A pyrazole ring-containing beta-carboline compound, a synthesis method thereof and antifouling applications thereof

Abstract

The present application relates to pyrazole ring containing beta-carboline compounds, its synthesis method and its antifouling application. D-tryptophan is reacted with acetaldehyde, Pictet-Spengler cyclization reaction occurs, and the required beta-carboline carboxylic acid compound is generated; then the carboxyl is esterified to obtain the esterified tetrahydro-beta-carboline; the 1-methyl-3-trifluoromethyl pyrazole group is introduced into the esterified tetrahydro-beta-carboline to obtain a key intermediate, which provides a key synthetic skeleton for the synthesis of pyrazole ring containing beta-carboline compounds; the skeleton compound is reacted with different acyl chlorides to obtain a series of pyrazole ring containing beta-carboline compounds. The synthesis process is simple, the raw materials are cheap and easy to obtain, the compounds have significant antibacterial activity, have high bactericidal effect on staphylococcus aureus and escherichia coli, have great potential in antifouling, and have wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of marine antifouling, and particularly relates to synthesis of a β-carboline compound containing a pyrazole ring and antifouling technology. BACKGROUND

[0002] Ships have always been a key component of international trade and globalization, and their operational efficiency directly affects the development of the global economy. As one of the important factors to improve the performance of ships and reduce operating costs, the technological progress of antifouling coatings has a profound impact on the shipping industry.

[0003] Historically, ancient mariners have been aware of the problem of hull fouling, for example, marine organisms such as shells, algae, and microorganisms will attach to the ship bottom, increasing water resistance, leading to increased fuel consumption and reduced speed. Initially, people used copper or other toxic metal coatings to inhibit biological attachment, which had a significant effect, but this method also caused considerable harm to the marine environment. In the 20th century, as concerns about environmental impact grew, people began to look for less ecologically damaging antifouling coating solutions. In the 1970s, self-polishing copolymer (SPC) coatings with organotin compounds (TBT) were introduced to the market, which could effectively control biological pollution and continuously release toxic substances as the ship sailed, keeping the ship clean. However, over time, organotin-based substances were banned due to their extremely adverse environmental and health effects. In 2008, the International Maritime Organization (IMO) issued the International Convention on the Control and Management of Ships' Ballast Water and Sediments (AFS), prohibiting the use of antifouling systems containing organotin.

[0004] Nowadays, antifouling coatings no longer contain organotin or other heavy metals, and instead use pollution-free or low-pollution alternatives. These alternatives include biodegradable materials, silicon-based polymers, and other non-toxic substances. Modern antifouling coatings not only need to be environmentally friendly, but also require long-term antifouling performance to reduce the dry-docking period of ships and reduce maintenance costs.

[0005] The beta-carboline derivatives exhibit various biological activities, including antibacterial, antiviral, anticancer, anti-inflammatory, and central nervous system activities, in addition to which, beta-carboline compounds are also studied for use in marine antifouling coatings because they have specific antimicrobial properties that can prevent marine organisms such as algae and bryozoans from adhering to the hulls of ships. By blocking the formation of biofilms, the adhesion of these harmful organisms to the surface of the ship can be greatly reduced. Compared with antifouling coatings containing heavy metals and other toxic chemicals (such as TBT, TBG), beta-carboline compounds are designed to be less toxic to non-target organisms and more environmentally friendly. Pyrazole is a heterocyclic compound widely used in drug development, and a variety of pyrazole-containing drugs are already on the market. The combination of a pyrazole ring and a beta-carboline increases the structural complexity of the molecule, which can be used to explore new drug active sites or manufacture more complex materials. Both can produce new drug activity, increase the force between the compound and the target, and improve the selectivity and efficacy of the drug.

[0006] Therefore, the antifouling agent prepared from the compound combining a pyrazole ring and a beta-carboline is an effective and environmentally friendly alternative that can reduce the adhesion of organisms to the surface of a ship. SUMMARY

[0007] In view of the deficiencies of the prior art, the purpose of the present application is to provide a beta-carboline compound containing a pyrazole ring, a synthesis method thereof, and an antifouling application thereof. The present application uses inexpensive and readily available D-tryptophan as a raw material to synthesize an antifouling agent, replacing antifouling coatings containing heavy metals and other toxic chemicals (such as TBT, TBG), and the synthesis process is simple, the synthesis cost is low, and it is environmentally friendly and pollution-free.

[0008] The technical scheme adopted by the present application to solve its technical problems is:

[0009] The beta-carboline compound containing a pyrazole ring has a general formula (I)

[0010]

[0011] The R is any one of the following groups:

[0012]

[0013] (The above groups correspond to formyl, acetyl, propionyl, butyryl, valeryl, hexanoyl, heptanoyl, isopropyl formyl, cyclopropyl formyl, respectively).

[0014] The specific synthesis route is as follows:

[0015]

[0016] (1) D-tryptophan reacts with acetaldehyde to undergo Pictet-Spengler cyclization to generate the required β-carboline carboxylic acid compound.

[0017] (2) The carboxyl group is esterified to obtain an esterified tetrahydro-β-carboline.

[0018] (3) A 1-methyl-3-trifluoromethylpyrazole group is introduced into the esterified tetrahydro-β-carboline to obtain a key intermediate, which provides a key synthetic skeleton for the synthesis of a β-carboline compound containing a pyrazole ring, which is a key reaction of the present scheme.

[0019] (4) The key skeleton reacts with different acyl chlorides to generate nine target compounds.

[0020] The different acyl chlorides acyl chloride correspond to: formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, isopropyl formyl chloride, cyclopropyl formyl chloride, corresponding to the obtained compounds b1-b9.

[0021] Specifically, the synthesis process of the β-carboline compound containing a pyrazole ring of formula (I) is as follows:

[0022] Step one:

[0023]

[0024] Weigh 2.0 g (10 mmol) of D-tryptophan into a reaction bottle, add 1.7 mL (3.0 eq.) of acetaldehyde solution and stir uniformly, slowly drop 0.3 mL of sulfuric acid, and stir the reaction at room temperature. After the reaction is completed, the reaction liquid is subjected to reduced pressure filtration, and finally compound 1 (1.55 g, 76%) is obtained.

[0025] Step two:

[0026]

[0027] Weigh 2.8 g (12 mmol) of compound 1 into a reaction bottle, dissolve with methanol, place the reaction in an ice water bath, slowly drop 1.3 mL (1.5 eq.) of thionyl chloride, heat to 80°C and reflux for 4 h, remove the solvent and excess thionyl chloride to obtain compound 2.

[0028] Step three:

[0029]

[0030] Take compound 2 (12 mmol, 2.76 g) in a reaction bottle, add 50 mL of methanol, add 5 mL of thionyl chloride under ice bath, reflux at 80 DEG C, after 4 hours, the reaction is complete, evaporate the solvent, dissolve the residue in water, separate the liquid, the inorganic phase is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent is removed under reduced pressure to obtain compound 3 (2.32 g, 83%).

[0031] Step four:

[0032]

[0033] Take 0.57 g (1.5 mmol) of reaction substrate 3 and place it in a reaction bottle, add 20 mL of DCM and stir to dissolve, then add 0.32 mL (2.3 mmol, 2.3 eq.) of triethylamine dropwise, stir for 20 min, then dissolve in 10 mL of dichloromethane, and then add different acyl chlorides dropwise, after the addition is complete, react at room temperature, add saturated sodium bicarbonate solution, extract with dichloromethane, wash with saturated sodium chloride solution, dry with anhydrous sodium sulfate, and obtain compound b1 (561 mg, 91%).

[0034] The pyrazole ring-containing β-carboline compound with general formula (I) has good fungicidal activity on Staphylococcus aureus and Escherichia coli.

[0035] Compared with the prior art, the present application has the following advantages and beneficial effects:

[0036] (1) The synthesis method of the pyrazole ring and the β-carboline provided by the present application uses cheap and readily available D-tryptophan as a raw material to synthesize an antifouling agent, which replaces antifouling paint containing heavy metals and other toxic chemicals (such as TBT and TBG), and the synthesis process is simple, the reaction conditions are mild, the synthesis cost is low, and it is environmentally friendly and pollution-free.

[0037] (2) The pyrazole ring-containing β-carboline compound provided by the present application increases the structural complexity of the molecule by combining the pyrazole ring with the β-carboline, produces new drug activity, and improves the selectivity and efficacy of the drug.

[0038] (3) The pyrazole ring-containing β-carboline compound provided by the present application has high antifouling activity. DETAILED DESCRIPTION

[0039] The present application is further described in detail below in conjunction with examples. If the reagents or equipment used are not specified by the manufacturer, they are all considered to be conventional products that can be purchased on the market.

[0040] The present application is described in detail below in conjunction with examples.

[0041] Synthesis of compound b1 in example 1

[0042]

[0043] The preparation method is as follows:

[0044] First step: weigh 2.0 g (10 mmol) of D-tryptophan in a reaction bottle, add 1.7 mL (3.0 eq.) of acetaldehyde solution and stir uniformly, slowly drop 0.3 mL of sulfuric acid, and stir the reaction at room temperature. After the reaction is complete, the reaction liquid is filtered under reduced pressure to obtain compound 1 (1.55 g, 76%).

[0045] Second step: weigh 2.8 g (12 mmol) of compound 1 in a reaction bottle, dissolve in methanol, place the reaction in an ice water bath, slowly drop 1.3 mL (1.5 eq.) of thionyl chloride, heat to 80°C and reflux for 4 h, remove the solvent and excess thionyl chloride to obtain compound 2.

[0046] Third step: weigh compound 2 (12 mmol, 2.76 g) in a reaction bottle, add 50 mL of methanol, add 5 mL of thionyl chloride under ice bath, reflux at 80°C, and the reaction is complete after 4 hours. The solvent is evaporated, the residue is dissolved in water, the inorganic phase is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate, and the solvent is evaporated under reduced pressure to obtain compound 3 (2.32 g, 83%).

[0047] Fourth step: weigh 0.57 g (1.5 mmol) of reaction substrate 3 in a reaction bottle, add 20 mL of DCM and stir to dissolve, then drop 0.32 mL (2.3 mmol, 2.3 eq.) of triethylamine, stir for 20 min, dissolve in 10 mL of dichloromethane, and then drop formyl chloride. After the drop is completed, the reaction is carried out at room temperature, saturated sodium bicarbonate solution is added, extracted with dichloromethane, washed with saturated sodium chloride solution, dried with anhydrous sodium sulfate to obtain compound b1 (561 mg, 80.5%).

[0048] Reagent: formyl chloride. Yellow liquid. Yield 80.5%.1H NMR (400 MHz, CDCl3) δ 8.67 (1H, s), 7.51 (1H, d, J = 7.4 Hz), 7.33-7.30 (2H, m), 7.14-7.09 (1H, m), 6.64 (1H, s), 5.70 (1H, q, J = 6.5 Hz), 4.97 (1H, d, J = 5.6 Hz), 3.57 (3H, s), 3.16-2.92 (2H, m), 2.88 (3H, s), 1.51 (3H, d, J = 6.8 Hz).

[0049] The resulting compounds (compounds b1-b9) of Examples 1-9 are pyrazole ring containing β-carbolines. The synthesis method of the examples is the same as that of Example 1 described above, except that different acyl chlorides are added. The reaction conditions and properties are shown in Table 1.

[0050] Table 1 Physico-chemical properties of antifouling compounds

[0051]

[0052] Synthesis of compound b2 of Example 2

[0053]

[0054] The difference from Example 1 is that the acyl chloride reagent used in step four is: acetyl chloride. Yellow liquid. Yield 84%. 1H NMR (400 MHz, CDC13) δ 8.96 (1H, s), 7.55 (1H, d, J = 7.4 Hz), 7.36-7.32 (2H, m), 7.17-7.11 (1H, m), 6.54 (1H, s), 5.8 (1H, q, J = 6.4 Hz), 4.89 (1H, d, J = 5.4 Hz), 3.53 (3H, s), 3.18-2.95 (2H, m), 2.26 (2H, q, J = 5.6 Hz), 1.54 (3H, d, J = 6.8 Hz), 1.06 (3H, t, J = 5.6 Hz).

[0055] Synthesis of compound b3 of Example 3

[0056]

[0057] The difference from Example 1 is that the acyl chloride reagent used in step four is: propionyl chloride. Yellow liquid. Yield 85%. 1H NMR (400 MHz, CDC13) δ 8.78 (1H, s), 7.51 (1H, d, J = 7.24 Hz), 7.31-7.26 (2H, m), 7.13-7.09 (1H, m), 6.48 (1H, s), 5.7 (1H, q, J = 6.6 Hz), 4.93 (1H, d, J = 5.7 Hz), 3.54 (3H, s), 3.13-2.92 (2H, m), 2.23 (2H, q, J = 5.2 Hz), 1.64-1.53 (2H, m), 1.53 (3H, d, J = 6.4 Hz), 1.03 (3H, t, J = 5.4 Hz).

[0058] Synthesis of compound b4 of Example 4

[0059]

[0060] The difference with example 1 is that the acyl chloride reagent used in step four is: butyryl chloride. Yellow liquid. Yield 81%.1H NMR (400 MHz, CDCI3) δ 8.71 (1 H, s), 7.52 (1 H, d, J = 7.4 Hz), 7.33 - 7.22 (2 H, m), 7.14 - 7.05 (1 H, m), 6.46 (1 H, s), 5.6 (1 H, q, J = 6.4 Hz), 4.97 (1 H, d, J = 5.5 Hz), 3.55 (3 H, s), 3.15 - 2.95 (2 H, m), 2.25 (2 H, q, J = 5.3 Hz), 1.55 - 1.35 (4 H, m), 1.55 (3 H, d, J = 6.4 Hz), 1.06 (3 H, t, J = 5.5 Hz).

[0061] Synthesis of compound b5 of example 5

[0062]

[0063] The difference with example 1 is that the acyl chloride reagent used in step four is: pentanoyl chloride. Yellow liquid. Yield 79%.1H NMR (400 MHz, CDCI3) δ 8.81 (1 H, s), 7.54 (1 H, d, J = 7.5 Hz), 7.35 - 7.27 (2 H, m), 7.17 - 7.07 (1 H, m), 6.47 (1 H, s), 5.7 (1 H, q, J = 6.7 Hz), 4.93 (1 H, d, J = 5.7 Hz), 3.57 (3 H, s), 3.17 - 2.97 (2 H, m), 2.27 (2 H, q, J = 5.6 Hz), 1.53 - 1.27 (6 H, m), 1.57 (3 H, d, J = 6.7 Hz), 0.89 (3 H, t, J = 5.2 Hz).

[0064] Synthesis of compound b6 of example 6

[0065]

[0066] Example 1 except that the acyl chloride reagent employed in step four was: hexanoyl chloride. Yellow liquid. Yield 78%.1H NMR (400 MHz, CDCI3) δ 8.80 (1 H, s), 7.51 (1 H, d, J = 7.2 Hz), 7.32 - 7.24 (2 H, m), 7.14 - 7.04 (1 H, m), 6.45 (1 H, s), 5.5 (1 H, q, J = 6.5 Hz), 4.94 (1 H, d, J = 5.4 Hz), 3.54 (3 H, s), 3.14 - 2.94 (2 H, m), 2.24 (2 H, q, J = 5.5 Hz), 1.54 - 1.24 (8 H, m), 1.54 (3 H, d, J = 6.7 Hz), 0.86 (3 H, t, J = 5.4 Hz).

[0067] Example 7 Synthesis of compound b7

[0068]

[0069] Example 1 except that the acyl chloride reagent employed in step four was: heptanoyl chloride. Yellow liquid. Yield 81%.1H NMR (400 MHz, CDCI3) δ 8.83 (1 H, s), 7.53 (1 H, d, J = 7.3 Hz), 7.33 - 7.23 (2 H, m), 7.13 - 7.03 (1 H, m), 6.43 (1 H, s), 5.3 (1 H, q, J = 6.3 Hz), 4.93 (1 H, d, J = 5.3 Hz), 3.53 (3 H, s), 3.13 - 2.93 (2 H, m), 2.23 (2 H, q, J = 5.3 Hz), 1.53 - 1.23 (10 H, m), 1.53 (3 H, d, J = 6.3 Hz), 0.89 (3 H, t, J = 5.3 Hz).

[0070] Example 8 Synthesis of compound b8

[0071]

[0072] Example 1 except that the acyl chloride reagent employed in step four was: isopropylcarbonyl chloride. Yellow liquid. Yield 83%.1H NMR (400 MHz, CDCI3) δ 8.84 (1 H, s), 7.55 (1 H, d, J = 7.6 Hz), 7.34 - 7.25 (2 H, m), 7.14 - 7.05 (1 H, m), 6.44 (1 H, s), 5.5 (1 H, q, J = 6.3 Hz), 4.94 (1 H, d, J = 5.3 Hz), 3.54 (3 H, s), 2.69 - 2.60 (1 H, m), 1.11 - 1.05 (6 H, m).

[0073] Synthesis of compound b9

[0074]

[0075] The difference between Example 1 is that the acyl chloride reagent used in step four is: cyclopropylcarbonyl chloride. Yellow liquid. Yield 81%. 1H NMR (400 MHz, CDC13) δ 8.85 (1H, s), 7.53 (1H, d, J = 7.6 Hz), 7.34-7.23 (2H, m), 7.13-7.04 (1H, m), 6.43 (1H, s), 5.3 (1H, q, J = 6.3 Hz), 4.94 (1H, d, J = 5.3 Hz), 3.55 (3H, s), 2.66-2.57 (1H, m), 1.41-0.87 (5H, m).

[0076] Example 10: Determination of bactericidal activity of the synthesized compounds

[0077] The bacteriostatic activity of the target compounds b1-b9 on Staphylococcus aureus and Escherichia coli was determined by microdilution method. The strains were purchased from the China General Microbiological Culture Collection Center.

[0078] Method for determining the minimum inhibitory concentration (MIC)

[0079] The concentration of the synthesized pyrazole ring-containing β-carboline compounds was diluted by two-fold, and then the diluted bacterial solution was added to the biphenyl heterocyclic compound dilution for culture. Escherichia coli and Staphylococcus aureus were shaken and cultured for 24 h. The positive control tube (test tube without adding test compounds but inoculated with bacteria) had bacterial growth and appeared turbid, and the negative control tube (test tube without adding test compounds and not inoculated with bacteria) had no bacterial growth and appeared transparent. The minimum inhibitory concentration of the test substance on the two test strains was determined in this way.

[0080] According to this judgment, the detection results of the indole-containing compounds on the two bacteria are shown in Table 2.

[0081] Table 2 MIC values of test compounds on two bacteria (unit: g / L)

[0082]

[0083] The results of Table 2 show that the target compounds have strong inhibitory effect on Escherichia coli and Staphylococcus aureus.

[0084] The nitrogen-containing heterocyclic compound provided by the present application not only has higher antifouling activity than traditional TBTO and cuprous oxide, but also has outstanding antifouling activity among similar indole antifouling compounds, for example, the performance of the product is superior to that of commercial TBG (the minimum inhibitory mass concentration of TBG to two kinds of bacteria is 0.0625 and 0.1250 g / L).

[0085] The basic principles and main features of the present application and the advantages of the present application are shown and described above. It should be understood by those skilled in the art that the present application is not limited by the above examples, and the above examples and descriptions in the specification are only to illustrate the principles of the present application. Without departing from the spirit and scope of the present application, various changes and improvements can be made to the present application, and these changes and improvements all fall within the scope of the present application. The scope of protection of the present application is defined by the appended claims and their equivalents.

Claims

1. A pyrazole ring containing β-carboline compound having general formula (I): ###0001### (I) wherein R is any one of the following groups: ###0002### 2. The synthesis route of the pyrazole ring containing β-carboline compound having general formula (I) according to claim 1 is as follows: ###0003### wherein R is any one of the following groups: ###0004### D-tryptophan reacts with acetaldehyde to undergo Pictet-Spengler cyclization to form the required β-carboline carboxylic acid compound; then the carboxyl group is esterified to obtain the esterified tetrahydro-β-carboline; the 1-methyl-3-trifluoromethyl pyrazole group is introduced into the esterified tetrahydro-β-carboline to obtain the key intermediate, which provides a key synthetic skeleton for the synthesis of the pyrazole ring containing β-carboline compound; the skeleton compound reacts with different acyl chlorides to obtain a series of pyrazole ring containing β-carboline compounds. The different acyl chlorides are selected from formyl chloride, acetyl chloride, propionyl chloride, butyryl chloride, valeryl chloride, hexanoyl chloride, heptanoyl chloride, isopropyl formyl chloride, and cyclopropyl formyl chloride.

3. The process for the synthesis of pyrazole ring containing β-carbolines of general formula (I) according to claim 1, characterized by that, 5. Use of the pyrazole ring containing β-carboline compound having general formula (I) according to claim 1 for ship antifouling.

4. The process for the synthesis of pyrazole ring containing β-carbolines according to claim 3, characterized in that, The bacteria targeted by the antifouling are Staphylococcus aureus and Escherichia coli. ​ 6. Use according to claim 5, characterized in that, ​

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