2-indolinimine spiropyrrolidinone compound and crystal form thereof, preparation method and application thereof

Abstract

This invention discloses a 2-indolineimine spiropyrrolidone compound with the structure shown in formula (A), its crystal form, preparation method, and applications. This invention provides crystal form I of the compound of formula (A), which is triclinic with space group P-1 and cell parameters α = 100.605(2)°, β = 106.706(2)°, and γ = 92.754(2)°. This invention also provides a method for preparing crystal form A, successfully obtaining a 2-indolineimine spiropyrrolidone compound and its crystal form. Furthermore, the compound or its crystal form exhibits certain antibacterial activity and good stability, greatly facilitating subsequent product transportation, storage, or formulation processes.

Description

Technical Field

[0001] This invention belongs to the field of compound technology, specifically a 2-indolineimine spiropyrrolidone compound, its crystal form, preparation method, and application. Background Technology

[0002] Indole rings are widely found in natural products and synthetic drugs, and related studies have shown that compounds containing indole skeletons possess a variety of important biological activities and pharmacological effects. Pyrrolidones are also present in many drug molecules. However, there is limited exploration of substances that simultaneously possess both indole and pyrrolidone spirocyclic structures. Research indicates that combining these two skeleton structures within the same molecule can yield novel substances with certain antibacterial activity, which may serve as promising lead compounds. Summary of the Invention

[0003] The purpose of this invention is to provide a novel 2-indolineimine spiropyrrolidone framework, its crystal form, preparation method, and applications, the structure of which is shown in Formula A:

[0004]

[0005] This invention provides a method for preparing the above-described compound of formula A:

[0006]

[0007] Take 4-methyl-N-((Z)-3-((E)-2-nitrophenylmethylene)indoline-2-ylidene)benzenesulfonamide (B) and N-(benzyloxy)-2-chloro-2-phenylacetamide (C), and react them at room temperature with tetrahydrofuran as solvent and cesium carbonate as base to obtain A:

[0008] Furthermore, the molar ratio of compound (B) to compound (C) is 5:1 to 1:5, with a preferred ratio of 3:1 to 1:3;

[0009] Furthermore, the reaction temperature is -20℃ to 50℃, with 15℃ to 25℃ being preferred;

[0010] This invention also provides a crystal form I of compound of formula A, which is triclinic, space group P-1, and has cell parameters of... α = 100.605(2)°, β=106.706(2)°, γ=92.754(2)°,

[0011] Furthermore, the melting point of the crystal form is 227-230℃.

[0012] The present invention also provides a method for preparing the above-mentioned crystal form I, comprising the following steps:

[0013] The compound of formula A is obtained by volatilization and crystallization at room temperature in an ethyl acetate-petroleum ether system at 25±3℃, wherein the petroleum ether content in the ethyl acetate-petroleum ether system is 80-90% (v / v).

[0014] The present invention also provides the application of the above-described compound A or its crystal form as an antibacterial agent.

[0015] Compared with the prior art, the present invention has the following beneficial effects:

[0016] This invention yields a novel compound with a 2-indolineimine spiropyrrolidone skeleton. Experimental results show that this novel compound possesses preliminary antibacterial activity. Attached Figure Description

[0017] Figure 1 This is a three-dimensional structural projection of crystal form I of the present invention. Detailed Implementation

[0018] The technical solution of the present invention will be further described in detail below through specific embodiments, but the present invention is not limited to these embodiments. All reagents used in the present invention are commercially available; unless otherwise specified, they are all produced using existing technology or under natural conditions of room temperature and pressure.

[0019] Example 1. Preparation of compound A of the present invention

[0020] Compound B (4-methyl-N-((Z)-3-((E)-2-nitrobenzyl)indoline-2-yl)benzenesulfonamide) 0.1 mmol, compound C (N-(benzyloxy)-2-chloro-2-phenylacetamide) 0.2 mmol, and cesium carbonate 0.22 mmol were added to a reaction tube, followed by 1 mL of tetrahydrofuran. The mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, 5 mL of water and 5 mL x 3 of ethyl acetate were added for extraction. The organic phases were combined and dried over anhydrous sodium sulfate. The sodium sulfate was removed by filtration, and the product was concentrated under reduced pressure and then subjected to silica gel column chromatography with petroleum ether:ethyl acetate = 10:1-3:1 as the eluent. The product was collected, concentrated, and dried to obtain the target compound A. 1H NMR (600MHz, CDCl3) δ (ppm): 9.63 (s, 1H), 8.08 (dd, J = 8.4, 1.2Hz, 1H), 7.86 (d, J = 7.8Hz, 2H), 7.81 ( t,J=7.2Hz,1H),7.72(d,J=7.8Hz,1H),7.59(t,J=8.4Hz,1H),7.30-7.27(m,7H),7.17-7.12(m,2H) ,6.96-6.94(m,2H),6.79(d,J=7.8Hz,1H),6.72(t,J=7.8Hz,1H),6.68(d,J=7.2Hz,2H),5.96(s,1H ),5.83(d,J=7.8Hz,1H),5.31(d,J=10.2Hz,1H),4.81(d,J=10.2Hz,1H),4.12(s,1H),2.41(s,3H). 13 C{ 1 H}NMR (151MHz, CDCl3) δ (ppm): 169.1, 166.5, 147.6, 143.7, 141.8, 138.5, 134.7, 134.4, 131.4, 130.0, 129.70, 129.66, 129.3, 12 8.8,128.4,128.11,128.08,126.8,126.5,126.2,123.2,122.8,111.1,77.1,62.6,59.7,53.1,21.5.HRMS(ESI-TOF)m / z:[M+Na] + Calculated for C 37 H 30 N4O6SNa + :681.1778,found:681.1771.

[0021] Example 2. Preparation of Crystal Form I of the Present Invention

[0022] Compound A prepared in Example 1 was slowly volatilized and crystallized at 25°C in an ethyl acetate-petroleum ether (15%:85% v / v) system to obtain crystal form I. The stereoscopic projection diagram of this crystal form is shown below. Figure 1 The crystal structure data of this crystal form are shown in Table 1, obtained by X-ray single-crystal diffraction.

[0023] The X-ray diffraction conditions for single crystals were as follows: X-ray diffraction data of the single crystal were collected under irradiation at a temperature of 150 K. Light source: molybdenum target; wavelength:

[0024] Table 1 Crystal structure data

[0025]

[0026]

[0027] Experimental Example 1: Study on Antibacterial Activity

[0028] The minimum inhibitory concentration (MIC) of compound A crystal form I against methicillin-resistant Staphylococcus aureus (MRSA), susceptible Staphylococcus aureus (MSSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and susceptible Staphylococcus epidermidis (MSSE) was determined using the micro-broth 2-fold dilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) antimicrobial susceptibility testing procedures (M02-A11, M07-A9, and M11-A8). The MIC was 64 μg / L, indicating that the crystal form of the present invention has certain antimicrobial activity.

[0029] Experimental Example 2: Stability and Hygroscopicity of the Crystal Form of the Present Invention

[0030] 1. Stability

[0031] The crystalline compound of this invention was subjected to accelerated stability testing in a stability test chamber under the following conditions: temperature, 40℃±2℃; humidity, RH 75%±5%, for 3 months. Results: TLC and HPLC analyses showed no significant changes in the crystalline compound, indicating good crystal stability of this invention.

[0032] 2. Hygroscopicity

[0033] The results were obtained by following the guidelines for hygroscopicity testing of drugs in Appendix XIX J of the 2015 edition of the Pharmacopoeia of the People's Republic of China, Part II:

[0034] Table 2. Hygroscopicity test

[0035] Time taken (days) 0 5 10 15 Compounds increase weight due to moisture absorption 1.2％ 1.3％ 1.3％ 1.3％

[0036] The results in the table above show that the crystals of the present invention do not show significant weight gain due to moisture absorption when placed in a humid environment for 15 days, indicating that the crystal form of the present invention can effectively prevent the compound from absorbing moisture and deliquescing.

[0037] The foregoing description illustrates and describes several preferred embodiments of the invention. However, as previously stated, it should be understood that the invention is not limited to the forms disclosed herein and should not be construed as excluding other embodiments. It can be used in various other combinations, modifications, and environments, and can be altered within the scope of the inventive concept described herein through the foregoing teachings or techniques or knowledge in related fields. Any modifications and variations made by those skilled in the art that do not depart from the spirit and scope of the invention should be within the protection scope of the appended claims.

Claims

1. A 2-indolineimine spiropyrrolidone compound, characterized in that, The compound has the following structural formula: 。 2. The method for preparing the compound according to claim 1, characterized in that, Take 4-methyl-N-((Z)-3-((E)-2-nitrobenzylmethyl)indoline-2-ylidene)benzenesulfonamide (B) and N-(benzyloxy)-2-chloro-2-phenylacetamide (C), and react them at room temperature with tetrahydrofuran as solvent and cesium carbonate as base to obtain A: 。 3. The crystal form of the 2-indolineimine spiropyrrolidone compound according to claim 1, characterized in that, The crystal form is triclinic, space group P-1, with cell parameters a = 11.7119(7) Å, α = 100.605(2)°, b = 15.7608(10) Å, β = 106.706(2)°, c = 18.3761(10) Å, γ = 92.754(2)°, and cell volume = 3174.9(3) Å. 3 The melting point of the crystal form is 227 – 230 ℃.

4. The method for preparing the crystal form of a 2-indolineimine spiropyrrolidone compound according to claim 3, characterized in that, The compound represented by formula A is obtained by volatilization and crystallization at room temperature in an ethyl acetate-petroleum ether system, wherein the volume fraction of petroleum ether in the ethyl acetate-petroleum ether system is 80-90%.

5. The use of the compound according to claim 1 in the preparation of antibacterial drugs.

6. The use of the crystal form according to claim 3 in the preparation of antibacterial drugs.

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