A p-chlorophenoxy compound, its preparation method and application

Abstract

The present invention belongs to the technical field of organic synthesis, and particularly relates to a p-chlorophenyl ether compound, a preparation method thereof, and an application thereof. Disclosed by the present invention is a novel p-chlorophenyl ether compound, 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol). Mainly using p-chlorophenol and 3-chloro-1,2-propanediol as raw materials, in a mixed solvent of isopropanol and water, a reaction occurs in the presence of a base, and the reaction solution is subjected to column chromatography to obtain 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol). The preparation process of this compound is simple, the synthesis route is short, and the antibacterial ability is strong.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a p-chlorophenyl ether compound and a preparation method and application thereof. Background Art

[0002] Parachlorophenyl ether compounds are a very important class of pharmaceutical intermediates, which have anti-tumor activity, anti-plant virus, bactericidal and anti-inflammatory effects, and therefore have a wide variety of uses.

[0003] Chlorphenesin, with the chemical name 3-(4-chlorophenoxy)-1,2-propanediol, is a typical para-chlorophenyl ether compound. It has inhibitory effects on most Gram-positive and Gram-negative bacteria and fungi, is non-irritating and low in toxicity. It is an important antifungal drug allowed for use in relevant EU and Chinese regulations. It is also often used as a cosmetic bactericide. In the past decade, it has been widely used in the pharmaceutical, daily chemical and other industries.

[0004] Chlorphenesin mainly has the following synthesis methods:

[0005] Route 1: Patent CN108440253A uses glycerol, p-chlorophenol and carbonate as raw materials to synthesize chlorphenesin under the action of an alkaline catalyst; this method is low-cost, green and environmentally friendly, has no solvent consumption, and has high reaction yield and purity.

[0006]

[0007] Route 2: Patent CN113149818A uses 3-chloro-1,2-propylene glycol and p-chlorophenol as main raw materials, and prepares chlorphenesin by adding a catalyst prepared by mixing fumed silica, vitamin E and alkylammonium bromide; this method can effectively control the progress of the reaction and improve the stability of the yield of chlorphenesin.

[0008]

[0009] Route 3: Patent CN101445436A uses epichlorohydrin to hydrolyze in dilute sulfuric acid and then react with sodium p-chlorophenol, and then purifies it with an ethanol-water mixed solvent to obtain chlorphenesin. The reaction process and post-treatment process of this method are simple to operate, have low energy consumption, high production safety, and the obtained product is stable.

[0010]

[0011] The above documents are all focused on the research of chlorphenesin, but few people pay attention to its by-products. The applicant found in in-depth research that in the production process of chlorphenesin, a new para-chlorophenyl ether compound is generated, which has two molecules of chlorophenyl groups and is similar to chlorphenesin in nature, but there is no document report on the structure, use and preparation and separation method of the compound at home and abroad. The discovery of new compounds is of great significance to para-chlorophenyl ether compounds, and can effectively promote the research and development of para-chlorophenyl ether compounds. Summary of the invention

[0012] The object of the present invention is to provide a novel p-chlorophenyl ether compound, the preparation process of the compound is simple, and antibacterial experiments show that the compound has good antibacterial properties.

[0013] A para-chlorophenyl ether compound, the compound structural formula is as follows:

[0014]

[0015] Another object of the present invention is to provide a method for preparing the above-mentioned para-chlorophenyl ether compounds, and the specific preparation process is as follows:

[0016] Dissolve p-chlorophenol in a mixed solvent of isopropanol and water, add a base, heat and stir, then dropwise add 3-chloro-1,2-propanediol to react. After the reaction is completed, the reaction solution is distilled under reduced pressure and separated by column chromatography to obtain compound I.

[0017] Preferably, in terms of molar ratio, p-chlorophenol:3-chloro-1,2-propylene glycol=1:1.05-1.15.

[0018] Preferably, p-chlorophenol: mixed solvent = 1 mol: 200-210 mL.

[0019] Preferably, the volume ratio of the mixed solvent is isopropanol:water=80:1.

[0020] Preferably, the base is selected from sodium hydroxide or potassium hydroxide; in terms of molar ratio, p-chlorophenol:base=1:1.1-1.2.

[0021] Preferably, the stirring time is 0.5 h, the reaction temperature is 60-80° C., and the reaction time is 18-22 h; more preferably, the reaction temperature is 70-75° C., and the reaction time is 20-21 h.

[0022] Preferably, the eluent for the column chromatography is: ethyl acetate: petroleum ether = 1:6 in volume ratio; the silica gel used for the column chromatography is 100-200 mesh.

[0023] The present invention also provides the use of the above-mentioned p-chlorophenyl ether compounds in antibacterial activity, which can be specifically used in preparing drugs with antibacterial activity or preparing products with antibacterial activity.

[0024] Preferably, the bacterial species is at least one of Staphylococcus aureus or Bacillus subtilis.

[0025] The beneficial effects of the present invention are as follows:

[0026] The p-chlorophenyl ether compound provided by the present invention has two molecular active reaction structure chlorophenyl groups, has enhanced reaction activity, and has obvious inhibitory effect on the growth of Staphylococcus aureus and Bacillus subtilis black variant; the compound has less p-chlorophenol taste, is very likely to replace chlorphenesin to exert antibacterial activity, and expands the application of p-chlorophenyl ether compounds; the preparation method of the p-chlorophenyl ether compound provided by the present invention has a short synthesis route and strong operability. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 The compound is 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol 1 H NMR spectrum;

[0028] Figure 2 The compound is 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol 13 C NMR spectrum;

[0029] Figure 3 This is the liquid chromatography-mass spectrum of compound 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol. DETAILED DESCRIPTION

[0030] The scheme of the present invention will be explained below in conjunction with embodiments. In the following embodiments, if no specific techniques or conditions are specified, the techniques or conditions described in the literature in the art or the conditions recommended by the manufacturer are used, and the methods used are all conventional methods known in the art unless otherwise specified.

[0031] Example 1

[0032] Dissolve p-chlorophenol (128.56 g, 1 mol) in a mixed solvent of isopropanol (200 mL) and water (2.5 mL), add sodium hydroxide (44.41 g, 1.11 mol), heat to 75°C, continue stirring for 0.5 h, then drop 3-chloro-1,2-propanediol (127.12 g, 1.15 mol), continue to react for 20 h after the addition is complete, distill the reaction solution under reduced pressure and elute through a chromatography column (silica gel 100-200 mesh) with ethyl acetate: petroleum ether = 1:6 (volume ratio) to separate compound I with a yield of 20.2%. The chemical name of compound I is 3,3'-oxybis(1-(4-chlorophenoxy)isopropyl-2-ol), 1 HNMR (400MHz, CDCl 3 ): TM 7.20(d,J=7.2Hz,4H),6.80(dd,J=7.2,2.8Hz,4H),4.18(m,2H),3.96(dd,J=4,1.6Hz,4H),3.68(m,4H),3.13(br,2H); 13 C NMR (100 MHz, CDCl 3 ): TM 157.11,129.42,128.12,115.84,72.61,72.57,69.18,69.15,69.12; LC-MS calcd for C 18 H 20 Cl 2 NaO 5 [M+Na] + 409,found409.

[0033] Example 2

[0034] p-Chlorophenol (128.56 g, 1 mol) was dissolved in a mixed solvent of isopropanol (207.2 mL) and water (2.59 mL), sodium hydroxide (46.01 g, 1.15 mol) was added, the temperature was raised to 70°C, stirring was continued for 0.5 h, 3-chloro-1,2-propanediol (116.07 g, 1.05 mol) was then added dropwise, and the reaction was continued for 22 h after the addition was complete. The reaction solution was distilled under reduced pressure and eluted through a chromatography column (silica gel 100-200 mesh) with ethyl acetate: petroleum ether = 1:6 (volume ratio) to separate compound I with a yield of 18.3%.

[0035] Example 3

[0036] p-Chlorophenol (128.56 g, 1 mol) was dissolved in a mixed solvent of isopropanol (197.6 mL) and water (2.47 mL), potassium hydroxide (63.4 g, 1.13 mol) was added, the temperature was raised to 60°C, stirring was continued for 0.5 h, 3-chloro-1,2-propanediol (121.6 g, 1.1 mol) was then added dropwise, and the reaction was continued for 18 h after the addition was complete. The reaction solution was distilled under reduced pressure and eluted through a chromatography column (silica gel 100-200 mesh) with ethyl acetate: petroleum ether = 1:6 (volume ratio) to separate compound I with a yield of 16.8%.

[0037] Example 4

[0038] p-Chlorophenol (128.56 g, 1 mol) was dissolved in a mixed solvent of isopropanol (204.8 mL) and water (2.56 mL), potassium hydroxide (66.21 g, 1.18 mol) was added, the temperature was raised to 80°C, stirring was continued for 0.5 h, 3-chloro-1,2-propanediol (123.8 g, 1.12 mol) was then added dropwise, and the reaction was continued for 21 h after the addition was complete. The reaction solution was distilled under reduced pressure and eluted through a chromatography column (silica gel 100-200 mesh) with ethyl acetate: petroleum ether = 1:6 (volume ratio) to separate compound I with a yield of 19.9%.

[0039] Example 5 In vitro antibacterial activity test

[0040] In this study, the in vitro antimicrobial activity of the compounds was evaluated by the minimum inhibitory concentration (MIC) value. The minimum inhibitory concentration of the compounds was determined by the microdilution method according to the Clinical and Laboratory Standards Institute (CLSI) guidelines.

[0041] Staphylococcus aureus (ATCC25923, ATCC31007, ATCC43300) and Bacillus subtilis (ATCC9372) were inoculated on Mueller-Hinton agar (MHA) plates and cultured at 37°C for 24 h. The bacterial concentration was adjusted to 1×10 6 CFU / mL was used to prepare bacterial suspension for use. First, chlorphenesin and compound I were dissolved in DMSO / H 2O mixed solution to prepare a stock solution (the final concentration of DMSO ≤ 2%), and then dilute the stock solution to 128 μg / mL with Mueller-Hinton Broth (MHB) medium as the initial solution. Subsequently, the initial solution was diluted twice with MHB to obtain a series of test solutions (128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 μg / mL). Finally, the bacterial suspension was mixed with the test solution in equal volumes, and the 96-well plate was incubated at 37°C for 24 hours. The turbidity was observed with the naked eye to determine whether there was bacterial growth. If turbidity appears in a well, it indicates that there is bacterial growth at this concentration. If the well is clear, it means that there is no bacterial growth at this concentration, indicating that the growth of bacteria is inhibited. The minimum concentration that inhibits bacterial growth is the MIC value. The smaller the MIC value, the greater the antibacterial activity. The test results are shown in Table 1. All MIC value determination experiments were performed three times to achieve the repeatability of biological experiments.

[0042] Table 1 Minimum inhibitory concentration of different tested bacteria

[0043]

[0044] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A p-chlorophenol ether compound, characterized in that, the structural formula of the compound is as follows: 。 2. Use of the p-chlorophenol ether compound according to claim 1 in terms of antibacterial activity.

3. Use of the p-chlorophenol ether compound according to claim 2 in terms of antibacterial activity, characterized in that, the bacterial strain is at least one of Staphylococcus aureus or Bacillus subtilis.

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