CN111574334B - Novel phenolic compound and preparation method and application thereof - Google Patents
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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
Technical Field
The invention relates to the technical field of preparation of phenolic compounds, and in particular relates to a novel phenolic compound and a preparation method and application thereof.
Background
Bacterial infections are increasingly becoming a public health hazard, and the abuse of antibiotics has led to the emergence of resistance in a large number of bacteria. Among the gram-positive bacteria, the most important drug-resistant bacteria are methicillin-resistant staphylococcus aureus, which seriously affect the physical health of human beings. The antibacterial agent is a core component of the antibacterial material, and has a function of killing or inhibiting microorganisms. Patent application CN106667994A discloses the application of oligomeric polyphenols in the preparation of anti-gram-positive drug-resistant bacteria products, and the oligomeric polyphenols are dimer and trimer oligomeric polyphenols with trans-structure, and the dimer and trimer resveratrol oligomeric polyphenols are compound 1: trans-D-viniferin and compound II: the dimer has stronger drug-resistant bacterium resistance than that of the trimer, the MIC value of the dimer trans-D-viniferin is 8 mug/mL, and the MIC value of the trimer Gentianh is 16 mug/mL. However, the MIC of these two oligomeric polyphenolic compounds was still high.
Therefore, how to prepare a product with better antibacterial effect against gram-positive drug-resistant bacteria becomes a technical problem to be solved urgently.
Disclosure of Invention
The invention aims to provide a novel phenolic compound, a preparation method and an application thereof, wherein the novel phenolic compound can obviously inhibit the growth of gram-positive bacteria, and the minimum inhibitory concentration to staphylococcus aureus, bacillus subtilis and methicillin-resistant staphylococcus aureus is 1-4 mu g/mL.
In order to achieve the above objects, one of the objects of the present invention is to provide a novel phenolic compound having the chemical formula:
wherein R = Br, cl or F.
Another object of the present invention is to provide a method for producing a novel phenolic compound of formula (1) wherein R = Br or Cl, the method comprising:
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 novel phenolic compound;
wherein the chemical general formula of the compound II is the following formula (2); the chemical general formula of the compound III is shown as a formula (3);
in the formulae (2) and (3), R1= Br or Cl.
Further, the reacting 4-hydroxydiphenylmethane with a halogen-containing compound comprises:
4-hydroxy diphenylmethane and halogen-containing compound are dissolved in acetic acid or methanol solvent and react at the temperature of 5-25 ℃.
Further, said reacting said compound II with acetyl chloride comprises:
dissolving the compound II and acetyl chloride in a dichloromethane solvent, and reacting in a catalyst AlCl 3 And reacting at 5-25 deg.c.
Further, the reacting the compound III with a phenol solution comprises:
dissolving the compound III in a phenol solution, adding toluenesulfonic acid at the temperature of 25-65 ℃, and stirring for reaction.
The present invention also provides a process for producing a novel phenolic compound of formula (1), wherein when R = F, the process comprises:
reacting 4-Br-2, 6-difluorophenol 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;
carrying out reduction reaction on 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-acetyl benzyl) -2, 6-difluorophenylacetic acid;
reacting the 4- (4-acetyl benzyl) -2, 6-bis (fluorophenyl) acetic acid with a phenol solution to obtain the novel phenolic compound.
Further, the reaction of 4-Br-2, 6-difluorophenol with bromotoluene comprises:
4-Br-2, 6-difluorophenol was dissolved in DMF solution and washed with N 2 Adding alkaline substances into the mixture under the atmosphere, stirring the mixture, and adding bromotoluene into the mixture to react.
Further, said reacting said 5-Br-1, 3-difluoro-2-phenyl-methoxybenzene with benzylmagnesium chloride comprises:
reacting ZnBr 2 Mixing with THF to obtain a first mixed solution;
in N 2 Mixing and stirring the benzyl magnesium chloride and the first mixed solution under the atmosphere, and adding 5-Br-1, 3-difluoro-2-phenyl-methoxybenzene for reaction after stirring.
The fourth purpose of the invention is to provide the application of the novel phenolic compound in preparing gram-positive bacteria antibacterial agent.
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:
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 subtilis 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, has a good antibacterial effect, and is a good antibacterial agent.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present invention, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are some embodiments of the present invention, and it is obvious for those skilled in the art to derive other drawings without creative efforts.
FIG. 1 is a mass spectrum of a novel phenolic compound prepared in example 1 of the present invention;
FIG. 2 is a mass spectrum of a novel phenolic compound prepared in example 2 of the present invention;
FIG. 3 is a mass spectrum of the novel phenolic compound prepared in example 3 of the present invention.
Detailed Description
The present invention will be described in detail below with reference to specific embodiments and examples, and the advantages and various effects of the present invention will be more clearly apparent therefrom. It will be understood by those skilled in the art that these specific embodiments and examples are for the purpose of illustrating the invention and are not to be construed as limiting the invention.
Throughout the specification, unless otherwise specifically noted, terms used herein should be understood as having meanings as commonly used in the art. Accordingly, unless defined otherwise, 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. If there is a conflict, the present specification will control.
Unless otherwise specifically stated, various raw materials, reagents, instruments, equipment and the like used in the present invention are commercially available or can be prepared by existing methods.
In order to solve the technical problems, the embodiment of the invention provides the following general ideas:
to achieve the above objectives, this example provides a novel phenolic compound, which has the chemical formula:
wherein R = Br, cl or F.
The embodiment of the invention also provides a preparation method of the novel phenolic compound, which comprises the following steps:
1. when R = Br or Cl in the novel phenolic compound of formula (1), the preparation method comprises:
step 1, reacting 4-hydroxy diphenylmethane with a halogen-containing compound to obtain a compound II, wherein the halogen comprises bromine or chlorine; in particular, the amount of the solvent to be used,
(1) When R = Br, 4-hydroxy diphenylmethane is dissolved in acetic acid solution, then bromine gas can be directly introduced for reaction, the halogen-containing compound is bromine gas, wherein the preferred range of the molar ratio of 4-hydroxy diphenylmethane to bromine gas is 15-17: 32 to 34, in which the reaction can be sufficiently carried out;
preferably, the reaction is also carried out with the addition of an organic solvent such as chloroform, acetic acid, methanol, etc., and acetic acid, acOH, is preferred in this example because it was experimentally found that acetic acid yield is highest for this structure.
(2) When R = Cl, the reaction efficiency is low due to the introduction of chlorine gas, 4-hydroxy diphenylmethane is dissolved in methanol solution, and then a mixture of NaOH, naCl and NaClO is added as the halogen-containing compound,
the mol ratio of NaOH to NaCl to NaClO is preferably 2-3: 4.5-5: 4.5 to 5; the reason for this choice of the molar ratios of NaOH, naCl and NaClO is that: the applicant first chooses a molar ratio of 1.5:3:3, the raw materials are found to be remained, and the reason analysis shows that the effective content of NaClO is probably insufficient, so that the screening is carried out, and the equivalent of NaClO is found to be increased to complete the reaction. Therefore, after a series of experiments, the application discovers that the molar ratio of NaOH, naCl and NaClO is selected from 2 to 3: 4.5-5: the range of 4.5 to 5 enables the reaction to be completed.
Preferably, the reaction also adds an organic solvent, such as chloroform, acetic acid, methanol, etc., methanol MeOH is preferred in this example because it was experimentally found that methanol yield was highest for this structure.
Step 2, reacting the compound II with acetyl chloride to obtain a compound III;
preferably, the reaction is carried out in a dichloromethane solvent with the addition of a catalyst AlCl 3 The reaction temperature is 5-25 ℃;
the reaction is typically a friedel-crafts acylation reaction, for which: the solvent for the reaction is most commonly dichloromethane, dichloroethane, carbon disulfide and the like; the most common catalysts for the reaction are aluminum trichloride, anhydrous zinc chloride, ferric trichloride, titanium tetrachloride and the like; the reaction selects dichloromethane as solvent, alCl 3 The catalyst is completely because the two substances are cheap and easy to obtain, and the yield is also high, so that the catalyst is suitable for amplification;
acetyl chloride is added firstly to protect phenolic hydroxyl; in this process, temperatures between 5 ℃ and 25 ℃ have little effect, but temperatures which are too high may lead to the acetyl groups protecting the phenolic hydroxyl groups falling off, so that AlCl is added later 3 When Friedel-crafts acylation reaction is carried out, side reaction can occur due to the strong positioning effect of phenolic hydroxyl; adding AlCl 3 When the temperature is too high (more preferably 5-15 ℃), firstly, the reaction is too violent, and secondly, side reactions caused by local too high temperature in the system are worried about; and after the addition is finished, naturally heating to room temperature.
Preferably, the molar ratio of the compound II to acetyl chloride is preferably in the range of 1 to 3:4 to 6, 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 to 3:5 to 7, in order to mix the substrate and phenol more homogeneously.
(1) When R = Br, dissolving the compound III in a phenol solution at 25-65 ℃ and N 2 Adding toluene sulfonic acid under the protection effect and stirring for reaction.
Phenol is solid at low temperature, and phenol is added, so that when the temperature is increased to 25-65 ℃ (more preferably 60-65 ℃), the compound III and phenol are mixed uniformly and are easy to react; the product has more phenolic hydroxyl groups, and nitrogen protection is added to prevent the product from being oxidized during heating; p-toluenesulfonic acid is a commonly used catalyst for such reactions (similar to the synthesis of bisphenol a), among others sulfuric acid, hydrochloric acid, trifluoromethanesulfonic acid, etc.; earlier we screened these acids and found that TsOH tosylate reacted best for this type of substrate.
(2) When R = Cl, the compound III is dissolved in a phenol solution, toluene sulfonic acid is added at 25 to 65 ℃ and the reaction is stirred. In this case, N is not required to be added 2 And (4) protecting.
Wherein the chemical general formula of the compound II is the following formula (2); the chemical general formula of the compound III is shown as a formula (3);
in the formulae (2) and (3), R1= Br or Cl.
2. When R = F in the novel phenolic compound of formula (1), the preparation method comprises the following steps:
step 1, reacting 4-Br-2, 6-difluorophenol with bromotoluene to obtain 5-Br-1, 3-difluoro-2-phenyl-methoxybenzene; specifically, 4-Br-2, 6-difluorophenol was dissolved in DMF solution in N 2 Then adding alkaline substance, stirring, and adding bromotoluene.
The nitrogen protection is added to prevent the product from being oxidized when being heated; the alkaline substance comprises NaOH and K 2 CO 3 Etc., K is selected in this embodiment 2 CO 3 Is in consideration of K 2 CO 3 Can completely meet the reaction requirement, is cheap and easy to obtain, and is convenient for post-treatment.
Preferably, the molar ratio of 4-Br-2, 6-difluorophenol to bromotoluene is from 40 to 50:50-60. Bromotoluene has strong irritation, lacrimation and is not beneficial in addition; this range of ratios is sufficient to complete the reaction.
Step 2, reacting the 5-Br-1, 3-difluoro-2-phenyl-methoxybenzene with benzyl magnesium chloride to obtain 4-benzyl-2, 6-dichloro-methoxybenzene;
specifically, to mixed ZnBr 2 In THF of (1) at N 2 The benzylmagnesium chloride is added at 10 ℃ and stirred to mix well and then added with a THF solution of 5-Br-1, 3-difluoro-2-phenyl-methoxybenzene. The reason why the benzylmagnesium chloride is added under such conditions is to rapidly convert the benzylmagnesium chloride into the organoZn reagent and to ensure that the formed Zn reagent is stably present and not deteriorated due to too strong a valorization.
Preferably, the molar ratio of benzylmagnesium chloride to compound 7 is in the range of 1:1-2. This range of ratios is sufficient to complete the reaction.
Step 3, carrying out reduction reaction on the 4-benzyl-2, 6-dichloro-methoxybenzene to obtain 4-benzyl-2, 6-difluorophenol; specifically, 4-benzyl-2, 6-dichloro-methoxybenzene is dissolved in methanol solution, and H is introduced under the condition of catalyst Pd/C 2 And carrying out reduction reaction.
Step 4, reacting the 4-benzyl-2, 6-difluorophenol with acetyl chloride to obtain 4- (4-acetyl benzyl) -2, 6-difluorophenylacetic acid; specifically, the 4-benzyl-2, 6-difluorophenol is dissolved in dichloromethane, acetyl chloride is added dropwise, and AlCl serving as a catalyst is added 3 . The solvent for the reaction is most commonly dichloromethane, dichloroethane, carbon disulfide and the like; the most common catalysts for the reaction are aluminum trichloride, anhydrous zinc chloride, ferric trichloride, titanium tetrachloride and the like; the reaction selects dichloromethane as solvent, alCl 3 The catalyst is obtained at low cost and easily available, and the yield is also suitable for scale-up.
Preferably, the molar ratio of 4-benzyl-2, 6-difluorophenol to acetyl chloride is preferably in the range of 1 to 2:1.1 to 4, can make the reaction complete.
And 5, reacting the 4- (4-acetyl benzyl) -2, 6-difluorophenyl acetic acid with a phenol solution to obtain the novel phenolic compound. P-toluenesulfonic acid is a commonly used catalyst for this type of reaction (similar to the synthesis of bisphenol a), among others sulfuric acid, hydrochloric acid, triflic acid, etc., which was previously screened by the applicant and TsOH was found to be the best for this type of substrate reaction. Preferably, the molar ratio of the 4- (4-acetylbenzyl) -2, 6-difluorophenylacetic acid to the phenol is 1 to 3:5 to 7, in order to mix the substrate and phenol more uniformly and to complete the reaction.
The novel phenolic compound can obviously inhibit the growth of gram-positive bacteria, and the minimum inhibitory concentration to staphylococcus aureus, bacillus subtilis and methicillin-resistant staphylococcus aureus is 1-4 mu g/mL
The present invention will now be described in detail with reference to examples and experimental data.
Example 1
When R = Br in formula (1), the structural formula of the novel phenolic compound in this example is:
the specific preparation method comprises the following steps:
step 1, add Compound 1 (4-hydroxydiphenylmethane, 3.00g,16.3mmol, 1.00eq) to AcOH (15.0 mL), drop-add Br at 10 deg.C 2 (5.23g, 32.7mmol,1.69mL, 2.01eq). The mixture was stirred at 5-25 ℃ for 2 hours.
After TLC (petroleum ether: ethyl acetate =5, 1, rf = 0.59) detected that the 4-hydroxydiphenylmethane reaction was complete, the reaction mixture was poured into two volumes of ice water and extracted twice with the same volume of ethyl acetate, and the resulting organic phase was extracted with NaHCO and then filtered and concentrated 3 Washing twice, then washing with strong brine and anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, concentrating to obtain residue, purifying by column chromatography to obtain yellowish oily solution A to obtain compound II, and detecting the compound by nuclear magnetic resonance;
step 2, compound 2 (3.00g, 8.77mmol, 1.00eq) was added to dichloromethane DCM (30.0 mL), acetyl chloride (1.45g, 18.4mmol,1.31mL, 2.10eq) was added dropwise at 10 deg.C, and after stirring for 1 hour at 0-15 deg.C, a mixture was obtained, and AlCl was added 3( 1.87g,14.0mmol,767uL, 1.60eq) was added to the mixture in proportion, and stirred at 0-15 ℃ 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, the obtained extracted organic phase was washed with concentrated brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain a residue, which was then purified by silica gel column chromatography to obtain a white solid B, i.e., compound 3;
step 3, adding TsOH (2.02g7mmol, 2.00eq) to a mixture of compound 3 (2.50g, 5.87mmol, 1.00eq), phenol (2.76g, 29.3mmol,2.58mL, 5.00eq) was added in N 2 The temperature is 5-25 ℃. The mixture was stirred at 65 ℃ for 12 hours. HPLC (ET 28324-9-P1 A1) and TLC (petroleum ether: ethyl acetate =5, 1, rf = 0.51) showed complete consumption of compound 3. The reaction mixture was dissolved in ethyl acetate EtOAc (15.0 mL) with the same volume of NaHCO 3 Washing with the solution, then washing the organic phase with half volume of concentrated brine, anhydrous Na 2 SO 4 Drying, filtering under reduced pressure, concentrating to obtain residue, purifying by column chromatography to obtain yellow solid, and further purifying by reverse high performance liquid chromatography to obtain light yellow solid to obtain the novel phenolic compound.
Example 2
When R = Cl in formula (1), the novel phenolic compound of the present example has the structural formula:
the specific preparation method comprises the following steps:
step 1, adding a solution of compound 1 (3.00g, 16.3mmol, 1eq) in MeOH (50.0 mL), adding NaOH (977mg, 24.4mmol, 1.5eq) and NaCl (2.85g, 48.9mmol, 3eq) at 5-15 deg.C to give a mixture. NaClO (45.5g, 48.9mmol,37.6mL,8% purity, 3 eq) was added dropwise to the mixture and stirred at 5-15 ℃ for 13 h.
TLC (petroleum ether: ethyl acetate = 5) indicates that reactant 1 has been completely consumed. The mixture was concentrated under reduced pressure to remove most of the MeOH. Diluted with water (15.0 mL) and extracted with EtOAc (20.0 mL × 2). The combined organic layers were washed with brine (15.0 mL) and dried over anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain residue. Subjecting the residue to column chromatography (SiO 2, petroleum ether/ethyl acetate = 100/1-10/1)And (5) purifying. Compound 4 (2.50g, 9.88mmol,60.7% yield) was identified as a pale yellow solid by HNMR (ET 25545-13-P1A).
Step 2, adding compound 4 (500mg, 1.98mmol, 1eq) to DCM (3 mL), adding acetyl chloride (325mg, 4.15mmol,296uL, 2.1eq) dropwise at 5 ℃, stirring for 1 hour at 0-15 ℃ to obtain a mixture, and adding AlCl 3 (579mg, 4.35mmol,237uL, 2.2eq) are added to the mixture in proportions and stirred at 0-15 ℃ for 2 hours.
TLC (petroleum ether: ethyl acetate = 5) indicated complete consumption of reaction 4, the reaction mixture was poured into ice water (5 ml) at 10 ℃ and then extracted with dichloromethane DCM (2ml × 2). The combined organic layers were washed with brine (2 ml) over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography to give Compound 5 (400g, 1.19mmol,60.1% yield) which was identified as a pale yellow solid by HNMR (ET 25545-16-P1B).
Step 3, compound 5 (400mg, 1.19mmol, 1eq) as a solution in phenol (558mg, 5.93mmol,522uL, 5eq) was added to TsOH (409mg, 2.37mmol, 2eq). The mixture was stirred at 60 ℃ for 12 hours. LCMS (ET 25545-19-P1A 1) and HPLC (ET 25545-19-P1A) showed complete consumption of Compound 5 and a major peak was detected. The reaction mixture was dissolved in ethyl acetate EtOAc (5.00 mL) with the same volume of NaHCO 3 Washing with the solution, then washing the organic phase with half volume of concentrated brine, anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain residue. High performance liquid chromatography (column: welch xc18 250 x 50mm 10um; mobile phase: [ water (10 mm-NH) ] 4 HCO 3 )-ACN](ii) a B%:55% -75% for 10 min) to obtain a white solid, and then obtaining the novel phenolic compound.
Example 3
When R = F in formula (1), the novel phenolic compound of the present example has the formula:
the specific preparation method comprises the following steps:
step 1, for Compound 6 (10g, 47.85mmol, 1eq) dissolved in DMF (100 mL) in N 2 Adding K at 15 deg.C 2 CO 3 (9.92g, 71.77mmol,1.5 eq), and after stirring at 15 ℃ for 0.5 hour, bromotoluene (9.82g, 57.42mmol,6.82mL, 1.2eq) was added and stirred at 15 ℃ for 12 hours to obtain a mixture.
TLC (petroleum ether: ethyl acetate = 3) indicated complete consumption of reaction 6, the mixture was poured into 300 ml of ice water and extracted with EtOAc (100 ml x 2). The combined organic layers were washed with brine (50ml × 3) and washed with anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain residue. By column chromatography (SiO) 2 Petroleum ether/ethyl acetate =100/1 to 20/1) to purify the residue. Compound 7 (10g, 33.43mmol, 69.87% yield) was a pale yellow oil as determined by HNMR (ET 25545-5-P1A).
Step 2, mixing ZnBr 2 (902.60mg, 4.01mmol,200.58uL, 2.4eq) in THF (10 mL) in N 2 Benzylmagnesium chloride (1M, 3.34mL, 2.0eq) was added dropwise at 10 ℃ and stirred at 15 ℃ for 0.5 hour to give a mixture. Compound 7 (0.5g, 1.67mmol, 1eq) and 1, 3-bis (2, 6-diisopropylphenyl) -2 h-imidazole, 3-chloropyridine, dichloropalladium (113.81mg, 167.00umol, 0.1eq) were dissolved in THF (5 mL) in N 2 Added dropwise to the mixture at 15 ℃ and stirred at 15 ℃ for 12.5 hours.
LCMS (ET 25545-10-P1A) showed complete consumption of Compound 7, with an ideal m/z peak detected. The mixture was poured into ice water (20 ml) and 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. By column chromatography (SiO) 2 Petroleum ether/ethyl acetate =50/1 to 5/1) of the residue. Compound 8 (0.3 g, crude) was a yellow oil.
Step 3, compound 8 (0.3 g,966.69umol, 1eq) is added to MeOH (3 mL) and Pd/H is added at 15 ℃C (0.3g, 10% purity) in H 2 (15 Psi), stirring at 15 ℃ for 12 hours. LCMS (ET 25545-33-P1A) indicated consumption of Compound 8 and an ideal MS peak was detected. The reaction mixture was filtered and concentrated under lower pressure to give a residue, and compound 9 (0.2 g, crude oil) was obtained as a tan oil.
Step 4, compound 9 (0.2g, 908.21umol, 1eq) was added to DCM (3 ml), acetyl chloride (149.71mg, 1.91mmol,136.10uL, 2.1eq) was added dropwise at 5 ℃ and after stirring for 1 hour at 5 ℃, alCl was added 3 (266.42mg, 2.00mmol,109.19uL, 2.2eq) and stirring at 15 ℃ for 2 hours to obtain a reaction mixture. TLC (petroleum ether: ethyl acetate = 5) and LCMS (ET 25545-40-P1A) indicated complete consumption of compound 9. The reaction mixture was poured into ice water (5 ml) at 10 ℃ and then extracted with DCM (2ml × 2). The combined organic layers were washed with brine (2 ml) and dried over anhydrous Na 2 SO 4 Dried, filtered and concentrated under reduced pressure to give a residue. With pretlc (SiO) 2 Petroleum ether/ethyl acetate = 5/1) to give compound 10 (0.3 g, crude) as a pale yellow solid.
Step 5, tsOH (226.36mg, 1.31mmol, 2.0eq) was added to a solution of compound 10 (0.2g, 657.27umol, 1eq) dissolved in phenol (309.28mg, 3.29mmol,289.05uL, 5.0eq), and the mixture was stirred at 60 ℃ for 12 hours to obtain a reaction mixture. LCMS (ET 25545-46-P1B) and HPLC (ET 25545-46-P1A) showed complete consumption of Compound 10 and a major peak was detected. The reaction mixture was dissolved in EtOAc (5 mL) with the same volume of NaHCO 3 Washing with the solution, washing the organic phase with half volume of concentrated brine, anhydrous Na 2 SO 4 Drying, filtering and concentrating under reduced pressure to obtain residue. Subjecting the crude product to reversed phase high performance liquid chromatography (0.1% 4 HCO 3 ) Purification gave a pale yellow solid, which was detected by LCMS (ET 25545-46-P1B 1) and HPLC (ET 25545-46-P1B). The resulting solid was subjected to prep-HPLC (column: waters Xbridge BEH C18 100 x 30mm x 10um; mobile phase: [ water (10 mM NH. RTM.) to 4 HCO 3 )-ACN](ii) a B%:30% -80%,10 min) to a white solid. The new phenol is obtained as a white solid (0.12g, 274.68umol, yield 41.79 percent and purity 98.99 percent) by HNMR measurementA kind of compound is provided.
Comparative example 1
The comparative example is an unsubstituted phenolic compound prepared by a conventional method and having the following structural formula:
test examples
The novel phenolic compounds of examples 1-3 and the unsubstituted phenolic compound of comparative example 1 were subjected to Minimum Inhibition Concentration (MIC) test experiments, and the MIC determination results are shown in table 1.
The specific experimental steps are as follows:
inoculating a little strain from a flat plate into a conical flask filled with LB culture medium (Luria-Bertani culture medium), and performing shake culture at 37 ℃ for 8-10h; wherein, the fungus comprises: gram-positive and gram-negative bacteria; the gram-positive bacteria comprise staphylococcus aureus, bacillus and methicillin-resistant staphylococcus aureus, and the bacillus subtilis is bacillus subtilis 168; the Staphylococcus aureus is Staphylococcus aureus 25923; the methicillin-resistant staphylococcus aureus is abbreviated as MRSA; the gram-negative bacterium used was Escherichia coli DH 5. Alpha.
The formulation of LB medium was as follows: 10g/L of Tryptone (Tryptone), 5g/L of Yeast extract (Yeast extract) and 10g/L of sodium oxide (NaCl).
The inoculum was aspirated from the Erlenmeyer flask on day 2 in the morning at a volume ratio of 1% and transferred to an Erlenmeyer flask containing 20mL of LB medium, and the flask was further incubated for 5h to 6h at 37 ℃ in a shaker until the OD600 (OD 600 represents the absorbance of the inoculum at 600 nm) was 0.6 to 0.8, and the specific OD (optical density) of the inoculum was recorded.
The cultured bacterial liquid was diluted 1000-fold with LB medium to a bacterial liquid concentration of 105CFU/ml, and the diluted bacterial liquid was aspirated and added to a 96-well plate at 150. Mu.l per well.
Prepare the phenol compound solution at a concentration of 128. Mu.g/ml, pipette 150. Mu.l of the triphenol compound solution into well 1 of a 96-well plate, then pipette 150. Mu.l into well 2, and so on. After the addition, the 96-well plate was placed in a shaker and incubated overnight at 37 ℃.
TABLE 1 MIC value results
As can be seen from table 1, the novel phenolic compounds of the present invention have a 1-fold higher inhibitory effect against gram-positive bacteria than comparative example 1. The novel phenolic compounds provided by the embodiments 1-3 of the invention can obviously inhibit the growth of gram-positive bacteria, the minimum inhibition concentration of the novel phenolic compounds to staphylococcus aureus, bacillus subtilis and methicillin-resistant staphylococcus aureus is 1-2 mu g/ml, and the trisphenol compounds have good antibacterial effect and can be used as good antibacterial agents of gram-positive bacteria.
Finally, it should be further noted that the terms "comprises," "comprising," or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
While preferred embodiments of the present invention have been described, additional variations and modifications in those embodiments may occur to those skilled in the art once they learn of the basic inventive concepts. Therefore, it is intended that the appended claims be interpreted as including preferred embodiments and all such alterations and modifications as fall within the scope of the invention. It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such 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:
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:
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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