Preparation and application of indoline-2-ketone compound derivative

Abstract

Cell parameters of the crystal compound are as follows: diffraction data are collected in an omega-theta scanning mode by using MoK alpha rays monochromatized by a graphite monochromator on an Oxford X-ray single crystal diffractometer at the temperature of 273 k, and the crystal compound is characterized in that the crystal belongs to a triclinic system, P-1; the cell parameters are as follows: alpha is equal to 79.857 (3) degrees; beta is equal to 87.082 (3) degrees; gamma is equal to 87.829 (3) degrees; the synthesis method of the crystal chlorine compound (I) comprises the following steps: weighing 0.02 35 g of benzophenone hydrazone and 0.6720 g of 1.0 g of 7-chloroisatin and acetic acid ketone monohydrate complex, putting into a 150mL flask, adding 100.0 mL of chlorobenzene as a solvent, stirring at room temperature for 48 hours, carrying out column chromatography separation, eluting with petroleum ether / dichloromethane (1 / 1), and carrying out vacuum drying to obtain the crystal chlorine compound (I). And naturally volatilizing the collected front component points to obtain the target crystal compound I, namely the 6-bromo-3-diphenylmethylene indoline-2-ketone crystal. The application of the crystal chlorine compound (I) is that the crystal chlorine compound (I) has a relatively strong inhibition effect on epidermophyton flocculent, and the IC50 value of the crystal chlorine compound (I) is 0.063 + / -0.008.

Description

I. Technical Field

[0001] This invention relates to the use of a compound, and more particularly to the preparation and use of an indoline-2-one, specifically the preparation and use of a 6-chloro-3-diphenylmethyleneindoline-2-one compound. II. Background Technology

[0002] Indoline-2-one compounds are important pharmaceutical intermediates with a wide range of applications. Similar synthetic methods and applications have been reported in the literature [1].

[0003] 1. References:

[0004] Synthesis and spectroscopic studies on the new Schiff base derived from the 1:1condensation of isatin with amines and its evaluating biological activity, Khubeiz, Mohamad Jawad, International Journal of ChemTech Research (2016), 9(7), 516-522. III. Summary of the Invention

[0005] The compound referred to in this invention is a compound represented by the following chemical formula (Ⅰ) formed by reacting benzophenone hydrazone, 6-chloroindigo, and ketone acetate monohydrate in a one-pot reaction under reflux in 100 mL of chlorobenzene solvent for 48 hours:

[0006]

[0007] Its chemical name is: 6-chloro-3-benzophenone hydrazone 2-indolone

[0008] Common name: Benzophenone-6-chloroindigo azine

[0009] The compound referred to in this invention is a compound represented by the following chemical formula (Ⅰ) obtained by reacting benzophenone hydrazone, 6-chloroindigo and ketone acetate monohydrate in a one-pot reaction in 100 mL of chlorobenzene solvent under reflux for 48 hours:

[0010] The synthesis of compound (I) involved weighing benzophenone hydrazone, 0.6914 g of 6-chloroindigo and 0.6720 g of the acetone monohydrate complex, placing them in a 100.0 mL flask, adding 100 mL of chlorobenzene as solvent, stirring at room temperature for 48 hours, followed by column chromatography separation with petroleum ether / dichloromethane (1 / 1). The slightly earlier fraction was allowed to evaporate naturally to obtain 6-chloro-3-diphenylmethyleneindololin-2-one crystals. Two crystalline compounds were obtained in this experiment: the slightly earlier fraction was a monomolecule of 6-chloro-3-diphenylmethyleneindololin-2-one crystal I, and the slightly later fraction was 6-chloro-3-diphenylmethyleneindololin-2-one monohydrate crystals. A patent application for this crystalline compound was filed on November 15, 2024, with application number 202410808698.3. The reaction mechanism can be deduced as follows: Benzophenone hydrazone first undergoes dimerization under the action of copper salt to form the benzophenone hydrazone dimer intermediate benzophenone azine, and then reacts with 6-chloroindigo to form the target product in one step.

[0011] This experiment screened the antifungal activity of crystalline sample I against *Epidermophyton floccosum*. The antifungal results showed that at a concentration of 2 μM, crystalline sample I exhibited strong inhibitory activity against *Epidermophyton floccosum* (Table 3), with an IC50 value of 0.063 ± 0.008. IV. Description of the attached drawings

[0012] Figure 1 Single-crystal diffraction pattern of the target product, benzophenone-6-chloroindigo acridine. V. Detailed Implementation Methods

[0013] Preparation of 1,6-chloro-diphenylmethyleneindololin-2-one

[0014] In a 100 mL two-necked flask under anhydrous and oxygen-free conditions, 0.0235 g of benzophenone hydrazone and 0.6720 g of the complex of 1.0 g of 7-chloroindigo and acetone monohydrate were weighed and placed in a 150 mL flask. 100.0 mL of chlorobenzene was added as solvent, and the mixture was stirred at room temperature for 48 hours. After separation by column chromatography, the mixture was eluted with petroleum ether / dichloromethane (1 / 1). The collected foreskin fraction was allowed to evaporate naturally to obtain 6-bromo-3-diphenylmethyleneindololin-2-one crystals; yield: 65%; light yellow crystals, melting point >200℃; 1 H NMR(500MHz,298K,CDCl3)δppm 10.98(s,1H),7.69(t,2H,ArH),7.68-7.69(m,2H,ArH),7.45-7.57(m,7H),7.15-7.16(m,2H),7.05-7.07(m,1H),6.93(d,J=1.69Hz,1H), 13C{1H}NMR(150MHz,298K,DMSO)164.5,159.1,146.3,146.2,138.3,136.7,134.2,131.3, 130.3,129.4,129.2,129.1,128.9,128.9,128.7,122.8,115.8,111.4; HRMSm / z(%)calcd for C21H14N3OCl:calcd.359.8050;found:359.7980;ν max (cm -1 )3618,3420,3242,1741,1720,1606,1545,1531,1479,1443,1368,1322,1302,1285,1244,1209,1181,1102,1071,999,823,681,607,572,530,515;

[0015] The data for nitrogen compound crystals are as follows:

[0016] Empirical formula C21H14N3OCl

[0017] Molecular weight 359.80

[0018] Temperature 170.00K

[0019] wavelength

[0020] Crystal system, space group triclinic, P-1

[0021] Unit cell parameters α = 79.857(3)°.

[0022] β=87.082(3)°.

[0023] γ=87.829(3)°

[0024] volume

[0025] Charge density 2, 1.338 Mg / m^3

[0026] Absorption correction parameter: 1.320 mm^-1

[0027] The number of electrons in a single cell is 372.

[0028] Crystal size: 0.17 x 0.17 x 0.05 mm

[0029] The range of the angle Theta is 2.441 to 54.867.

[0030] HKL's index collection range is -6 <= h <= 6, -13 <k<=13,-19<l<=19

[0031] Collected / independent diffraction data 15408 / 3377 [R(int)=0.0622]

[0032] Absorption correction method multi-scan

[0033] The method used for refinement is the matrix least squares method of F^2.

[0034] Number of data points / Number of usage restrictions / Number of parameters: 3377 / 0 / 235

[0035] Method 1.071 for fine-tuning

[0036] The uniformity factors of the diffraction points are R1 = 0.0552 and ωR2 = 0.1491.

[0037] The observed diffraction coincidence factors are R1 = 0.0672 and ωR2 = 0.1609.

[0038] Maximum peaks and valleys on the difference Fourier plot Table 2 Typical bond length data for crystals:

[0039]

[0040]

[0041] Table 3 Typical bond angle data for crystals

[0042]

[0043]

[0044]

[0045] 4. Application of antibacterial activity

[0046] (1) Antifungal test

[0047] A 96-well culture plate was used. The sample to be tested was diluted, and fungal culture was added to each well to a final concentration of 5 × 10⁵ CFU / mL. The plate was incubated at 25°C for 5 days, and the absorbance at 625 nm was measured using a microplate reader. A blank control of the culture medium, a fungal control, and a terbinafine hydrochloride positive control were also included in the experiment. The results are shown in Table 3.

[0048] Table 3. Inhibitory effect of crystal sample I on one fungal strain: Epidermophyton floccosum

[0049]

Claims

1. A crystalline compound represented by the following chemical formula (Ⅰ):

2. The chlorine compound crystal I according to claim 1, wherein the unit cell parameters are as follows: at 273 K, using MoKα rays monochromated by a graphite monochromator on an Oxford X-ray single crystal diffractometer, The diffraction data is collected using the ω-θ scanning method, characterized in that... The crystal belongs to the triclinic crystal system, P-1; Its unit cell parameters: α = 79.857(3)°; β=87.082(3)°; γ=87.829(3)°.

3. The method for synthesizing the chlorine compound (I) according to claim 1, comprising synthesis, separation and purification, wherein the synthesis comprises weighing 0.0235 g of benzophenone hydrazone and 1.0 g of 7-chloroindigo and 0.6720 g of the acetone monohydrate complex, placing them in a 150 mL flask, adding 100.0 mL of chlorobenzene as solvent, stirring at room temperature for 48 hours, separating by column chromatography, eluting with petroleum ether / dichloromethane (1 / 1), and allowing the collected pre-component to evaporate naturally to obtain the target crystalline compound I, 6-bromo-3-diphenylmethyleneindololin-2-one crystals.

4. The use of the chlorine compound (I) according to claim 1, characterized in that: The crystalline compound I exhibits a strong inhibitory effect on Epidermophyton floccosum, with an IC50 value of 0.063 ± 0.008.

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