CN102911177A - 7-(4-chlorphenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone and synthetic method thereof - Google Patents

Abstract

The invention provides 7-(4-chlorphenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone and a synthetic method thereof. The method comprises the following steps of: uniformly mixing 3-amino-1,2,4-triazole, p-chlorobenzaldehyde, 2-hydroxyl-1,4-naphthaquinone and p-methylbenzene sulfonic acid with a usage amount of catalyst, heating and stirring, controlling the temperature at 110-125 DEG C and reacting for 2.5-3 hours. The 7-(4-chlorphenyl)5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-diketone prepared according to the invention introduces chlorine atoms, thus having stronger activity and being more beneficial to absorption. The method provided by the invention is green and environment-friendly, and has the characteristics that the raw materials are available, the operation is simple and the yield is high.

Description

7-(4-Chlorophenyl)-5,6-dihydro-7aH-benzo[h]1,2,4-triazolo[3,4-b]quinazoline-5,6-di Ketones and their synthesis

technical field

The present invention relates to a 1,2-naphthoquinone derivative, in particular to a 7-(4-chlorophenyl)-5,6-dihydro-7a H -benzo[ h ][1,2 ,4]-triazolo[3,4- b ]quinazoline-5,6-dione.

Background technique

Cancer is a kind of disease that seriously threatens human health. Finding effective anticancer drugs is an important research topic in the world medical field. According to literature reports, 1,2-Naphthoquinone derivatives have anti-tumor, anti-inflammatory, antibacterial and other properties. biological activity. In recent years, the antitumor activity of 1,2-naphthoquinone derivatives has attracted increasing attention. Some natural 1,2-naphthoquinone compounds such as: β -lapachone, Rhinacanthone, Biflorin, mansone E and artificial Synthetic 1,2-naphthoquinone compounds such as: salvexin have shown unique anti-tumor effects. Compared with 1,4-naphthoquinones, the antitumor effect of 1,2-naphthoquinones has the following three advantages; 1) Strong anticancer activity, 1,4-naphthoquinones with similar structure and 1,2 -Naphthoquinone compounds, the anticancer activity of the latter is 2-5 times greater than that of the former; 2) Good selectivity, 1,2-Naphthoquinone compounds have weak killing effect on normal cells and have strong selectivity; 3) It has a strong inhibitory effect on topoisomerase, which points out a direction for us to develop selective topoisomerase inhibitors.

Nitrogen heterocycles are an important intermediate in organic synthetic chemistry, and are widely used in fine chemicals, pesticides and other related industries. Nitrogen heterocycles are also key structural fragments of some biologically active substances and drugs. Combining the nitrogen heterocycle with 1,2-naphthoquinone can significantly increase the activity of the compound.

Due to their unique physical, chemical properties and biological activity, chlorine-containing organic compounds are used in many medicines, such as the antibiotic chloramphenicol, the antipsychotic drug chlorpromazine hydrochloride, the anti-inflammatory and analgesic drug diclofenac, etc. .

The innovation of the present invention lies in the synthesis of a chlorine-substituted azacyclic 1,2-naphthoquinone compound, which has not been reported yet. The preliminary pharmacological activity test shows that the compound has strong anticancer activity.

Contents of the invention

The object of the present invention is to provide a new compound 7-(4-chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3, 4- b ]quinazoline-5,6-dione.

Another object of the present invention is to provide a synthesis method of the compound.

In order to achieve the purpose of the present invention, 7-(4-chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3,4 -b ] quinazoline-5,6-dione, which is a compound having a structure shown in formula I:

。

.

Specifically, the 1,2-naphthoquinone compound of the present invention is 7-(4-chlorophenyl)-5,6-dihydro-7a H -benzo[ h ][1,2,4]-tri Azozolo[3,4- b ]quinazoline-5,6-dione, molecular formula: C ₁₉ H ₉ ClN ₄ O ₂ , molecular weight: 360.04, appearance: yellow solid, melting point: 245-246°C.

7-(4-chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3,4- b ]quinazoline of the present invention The synthetic method of -5,6-diketone adopts the p-toluene of 3-amino-1,2,4-triazole, 4-chlorobenzaldehyde, 2-hydroxyl-1,4-naphthoquinone and catalyst consumption The sulfonic acid is mixed evenly, heated and stirred, the temperature is controlled at 110-125° C., and reacted for 2.5-3 hours.

Wherein, the molar ratio of 3-amino-1,2,4-triazole, 4-chlorobenzaldehyde and 2-hydroxy-1,4-naphthoquinone is 1:1-1.1:1. After the reaction, the reaction mixture was dissolved in dichloromethane, washed twice with water, evaporated to remove the solvent, and recrystallized with 95% ethanol to obtain 7-(4-chlorophenyl)-5,6-dihydro- 7aH -benzo [ h ][1,2,4]-triazolo[3,4- b ]quinazoline-5,6-dione.

Its reaction formula is:

。

.

Detailed ways

The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

Put 0.84g 3-amino-1,2,4-triazole, 1.40g 4-chlorobenzaldehyde, 1.74g 2-hydroxy-1,4-naphthoquinone and 0.2g p-toluenesulfonic acid together in 50ml reaction Mix well in the bottle, heat and stir, the temperature is controlled at 110°C, and react for 2.5 hours. The reaction mixture was dissolved in 20 ml of dichloromethane, washed twice with 20 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized with 95% ethanol to obtain the yellow corresponding product 7-(4-chlorophenyl)-5 , 6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3,4- b ]quinazoline-5,6-dione 3.17g, the yield is 88 %.

After testing, molecular formula: C ₁₉ H ₉ ClN ₄ O ₂ , molecular weight: 360.04, appearance: yellow solid, melting point: 245-246°C;

IR (KBr) ν : 3074, 2923, 1684, 1598, 1586, 1512, 1501, 1478, 1449, 1296, 1281, 1273, 1228, 1093, 766 cm ^-1 ;

¹ H NMR (CDCl ₃ , 400 MHz) δ : 8.99 (d, J = 7.6 Hz, 1H, ArH), 8.59 (s, 1H, CH), 8.26 (d, J = 7.6 Hz, 1H, ArH), 7.97 -7.50 (m, 6H, ArH);

¹³ C NMR (CDCL ₃ , 100 MHz) Δ : 178.6, 178.2, 159.3, 157.3, 155.6, 152.9, 138.2, 135.5, 134.9, 133.5, 132.4, 130.1, 129.6, 129.1, 126.4, 113.9;

C ₁₉ H ₉ ClN ₄ O ₂ element content: C 63.26%, H 2.51%, N 15.53%; confirmed: C 63.32%, H 2.42%, N 15.60%.

Put 8.4g of 3-amino-1,2,4-triazole, 14.7g of 4-chlorobenzaldehyde, 17.4g of 2-hydroxy-1,4-naphthoquinone and 2g of p-toluenesulfonic acid into a 250ml reaction flask Mix evenly in the medium, heat and stir, the temperature is controlled at 120°C, and react for 3 hours. The reaction mixture was dissolved in 200 ml of dichloromethane, washed twice with 200 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized with 95% ethanol to obtain the yellow corresponding product 7-(4-chlorophenyl)-5 , 6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3,4- b ]quinazoline-5,6-dione 31.0g, yield 85 %.

Mix 42g of 3-amino-1,2,4-triazole, 77.6g of 4-chlorobenzaldehyde, 87g of 2-hydroxy-1,4-naphthoquinone and 10g of p-toluenesulfonic acid in a 1000ml reaction flask Evenly, heat and stir, the temperature is controlled at 125°C, and react for 2.5 hours. The reaction mixture was dissolved in 1000 ml of dichloromethane, washed twice with 1000 ml of water, dried over anhydrous sodium sulfate, evaporated to remove the solvent, and recrystallized with 95% ethanol to obtain the yellow corresponding product 7-(4-chlorophenyl)-5 , 6-dihydro- 7aH -benzo[ h ][1,2,4]-triazolo[3,4- b ]quinazoline-5,6-dione 162g, yield 90% .

The antitumor activity of the target compounds was tested by MTT method. The breast cancer cell MCF-7 was used as the test cell line, and the adherent tumor cells in the logarithmic growth phase were selected. After digesting with trypsin, the RPMI l640 medium containing 10% calf serum was used to make a cell suspension of 5000 cells/mL. solution, inoculated in a 96-well culture plate, inoculated 200 μL per well, and incubated at 37°C, 5% CO ₂ for 24 h. Set up a negative control group, a positive control group and an administration group. The experimental group was replaced with a new medium containing different concentrations of the tested samples, the control group was replaced with a medium containing an equal volume of solvent, and the positive control group was given the positive control drug doxorubicin (diluted with complete medium to a concentration of 10 μmol ^{L- 1} ) Set up 3-5 parallel wells for each group, culture at 37°C, 5% CO ₂ for 4-5 days. The supernatant was discarded, and 200 μL of freshly prepared serum-free medium containing 0.2 mg/mL MTT was added to each well. Continue culturing at 37°C for 4h. Carefully discard the supernatant, and add 200 μL DMSO, mix with a micro-ultrasonic oscillator, and measure the optical density on a microplate reader with a test wavelength of 570 nm and a reference wavelength of 450 nm. The inhibitory rate of the drug on tumor cell growth was calculated according to the following formula: tumor cell growth inhibitory rate%=(1-OD experiment/OD control)×100%. With 7-(4-chlorophenyl)-5,6-dihydro-7a H -benzo[ h ][1,2,4]-triazolo[3,4- b ]quinazoline-5 , The dose-response curve can be obtained by plotting different concentrations of 6-diketone against the growth inhibition rate of tumor cells, from which the IC ₅₀ of the half maximal killing concentration of the sample can be calculated. Its IC ₅₀ value is 5.84 μg/mL.

Although the present invention has been described in detail with general descriptions and specific embodiments above, it is obvious to those skilled in the art that some modifications or improvements can be made on the basis of the present invention. Therefore, the modifications or improvements made on the basis of not departing from the spirit of the present invention all belong to the protection scope of the present invention.

Claims (4)

1.7-(4-Chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ]1,2,4-triazolo[3,4- b ]quinazoline-5,6- Diketone, its structural formula is as follows: . 2. prepare 7-(4-chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ]1,2,4-triazolo[3,4- b as claimed in claim 1 ] The synthetic method of quinazoline-5,6-diketone is characterized in that, it adopts first 3-amino-1,2,4-triazole, 4-chlorobenzaldehyde, 2-hydroxyl-1,4 - The naphthoquinone and the p-toluenesulfonic acid used as catalyst are uniformly mixed, heated and stirred, and reacted at 110-125° C. for 2.5-3 hours. 3. method according to claim 2, is characterized in that, the mol ratio of 3-amino-1,2,4-triazole, 4-chlorobenzaldehyde, 2-hydroxyl-1,4-naphthoquinone is 1 :1~1.1:1. 4. according to the described method of claim 2 or 3, it is characterized in that, after reaction, reaction mixture dissolves with dichloromethane, water washes twice, evaporates solvent, with 95% ethanol recrystallization, obtains 7-(4- Chlorophenyl)-5,6-dihydro- 7aH -benzo[ h ]1,2,4-triazolo[3,4- b ]quinazoline-5,6-dione.