CN101704791B - Method for synthesizing 1H,3H-quinazoline-2,4-diketone - Google Patents
Method for synthesizing 1H,3H-quinazoline-2,4-diketone Download PDFInfo
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- CN101704791B CN101704791B CN2009102374234A CN200910237423A CN101704791B CN 101704791 B CN101704791 B CN 101704791B CN 2009102374234 A CN2009102374234 A CN 2009102374234A CN 200910237423 A CN200910237423 A CN 200910237423A CN 101704791 B CN101704791 B CN 101704791B
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- quinazoline
- diketone
- chloride
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Abstract
The invention relates to a method for synthesizing 1H,3H-quinazoline-2,4-diketone, belonging to the filed of organic synthesis. The method comprises the following steps: taking o-amino-nitrile as raw materials, catalyzing the raw materials by Lewis acid and protonic acid, condensing the raw materials with N-alkyl formamide, and synthesizing the 1H,3H-quinazoline-2,4-diketone and derivative thereof by one step. The method avoids the use of cyanide (toxic) in the traditional method, and simultaneously improves the productivity to a greater extent.
Description
Technical field
The present invention relates to a kind of synthetic 1H, 3H-quinazoline-2, (4-diones) method of compound belongs to the synthetic field of medicine to the 4-diketone for English name 1H, 3H-quinazoline-2.
Background technology
1H, 3H-quinazoline-2,4-diketone heterocyclic compounds has good biological activity and pharmaceutical activity, is one type of important medicine and fine-chemical intermediate; Can be used for the synthetic of various medicines, as via 1H, 3H-quinazoline-2; The 4-diketone can synthesize N-phenyl lungy-1H-quinazoline-2 that strong anti-mycobacterium is active, 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 with reductase inhibitor and diabetic complication,
And be used to treat 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), Alfuzosin (J.Med.Chem.1986; 29:19-25.), IAAP (J.Org.Chem.2002; 67 (23): 8284-8286.) and Vasocard (Chinese Journal of Pharmaceuticals, 2000,31 (9): 385); 1H, 3H-quinazoline-2,4-cyclohexadione compounds also can be used for 8-hydroxyl-1-(the 3-N-morpholinyl)-n-propyl-1H of synthetic ADP ribose polymerase suppressor factor; 3H-quinazoline-2,4-diketone, 8-hydroxyl-1-(3-phenoxy)-n-propyl-1H; 3H-quinazoline-2; 4-diketone (Biochimica et Biophysica Acta, 2006,17 (4): 913-919); 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 compound 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 Potssium Cyanide with fennel acid and make (Org.Synth., 1943,2:79-80); 4) react with the chlorosulfonyl phenylcarbimide with fennel acid 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 verivate 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; 7) with facing anthranilo nitrile and DMF in sealed vessel, ZnCl
2Cyclisation under the catalytic condition (Org.Lett., 2009,11 (6): 1193-1196.) make.All there is deficiency in these compound methods, and are high like reagent costliness or toxicity, reaction conditions is too violent, operational hazards, 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 objective of the invention is in order to solve the synthetic 1H of tradition, 3H-quinazoline-2, the method complicated operation of 4-diketone, productive rate are low; Problems such as reagent costs an arm and a leg, toxicity is big; Synthesize 1H and propose a kind of the reaction, 3H-quinazoline-2, the method for 4-diketone with adjacent amino fragrant nitrile and N-alkyl formamides.
The objective of the invention is to realize through following technical scheme.
A kind of synthetic 1H of the present invention; 3H-quinazoline-2; The method of 4-diketone, its concrete steps are: with the amino fragrant nitrile of neighbour, Lewis catalyzer, acid or alkali, N-alkyl formamides, solvent is 1: 0.1～5: 0.2～0.5: 2: 10～20 ratio in molar ratio, adds in the autoclave respectively; Temperature of reaction is more than 190 ℃, and the reaction times is 1～5 hour.After reaction finished, placement was cooled to room temperature and uses distilled water diluting, separates out white precipitate, filtration, recrystallization, and obtaining white crystal is 1H, 3H-quinazoline-2,4-diketone.
Its reaction expression is:
Wherein, the amino fragrant nitrile structure of described neighbour is shown below:
In the formula, R
1, R
2, R
3, R
4Be H, F, Cl, Br, I, alkyl, alkoxyl group, nitro, 4,5-OCH
2O-, four methynes.R
5Be H, alkyl, phenyl.
Described N-alkyl formamides structure is shown below:
In the formula, R
6, R
7Be all methyl or be all ethyl.
Described N-alkyl formamides be following any one: N (DMF) or DEF.
Said solvent be following any one: benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone, DMSO, N (DMF) or DEF etc.
Said Lewis catalyzer be following any one: zinc chloride, aluminum chloride, cupric chloride, cuprous chloride, toluene sulfonic acide, p-methyl benzenesulfonic acid, mercury chloride, cuprous chloride, titanium tetrachloride, tin chloride etc.
Described acid be following any one: HCl, H
2SO
4, H
3PO
4, acetic acid, (CH
2)
3-SO
3H,
Described alkali be following any one: sodium methylate, sodium ethylate, pyridine, ammoniacal liquor, NaOH, KOH, Na
2CO
3, NaHCO
3, K
2CO
3, KHCO
3
Beneficial effect:
The present invention uses adjacent nitrile compound to be reaction substrate, process and DMF condensation, and single step reaction can obtain 1H, 3H-quinazoline-2,4-diketone and verivate thereof.Use Lewis acid and the common catalysis of protonic acid, avoided using the prussiate that relates in the traditional method, reduce injury, reduced pollution environment to operator; Productive rate improves a lot simultaneously, reduces cost and has improved production efficiency.
Specific embodiment
Embodiment 1
The 2-anthranilo nitrile (0.3g, 0.002mol), DMF (8.0mL), Zinc Chloride Anhydrous (0.27g, 0.002mol), mixed solution join in the autoclave, drip the 0.1ml concentrated hydrochloric acid, oil bath is heated with stirring to 190 ℃ of reactions 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 filtrating is carried out vacuum rotary steam, obtains light yellow solid, uses the mixed solvent recrystallization of methyl alcohol and THF then, and productive rate is 95%, m.p.＞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 59.25H 3.70N 17.28; Found C 58.89H 3.71N17.17.
Embodiment 2
The 2-anthranilo nitrile (0.59g, 0.005mol), DMF (8.0mL), Zinc Chloride Anhydrous (0.67g, 0.005mol), mixed solution join in the autoclave, add 0.04gCH again
3ONa, oil bath is heated with stirring to 190 ℃ of reactions 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 filtrating is carried out vacuum rotary steam, obtains light yellow solid, uses the mixed solvent recrystallization of methyl alcohol and THF then, and productive rate is 93%, m.p.＞300 ℃.
Embodiment 3
The 2-anthranilo nitrile (0.59g, 0.005mol), DMF (8.0mL), anhydrous cupric chloride (0.67g, 0.005mol), mixed solution join in the autoclave, drip the 0.1ml concentrated hydrochloric acid, oil bath is heated with stirring to 190 ℃ of reactions 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 filtrating is carried out vacuum rotary steam, obtains light yellow solid, uses the mixed solvent recrystallization of methyl alcohol and THF then, and productive rate is 78%, m.p.＞300 ℃.
Claims (1)
1. one kind is synthesized suc as formula the 1H shown in 1; 3H-quinazoline-2; The method of 4-diketone is characterized in that concrete steps are: with the amino fragrant nitrile of neighbour, Lewis catalyzer, acid or alkali, N-alkyl formamides, solvent is 1: 0.1～5: 0.2～0.5: 2: 10～20 ratio in molar ratio, adds in the autoclave respectively; Temperature of reaction is more than 190 ℃, and the reaction times is 1～5 hour; After reaction finished, placement was cooled to room temperature and uses distilled water diluting, separates out white precipitate, filtration, recrystallization, and obtaining white crystal is the 1H shown in the formula 1,3H-quinazoline-2,4-diketone;
Wherein, the amino fragrant nitrile structure of described neighbour is suc as formula shown in 2:
Formula 1 formula 2
In the formula, R
1, R
2, R
3, R
4Be H, F, Cl, Br, I, alkyl, alkoxyl group, nitro; R
5Be H;
Described N-alkyl formamides structure is shown below:
In the formula, R
6, R
7Be all methyl or be all ethyl;
Said solvent be following any one: benzene,toluene,xylene, oil of mirbane, chlorobenzene, tetramethylene sulfone, DMSO, DMF or DEF;
Said Lewis catalyzer be following any one: zinc chloride, aluminum chloride, cupric chloride, cuprous chloride, mercury chloride, titanium tetrachloride, tin chloride;
Described acid is HCl; Described alkali is sodium methylate.
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| CN2009102374234A CN101704791B (en) | 2009-11-06 | 2009-11-06 | Method for synthesizing 1H,3H-quinazoline-2,4-diketone |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096360A (en) * | 2006-10-10 | 2008-01-02 | 北京理工大学 | Method for synthesizing 1H,3H-quinazoline-2,4-diketone compound |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101096360A (en) * | 2006-10-10 | 2008-01-02 | 北京理工大学 | Method for synthesizing 1H,3H-quinazoline-2,4-diketone compound |
Non-Patent Citations (2)
| Title |
|---|
| Li Jiarong, et al..A New and Facile Synthesis of Quinazoline-2,4(1H,3H)-diones.《ORAGANIC LETTERS》.2009,第11卷(第6期),1193-1196. * |
| LiJiarong et al..A New and Facile Synthesis of Quinazoline-2 |
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