CN111574334B - Novel phenolic compound and preparation method and application thereof - Google Patents

Abstract

The invention provides a novel phenolic compound and a preparation method and application thereof, wherein the chemical general formula of the novel phenolic compound is shown as a formula (1), wherein R = Br, cl or F. The novel phenolic compound provided by the invention can obviously inhibit the growth of gram-positive bacteria, has the minimum inhibitory concentration of 1-4 mu g/mL on staphylococcus aureus, bacillus and methicillin-resistant staphylococcus aureus, does not generate drug resistance under long-time low-dose exposure, can be used as a gram-positive bacteria antibacterial agent, and has a good antibacterial effect.

Description

A kind of novel phenolic compound and its preparation method and application

technical field

The invention relates to the technical field of preparation of phenolic compounds, in particular to a novel phenolic compound and its preparation method and application.

Background technique

Bacterial infection has increasingly become a hidden danger to public health, and the abuse of antibiotics has led to the emergence of drug resistance in a large number of bacteria. Among Gram-positive bacteria, the most important drug-resistant bacteria is methicillin-resistant Staphylococcus aureus, which seriously affects human health. Antibacterial agents are the core components of antibacterial materials, which have the function of killing or inhibiting microorganisms. Patent application CN106667994A discloses the application of oligomeric polyphenolic compounds in the preparation of products against Gram-positive drug-resistant bacteria, and the oligomeric polyphenolic compounds are trans-structure dimers and trimers of oligomeric polyphenols Phenolic compounds, the dimer and trimer resveratrol oligomeric polyphenolic compounds are compound 1: trans-D-glucoside and compound II: gentian H, the dimer anti The resistance to drug-resistant bacteria is stronger than that of the trimer. The MIC value of the anti-drug-resistant bacteria of the dimer trans-D-glucose is 8 μg/mL, and the anti-drug-resistant bacteria of the trimeric gentian H The MIC value was 16 μg/mL. But the MICs of these two oligomeric polyphenolic compounds were still high.

Therefore, how to prepare a product with better antibacterial effect against Gram-positive drug-resistant bacteria has become an urgent technical problem to be solved.

Contents of the invention

The object of the present invention is to provide a kind of novel phenolic compound and its preparation method and application, described novel phenolic compound can significantly inhibit the growth of Gram-positive bacteria, and is resistant to Staphylococcus aureus, Bacillus subtilis, methicillin The minimum inhibitory concentration of Staphylococcus aureus is 1-4 μg/mL.

In order to achieve the above object, one of the objects of the present invention is to provide a novel phenolic compound, the general chemical formula of the novel phenolic compound is:

where R=Br, Cl or F.

The second object of the present invention is to provide a kind of preparation method of novel phenolic compound, when R=Br or Cl in the novel phenolic compound of described formula (1), described preparation method comprises:

4-hydroxydiphenylmethane is reacted with a halogen-containing compound to obtain compound II, and the halogen includes bromine or chlorine;

Reaction of the compound II with acetyl chloride to obtain the compound III;

reacting the compound III with a phenol solution to obtain the novel phenolic compound;

Wherein the general chemical formula of the compound II is the following formula (2); the general chemical formula of the compound III is the formula (3);

In the formula (2) and formula (3), R1=Br or Cl.

Further, the reaction of 4-hydroxydiphenylmethane with halogen-containing compounds includes:

Dissolving 4-hydroxydiphenylmethane and halogen-containing compounds in acetic acid or methanol solvent, and reacting at a temperature of 5-25°C.

Further, the reaction of the compound II with acetyl chloride includes:

The compound II and acetyl chloride were dissolved in dichloromethane solvent, and reacted under the conditions of catalyst AlCl ₃ and temperature of 5-25°C.

Further, the reaction of the compound III with a phenol solution includes:

The compound III is dissolved in a phenol solution, and toluenesulfonic acid is added under the temperature condition of 25-65° C. and stirred for reaction.

The third object of the present invention is to provide a kind of preparation method of novel phenolic compound, when R=F in the novel phenolic compound of described formula (1), described preparation method comprises:

4-Br-2,6-difluorophenol was reacted with bromotoluene to obtain 5-Br-1,3-difluoro-2-phenyl-methoxybenzene;

reacting the 5-Br-1,3-difluoro-2-phenyl-methoxybenzene with benzylmagnesium chloride to obtain 4-benzyl-2,6-dichloro-methoxybenzene;

Reducing the 4-benzyl-2,6-dichloro-methoxybenzene to obtain 4-benzyl-2,6-difluorophenol;

reacting the 4-benzyl-2,6-difluorophenol with acetyl chloride to obtain 4-(4-acetylbenzyl)-2,6-difluorophenylacetic acid;

The 4-(4-acetylbenzyl)-2,6-difluorophenylacetic acid is reacted with a phenol solution to obtain the novel phenolic compound.

Further, the reaction of 4-Br-2,6-difluorophenol with bromotoluene includes:

Dissolve 4-Br-2,6-difluorophenol in DMF solution, and add basic substance to stir under N ₂ atmosphere, after stirring, add bromotoluene to react.

Further, the reaction of the 5-Br-1,3-difluoro-2-phenyl-methoxybenzene with benzylmagnesium chloride includes:

ZnBr ₂ and THF are mixed to obtain the first mixed solution;

Under N ₂ atmosphere, the benzylmagnesium chloride and the first mixed solution were mixed and stirred, and after stirring, 5-Br-1,3-difluoro-2-phenyl-methoxybenzene was added for reaction.

The fourth object of the present invention is to provide the application of the novel phenolic compound in the preparation of antibacterial agents for Gram-positive bacteria.

Further, the Gram-positive bacteria include Staphylococcus aureus, Bacillus subtilis, and methicillin-resistant Staphylococcus aureus.

One or more technical solutions in the embodiments of the present invention have at least the following technical effects or advantages:

A novel phenolic compound provided by the invention can significantly inhibit the growth of Gram-positive bacteria, and the minimum inhibitory concentration for Staphylococcus aureus, Bacillus subtilis, and methicillin-resistant Graupus aureus is 1-4 μg/mL , and does not produce drug resistance under long-term low-dose exposure, it can be seen that the new phenolic compound can be used as an antibacterial agent for Gram-positive bacteria, with good antibacterial effect, and is a good antibacterial agent.

Description of drawings

In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the following will briefly introduce the drawings that need to be used in the description of the embodiments. Obviously, the drawings in the following description are some embodiments of the present invention. For those skilled in the art, other drawings can also be obtained based on these drawings without any creative effort.

Fig. 1 is the mass spectrogram of the novel phenolic compound prepared in Example 1 of the present invention;

Fig. 2 is the mass spectrogram of the novel phenolic compound prepared by Example 2 of the present invention;

Fig. 3 is the mass spectrogram of the novel phenolic compound prepared in Example 3 of the present invention.

Detailed ways

The present invention will be described in detail below in conjunction with specific embodiments and examples, and the advantages and various effects of the present invention will be presented more clearly. Those skilled in the art should understand that these specific implementations and examples are used to illustrate the present invention, not to limit the present invention.

Throughout the specification, unless otherwise specified, terms used herein should be understood as commonly used in the art. Therefore, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In case of conflict, this specification shall take precedence.

Unless otherwise specified, various raw materials, reagents, instruments and equipment used in the present invention can be purchased from the market or prepared by existing methods.

The technical solutions provided by the embodiments of the present invention are to solve the above-mentioned technical problems, and the general idea is as follows:

In order to achieve the above purpose, this embodiment provides a novel phenolic compound, the general chemical formula of which is:

where R=Br, Cl or F.

The embodiment of the present invention also provides the preparation method of described novel phenolic compound:

1. When R=Br or Cl in the novel phenolic compound of the formula (1), the preparation method comprises:

Step 1, reacting 4-hydroxydiphenylmethane with a halogen-containing compound to obtain compound II, and the halogen includes bromine or chlorine; specifically,

(1) when R=Br, after 4-hydroxyl diphenylmethane is dissolved in the acetic acid solution, can directly pass into bromine gas reaction, and described halogen-containing compound is bromine gas, and wherein 4-hydroxyl diphenylmethane and The molar ratio of bromine gas preferably ranges from 15 to 17:32 to 34, and can fully react within this molar ratio range;

Preferably, the reaction has also added an organic solvent, such as chloroform, acetic acid, methanol, etc., the preferred AcOH acetate in the present embodiment, because according to experiments, it is found that the yield of acetic acid is the highest for this structure.

(2) When R=Cl, due to the low reaction efficiency of introducing chlorine gas, the applicant dissolves 4-hydroxydiphenylmethane in methanol solution, and then adds a mixture of NaOH, NaCl, and NaClO as the halogen-containing compound,

The molar ratio of NaOH, NaCl, and NaClO is preferably 2 to 3:4.5 to 5:4.5 to 5; the reason why the molar ratio of NaOH, NaCl, and NaClO is selected in this way is that the applicant first chooses a molar ratio of 1.5:3: 3. It was found that there was a surplus of raw materials. After reason analysis, it was found that this may be due to insufficient effective content of NaClO, so we screened and found that increasing the equivalent of NaClO can make the reaction complete. Therefore, after a series of experiments, the present application finds that the final molar ratio of NaOH, NaCl, and NaClO in the range of 2-3:4.5-5:4.5-5 can make the reaction complete.

Preferably, the reaction has also added an organic solvent, such as chloroform, acetic acid, methanol, etc., the preferred methanol MeOH in this embodiment, because according to the experiment, it is found that the yield of methanol is the highest for this structure.

Step 2, reacting the compound II with acetyl chloride to obtain compound III;

Preferably, the reaction is carried out in a dichloromethane solvent, and a catalyst AlCl ₃ is added, and the reaction temperature is 5-25°C;

Described reaction is very typical Friedel-Crafts acylation reaction, for this type of reaction: the solvent of reaction is the most commonly used methylene dichloride, also has dichloroethane and carbon disulfide etc.; The catalyzer of reaction is most commonly used as aluminum trichloride, also There are anhydrous zinc chloride, iron trichloride, titanium _{tetrachloride} etc.; This reaction selects dichloromethane as solvent, AlCl as catalyst, because these two things are all cheap and easy to get, and the yield is OK, suitable to enlarge;

The purpose of adding acetyl chloride first is to protect the phenolic hydroxyl group; in this process, the temperature has little effect between 5 and 25°C, but if the temperature is too high, the acetyl group protecting the phenolic hydroxyl group may fall off, so AlCl is added later _3. When carrying out Friedel-Crafts acylation reaction, side reactions will occur due to the strong positioning effect of phenolic hydroxyl groups; when adding AlCl ₃ , the temperature should not be too high (more preferably 5-15°C), so as to prevent the reaction from being too violent , The second is to worry that the local temperature in the system is too high to cause side reactions;

Preferably, the molar ratio range of the compound II to acetyl chloride is preferably 1-3:4-6, which can make the reaction complete.

Step 3, reacting the compound III with a phenol solution to obtain the novel phenolic compound;

Preferably, the molar ratio of the compound III to the phenol is 1-3:5-7, in order to make the substrate and phenol mix more uniformly.

(1) When R=Br, dissolve the compound III in a phenol solution, add toluenesulfonic acid under the protection of N ₂ at 25-65° C., and stir to react.

Phenol is solid at low temperature, and we added phenol, so that when the temperature rises to 25-65°C (more preferably 60-65°C), compound III and phenol are mixed evenly and are easy to react; and the phenolic hydroxyl group in the product More, adding nitrogen protection is to prevent the product from being oxidized when heated; p-toluenesulfonic acid is a commonly used catalyst for this type of reaction (similar to the synthesis of bisphenol A), and there are other sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, etc.; In the early stage, we screened these acids and found that TsOH tosylate reacted best for this kind of substrate.

(2) When R=Cl, dissolve the compound III in a phenol solution, add toluenesulfonic acid at 25-65° C. and stir for reaction. There is no need to add _N2 protection at this time.

Wherein, the general chemical formula of the compound II is the following formula (2); the general chemical formula of the compound III is the formula (3);

In the formula (2) and formula (3), R1=Br or Cl.

2. When R=F in the novel phenolic compound of the formula (1), the preparation method comprises:

Step 1, react 4-Br-2,6-difluorophenol with bromotoluene to obtain 5-Br-1,3-difluoro-2-phenyl-methoxybenzene; specifically, 4-Br- Dissolve 2,6-difluorophenol in DMF solution, add basic substance under N ₂ and stir, then add bromotoluene.

Nitrogen protection is used to prevent the product from being oxidized during heating; the alkaline substances include NaOH, K ₂ CO ₃ , etc. K ₂ CO ₃ is selected in this example because K ₂ CO ₃ can fully meet the reaction requirements and is cheap Easy to obtain and convenient for post-processing.

Preferably, the molar ratio of 4-Br-2,6-difluorophenol to bromotoluene is 40-50:50-60. Toluene bromide is highly irritating and tear-jerking, and adding more is useless; this ratio range is sufficient to make the reaction complete.

Step 2, reacting the 5-Br-1,3-difluoro-2-phenyl-methoxybenzene with benzylmagnesium chloride to obtain 4-benzyl-2,6-dichloro-methoxybenzene ;

Specifically, add the benzylmagnesium chloride to THF mixed with _ZnBr2 under _N2 at 10°C, stir and mix well, then add 5-Br-1,3-difluoro-2-phenyl-methoxybenzene of THF solution. Adding benzylmagnesium chloride under this condition is because benzylmagnesium chloride can be quickly converted into organic Zn reagent, and also to ensure that the generated Zn reagent can exist stably, so as not to deteriorate due to excessive price adjustment.

Preferably, the molar ratio of the benzylmagnesium chloride to compound 7 is in the range of 1:1-2. This ratio range is sufficient to complete the reaction.

Step 3. Reducing the 4-benzyl-2,6-dichloro-methoxybenzene to obtain 4-benzyl-2,6-difluorophenol; specifically, the 4-benzyl -2,6-dichloro-methoxybenzene was dissolved in methanol solution, and the reduction reaction was carried out by feeding _H2 under the catalyst Pd/C.

Step 4, reacting the 4-benzyl-2,6-difluorophenol with acetyl chloride to obtain 4-(4-acetylbenzyl)-2,6-difluorophenylacetic acid; specifically, the The 4-benzyl-2,6-difluorophenol was dissolved in dichloromethane, then acetyl chloride was added dropwise, and the catalyst AlCl ₃ was added at the same time. The most commonly used solvent for the reaction is methylene chloride, as well as dichloroethane and carbon disulfide, etc.; the most commonly used catalyst for the reaction is aluminum trichloride, as well as anhydrous zinc chloride, ferric chloride, titanium tetrachloride, etc.; This reaction chooses dichloromethane as a solvent and _AlCl3 as a catalyst, entirely because these two things are cheap and easy to get, and the yield is acceptable, which is suitable for scale-up.

Preferably, the molar ratio range of the 4-benzyl-2,6-difluorophenol to acetyl chloride is preferably 1-2:1.1-4, which can make the reaction complete.

Step 5, reacting the 4-(4-acetylbenzyl)-2,6-difluorophenylacetic acid with a phenol solution to obtain the novel phenolic compound. P-toluenesulfonic acid is a catalyst commonly used for this type of reaction (similar to the synthesis of bisphenol A), and other also have sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, etc., the applicants have screened these acids in the early stage, and found that TsOH is suitable for this type of reaction. The substrate reacts best. Preferably, the molar ratio of the 4-(4-acetylbenzyl)-2,6-difluorophenylacetic acid to the phenol is 1-3:5-7, in order to make the substrate and phenol mix more efficiently. Uniform, complete reaction.

The novel phenolic compound can significantly inhibit the growth of Gram-positive bacteria, and the minimum inhibitory concentration for Staphylococcus aureus, Bacillus subtilis, and methicillin-resistant Staphylococcus aureus is 1-4 μg/mL

A new type of phenolic compound of the present application, its preparation method and application will be described in detail below in combination with examples and experimental data.

Example 1

When R=Br in formula (1), the structural formula of the novel phenolic compound in the present embodiment is:

The flow process of concrete preparation method is:

Step 1. Compound 1 (4-hydroxydiphenylmethane, 3.00g, 16.3mmol, 1.00eq) was added to AcOH (15.0mL), and Br ₂ (5.23g, 32.7mmol, 1.69mL, 2.01 eq). The mixture was stirred at 5-25°C for 2 hours.

TLC (petroleum ether: ethyl acetate = 5: 1, Rf = 0.59) detected that after the reaction of 4-hydroxydiphenylmethane was complete, the reaction mixture was poured into twice the volume of ice water, and extracted twice with the same volume of ethyl acetate, The obtained organic phase was washed twice with NaHCO ₃ , then washed with concentrated brine, dried with anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain a residue, and then purified by column chromatography to obtain a light yellow oily solution A, that is, compound II was obtained and analyzed by NMR Resonance detection of the compound;

Step 2. Compound 2 (3.00g, 8.77mmol, 1.00eq) was added to dichloromethane DCM (30.0mL), and acetyl chloride (1.45g, 18.4mmol, 1.31mL, 2.10eq) was added dropwise at 10°C, 0 After stirring at -15°C for 1 hour to obtain a mixture, AlCl _{3 (} 1.87g, 14.0mmol, 767uL, 1.60eq) was added to the mixture in proportion and stirred at 0-15°C for 12 hours.

After TLC (petroleum ether: ethyl acetate = 5: 1, Rf = 0.30) detected that compound II was completely reacted, the reaction mixture was poured into ice water, extracted with dichloromethane, and the obtained extracted organic phase was concentrated Washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, and then purified by silica gel column chromatography to obtain a white solid B, namely compound 3;

Step 3, TsOH (2.02g, 11.7mmol, 2.00eq) was added to the mixture of compound 3 (2.50g, 5.87mmol, 1.00eq), phenol (2.76g, 29.3mmol, 2.58mL, 5.00eq) was added, and Under _N2 , the temperature is 5-25 °C. The mixture was stirred at 65°C for 12 hours. HPLC (ET28324-9-P1A1) and TLC (petroleum ether:ethyl acetate=5:1, Rf=0.51) showed that compound 3 was completely consumed. The reaction mixture was dissolved in ethyl acetate EtOAc (15.0 mL), washed with the same volume of NaHCO ₃ solution, and then the organic phase was washed with one-half volume of concentrated brine, dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure to obtain The residue was then purified by column chromatography to obtain a yellow solid, and further purified by reverse-phase high-performance liquid chromatography to obtain a light yellow solid, that is, the novel phenolic compound was obtained.

Example 2

When R=Cl in formula (1), the structural formula of the novel phenolic compound of the present embodiment is:

The flow process of concrete preparation method is:

Step 1, add NaOH (977mg, 24.4mmol, 1.5eq) and NaCl (2.85g, 48.9mmol, 3eq) to the solution of compound 1 (3.00g, 16.3mmol, 1eq) in MeOH (50.0mL), the temperature is 5-15°C, a mixture was obtained. NaClO (45.5 g, 48.9 mmol, 37.6 mL, 8% purity, 3 eq) was added dropwise to the mixture and stirred at 5-15°C for 13 hours.

TLC (petroleum ether:ethyl acetate=5:1) indicated that reactant 1 had been completely consumed. The mixture was concentrated under reduced pressure to remove most of the MeOH. Dilute with water (15.0 mL), extract with EtOAc (20.0 mL*2). The combined organic layers were washed with brine (15.0 mL), dried over anhydrous _Na2SO4 , filtered, and concentrated _under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether/ethyl acetate=100/1-10/1). Compound 4 (2.50 g, 9.88 mmol, 60.7% yield) was identified as a pale yellow solid by HNMR (ET25545-13-P1A).

Step 2. Add compound 4 (500mg, 1.98mmol, 1eq) to DCM (3mL), add acetyl chloride (325mg, 4.15mmol, 296uL, 2.1eq) dropwise at 5°C, and stir at 0-15°C for 1 hour to obtain mixture, AlCl ₃ (579mg, 4.35mmol, 237uL, 2.2eq) was added in proportion to the mixture, and stirred at 0-15°C for 2 hours.

TLC (petroleum ether:ethyl acetate=5:1) indicated that reactant 4 was completely consumed, and the reaction mixture was poured into ice water (5ml) at 10°C, and then extracted with dichloromethane DCM (2ml*2). The combined organic layers were washed with brine (2ml) _, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to obtain compound 5 (400 g, 1.19 mmol, 60.1% yield) as a pale yellow solid identified by HNMR (ET25545-16-P1B).

Step 3. A solution of compound 5 (400mg, 1.19mmol, 1eq) in phenol (558mg, 5.93mmol, 522uL, 5eq) was added to TsOH (409mg, 2.37mmol, 2eq). The mixture was stirred at 60°C for 12 hours. LCMS (ET25545-19-P1A1) and HPLC (ET25545-19-P1A) showed that compound 5 was completely consumed and one main peak was detected. The reaction mixture was dissolved in ethyl acetate EtOAc (5.00 mL), washed with the same volume of NaHCO ₃ solution, and then the organic phase was washed with one-half volume of concentrated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure, get residue. Using high performance liquid chromatography (column: Welch xc18 250*50mm*10um; mobile phase: [water (10mm-NH ₄ HCO ₃ )-ACN]; B%: 55%-75%, 10min) to obtain a white solid, namely The novel phenolic compound was obtained.

Example 3

When R=F in formula (1), the structural formula of the novel phenolic compound of the present embodiment is:

The flow process of concrete preparation method is:

Step 1. Add K ₂ CO ₃ (9.92g, 71.77mmol, 1.5eq) to compound 6 (10g, 47.85mmol, 1eq) dissolved in DMF (100mL) at 15°C under N ₂ , and stir at 15°C for 0.5 hours Afterwards, toluene bromide (9.82 g, 57.42 mmol, 6.82 mL, 1.2 eq) was added and stirred at 15° C. for 12 hours to obtain a mixture.

TLC (petroleum ether:ethyl acetate=3:1) showed that reactant 6 was completely consumed, and the mixture was poured into 300 mL of ice water and extracted with EtOAc (100 mL*2). The combined organic layers were washed with brine (50 mL*3), dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=100/1 to 20/1). As determined by HNMR (ET25545-5-P1A), compound 7 (10 g, 33.43 mmol, yield 69.87%) was a pale yellow oil.

Step 2. To THF (10 mL) mixed with ZnBr ₂ (902.60 mg, 4.01 mmol, 200.58 uL, 2.4 eq), benzylmagnesium chloride (1M, 3.34 mL, 2.0 eq) was added dropwise at 10° C. under N ₂ . Stirring at 15°C for 0.5 hours gave a mixture. Compound 7 (0.5g, 1.67mmol, 1eq) and 1,3-bis(2,6-diisopropylphenyl)-2h-imidazole, 3-chloropyridine, dichloropalladium (113.81mg, 167.00umol, 0.1 eq) was dissolved in THF (5 mL), added dropwise to the mixture at 15° C. under N ₂ , and stirred at 15° C. for 12.5 hours.

LCMS (ET25545-10-P1A) showed that compound 7 was completely consumed and an ideal m/z peak was detected. The mixture was poured into ice water (20ml), extracted with EtOAc (10ml*2). The combined organic extracts were washed with brine (10 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue. The residue was purified by column chromatography (SiO ₂ , petroleum ether/ethyl acetate=50/1-5/1). Compound 8 (0.3 g, crude oil) was a yellow oil.

Step 3, add compound 8 (0.3g, 966.69umol, 1eq) in MeOH (3mL), add Pd/C (0.3g, 10% purity) at 15°C, under the condition of H ₂ (15Psi), at 15 Stir at °C for 12 hours. LCMS (ET25545-33-P1A) indicated that compound 8 was consumed and a desirable MS peak was detected. The reaction mixture was filtered and concentrated under lower pressure to yield a residue to give compound 9 (0.2 g, crude oil) as a tan oil.

Step 4. Add compound 9 (0.2g, 908.21umol, 1eq) to DCM (3ml), add acetyl chloride (149.71mg, 1.91mmol, 136.10uL, 2.1eq) dropwise at 5°C, and stir at 5°C for 1 hour , AlCl ₃ (266.42mg, 2.00mmol, 109.19uL, 2.2eq) was added, and stirred at 15°C for 2 hours to obtain a reaction mixture. TLC (petroleum ether:ethyl acetate=5:1) and LCMS (ET25545-40-P1A) indicated that compound 9 was completely consumed. The reaction mixture was poured into ice water (5ml) at 10°C, then extracted with DCM (2ml*2). The combined organic layers were washed with brine (2ml) _, dried over anhydrous _Na2SO4 , filtered and concentrated under reduced pressure to give a residue. The residue was purified by pre-tlc (SiO ₂ , petroleum ether/ethyl acetate=5/1) to obtain compound 10 (0.3 g, crude) as a pale yellow solid.

Step 5. Add TsOH (226.36mg, 1.31mmol, 2.0eq) to a solution of compound 10 (0.2g, 657.27umol, 1eq) dissolved in phenol (309.28mg, 3.29mmol, 289.05uL, 5.0eq), Stirring at 60°C for 12 hours gave a reaction mixture. LCMS (ET25545-46-P1B) and HPLC (ET25545-46-P1A) showed complete consumption of compound 10 and one main peak was detected. The reaction mixture was dissolved in EtOAc (5 ml), washed with the same volume of NaHCO ₃ solution, then the organic phase was washed with one-half volume of concentrated brine, dried over anhydrous Na ₂ SO ₄ , filtered, and concentrated under reduced pressure to give the remains. The crude product was purified by reverse-phase high-performance liquid chromatography (0.1% NH ₄ HCO ₃ ) to obtain a light yellow solid, which was detected by LCMS (ET25545-46-P1B1) and HPLC (ET25545-46-P1B). The obtained solid was subjected to prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um; mobile phase: [water (10mM NH ₄ HCO ₃ )-ACN]; B%: 30%-80%, 10min) to give a white solid. As determined by HNMR, (0.12g, 274.68umol, yield 41.79%, purity 98.99%) was obtained as a white solid, which was the novel phenolic compound.

Comparative example 1

This comparative example is an unsubstituted phenolic compound prepared by a conventional method, and its structural formula is as follows:

Test case

The novel phenolic compounds of Examples 1-3 and the unsubstituted phenolic compound of Comparative Example 1 were subjected to minimum inhibitory concentration (Minimum Inhibition Concentration, MIC) testing experiments, and the MIC measurement results are shown in Table 1.

The specific experimental steps are as follows:

Inoculate a little bacteria from the plate in an Erlenmeyer flask equipped with LB medium (Luria-Bertani medium), and culture on a shaker at 37°C for 8-10h; wherein, the bacteria include: Gram-positive bacteria and Gram-negative bacteria Described Gram-positive bacterium comprises Staphylococcus aureus, Bacillus, methicillin-resistant Staphylococcus aureus, and described Bacillus subtilis is Bacillussubtilis 168; Used Staphylococcus aureus is Staphylococcus aureus 25923; Described resistant Methicillin Staphylococcus aureus is abbreviated as MRSA; the Gram-negative bacteria used is Escherichia coli DH5α.

The formula of LB medium is as follows: tryptone (Tryptone) 10g/L, yeast extract (Yeast extract) 5g/L, sodium oxide (NaCl) 10g/L.

In the morning of the second day, the bacterial solution was drawn from the Erlenmeyer flask and transferred to the Erlenmeyer flask containing 20 mL of LB medium at a volume ratio of 1%, and continued to cultivate in a shaker at 37°C for 5h-6h until OD600 (OD600 Indicates that the absorbance value of the bacterial liquid at a wavelength of 600nm) is 0.6-0.8, and the specific OD value (optical density, optical density °C) of the bacterial liquid is recorded.

Dilute the cultured bacterial solution 1000 times with LB medium to make the concentration of the bacterial solution 105 CFU/ml, draw the diluted bacterial solution, and add it to a 96-well plate, 150 μl per well.

Prepare the phenolic compound solution with a concentration of 128 μg/ml, pipette 150 μl of the triphenolic compound solution into the first well of a 96-well plate, then pipette 150 μl into the second well, and so on. After the dropwise addition, the 96-well plate was placed in a shaker and incubated overnight at 37°C.

Table 1 - MIC value results

It can be seen from Table 1 that compared with Comparative Example 1, the inhibitory effect of the novel phenolic compound of the present invention on Gram-positive bacteria is doubled. The novel phenolic compounds provided by Examples 1-3 of the present invention can significantly inhibit the growth of Gram-positive bacteria, and the minimum inhibitory concentration for Staphylococcus aureus, Bacillus subtilis, and methicillin-resistant Staphylococcus aureus is 1-2 μg /ml, it can be seen that the antibacterial effect of the triphenol compound is good, and it can be used as a good antibacterial agent for Gram-positive bacteria.

Finally, it should also be noted that the term "comprises", "comprises" or any other variation thereof is intended to cover a non-exclusive inclusion such that a process, method, article or apparatus comprising a set of elements includes not only those elements, but also Other elements not expressly listed, or inherent to the process, method, article, or apparatus are also included.

While preferred embodiments of the invention have been described, additional changes and modifications to these embodiments can be made by those skilled in the art once the basic inventive concept is appreciated. Therefore, it is intended that the appended claims be construed to cover the preferred embodiment as well as all changes and modifications which fall within the scope of the invention. Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and equivalent technologies thereof, the present invention also intends to include these modifications and variations.

Claims (3)

1. A process for the preparation of a phenolic compound, characterized in that,

the chemical general formula of the phenolic compound is as follows:

wherein R is Br and Cl;

the preparation method comprises the following steps:

reacting 4-hydroxydiphenylmethane with a halogen-containing compound to obtain a compound II, wherein the halogen comprises bromine or chlorine;

reacting the compound II with acetyl chloride to obtain a compound III;

reacting the compound III with a phenol solution to obtain the phenol compound;

wherein the chemical general formula of the compound II is a formula (2); the chemical general formula of the compound III is shown as a formula (3);

in the formulas (2) and (3), R1 is Br or Cl;

the reaction of 4-hydroxydiphenylmethane with a halogen-containing compound comprises:

when R is Br, dissolving 4-hydroxy diphenylmethane and a halogen-containing compound in an acetic acid solvent, and reacting at the temperature of 5-25 ℃, wherein the halogen-containing compound is bromine gas; when R is Cl, dissolving 4-hydroxy diphenylmethane and a halogen-containing compound in a methanol solvent, and reacting at the temperature of 5-25 ℃, wherein the halogen-containing compound is a mixture of NaOH, naCl and NaClO;

reacting the compound II with acetyl chloride, comprising:

dissolving the compound II and acetyl chloride in a dichloromethane solvent and stirring for 1 hour, and then adding the mixture in a catalyst AlCl ₃ And 5Carrying out reaction at the temperature of 25 ℃;

reacting said compound III with a phenol solution comprising:

dissolving the compound III in a phenol solution, adding toluenesulfonic acid at the temperature of 25-65 ℃, and stirring for reaction.

2. A method for preparing phenolic compounds is characterized in that,

the chemical general formula of the phenolic compound is as follows:

wherein R is F;

the preparation method comprises the following steps:

reacting 4-bromo-2, 6-difluorophenol with alpha-bromotoluene to obtain 5-bromo-1, 3-difluoro-2-benzyloxybenzene;

reacting the 5-bromo-1, 3-difluoro-2-benzyloxy benzene with benzyl magnesium chloride to obtain 4-benzyl-2, 6-difluoromethoxybenzene;

carrying out reduction reaction on the 4-benzyl-2, 6-difluoromethoxybenzene to obtain 4-benzyl-2, 6-difluorophenol;

reacting the 4-benzyl-2, 6-difluorophenol with acetyl chloride to obtain [ acetic acid (4- (4-acetoacetyl-benzyl) -2, 6-difluoro) phenol ] ester;

reacting the [ 4- (4-acetylbenzyl) -2, 6-difluoro) phenol ] acetate with a phenol solution to obtain the phenolic compound;

reacting 4-bromo-2, 6-difluorophenol with α -bromotoluene, comprising:

4-bromo-2, 6-difluorophenol was dissolved in DMF solution and washed with N ₂ Adding K under atmosphere ₂ CO ₃ Stirring, and adding alpha-bromotoluene to react;

reacting the 5-bromo-1, 3-difluoro-2-benzyloxybenzene with benzylmagnesium chloride comprising:

reacting ZnBr ₂ Mixing with THF to obtain a first mixed solution;

in N ₂ Under the atmosphere, the benzyl magnesium chloride and the second catalyst are mixedMixing and stirring the mixed solution, and adding 5-bromo-1, 3-difluoro-2-benzyloxy-benzene for reaction after stirring;

dissolving the 4-benzyl-2, 6-difluorophenol and acetyl chloride in a dichloromethane solvent and stirring for 1 hour, and then adding the mixture in a catalyst AlCl ₃ The reaction was carried out as follows.

3. Use of the phenolic compound obtained by the process according to claim 1 or 2 for the preparation of gram-positive antibacterial agents; the gram-positive bacteria are staphylococcus aureus, bacillus and methicillin-resistant staphylococcus aureus.

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