Spiro quinazoline derivative and preparation method thereof

A technology for quinazoline and derivatives, which is applied in the field of spirocyclic quinazoline derivatives and their preparation, can solve the problems of harsh reaction conditions, low reaction yield, and many by-products, and achieve simple post-processing and high product activity , the effect of less by-products

Active Publication Date: 2013-12-11
INST OF CHEM IND OF FOREST PROD CHINESE ACAD OF FORESTRY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, the traditional multi-component reaction synthesis of spirocyclic compounds has the disadvantages of harsh reaction conditions, many by-products, low reaction yield, and serious pollution.

Method used

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  • Spiro quinazoline derivative and preparation method thereof
  • Spiro quinazoline derivative and preparation method thereof
  • Spiro quinazoline derivative and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] The preparation of compound a:

[0040]

[0041] Add 1mmol of 5-amino-1H-tetrazolium, 1mmol of isatin, 1mmol of 5,5-dimethyl-1,3-cyclohexanedione, 4002mL of polyethylene glycol, 2mL of water and para Toluenesulfonic acid 0.5mmol, warmed up to 80°C, and reacted under stirring for 12h. The reaction solution was cooled to 40-50°C, poured into 30 mL of cold water, and centrifuged to obtain a solid. The solid was recrystallized with 4 mL of acetonitrile, and the recrystallized solid was vacuum-dried at a vacuum degree of 0.1Mpa and a temperature of 50°C to obtain spiro[indoline-3,9'-tetrazole[5,1-b ]quinazoline]-2,8'(5'hydrogen)-one derivatives. Yield: 86%, white solid; mp310-312℃; 1 H NMR (400MHz, DMSO-d 6 )δ12.03(s,1H),10.88(s,1H),7.28(t,J=7.6Hz,1H),7.10(d,J=7.3Hz,1H),6.91(dd,J=15.0,7.6 Hz,2H),2.66(dd,J=35.1,17.1Hz,2H),2.15(dt,J=24.9,12.5Hz,2H),1.05(d,J=10.0Hz,6H); 13 C NMR (101MHz, DMSO-d 6 )δ193.14, 173.55, 153.15, 148.74, 143.02, 130.75, 130.16, 123.99, 122.66...

Embodiment 2

[0043]Preparation of compound b:

[0044]

[0045] Add 1mmol of 5-amino-1H-tetrazolium, 1mmol of 5-fluoroisatin, 1mmol of 5,5-dimethyl-1,3-cyclohexanedione, 4004mL of polyethylene glycol and 36 % concentrated hydrochloric acid 0.5mmol, warmed up to 80°C, and reacted under stirring for 12h. The reaction solution was cooled to 40-50°C, poured into 30 mL of cold water, and centrifuged to obtain a solid. The solid was recrystallized with 4 mL of acetonitrile, and the recrystallized solid was vacuum-dried at a vacuum degree of 0.1Mpa and a temperature of 50°C to obtain spiro[indoline-3,9'-tetrazole[5,1-b ]quinazoline]-2,8'(5'hydrogen)-one derivatives. Yield: 90%, white solid; mp308-310℃; 1 H NMR (400MHz, DMSO-d 6 )δ12.08(s,1H),10.92(s,1H),7.21(dd,J=7.9,2.2Hz,1H),7.12(s,1H),6.93(d,J=4.2Hz,1H), 2.65(q,J=17.1Hz,2H),2.18(d,J=10.9Hz,2H),1.05(s,6H); 13 C NMR (101MHz, DMSO-d 6 )δ193.25, 173.68, 159.85, 157.49, 153.47, 148.69, 139.36, 131.44, 117.02, 112.45, 111.36, 104.57, 65.63...

Embodiment 3

[0047] Preparation of compound c:

[0048]

[0049] Add 1mmol of 5-amino-1H-tetrazolium, 1mmol of 7-fluoroisatin, 1mmol of 5,5-dimethyl-1,3-cyclohexanedione, 4mL of water and 98% concentrated sulfuric acid in a 25mL single-necked flask. 0.5mmol, heated to 80°C, and reacted for 16h under stirring. The reaction solution was cooled to 40-50°C, poured into 30 mL of cold water, and centrifuged to obtain a solid. The solid was recrystallized with 4 mL of acetonitrile, and the recrystallized solid was vacuum-dried at a vacuum degree of 0.1Mpa and a temperature of 50°C to obtain spiro[indoline-3,9'-tetrazole[5,1-b ]quinazoline]-2,8'(5'hydrogen)-one derivatives. Yield: 83%, white solid; mp297-299℃; 1 H NMR (400MHz, DMSO-d 6 )δ12.14(s,1H),11.47(s,1H),7.51–7.11(m,1H),7.02(d,J=7.1Hz,1H),6.98–6.66(m,1H),2.67(dd ,J=38.8,17.1Hz,2H),2.18(dd,J=41.4,16.3Hz,2H),1.05(d,J=11.1Hz,6H); 13 C NMR (101MHz, DMSO-d 6 )δ193.34, 173.38, 153.46, 148.65, 145.67, 132.63, 130.18, 123.67, 120.25, 117....

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Abstract

The invention discloses a spiro quinazoline derivative and a preparation method thereof. The molecular structural formula of the spiro quinazoline derivative is as shown in the specification, wherein R1 is any one or two out of hydrogen, methyl, trifluoromethyl, fluorine or chlorine, and R2 is hydrogen, methyl or phenyl. The spiro quinazoline derivative has an excellent antibacterial effect particularly on pseudomonas aeruginosa, enterobacter aerogenes and staphylococcus epidermidis, and has the better antibacterial effect on the pseudomonas aeruginosa, the enterobacter aerogenes and the staphylococcus epidermidis than a marketed bactericide bromogeramine, and the preparation method has the advantages of simple process, mild condition, high productivity, simple and convenient post treatment, high activity of an obtained product and the like.

Description

technical field [0001] The present invention relates to spiro[dihydroindoline-3,9'-tetrazole[5,1-b]quinazoline]-2,8'(5'hydrogen)-one derivatives, their preparation method and application , belonging to the field of mechano-synthetic chemistry. Background technique [0002] Multicomponent Coupling Reactions (Multicomponent Coupling Reactions), that is, "one pot method", is to put three or more reactant raw materials into the reactor and give them certain reaction conditions to make them react. Multicomponent chemical reactions are characterized by simple operation, high resource utilization and high atom economy. They are an important class of organic chemical reactions and have wide applications in the design and synthesis of new drugs, combinatorial chemistry and natural product synthesis. [0003] Organic spirocyclic compounds have structural advantages that general organic compounds do not have, such as spiro conjugation, spiro hyperconjugation or heteroprojection effect...

Claims

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Application Information

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IPC IPC(8): C07D487/20A61P31/04A01P1/00
Inventor 商士斌沈明贵王娟王丹宋杰
Owner INST OF CHEM IND OF FOREST PROD CHINESE ACAD OF FORESTRY
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