CN106866618A - Two（The methylene of thiophene 2）The preparation and use of the diamines of butane 1,4 - Google Patents

Abstract

The invention relates to a butyl-linked thiophene-Sieffer base dimer crystal, which has a colorless and transparent block shape, a melting point of 68.9-69.6°C, a molecular formula of C ₁₄ H ₁₆ N ₂ S ₂ , a molecular weight of 276.42, and a chemical name of: (N ¹ E,N ⁴ E)-N ¹ ,N ⁴ -bis(thiophene-2-methylene)butane-1,4-diamine, the structure of which is as follows: The crystal belongs to orthorhombic system, space group P2 ₁ 2 ₁ 2 ₁ , α=β=γ=90°, Z=4. The preparation method of the Schiff base dimer crystal is simple, and has strong fluorescence emission between 400nm and 500nm. The schiff base dimer crystal has mild antitumor activity on lung cancer cells.

Description

Preparation and application of bis(thiophene-2-methylene)butane-1,4-diamine

Technical field:

The invention relates to the fields of organic synthesis, optical materials and medicinal chemistry, and uses relatively simple raw materials and methods to synthesize target products in one step.

Background technique:

Symmetry plays an important role in life activities, so dimers are a ubiquitous structural type in natural products. In the field of material chemistry, dimer structures are often used in the construction of new materials such as optoelectronic materials, supramolecular materials, functional dyes, and fluorescent materials; fluorescent materials based on organic dimer structures are widely used in optical and electronic devices , DNA diagnostics, photochemical sensors, organic pigments, dyes, fluorescent whitening agents, photooxidants, fluorescent paints, laser dyes, organic electroluminescent devices (ELD) chemical and biochemical analysis, solar collectors, anti-counterfeiting marks, drug tracers and laser and other fields; in the field of medicinal chemistry, dimers often show better activity than corresponding monomers; the design and synthesis of new dimer materials with excellent properties have always been the efforts of materials scientists and medicinal chemists direction.

Schiff base is a compound with a relatively special structure. Different types of Schiff bases can be synthesized according to the different groups introduced; Schiff bases have important applications in the fields of medicine, catalysis, analytical chemistry, corrosion, and photochromism. For example, in the medical field, Schiff base has antibacterial, bactericidal, antitumor, and antiviral biological activities; in the field of optical materials, due to its electron-rich and rigid plane characteristics, it has good fluorescence properties and nonlinear optical properties. Properties; Considering that the connecting chain of the Schiff base dimer itself can have abundant changes, it also has good application prospects in the fields of optical materials and medicinal chemistry.

Contents of the invention

1. Structural characterization

The content of the present invention is that a kind of Schiff base conjugated dimer crystal with butyl (i.e. -(CH ₂ ) ₄ -) as the connecting chain has been prepared by various methods. The structure of the dimer crystal and related The characterization parameters are as follows:

The appearance of the compound is colorless transparent block crystal, melting point 68.9-69.6℃, molecular formula C ₁₄ H ₁₆ N ₂ S ₂ , molecular weight 276.42, chemical name: (N ¹ E,N ⁴ E)-N ¹ ,N ⁴ -Bis(thiophene-2-methylene)butane-1,4-diamine, the English system name is: (N ¹ E,N ⁴ E)-N ¹ ,N ⁴ -bis(thiophen-2-ylmethylene) Butane-1,4-diamine, its structure is as follows:

Elemental analysis shows that the percentages of the dimer C, H, and N are 60.98%, 5.96%, and 10.27% (theoretical values calculated by the molecular formula C ₁₄ H ₁₆ N ₂ S ₂ are 60.83%, 5.83%, and 10.13%); single crystal structure analysis shows that its crystal is orthorhombic, space group P2 ₁ 2 ₁ 2 ₁ , α=β=γ=90°, Z=4, accompanying drawings 1 and 2 are the thermal ellipsoidal crystal structure diagram and crystal structure packing diagram of the compound respectively, and the relevant ¹ HNMR spectrum and ¹³ CNMR spectrum are shown in accompanying drawings 3 and 4 respectively.

2. Synthesis method

The synthesis method of the compound is characterized in that: 2-thiophenecarbaldehyde and butanediamine are used as raw materials, and a solution synthesis or a solid phase synthesis method is adopted. Proceed as follows:

1) Dissolve 2-thiophenecarbaldehyde and butanediamine in suitable organic solvents respectively, then mix them in a certain molar ratio, stir and react at a certain temperature for a certain period of time; you can also directly mix the two reactants without organic solvents , grinding reaction.

2) During the liquid phase reaction, remove most of the solvent from the obtained solution by a certain method to obtain powder or crystal, which is the target product; during the solid phase reaction, grind for a certain period of time to obtain the target product.

3) The target product can be recrystallized in a suitable organic solvent to purify the product.

Preferably, the above-mentioned reaction solvent or solvent for recrystallization is selected from methanol, ethyl acetate, dichloromethane, ethanol, acetonitrile, acetone, chloroform, tetrahydrofuran, toluene, and N,N-dimethylformamide.

Preferably, the reaction molar ratio of 2-thiophenecarbaldehyde and butanediamine is 1:2 to 4:1.

Preferably, the reaction temperature is from room temperature to heating to reflux.

Preferably, the reaction time is 0.5-12 hours.

Preferably, the method for removing the solvent is natural volatilization or normal/vacuum distillation.

The beneficial effect of the invention is that relatively complex functional molecular materials can be synthesized in one step with relatively simple steps and reactants, and the separation method is simple.

3. Ultraviolet and fluorescent properties.

Test the ultraviolet spectrum of this compound in 10 ^-5 mol/L ethanol solution, find that it has ultraviolet absorption peak at 261nm and 279nm place, as shown in accompanying drawing 5; By Gaussian03 software, use TD-DFT theory, in b3lyp/6 -311+g(d,p) method/basis set calculated the ultraviolet spectrum of the compound, and the calculated results are shown in accompanying drawing 6; it can be found that the calculated spectrum is in good agreement with the experimental results, as the calculated two The main strong absorption peaks are located at 249nm and 279nm, respectively, one of which differs from the experimental result by only 12nm, and the other absorption peak is the same; it is found by orbital analysis that these two absorption peaks are produced by the π→π* transition.

In 10 ^-5 mol/L ethanol solution, excited by ultraviolet light with wavelengths of 361nm and 379nm respectively, the fluorescence properties of this compound were tested, and it was found that it had strong fluorescence emission between 400-500nm, and the fluorescence spectrum is shown in Figure 7 ; Irradiated by ultraviolet light, blue fluorescence is visible to the naked eye.

It is worth noting that the dimer compound has been reported in multiple documents, such as the following documents: L.N.Khokhlova, S.Germane, N.P.Erchak, _E.Lukevits, Chem.Heterocycl.Com.30 (1994) 279- 282 (the reported melting point is 75°C), but no one has obtained a high-purity single crystal of this compound so far, so the melting point reported in the literature is different from the crystal we obtained; we compared the uncrystallized and purified primary product with the recrystallized Fluorescent properties of the crystal, found that the fluorescence intensity of the two is very different, testing the same quality of solid fluorescence, the fluorescence intensity of the crystal is more than twice that of the original product; irradiated with ultraviolet light, the original product cannot be observed with the naked eye. Fluorescence, even if the amount of solid is increased, the fluorescence intensity is far less than that of the crystal state.

4. Antitumor activity in vitro.

Digest the A549 lung cancer cells in the logarithmic phase with 0.25% trypsin to make them single cells, and use F12K culture medium containing 10% fetal bovine serum to make single cells with a concentration of 1.25× ¹⁰⁷ cells/L Suspension, the cells were seeded in a 96-well culture plate, 200 μL per well (2.5×10 ³ cells per well). The 96-well cell culture plate was placed in a CO ₂ incubator at 37°C and 5% CO ₂ for 48 hours.

When the cells in the wells are overgrown (90% full), add different doses of Bencifer base solution (200 μL/well) according to the experimental grouping, so that the final concentrations of the compounds to be tested are 5 μM, 10 μM, 50 μM, 100 μM, 200μM, each group set up 3 duplicate wells, cultured for 96h.

20 μL of MTT at a concentration of 0.5 g/L was added to each well, and the culture was continued for 4 hours to reduce MTT to formazan. After aspirating all the supernatant, add 200 μL of DMSO to each well and shake for 15 min to fully dissolve formazan, then measure the absorbance (OD value) at 490 nm with an enzyme-linked immunosorbent assay. Then calculate according to the following formula:

Cell inhibition rate%=(OD value of control group-OD value of experimental group)/OD value of control group×100%

The test results showed that the IC50 (half inhibitory concentration of the drug) of the Schiff base on the lung cancer cell A549 was 182.0 μM, which indicated that the compound had a mild inhibitory effect on the lung cancer cell.

detailed description

In order to better understand the content of the present invention, the technical solution of the present invention is further described below through a specific embodiment:

Example 1.

Weigh 1.12g (0.01mol) of 2-thiophenecarbaldehyde and dissolve it in 30mL of absolute ethanol, heat and stir until completely dissolved, add 0.44g (0.005mol) of butanediamine, heat and reflux for 6 hours under stirring, cool to room temperature and filter, Put the filtrate in a beaker and let it stand for volatilization, and a large amount of crystal-like precipitates can be obtained. After filtering the obtained precipitates, the primary product can be obtained. The primary product can be recrystallized with methanol to obtain colorless blocky crystals, which is the target product.

Example 2.

Weigh 1.12g (0.01mol) of 2-thiophenecarbaldehyde, add 0.44g (0.005mol) of butanediamine, and grind for 8 hours at room temperature to obtain a paste, then add 20ml of absolute ethanol, heat to dissolve, and obtain a colorless Blocky crystals are the target product, and recrystallization can purify the product.

Description of drawings

Accompanying drawing 1 is the crystal structure figure of target compound, and the probability of ellipsoid is 30%.

Accompanying drawing 2 is the crystal structure stacking diagram of the target compound, viewed along the b-axis direction.

Accompanying drawing 3 is the ¹ H NMR spectrogram of the target compound.

Accompanying drawing 4 is the ¹³ CNMR spectrogram of target compound.

Accompanying drawing 5 is the ultraviolet spectrogram (experimental result) of target compound.

Accompanying drawing 6 is the ultraviolet spectrogram (Gaussian 03 calculation result) of target compound.

Accompanying drawing 7 is the fluorescence spectrogram (experimental result) of target compound.

Claims (2)

1. A butyl-linked thiophene-Sieffer base dimer crystal is used in optical electronic devices, DNA diagnosis, photochemical sensors, organic pigments, dyes, fluorescent whitening agents, photooxidants, fluorescent coatings, laser dyes, organic electroluminescence Applications in the field of devices, chemical and biochemical analysis, solar collectors, anti-counterfeiting marks, drug tracers and lasers, based on its fluorescent properties; the appearance of the crystal is colorless and transparent, with a melting point of 68.9-69.6°C and a molecular formula of C ₁₄ H ₁₆ N ₂ S ₂ , molecular weight 276.42, chemical name: (N ¹ E,N ⁴ E)-N ¹ ,N ⁴ -di(thiophene-2-methylene)butane-1,4-diamine , whose structure is as follows: The crystal belongs to orthorhombic system, space group P2 ₁ 2 ₁ 2 ₁ , α=β=γ=90°, Z=4. 2. The use of a butyl-linked thiophene-Sieffer base dimer crystal or a pharmaceutically acceptable salt thereof in the preparation of a drug for the prevention and/or treatment of tumors, characterized in that: the tumor is lung cancer; the The molecular formula and structure of the compound crystal are as shown in claim 1.