Synthetic method and application of 1, 7-dichloroindolo [2, 1-b] quinazoline-6, 12-diketone compound

Abstract

The invention relates to a synthesis method and application of a 1, 7-dichloroindolo [2, 1-b] quinazoline-6, 12-diketone compound. A synthesis method of the crystal compound I comprises synthesis and separation, the synthesis comprises the following steps: dissolving 1.2511 g of benzamide, 1.0832 g of 4-chloroisatin and 1.9900 g of sodium hydroxide in 90 ml of absolute methanol and 10 ml of distilled water, heating, stirring and refluxing for 2 h, then adding 0.5799 g of cupric acetate monohydrate, and carrying out column chromatography to obtain a faint yellow crystal compound; the chemical formula of the crystal compound I is as follows: # imgabs0. The application of the crystal compound (I) is as follows: the organic compound crystal I shows certain inhibitory activity in antifungal activity screening tests of antibacterial cells such as epidermophyton flocculent and microsporum gypsum; an antifungal result shows that when the concentration is 100 [mu] M, a crystal sample I has a very strong inhibition effect on epidermophyton flocculent and microsporum gypsum, and the inhibition rates of the epidermophyton flocculent and microsporum gypsum are 93.435 + / -1.212 and 74.385 + / -2.743 respectively.

Description

Technical Field

[0001] The present invention relates to a ketone compound and its application, and in particular to a method for synthesizing a quinazoline dione compound, and more specifically to a method for preparing indolo[2,1-b]quinazoline-6,12-dione and its application. Background Art

[0002] 1,7-Dichloroindole indole [2,1-b] quinazoline-6,12-dione is an important class of pharmaceutical intermediates. This compound has been reported in the literature [1-2].

[0003] References:

[0004] 1.Divergent Synthesis of Quinazolin-4(3H)-ones and TryptanthrinsEnabled by a tert-B utyl Hydroperoxide / K3PO4-Promoted Oxidative Cyclization of Isatins at Room Temperature, Jia, Feng-Cheng; Zhou, Zhi-Wen; Xu, Cheng; Wu, Yan-Dong; Wu, An-Xin, Organic Letters(2016),18(12),2942-2945.

[0005] 2. Copper(I)-catalyzed synthesis of natural alkaloid tryptanthrin and its derivatives, Hong, Jiankai; Zhang, Min; Shi, Liang; Liu, Peng; Guo, Yuchao; Zhao, Ting; Li, Qing X.; Ya ng, Liuqing, New Journal of Chemistry (2022), 46(28), 13540-13545. Summary of the invention

[0006] The compound referred to in the present invention is prepared by reflux benzamide and 4-chloroindigo red in a solvent of 20% (mass ratio) sodium hydroxide, anhydrous methanol and deionized water in a volume ratio of 9:1 for 2 hours, and then adding 0.5-0.6g of copper acetate monohydrate and 100mL of chlorobenzene to perform a one-pot reflux reaction, and the compound is represented by the following chemical formula:

[0007]

[0008] Chemical name: 1,7-dichloroindolo[2,1-b]quinazoline-6,12-dione, referred to as compound (I).

[0009] The synthesis method includes synthesis and separation. The synthesis is as follows: 1.2511 g of benzamide, 1.0832 g of 4-chloroindigo red and 1.9900 g of sodium hydroxide are dissolved in 90 mL of anhydrous methanol and 10 mL of distilled water, heated and stirred under reflux for 2 hours, and then 0.5799 g of monohydrated copper acetate is added, and a light yellow crystalline compound is obtained after column chromatography.

[0010] The synthetic reaction is as follows:

[0011]

[0012] The synthetic method can obtain the target product in one step, and the process is simple and the operation is convenient.

[0013] The organic compound crystal I showed certain inhibitory activity in the antifungal activity screening test of antibacterial cells such as Epidermophyton floccosum and Microsporum gypseum. The antifungal results showed that at a concentration of 100 μM, the crystal sample 1 had a strong inhibitory effect on Epidermophyton floccosum and Microsporum gypseum. The inhibition rates were 93.435±1.212 and 74.385±2.743, respectively.

[0014] The reaction mechanism of this reaction can be inferred to be that 4-chloroindigo carmine undergoes a dimerization reaction under the action of benzamide, sodium hydroxide and 4-chloroindigo carmine to form a crystalline compound I. The reaction mechanism has been reported in the literature, see reference 1 of this article. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 This is the X-ray diffraction analysis diagram of crystalline compound I. DETAILED DESCRIPTION

[0016] 1. Preparation of crystalline compound I:

[0017] In a 100mL two-necked bottle, under anhydrous and oxygen-free conditions, add benzamide 0.7283g (5.23mmol), 4-chloroindigo red 1.0g (5.52mmol), and sodium hydroxide 0.9036g, dissolve the mixture in a mixed solvent of 90mL anhydrous methanol and 10mL distilled water, reflux for 60h, stop the reaction, and remove the solvent under reduced pressure. Dissolve the residue in water and extract with CH2Cl2 (20mLx2), dry the organic phase with anhydrous sodium sulfate, and remove the solvent by rotation to obtain a light red viscous liquid. The crude product is chromatographed on a petroleum ether / dichloromethane (1:9) column to obtain light yellow crystals, mp104.0-106.2℃, yield 75%; 1HNMR (600MHz, CDCl3, 27℃), δ (ppm) = 8.48 (d, J = 7.0Hz, 1H), 7.83-7.93 (m, 3H), 7.64 (t, 1.3Hz, 1H), 7.53 (t, J = 7.5Hz, 1H); 13 CNMR: IR: 3404, 2975, 2044, 1735, 1690, 1599, 1582,, 1452, 1287, 1262, 1089, 1050, 881, 799. HRMS for C15H6Cl2N2O2: calcd for C15H6Cl2N2O2: 315.9806; found: 315.9790. The crystal data are shown in Table 1 below:

[0018] Table 1: Crystal data of crystalline compound I:

[0019]

[0020]

[0021] Table 2. Typical bond length data of crystals:

[0022]

[0023]

[0024] Table 3. Bond angle data of crystals

[0025]

[0026] .

[0028] 2. Antimicrobial activity application

[0029] (1) Antifungal test

[0030] Take a 96-well culture plate, dilute the sample to be tested, add fungal liquid to each well, the final concentration is 5×105CFU / mL, culture at 25°C for 5 days, and detect the absorbance at 625nm with an enzyme marker. The experiment also sets up a culture medium blank control, a fungal control, and a terbinafine hydrochloride positive drug control. The results are shown in Table 4:

[0031] Table 4 Inhibitory effect of crystal sample I on two fungi

[0032]

[0033] In this experiment, the antifungal activity of 1 crystal sample I against Epidermophyton floccosum and Microsporum gypseum was screened. The antifungal results showed that at a concentration of 100 μM, crystal sample 1 had a strong inhibitory effect on Epidermophyton floccosum and Microsporum gypseum (Table 4).

Claims

1. A crystalline compound I shown by the following chemical formula and unit cell parameters, wherein the synthesis method is: The synthesis method includes synthesis and separation, wherein 1.2511 g of benzamide, 1.0832 g of 4-chloroindigo red and 1.9900 g of sodium hydroxide are dissolved in 90 ml of anhydrous methanol and 10 ml of distilled water, heated and stirred under reflux for 2 h, and then 0.5799 g of monohydrated copper acetate is added, and a light yellow crystalline compound is obtained after column chromatography, wherein the chemical formula is as follows: The unit cell parameters are as follows: At 100(2)K, on ​​an Oxford X-ray single crystal diffractometer, using MoKα rays monochromatized by a graphite monochromator, The diffraction data was collected by ω-θ scanning, which is a monoclinic system with a space group of P 21 / n. Its unit cell parameters are alpha=90deg; beta = 93.258 (5) degrees; gamma=90deg.

2. The use of the crystalline compound (I) according to claim 1, characterized in that: The organic compound crystal I showed certain inhibitory activity in the antifungal activity screening test of antibacterial cells such as Epidermophyton floccosum and Microsporum gypseum; the antifungal results showed that at a concentration of 100 μM, the crystal sample I had a strong inhibitory effect on Epidermophyton floccosum and Microsporum gypseum, and the inhibition rates were 93.435±1.212 and 74.385±2.743, respectively.

Images