Indole delta-sulfonamide compound and its crystal form and preparation method

Abstract

The present invention discloses an indole and δ-internal sulfonamide compound having a structure as shown in formula (A), a crystal form thereof and a preparation method thereof. The present invention also provides a crystal form I of the compound of formula (A), which is a triclinic system, a space group is P-1, and a unit cell parameter is α=97.888(5)°, β=104.191(6)°, γ=106.581(6)°, and the present invention also provides a preparation method of the crystal form A. The present invention successfully prepares an indole and δ-internal sulfonamide compound and a crystal form thereof, and the compound of the present invention or its crystal form has certain anti-inflammatory activity, good stability, and provides great convenience for later product transportation, storage or preparation process.

Description

Technical Field

[0001] The invention belongs to the technical field of compounds, and specifically relates to an indole delta-sulfonamide compound and a crystal form and a preparation method thereof. Background Art

[0002] Indole rings are widely present in natural products and synthetic drugs. Related studies have shown that compounds containing indole skeleton structures have a variety of important biological activities and pharmacological effects. δ-lactam is also present in many drug molecules. However, there are relatively few studies on substances that have both indole rings and δ-lactam structures. Studies have shown that by combining the two skeleton structures in the same molecular structure, the new substance obtained has certain anti-inflammatory activity and can be used as a lead compound. Summary of the invention

[0003] The object of the present invention is to provide a new indole δ-internal sulfonamide skeleton and its crystal form and preparation method, the structure of which is shown in formula A:

[0004]

[0005] The present invention provides a method for preparing the compound of formula A:

[0006]

[0007] Take N-(indoline-2-yl)-4-methylbenzenesulfonamide (B) and β-phenylvinylsulfonyl fluoride (C), use N,N-dimethylformamide as solvent and sodium carbonate as base, and react at room temperature to obtain A;

[0008] Further, the molar ratio of compound B to compound C is 5:1-1:5, and the preferred ratio is 2:1-1:2;

[0009] Furthermore, the reaction temperature is -20°C-50°C, preferably 15-25°C.

[0010] The present invention also provides a crystalline form I of the compound of formula A, which is a triclinic crystal system, has a space group of P-1, and a unit cell parameter of α=97.888(5)°, β=104.191(6)°, γ=106.581(6)°,

[0011] Furthermore, the melting point of the crystalline form is 164-166°C.

[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 volatilized and crystallized at room temperature in an ethyl acetate-petroleum ether system at 25±3°C to obtain the compound, wherein the content of petroleum ether in the ethyl acetate-petroleum ether system is 80-90% v / v.

[0014] The present invention also provides the use of the compound of formula A or its crystal form as an anti-inflammatory drug.

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

[0016] The invention obtains a new compound which has an indole delta-sulphonamide skeleton structure. Experimental results show that the new compound has preliminary anti-inflammatory activity. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 It is a three-dimensional structural projection diagram of the crystal form I of the present invention. DETAILED DESCRIPTION

[0018] The technical scheme of the present invention is further specifically described below through specific examples, but the present invention is not limited to these examples. The reagents used in the present invention are all commercially available, and unless otherwise specified, all are prepared using existing technologies or natural conditions at normal temperature and pressure.

[0019] Example 1. Preparation of Compound A of the Invention

[0020] Compound B (N-(indoline-2-yl)-4-methylbenzenesulfonamide) 0.1mmol, compound C (β-phenylvinylsulfonyl fluoride) 0.2mmol, sodium carbonate 0.11mmol, added to a reaction tube, added 1mL DMF, then stirred at 20℃ for 4h, monitored by TLC until the reaction was completed, added 5mL water, 5mL ethyl acetate x 3 extraction, combined organic phases, dried over anhydrous sodium sulfate. Filter to remove sodium sulfate, concentrate under reduced pressure, and then silica gel column chromatography, the eluent is petroleum ether: ethyl acetate = 10: 1-6: 1, collect the product, concentrate to dryness, and obtain the target compound A. 1H NMR (600MHz, CDCl3) δ (ppm): 8.83 (s, 1H), 7.82 (d, J=8.4Hz, 2H), 7.42 (d, J=8. 4Hz, 1H), 7.37 (d, J=8.4Hz, 2H), 7.30 (m, 3H), 7.23 (t, J=7.8Hz, IH), 7.07-7.01 (m, 2H), 6.91 (t, J=7.8Hz, 1H), 6.68 (d, J=8.4Hz, 1H), 4.53 (dd, J=6.0, 12.0Hz, 1H), 3.36 (dd, J=6.6, 13.8Hz, 1H), 2.42 (s, 3H), 2.30 (dd, J=12.2, 13.8Hz, 1H). 13 CNMR (151MHz, CDCl3) δ (ppm): 146.6, 138.9, 134.6, 132.0, 130.1, 129.1, 129.0, 128.1, 127.9, 127.5, 124.6, 123.8, 120.4, 120.1, 111.5, 104.5, 52.9, 39.0, 21.8.HRMS (ESI): m / zcalculated for C 23 H 20 N2O4S2+Na + :475.0757, found:475.0760.

[0021] Example 2. Preparation of Form I of the present invention

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

[0023] The single crystal X-ray diffraction conditions are: irradiation at a temperature of 293K to collect the single crystal X-ray diffraction data. Light source: copper target; wavelength:

[0024] Table 1 Crystal structure data

[0025]

[0026]

[0027] Test Example 1: Study on anti-inflammatory activity

[0028] The anti-inflammatory activity experiment is determined by measuring the NO content. The experimental principle is: NO is an inflammatory factor. By establishing an inflammatory model in which LPS induces RAW264.7 macrophages to produce NO, the changes in NO content are detected to reflect the anti-inflammatory activity of the compound.

[0029] The experimental results showed that the inhibition rate of compound A on NO production in RAW264.7 cells was 12.79% (the control substance celecoxib was 65.12%, and the concentration was 10 μM).

[0030] Test Example 2: Investigation of the stability and hygroscopicity of the crystal form of the present invention

[0031] 1. Stability

[0032] The crystalline compound of the present invention was placed in a stability test chamber for accelerated testing, and the test conditions were: temperature, 40°C ± 2°C; humidity, RH75% ± 5%, and the time was 3 months. Results: TLC and HPLC were used to determine that the crystalline compound did not undergo significant changes, indicating that the crystalline form of the present invention has good stability.

[0033] 2. Hygroscopicity

[0034] The test results were as follows:

[0035] Table 3 Hygroscopicity investigation

[0036] Time (days) 0 5 10 15 Compound weight gain due to moisture absorption 1.3％ 1.5％ 1.5％ 1.5％

[0037] The results in the above table show that the crystals of the present invention do not significantly increase in weight 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 hygroscopic deliquescence.

[0038] The above description shows and describes several preferred embodiments of the invention, but as mentioned above, it should be understood that the invention is not limited to the form disclosed herein, and should not be regarded as excluding other embodiments, but can be used in various other combinations, modifications and environments, and can be modified within the scope of the invention concept described herein through the above teachings or the technology or knowledge of the relevant field. Changes and modifications made by those skilled in the art should be within the scope of protection of the claims attached to the invention without departing from the spirit and scope of the invention.

Claims

1. An indole δ-sulfonamide compound, characterized in that: The compound has the following structural formula:

2. The method for preparing a compound according to claim 1, characterized in that: Take N-(indoline-2-yl)-4-methylbenzenesulfonamide (B) and β-phenylvinylsulfonyl fluoride (C), use N,N-dimethylformamide as solvent and sodium carbonate as base, and react at room temperature to obtain A:

3. The crystalline form I of the compound represented by formula A according to claim 1, characterized in that: The crystal form is triclinic, the space group is P-1, and the unit cell parameters are α=97.888(5)°, β=104.191(6)°, γ=106.581(6)°, The melting point of the crystalline form is 164-166°C.

4. The method for preparing the crystalline form I of the compound represented by formula A according to claim 3, characterized in that: The compound shown in formula A is volatilized and crystallized in an ethyl acetate-petroleum ether system at room temperature to obtain the compound, wherein the content of petroleum ether in the ethyl acetate-petroleum ether system is 80-90% v / v.

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