CN101759653B - Preparation method of 6, 7-dimethoxy quinazoline-4-ketone - Google Patents
Preparation method of 6, 7-dimethoxy quinazoline-4-ketone Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 239000002994 raw material Substances 0.000 claims abstract description 11
- 150000003951 lactams Chemical group 0.000 claims abstract description 4
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- WTDHULULXKLSOZ-UHFFFAOYSA-N Hydroxylamine hydrochloride Chemical compound Cl.ON WTDHULULXKLSOZ-UHFFFAOYSA-N 0.000 claims description 7
- RNFNDJAIBTYOQL-UHFFFAOYSA-N chloral hydrate Chemical compound OC(O)C(Cl)(Cl)Cl RNFNDJAIBTYOQL-UHFFFAOYSA-N 0.000 claims description 7
- 229960002327 chloral hydrate Drugs 0.000 claims description 7
- -1 methane amide Chemical class 0.000 claims description 7
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Natural products C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 claims description 6
- 150000002978 peroxides Chemical class 0.000 claims description 6
- LGDHZCLREKIGKJ-UHFFFAOYSA-N 3,4-dimethoxyaniline Chemical compound COC1=CC=C(N)C=C1OC LGDHZCLREKIGKJ-UHFFFAOYSA-N 0.000 abstract description 4
- 238000006396 nitration reaction Methods 0.000 abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- HJVAVGOPTDJYOJ-UHFFFAOYSA-N 2-amino-4,5-dimethoxybenzoic acid Chemical compound COC1=CC(N)=C(C(O)=O)C=C1OC HJVAVGOPTDJYOJ-UHFFFAOYSA-N 0.000 abstract 4
- 239000008346 aqueous phase Substances 0.000 abstract 1
- 238000012805 post-processing Methods 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000543 intermediate Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 15
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 10
- 238000005406 washing Methods 0.000 description 9
- 238000001228 spectrum Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 238000007605 air drying Methods 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 5
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 229960005073 erlotinib hydrochloride Drugs 0.000 description 4
- 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 4
- 239000012074 organic phase Substances 0.000 description 4
- 238000010792 warming Methods 0.000 description 4
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 3
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 2
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 2
- 238000005352 clarification Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 201000002528 pancreatic cancer Diseases 0.000 description 2
- 208000008443 pancreatic carcinoma Diseases 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical compound CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
- DFPYXQYWILNVAU-UHFFFAOYSA-N 1-hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1.C1=CC=C2N(O)N=NC2=C1 DFPYXQYWILNVAU-UHFFFAOYSA-N 0.000 description 1
- XOKNSELNVHYYMP-UHFFFAOYSA-N 6,7-dimethoxy-1,4-dihydroquinazoline Chemical compound COC=1C=C2CNC=NC2=CC1OC XOKNSELNVHYYMP-UHFFFAOYSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 206010027336 Menstruation delayed Diseases 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000006229 amino acid addition Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
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- 239000003054 catalyst Substances 0.000 description 1
- 238000009903 catalytic hydrogenation reaction Methods 0.000 description 1
- 239000007806 chemical reaction intermediate Substances 0.000 description 1
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- 238000009104 chemotherapy regimen Methods 0.000 description 1
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- 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
- 229960002584 gefitinib Drugs 0.000 description 1
- 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 1
- 229960005277 gemcitabine Drugs 0.000 description 1
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000463 material Substances 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
- 239000002547 new drug Substances 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910000510 noble metal Inorganic materials 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011946 reduction process Methods 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Indole Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention provides a preparation method of 6, 7-dimethoxy quinazoline-4-ketone, comprising the following steps of: acylating the amino of 3, 4-dimethoxyaniline as the raw material to generate 2-oximido-N-(3, 4-dimethoxy phenyl) acetamide; (b) cyclizing the 2-oximido-N-(3, 4-dimethoxy phenyl) acetamide to form 5, 6-dimethoxy indoline-2, 3-diketone; (c) decyclizing the 5, 6-dimethoxy indoline-2, 3-diketone to form carboxylic acid and generate 2-amino-4, 5 dimethoxy benzoic acid; and (d) enabling the 2-amino-4, 5 dimethoxy benzoic acid to form a molecule lactam ring and generate 6, 7-dimethoxy quinazoline-4-ketone. The preparation method prevents N from being introduced through nitration and hydrogenation reduction, greatly enhances the reaction safety, has most aqueous-phase reaction and mild condition in the reaction process, very easy and convenient post-processing and easy industrialized production.
Description
Technical field
The present invention relates to the synthetic important intermediate 6 of a kind of Erlotinib hydrochloride and ZD1939, the preparation method of 7-dimethoxyquinazoline-4-ketone.
Background technology
Erlotinib hydrochloride (Erlotinib Hydrochloride); Develop jointly by Genetech, OSI, Roche three companies; Being produced by Roche (Roche Holding Ag), is to be used to treat the local late period of at least a chemotherapy regimen failure or the original new drug of transitivity nonsmall-cell lung cancer (NSCLC).Obtain drugs approved by FDA in November, 2004, and obtain European Union's approval listing, go on the market in China in April, 2006 in September, 2005.FDA2005 has also ratified erlotinib and gemcitabine is united the treatment that is used for advanced pancreatic cancer, becomes first approved advanced pancreatic cancer medicine over nearly 10 years.
ZD1939 (Gefitinib) is a kind of new antitumoral medicine by the exploitation of AstraZeneca company, and it is the micromolecular inhibitor to EGFR the kinase whose taking orally of propylhomoserin, is mainly used in the nonsmall-cell lung cancer treatment, goes on the market in September, 2003.
6,7-dimethoxyquinazoline-4-ketone is the important intermediate of synthetic hydrochloric acid erlotinib and ZD1939.According to WO96/33980 (the former technology of grinding of AstraZeneca), this midbody can be easily as the starting raw material of ZD1939.JyothiPrasad etc. have reported also that in patent WO2007060691 with 6,7-dimethoxy-3,4-dihydroquinazoline are starting raw material, the compound method of preparation Erlotinib hydrochloride.
At present about 6,7-dimethoxyquinazoline-4-ketone intermediates preparation, independent bibliographical information is less.The synthetic route that it is common is with 3 basically, and 4-dimethoxybenzoic acid ethyl ester or its analogue are raw material, obtains through nitrated, reduction, cyclization three-step reaction.Raw material 3, the manufacturer of 4-dimethoxybenzoic acid ethyl ester is less, on the high side.And in this route, introduce N with nitration reaction, reaction is prone to produce polynitration, and polarization is poor, and impurity is more.
Bibliographical information is also arranged, and denitrification step adopts the vitriol oil and concentrated nitric acid nitration mixture to carry out nitrated.Temperature is uncontrollable after our experimental study is found that this method heat release is violent, amplified; Reaction very easily produces not exclusively or the polynitration phenomenon, and the vitriol oil can cause the charing of partial reaction thing rotten; Reaction product is the dark-brown oily liquids, and content is low, and unsuitable purifying.And the reduction of nitro, the general catalytic hydrogenation that adopts in the document needs special-purpose hydrogenation workshop and equipment and noble metal catalyst; Reduzate still is a liquid, and needing to increase special salify step could purifying.Above-mentioned hydrogenating reduction process nitrated, nitro all has higher danger.
Summary of the invention
The purpose of this invention is to provide a kind ofly 6, the synthetic route of 7-dimethoxyquinazoline 4-ketone and preparation method are to overcome the deficiency that prior art exists.
The present invention adopts following technical scheme to solve above-mentioned technical problem:
A kind of 6, the preparation method of 7-dimethoxyquinazoline-4-ketone may further comprise the steps:
A) with 3, the 4-dimethoxyaniline is a raw material, makes the amino acidylate of said raw material, generates 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide;
B) make 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide closed loop form 5,6-dimethoxy indoline-2,3-diketone;
C) make 5,6-dimethoxy indoline-2, the open loop of 3-diketone forms carboxylic acid, generates 2-amino-4, the 5-dimethoxybenzoic acid;
D) make 2-amino-4, the 5-dimethoxybenzoic acid forms the molecule lactam nucleus, generates 6,7-dimethoxyquinazoline-4-ketone.
Among the above-mentioned preparation method, the concrete processing condition of each process step are following:
(1) in the step a):
The amino acylation reaction of said raw material is through with 3, and 4-dimethoxyaniline and Chloral Hydrate and oxammonium hydrochloride react to be accomplished.Wherein, 3, the mol ratio of 4-dimethoxyaniline, Chloral Hydrate and oxammonium hydrochloride preferably is controlled to be 1: (1～2): (3～5).
Said being reflected under the condition that sodium sulfate and Hydrogen chloride exists carried out in the aqueous solution, and its reactions step comprises:
1. mix water, Chloral Hydrate and SODIUM SULPHATE ANHYDROUS 99PCT for use;
2. with 3,4-dimethoxyaniline and oxammonium hydrochloride are dissolved in the Hydrogen chloride of 5%～20% (v/v);
3. with step 2. the gained drips of solution be added to step 1. in the gained solution, react in 40～100 ℃;
After above-mentioned reaction was accomplished, direct filtration can obtain product 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide, adopted conventional method like washing, recrystallization products therefrom to be purified again, to be used for step b).
Preferable, said SODIUM SULPHATE ANHYDROUS 99PCT and 3, the weight ratio of 4-dimethoxyaniline is 10～30, and said water and 3, the envelope-bulk to weight ratio of 4-dimethoxyaniline are 10～30ml/g, and said Hydrogen chloride and 3, the envelope-bulk to weight ratio of 4-dimethoxyaniline are 10～15ml/g.
(2) in the step b):
Said reacting in the vitriol oil of ethanamide closed loop of 2-oximido-N-(3, the 4-Dimethoxyphenyl) carried out, the envelope-bulk to weight ratio of the said vitriol oil and 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide is 5～20ml/g.Temperature of reaction preferably is controlled to be 20～80 ℃.
Reaction can be poured reaction solution in the frozen water into after accomplishing, and makes product 5,6-dimethoxy indoline-2, and the 3-diketone is separated out with solid form, adopts conventional washing methods to purify again, promptly can be used in the step b).
(3) in the step c):
Reaction in the step c) is in aqueous sodium hydroxide solution, and through with 5,6-dimethoxy indoline-2,3-diketone and ydrogen peroxide 50 react to be accomplished.Preferable, said ydrogen peroxide 50 and 5,6-dimethoxy indoline-2, the mol ratio of 3-diketone is 1～3; Said sodium hydroxide and 5,6-dimethoxy indoline-2, the mol ratio of 3-diketone is 2～4; Said water and 5,6-dimethoxy indoline-2, the envelope-bulk to weight ratio of 3-diketone are 0.2～2L/g.Temperature of reaction preferably is controlled to be-5 ℃～30 ℃.
After reaction is accomplished, can adopt conventional extraction mode with product-amino-4, the 5-dimethoxybenzoic acid separates purification, to be used for step d).
(4) in the step d):
The said 2-that makes is amino-4, and the 5-dimethoxybenzoic acid forms the reaction of molecule lactam nucleus, be that 2-is amino-4, and 5-dimethoxybenzoic acid and methane amide react to be accomplished, and is preferable in the presence of CDI and HOBt and carries out.Said methane amide is pressed 2-amino-4 simultaneously as reaction reagent and solvent, and the 5-dimethoxybenzoic acid is the 1mol meter; Said CDI and 2-amino-4; The mol ratio of 5-dimethoxybenzoic acid is 1～2, said HOBt and 2-amino-4, and the mol ratio of 5-dimethoxybenzoic acid is 1～1.5; Said methane amide and 2-amino-4, the envelope-bulk to weight ratio of 5-dimethoxybenzoic acid is 5～20ml/g.Temperature of reaction preferably is controlled to be 80～200 ℃.
After reaction is accomplished, with the reaction solution cooling, can make product 6,7-dimethoxyquinazoline-4-ketone is separated out with solid form, adopts conventional washing methods to purify again, can obtain purer product.
Said CDI is N, and (said HOBt is the abbreviation of 1-hydroxy benzo triazole (1-Hydroxybenzotriazole) to N '-carbonyl dimidazoles for N, the abbreviation of N '-Carbonyldiimidazole).
The concrete structure formula and the synthetic route of related compound are following among the preparation method of the present invention:
Compared with prior art, the invention has the beneficial effects as follows:
1) with 3, the 4-dimethoxyaniline is a raw material, and this material supplier is many, and is cheap and easy to get, can effectively reduce cost;
2) avoided having improved reaction safety greatly through nitrated introducing N and hydrogenating reduction;
3) stable reaction is controlled: be mostly water react, reaction conditions is gentle, need not high temperature, deep cooling, save energy, environmental friendliness;
4) whole piece route yield and quality are better, and per step reaction intermediate is solid, purify easily, and aftertreatment is very easy, is easy to carry out suitability for industrialized production.
Embodiment
Further set forth the present invention below in conjunction with specific embodiment, should be understood that these embodiment only are used to the present invention is described and are not used in restriction protection scope of the present invention.
Embodiment 1
The preparation of intermediate compound I:
10.0L water, Chloral Hydrate 0.64kg, SODIUM SULPHATE ANHYDROUS 99PCT 9.1kg are joined in the reaction kettle, be warmed up to 30 ℃ for use.
With 3,4-dimethoxyaniline 0.53kg, oxammonium hydrochloride 0.78kg are dissolved in 6.23% Hydrogen chloride (v/v) of 6L, stir to make clarification.Controlled temperature is added to this drips of solution in the reaction kettle below 30 ℃, drips to finish to be warming up to 70 ℃, reacts 4 hours.The TLC monitoring (developping agent: petrol ether/ethyl acetate=2/1), the after-filtration that reacts completely, filter cake is used the 2.0L ethyl alcohol recrystallization to wash (0.5L * 3) three times, filters.70 ℃ of forced air dryings of gained solid 6 hours get off-white color solid 0.43kg, are product, yield 55.0%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide.
The preparation of intermediate II:
The 4L vitriol oil is added in the reaction kettle, be warmed up to 50 ℃.Stir down with the adding of 0.84kg intermediate compound I wherein, controlled temperature is below 50 ℃.Finish and be warming up to 60 ℃ of reactions 30 minutes.TLC monitoring (developping agent: petrol ether/ethyl acetate=2/1), after reacting completely, reaction solution is slowly poured in the frozen water, and continued stirring and crystallizing 1 hour, filter.Filter cake is neutral with water washing 3 times to washing lotion.70 ℃ of forced air dryings 6 hours, brown solid 0.66kg, yield 84.8%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 5,6-dimethoxy indoline-2,3-diketone.
The preparation of intermediate III:
0.3kg sodium hydroxide is dissolved in the 2L water, adds intermediate II 0.5kg under the room temperature.The ice bath cooling drips the 1.05eq ydrogen peroxide 50 down, adds the back and recovers stirring at room 4 hours, and (developping agent: petrol ether/ethyl acetate=2/1), after reacting completely, reaction solution washs with 2L ETHYLE ACETATE in the TLC monitoring.Discard organic phase, water is regulated pH to neutrality with 2N hydrochloric acid, with dichloromethane extraction 3 times (3L * 3), merges organic phase, uses 3L water and the water washing of 3L saturated common salt 1 time respectively, the 0.2kg anhydrous sodium sulfate drying.The filtering siccative, methylene dichloride is concentrated into dried, gets off-white color solid 0.33kg, yield 69.5%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is a 2-amino-4, the 5-dimethoxybenzoic acid.
6, the preparation of 7-dimethoxyquinazoline-4-ketone:
The 0.3kg intermediate III is dissolved in the 3L methane amide, adds 0.3kg CDI, 0.21kgHOBt, be heated to 160 ℃ of reactions 4 hours; Naturally cool to room temperature, separate out solid, filter; Filter cake is with methanol wash 3 times (0.5L * 3), filters 80 ℃ of forced air dryings 6 hours; Get white solid 0.28kg, yield 89.4%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 6,7-dimethoxyquinazoline-4-ketone.
Embodiment 2
The preparation of intermediate compound I:
5.0L water, Chloral Hydrate 0.86kg, SODIUM SULPHATE ANHYDROUS 99PCT 5.0kg are joined in the reaction kettle, be warmed up to 40 ℃ for use.With 3,4-dimethoxyaniline 0.53kg, oxammonium hydrochloride 0.96kg are dissolved in 10% Hydrogen chloride (v/v) of 6L, stir to make clarification.Controlled temperature is added to this drips of solution in the reaction kettle below 40 ℃, drips to finish to be warming up to 100 ℃ of backflows, reacts 3 hours.The TLC monitoring (developping agent: petrol ether/ethyl acetate=2/1), the after-filtration that reacts completely, filter cake is used the 2.5L ethyl alcohol recrystallization to wash (0.5L * 3) three times, filters.70 ℃ of forced air dryings of gained solid 6 hours get off-white color solid 0.40kg, are product, yield 51.6%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide.
The preparation of intermediate II:
The 5L vitriol oil is added in the reaction kettle, be warmed up to 30 ℃.Stirring adds the 0.5kg intermediate compound I wherein, and controlled temperature is below 40 ℃.Finish and be warming up to 55 ℃ of reactions 2.5 hours.TLC monitoring (developping agent: petrol ether/ethyl acetate=2/1), after reacting completely, reaction solution is slowly poured in the frozen water, and continued stirring and crystallizing 1 hour, filter.Filter cake is neutral with water washing 3 times to washing lotion.70 ℃ of forced air dryings 6 hours, brown solid 0.42kg, yield 90.0%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 5,6-dimethoxy indoline-2,3-diketone.
The preparation of intermediate III:
0.24kg sodium hydroxide is dissolved in the 2L water, adds intermediate II 0.42kg under the room temperature.The ice bath cooling drips 0.45L 30% ydrogen peroxide 50 (2eq) down, adds the back insulated and stirred 14 hours, and (developping agent: petrol ether/ethyl acetate=2/1), after reacting completely, reaction solution washs with 2L ETHYLE ACETATE in the TLC monitoring.Discard organic phase, water is regulated pH to neutrality with 2N hydrochloric acid, with dichloromethane extraction 3 times (2.5L * 3), merges organic phase, uses 2.5L water and the water washing of 2.53L saturated common salt 1 time respectively, the 0.2kg anhydrous sodium sulfate drying.The filtering siccative, methylene dichloride is concentrated into dried, gets off-white color solid 0.29kg, yield 73.2%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is a 2-amino-4, the 5-dimethoxybenzoic acid.
6, the preparation of 7-dimethoxyquinazoline-4-ketone:
The 0.39kg intermediate III is dissolved in the 5.0L methane amide, adds 0.65kg CDI, 0.41kgHOBt, be heated to 120 ℃ of reactions 8 hours; Naturally cool to room temperature, separate out solid, filter; Filter cake is with methanol wash 3 times (1.0L * 3), filters 80 ℃ of forced air dryings 6 hours; Get white solid 0.35kg, yield 84.9%.Identify that through nucleus magnetic resonance H spectrum products obtained therefrom is 6,7-dimethoxyquinazoline-4-ketone.
Claims (6)
1. one kind 6, the preparation method of 7-dimethoxyquinazoline-4-ketone may further comprise the steps:
A) with 3, the 4-dimethoxyaniline is a raw material, makes the amino acidylate of said raw material, generates 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide; This reaction is with 3, and 4-dimethoxyaniline and Chloral Hydrate and oxammonium hydrochloride react;
B) make 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide closed loop form 5,6-dimethoxy indoline-2,3-diketone;
C) make 5,6-dimethoxy indoline-2, the open loop of 3-diketone forms carboxylic acid, generates 2-amino-4, the 5-dimethoxybenzoic acid; This reaction is with 5,6-dimethoxy indoline-2, and 3-diketone and ydrogen peroxide 50 react in aqueous sodium hydroxide solution;
D) make 2-amino-4, the 5-dimethoxybenzoic acid forms the molecule lactam nucleus, generates 6,7-dimethoxyquinazoline-4-ketone.
2. the method for claim 1 is characterized in that, 3, and the mol ratio of 4-dimethoxyaniline, Chloral Hydrate and oxammonium hydrochloride is 1: (1～2): (3～5).
3. the method for claim 1 is characterized in that, reacting in the vitriol oil in the step b) carried out.
4. method as claimed in claim 3 is characterized in that, in the step b), the envelope-bulk to weight ratio of the said vitriol oil and 2-oximido-N-(3, the 4-Dimethoxyphenyl) ethanamide is 5～20mL/g.
5. the method for claim 1 is characterized in that, in the step c), and said ydrogen peroxide 50 and 5,6-dimethoxy indoline-2, the mol ratio of 3-diketone is 1～3.
6. the method for claim 1 is characterized in that, the reaction in the step d) is that 5-dimethoxybenzoic acid and methane amide react with 2～amino-4.
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