-two-(2-methoxy ethoxy)-ethyl 2-aminobenzoate is 2～10ml/g;
F. with 6,7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones are dissolved in organic solvent and chlorination reagent reacted 2～20 hours at 0～150 ℃, and alkali lye is poured in cooling into, and separatory concentrates and obtains 4-chloro-6,7-two-(2-methoxy ethoxy)-quinazoline; 6, the mol ratio of 7-two-(2-methoxy ethoxy)-4 (3H)-quinazolinones and chlorination reagent is 1:1～10.
2. a kind of 4-chloro-6 according to claim 1, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline is characterized in that: in step a, the mass percentage concentration of said concentrated nitric acid is 50～70%; Said organic solvent is one or more in formic acid, acetate, propionic acid or the butyric acid.
3. a kind of 4-chloro-6 according to claim 1, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline is characterized in that: in step b, said organic solvent is acetone, methyl alcohol, ethanol, butanols or dioxane; The used acid of said acidifying is sulfuric acid, hydrochloric acid, phosphoric acid or nitric acid; The mass percentage concentration of said potassium permanganate solution is 20%.
4. a kind of 4-chloro-6 according to claim 1, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline is characterized in that: in step c, described alcohol is the alcohol or the benzylalcohol of carbon atom 1～6; Described catalyzer is the vitriol oil, phosphoric acid, methylsulfonic acid or tosic acid; Described weak base is yellow soda ash, salt of wormwood, sodium hydrogencarbonate or saleratus.
5. a kind of 4-chloro-6 according to claim 1,7-two-(2-methoxy ethoxy)
The preparation method of-quinazoline is characterized in that: in steps d, described organic solvent dissolves
Agent is that carbonatoms is 1～4 alcohol, acetic acid or ETHYLE ACETATE; Reductive agent is hydrogen, iron powder, zinc powder, vat powder or ammonium formiate.
6. a kind of 4-chloro-6 according to claim 1, the preparation method of 7-two-(2-methoxy ethoxy)-quinazoline is characterized in that: in step e, described cyclization reagent is formic acid or methane amide.
7. a kind of 4-chloro-6 according to claim 1; The preparation method of 7-two-(2-methoxy ethoxy)-quinazoline; It is characterized in that: in step f, described organic solvent is benzene,toluene,xylene, methylene dichloride, chloroform, ethylene dichloride or DMSO 99.8MIN.; Described chlorination reagent is sulfur oxychloride, oxalyl chloride, POCl3, phosphorus pentachloride or phosphorus trichloride.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012102762299A CN102827086A (en) | 2012-08-03 | 2012-08-03 | Preparation method for 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104193688A (en) * | 2014-09-04 | 2014-12-10 | 埃斯特维华义制药有限公司 | Synthetic method for erlotinib intermediate |
| CN104211648A (en) * | 2014-08-25 | 2014-12-17 | 天津市中央药业有限公司 | Synthetic process method of erlotinib intermediate |
| CN104892529A (en) * | 2015-05-27 | 2015-09-09 | 烟台大学 | Thiourea compound containing quinazoline structure as well as preparation method and application of thiourea compound |
| CN104892530A (en) * | 2015-05-27 | 2015-09-09 | 烟台大学 | Diaryl urea compound containing quinazoline structure as well as preparation method and application thereof |
| CN104910080A (en) * | 2015-05-26 | 2015-09-16 | 大连理工大学 | Novel erlotinib-related substance and preparation method thereof |
| CN106928069A (en) * | 2017-03-21 | 2017-07-07 | 上海玉函化工有限公司 | A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
| CN111302945A (en) * | 2020-02-21 | 2020-06-19 | 上海再启生物技术有限公司 | Preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid |
| CN112939888A (en) * | 2021-03-03 | 2021-06-11 | 吉林大学 | Star-shaped D-A type conjugated molecule and synthetic method and application thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104211648A (en) * | 2014-08-25 | 2014-12-17 | 天津市中央药业有限公司 | Synthetic process method of erlotinib intermediate |
| CN104193688A (en) * | 2014-09-04 | 2014-12-10 | 埃斯特维华义制药有限公司 | Synthetic method for erlotinib intermediate |
| CN104910080A (en) * | 2015-05-26 | 2015-09-16 | 大连理工大学 | Novel erlotinib-related substance and preparation method thereof |
| CN104892529A (en) * | 2015-05-27 | 2015-09-09 | 烟台大学 | Thiourea compound containing quinazoline structure as well as preparation method and application of thiourea compound |
| CN104892530A (en) * | 2015-05-27 | 2015-09-09 | 烟台大学 | Diaryl urea compound containing quinazoline structure as well as preparation method and application thereof |
| CN106928069A (en) * | 2017-03-21 | 2017-07-07 | 上海玉函化工有限公司 | A kind of preparation method of 4,5 2 (2 methoxy ethoxy) 2 ethyl nitrobenzoates |
| CN108358798A (en) * | 2018-02-12 | 2018-08-03 | 黑龙江鑫创生物科技开发有限公司 | A kind of method of micro passage reaction synthesis Tarceva intermediate |
| CN111302945A (en) * | 2020-02-21 | 2020-06-19 | 上海再启生物技术有限公司 | Preparation method of 3-hydroxy-4-methoxy-2-nitrobenzoic acid |
| CN112939888A (en) * | 2021-03-03 | 2021-06-11 | 吉林大学 | Star-shaped D-A type conjugated molecule and synthetic method and application thereof |
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