CN101096360A - Method for synthesizing 1H,3H-quinazoline-2,4-diketone compound - Google Patents
Method for synthesizing 1H,3H-quinazoline-2,4-diketone compound Download PDFInfo
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- CN101096360A CN101096360A CNA200610140485XA CN200610140485A CN101096360A CN 101096360 A CN101096360 A CN 101096360A CN A200610140485X A CNA200610140485X A CN A200610140485XA CN 200610140485 A CN200610140485 A CN 200610140485A CN 101096360 A CN101096360 A CN 101096360A
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Abstract
The invention discloses a synthesizing method of 1H, 3H-quinazoline2, 4-diones in the chemical synthesizing domain, wherein R and R1 is H, X, alkyl and alkoxy; X is F, Cl, Br, I; R and R1 can be fused-ring 4, 5-OCH2O-, tetramethylidyne, phenyl and so on; R2 is H, alkyl, phenyl and so on; R3 is methyl or ethyl; the original raw material is o-aminoaromatic cyanogen to condense with N-alkyl formamide acted by catalyst to synthesize the product. The invention simplifies the technique with high productivity and widely applying scale, which is fit for synthesizing 1H, 3H-quinazoline2, 4-diones and their derivants as different substrates.
Description
Affiliated technical field
The present invention relates to a kind of 1H, 3H-quinazoline-2, (English name 1H-quinazo1ine-2,4-diones) synthetic method of compound belongs to the field of chemical synthesis to the 4-diketone.
Background technology
1H, 3H-quinazoline-2,4-diketone heterocyclic compounds has good biological activity and pharmaceutical activity, be important medicine of a class and fine-chemical intermediate, can be used for the synthetic of various medicines, as via 1H, 3H-quinazoline-2, the 4-diketone can synthesize strong anti-mycobacterium activity, N-phenyl lungy-1H-quinazoline-2 that the treatment mycobacterium causes, 4-cyclohexadione compounds (Farmaco, 2001,56:803-807), the mother of synthetic a series of PDE-4 of having (phosphodiesterase IN) selective depressant encircles material 3-N-ethyl-1-N-(2-nitro)-phenyl-1H, 3H-quinazoline-2,4-diketone (Eur.J.Med.Chem, 2000,35 (5): 4632-480); Via 7-chloro-1H, 3H-quinazoline-2, the synthetic FK366 of 4-diketone, Zenarestat with reductase inhibitor and diabetic complication
And be used for the treatment of cardiotropic formulation KF31327 (Tetrahedron, 2002,58:3155), and 6,7-dimethoxy-1H, 3H-quinazoline-2,4-diketone can be used for synthetic α
1-adrenergic receptor blocker medicine Prazosin (Minipress), Bunazosin (Detantol) and Doxazosin (Cardenalin) (Tetrahedron Letter, 2004,45,7073) and Vasocard (Chinese Journal of Pharmaceuticals, 2000,31 (9): 385); 1H, 3H-quinazoline-2, the 4-cyclohexadione compounds also can be used for 8-hydroxyl-1-(the 3-N-morpholinyl)-n-propyl-1H of synthetic ADP ribose polymerase inhibitor, 3H-quinazoline-2,4-diketone, 8-hydroxyl-1-(3-phenoxy group)-n-propyl-1H, 3H-quinazoline-2,4-diketone (Biochimica etBiophysica Actd, 2006,17 (4): 913-9l9); In addition, 1H, 3H-quinazoline-2,4-diketone also can be used for synthetic agricultural chemicals SYP-298 (ZL00123348.3,2000-11-30 with higher weeding activity and crop safety; Modern agricultural chemicals, 2004,3 (6): 14) etc.
Known 1H, 3H-quinazoline-2, the synthetic method of 4-dione compounds mainly contains: 1) with fennel acid and urea reaction make (Pharmazie, 1982,37,115-117); 2) with anthranilamide photoreactive gas reaction make (Org.Prep.Proced.Int., 1978,10,13-16); 3) react with fennel acid and potassium cyanide and make (Org.Synth., 1943,2,79-80); 4) react with fennel acid and chlorosulfonyl phenylcarbimide and make (Tetrahedron, 1994,50,6549-6558); 5) with the reaction of the phenylcarbimide of 2-anthranilo nitrile and equivalent again with acid hydrolysis make (J.Amer.Chem.Soc., 1961,27,2622-2627); 6) with 2-anthranilo nitrile and derivative and CO
2Under excess catalyst catalysis be with DMF solvent reaction 24 hours (Tetrahedron, 2002,58,3155-3158) or solvent-free high pressure use postcritical CO down
2(scCO
2) reaction 4 hours (Tetrahedron Letter, 2004,45,7073-7075) make.All there is deficiency in these synthetic methods, and, operational hazards too violent as reagent costliness or toxicity height, reaction conditions, productive rate are too low etc.
In sum, the price of these methods or reagent is too expensive, toxicity is high, the perhaps too violent operational hazards of reaction conditions, and perhaps complicated operation, perhaps productive rate is too low, and these deficiencies all have inconvenience for their synthetic particularly industrial production.
Summary of the invention
The present invention proposes a kind of with adjacent amino fragrant nitrile and the synthetic easily 1H of N-alkyl formamides reaction, 3H-quinazoline-2, the method for 4-diketone.Reaction expression is:
R, R
1Be H, X, alkyl, alkoxyl group, wherein, X is F, Cl, Br, I; R, R
1Can be 4 of condensed ring, 5-OCH
2O-, four methynes, phenyl etc.
R
2Be H, alkyl, phenyl etc.
R
3Be methyl or ethyl.
The reaction of being addressed is to be starting raw material with the amino fragrant cyanogen of neighbour, closes cyclic condensation one-step synthesis target compound with the N-alkyl formamides under catalyst action.
The aromatic nitriles compound of participating in reaction can be, but is not limited to o-Cyanoaniline, also can contain different substituted radicals on phenyl ring and amino.As various single replacements, polysubstituted adjacent amino (amido) fragrant nitrile.In polysubstituted adjacent amino (amido) fragrant nitrile, can be 4,5-OCH
2O-, four methynes, phenyl etc.During operation the amino fragrant nitrile of neighbour, Zinc Chloride Anhydrous, DMF are added in the autoclave oil bath heated and stirred, back flow reaction respectively.After reaction finishes, place and be cooled to room temperature water dilution, the white precipitate suction filtration of separating out.Crude product hot solvent recrystallization.
Participating in the used N-alkyl formamides of reaction can be, but is not limited to dimethyl formamide (DMF) or diethylformamide.They both can make raw material, can make solvent again.
The solvent of participating in reaction can be, but be not limited to benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone, DMSO etc.
Catalyst for reaction can be (anhydrous) zinc chloride, (anhydrous) aluminum chloride, cupric chloride, cuprous chloride, toluene sulfonic acide, p-methyl benzenesulfonic acid etc., and the mol ratio of adjacent amino fragrant nitrile and catalyzer is 1: 0.1～5.
Reaction needed is carried out in the high pressure seal container, and the normal temperature and pressure reaction is difficulty, is generally reflux temperature; Reaction times is 1-5 hour, and the yield of product is that 10-92.6% does not wait.Reaction solution is placed and is cooled to room temperature, and dilute with water is separated out white precipitate.Crude product can be with 1, and 4-dioxane, DMF, DMSO equal solvent carry out recrystallization.
The invention has the advantages that: raw material is easy to get, and technology is simple, and the productive rate height has wide range of applications, available different substrate 1H, 3H-quinazoline-2,4-diketone and derivative thereof synthetic.
Description of drawings
Accompanying drawing 1-1H, 3H-quinazoline-2,4-diketone infared spectrum, accompanying drawing 2-1H, 3H-quinazoline-2,4-diketone mass spectrum
Accompanying drawing 3-1H, 3H-quinazoline-2,4-diketone proton nmr spectra
Accompanying drawing 4-6-chloro-1H, 3H-quinazoline-2,4-diketone infared spectrum
Accompanying drawing 5-6-chloro-1H, 3H-quinazoline-2,4-diketone mass spectrum
Accompanying drawing 6-6-chloro-1H, 3H-quinazoline-2,4-diketone proton nmr spectra
Accompanying drawing 7-7-chloro-1H, 3H-quinazoline-2,4-diketone infared spectrum
Accompanying drawing 8-7-chloro-1H, 3H-quinazoline-2,4-diketone mass spectrum
Accompanying drawing 9-7-chloro-1H, 3H-quinazoline-2,4-diketone proton nmr spectra
Accompanying drawing 10-synthesizes 1H, 3H-quinazoline-2, the reaction expression of the method for 4-diketone
Embodiment
The reagent that uses among the embodiment all is chemical.The fusing point instrument is an X-6 type fusing point instrument, and fusing point is not proofreaied and correct; Infrared spectrometer is the NicoletMagaIR-560 type, the KBr compressing tablet; Nuclear magnetic resonance analyser is the ARX-400 type; Mass spectrograph is the ZAB-HS type.
The 2-anthranilo nitrile (0.20g, 1.7mmol), DMF (6.0mL), Zinc Chloride Anhydrous (1.2g, 8.5mmol), mixed solution joins in the autoclave, and oil bath is heated with stirring to about 200 ℃ reacted 5 hours.Stop heating, reaction finishes, and places and is cooled to room temperature.With the reaction solution dilute with water, separate out white precipitate.Suction filtration, water washing.Use 1 again, 4-dioxane thermosol, filtered while hot is removed insoluble impurity then.Gained filtrate is carried out vacuum rotary steam, obtains light yellow solid, uses 1 then, and 4-dioxane recrystallization, productive rate are 91%, mp＞300 ℃.The structural characterization data of reaction formula and product thereof are as follows:
The structural characterization data of product:
IR(KBr)，σ/cm
-1：3302，3055，1701，1682，1617，1444，1300，1142，757
1H?NMR(400MHz，DMSO)δ：11.3(s，1H，-CO-NH-CO-)，11.2(s，1H，Ar-NH-CO-)，7.91(d，1H，ArH)，7.65(d，1H，ArH)，6.94(m，2H，ArH)
MS(m/z)：163(M+H
+)
Ultimate analysis: calcd.C 59.25 H 3.70 N 17.28; Found C 58.89 H3.71 N17.17.
Concrete implementation step is with embodiment 1, and just the amount with Zinc Chloride Anhydrous changes 0.02g (0.17mmol) into.Productive rate is 43.7%.
Concrete implementation step is with embodiment 1, and just the amount with Zinc Chloride Anhydrous changes 2g (17mmol) into.Productive rate is 65.4%.
Concrete implementation step is with embodiment 1, and just the reaction times increases to 7 hours.Productive rate is 65.6%.
Embodiment 5
Concrete implementation step is with embodiment 1, and just catalyzer is used aluminum chloride instead, and product obtains thin-layer chromatography and confirms yield 92.6%
Concrete implementation step is with embodiment 1, and just catalyzer is used cupric chloride instead, and product obtains thin-layer chromatography and confirms yield 22%.
Concrete implementation step is with embodiment 1, and just catalyzer is used cuprous chloride instead, and product obtains thin-layer chromatography and confirms yield 25%.
Embodiment 8
Concrete implementation step is with embodiment 1, and just catalyzer is used toluene sulfonic acide instead, and product obtains thin-layer chromatography and confirms yield 47.8%.
Embodiment 9
Concrete implementation step is with embodiment 1, and just catalyzer is used p-methyl benzenesulfonic acid instead, and product obtains thin-layer chromatography and confirms yield 42%.
Concrete implementation step is with embodiment 1, just the 2-anthranilo nitrile is changed into 4-chloro-2-anthranilo nitrile (0.20g, 1.3mmol), Zinc Chloride Anhydrous (0.88g, 6.5mmol).The structural characterization data of reaction formula and product thereof are as follows:
The structural characterization data of product:
IR，σ/cm
-1：3198，3057，2819，1712，1668，1619，1484，1428，1285，1145，829.1，752.2
1H?NMR(400MHz，DMSO)δ：11.4(s，2H，＝NH)，7.79(s，1H，ArH)，7.66(d，1H，ArH)，7.17(d，1H，ArH)
MS(m/z)：194.9(M-H
+)。
Embodiment 11
Concrete implementation step is with embodiment 1, just the 2-anthranilo nitrile is changed into 5-chloro-2-anthranilo nitrile (0.20g, 1.3mmol), Zinc Chloride Anhydrous (0.88g, 6.5mmol).The structural characterization data of reaction formula and product thereof are as follows:
The structural characterization data of product:
IR，σ/cm
-1：3306，3054，2833，1743，1683，1619，1430，1286，754.7
1H?NMR(400MHz，DMSO)δ：11.4(s，1H，-CO-NH-CO-)，11.3(s，1H，Ar-NH-CO-)，7.88(s，1H，ArH)，7.21(d，2H，ArH)
MS(m/z)：194.9(M-H
+)。
Embodiment 12
Concrete implementation step just changes DMF into diethylformamide with embodiment 1.Productive rate 56.4%.Reaction formula is as follows:
Claims (6)
1. 1H, 3H-quinazoline-2, the synthetic method of 4-dione compounds, with adjacent amino fragrant nitrile and N, the reaction of N-dialkylformamide, synthetic 1H, 3H-quinazoline-2, the 4-diketone, the compound of being addressed is a starting raw material with amino fragrant nitrile of neighbour and N-alkyl formamides, one step of effect ShiShimonoseki cyclic condensation at catalyzer makes target compound, and reaction expression is:
R, R
1Be H, X, alkyl, alkoxyl group, wherein X is F, Cl, Br, I;
R
2Be H, alkyl, phenyl;
R
3Be methyl, ethyl.
2. a kind of 1H as claimed in claim 1,3H-quinazoline-2, the synthetic method of 4-dione compounds is characterized in that: as R, R
1When being adjacent condensed ring group, can be 4,5-OCH
2O-, four methynes, phenyl.
3. a kind of 1H as claimed in claim 1,3H-quinazoline-2, the synthetic method of 4-dione compounds is characterized in that: the N-alkyl formamides that reacts used can be dimethyl formamide (DMF) or diethylformamide.
4. a kind of 1H as claimed in claim 1,3H-quinazoline-2, the synthetic method of 4-dione compounds is characterized in that: the solvent of reaction is benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone or DMSO.
5. a kind of 1H as claimed in claim 1,3H-quinazoline-2, the synthetic method of 4-dione compounds, it is characterized in that: catalyst for reaction is (anhydrous) zinc chloride, (anhydrous) aluminum chloride, cupric chloride, cuprous chloride, toluene sulfonic acide or p-methyl benzenesulfonic acid, and the mol ratio of adjacent amino fragrant nitrile and catalyzer is 1: 0.1～5.
6. a kind of 1H as claimed in claim 1,3H-quinazoline-2, the synthetic method of 4-diketone compound is characterized in that: the reaction times is 1-5 hour.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704791B (en) * | 2009-11-06 | 2012-06-20 | 北京理工大学 | Method for synthesizing 1H,3H-quinazoline-2,4-diketone |
| CN106946800A (en) * | 2017-03-21 | 2017-07-14 | 华东师范大学 | A kind of synthetic method of (1H, the 3H) diketone of quinazoline 2,4 and its derivative |
| CN109206377A (en) * | 2018-09-19 | 2019-01-15 | 江苏食品药品职业技术学院 | A kind of new method preparing the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7- |
-
2006
- 2006-10-10 CN CNA200610140485XA patent/CN101096360A/en active Pending
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101704791B (en) * | 2009-11-06 | 2012-06-20 | 北京理工大学 | Method for synthesizing 1H,3H-quinazoline-2,4-diketone |
| CN106946800A (en) * | 2017-03-21 | 2017-07-14 | 华东师范大学 | A kind of synthetic method of (1H, the 3H) diketone of quinazoline 2,4 and its derivative |
| CN106946800B (en) * | 2017-03-21 | 2019-11-15 | 华东师范大学 | A kind of synthetic method of -2,4 (1H, 3H)-diketone of quinazoline and its derivative |
| CN109206377A (en) * | 2018-09-19 | 2019-01-15 | 江苏食品药品职业技术学院 | A kind of new method preparing the fluoro- 6- nitro -4- quinazoline amine of N- (the chloro- 4- fluorophenyl of 3-) -7- |
| CN109206377B (en) * | 2018-09-19 | 2021-08-27 | 江苏食品药品职业技术学院 | Novel method for preparing N- (3-chloro-4-fluorophenyl) -7-fluoro-6-nitro-4-quinazolinamine |
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