Azetidine derivative and its preparation method and application

Abstract

This solution discloses an azetidine derivative in the field of organic chemistry and its preparation and application. The chemical structure of the azetidine derivative is generally represented by formula III: #imgabs0# wherein R 1 is one of methyl, ethyl, cyclopropyl, phenyl, substituted phenyl, and thiazolyl; R 2 The azetidine derivative has significant antibacterial activity and can be used to prepare drugs for treating S. aureus, E. coli, and MRSA infections. It can also be used in combination with other antibacterial active substances.

Description

Technical Field

[0001] The present invention belongs to the field of organic chemistry, and specifically relates to an azetidine derivative and a preparation method and application thereof. Background Art

[0002] The widespread use of antimicrobial drugs has led to the development of bacterial resistance and even the emergence of superbugs, seriously compromising the efficacy of these drugs. The emergence of multidrug-resistant and superbug-resistant bacteria poses a serious threat to human health, rendering many infectious diseases clinically incurable. Therefore, the development of novel antimicrobial drugs to address these concerns is of great significance. Summary of the Invention

[0003] The present invention aims to address the shortcomings of currently used antibiotics and provide a series of azetidine derivatives that can replace antibiotics in clinical medicine.

[0004] The chemical structure of an azetidine derivative in this scheme is shown in the general formula III:

[0005] Among them, R 1 is one of methyl, ethyl, cyclopropyl, phenyl, substituted phenyl, and thiazolyl; R 2 It is one of hydrogen, methyl and ethyl.

[0006] Furthermore, the compounds include IIIc, IIId, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp, and their structural formulas are as follows:

[0007]

[0008]

[0009] The azetidine derivatives of the present invention can be used as the sole active ingredient of an antibacterial drug or in combination with other antibacterial drugs or antibacterial active ingredients to prepare antibacterial drugs or pharmaceutical compositions.

[0010] Among them, the IIIc, IIId, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, and IIIo have significant activity in resisting Staphylococcus aureus infection and can be used to prepare anti-Staphylococcus aureus drugs.

[0011] The IIIc, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, IIIo and IIIp have significant activity in resisting Escherichia coli infection and can be used in the preparation of anti-Escherichia coli drugs.

[0012] The IIIc, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm and IIIn have significant activity in resisting methicillin-resistant Staphylococcus aureus infection and can be used to prepare anti-methicillin-resistant Staphylococcus aureus drugs.

[0013] The synthetic route of the azetidine derivatives of the present invention is as follows:

[0014]

[0015] Specifically, the preparation of the azetidine derivative comprises the following steps:

[0016] Preparation of Intermediate I: Mix 1,3-diethyl 2,2-dihydroxymethylmalonate, Et3N, and dichloromethane, slowly add methanesulfonyl chloride at 0-5°C, complete the reaction at 0-40°C, concentrate the solvent, dry the mixture, react with dibenzylamine, toluene, and Et3N at 90-110°C, filter to remove the solid, wash the organic layer with water, concentrate the solvent, dry the mixture, add hydrochloric acid, complete the reaction at 50-100°C, extract with dichloromethane, and concentrate the solvent to obtain a brown-yellow oil, which is recrystallized from acetone to obtain Intermediate I.

[0017] Preparation of Intermediate II: α-bromoketone, thiourea and anhydrous ethanol were added to a reaction flask in sequence and reacted at 50-80°C for completion, monitored by thin-layer chromatography. After completion of the reaction, the solvent was concentrated, distilled water was added for recrystallization, filtered and dried to obtain Intermediate II.

[0018] Preparation of compound III: Take intermediate I, intermediate II and dichloromethane, mix them, add 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, and slowly add N,N-diisopropylethylamine dropwise. The reaction is completed at 0-30°C and monitored by thin layer chromatography. After the reaction is completed, wash with saturated NaCl solution, extract with dichloromethane, dry over anhydrous MgSO4, filter, concentrate the solvent, and separate and purify by thin layer chromatography on silica gel to obtain compound III. DETAILED DESCRIPTION

[0019] The present invention is further described below with reference to the following embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various variations may occur in the implementation by those skilled in the art in combination with the prior art.

[0020] The azetidine derivative shown in the general structural formula III of the present invention, Among them, R 1 is one of methyl, ethyl, cyclopropyl, phenyl, substituted phenyl, and thiazolyl; R 2 It is one of hydrogen, methyl and ethyl.

[0021] This application cites the specific compounds shown in Table 1:

[0022] Table 1

[0023]

[0024]

[0025]

[0026] The preparation route of the azetidine derivative is as follows:

[0027]

[0028] The following is a detailed description of the preparation process using some compounds as examples, among which: HOBT: 1-hydroxybenzotriazole

[0029] EDCI: 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride DMAP: 4-dimethylaminopyridine

[0030] DIPEA: N,N-diisopropylethylamine

[0031] Example 1: Preparation of Compound IIIf

[0032] First, weigh 20 mmol of 1,3-diethyl 2,2-dihydroxymethylmalonate and 60 mmol of Et3N and react at 25°C. After completion, concentrate the solvent, dry the mixture, and use it directly in the next reaction. Separately, weigh 10 mmol of the product from the previous step, 11 mmol of benzhydrylamine, 30 mL of toluene, and 30 mmol of Et3N in a 100 mL reaction flask. React at 110°C. After completion, filter to remove the solids, wash the organic layer with water, concentrate the solvent, dry the mixture, and use it directly in the next reaction. Weigh 3 mmol of the product from the previous step in a 50 mL reaction flask, add 12 mL of 5 mol / L hydrochloric acid, and react at 50°C. After completion, extract with dichloromethane and concentrate the solvent to obtain a brown oil. Recrystallize the oil from acetone to obtain Intermediate I.

[0033] Next, 1 mmol of 2-bromo-3'-fluoroacetophenone, 1.3 mmol of thiourea, and 10 mL of anhydrous ethanol were added to a 50 mL reaction flask in sequence and reacted at 60°C until completion, monitored by thin-layer chromatography. After completion of the reaction, the solvent was concentrated, and distilled water was added for recrystallization, filtered, and dried to obtain intermediate IIf.

[0034] Finally, 0.45 mmol of intermediate I, 0.3 mmol of intermediate II, and 15 mL of dichloromethane were weighed into a 50 mL flask, and then 0.45 mmol of HOBT, 0.45 mmol of EDCI, and 0.15 mmol of DMAP were added, and 0.4 mmol of DIPEA was slowly added dropwise. The reaction was carried out at 25°C until completion, and thin layer chromatography was used for tracking. After the reaction was completed, the product was washed with saturated NaCl solution, extracted with dichloromethane, dried over anhydrous MgSO4, filtered, and the solvent was concentrated. The product was separated and purified by thin layer chromatography on silica gel to obtain compound IIIf.

[0035] Example 2: Preparation of Compound III1

[0036] First, 20 mmol of 1,3-diethyl 2,2-dihydroxymethylmalonate, 60 mmol of Et3N, and 60 mL of dichloromethane were weighed into a 250 mL reaction flask. 42 mmol of methanesulfonyl chloride was slowly added at 0-5°C. The reaction was allowed to proceed at 10°C. After completion, the solvent was concentrated, dried, and used directly in the next reaction. Separately, 10 mmol of the product from the previous step, 11 mmol of diphenylmethane, 30 mL of toluene, and 30 mmol of Et3N were weighed into a 100 mL reaction flask. The reaction was allowed to proceed at 90°C. After completion, the solid was filtered off, the organic layer was washed with water, the solvent was concentrated, dried, and used directly in the next reaction. 3 mmol of the product from the previous step was weighed into a 50 mL reaction flask. 12 mL of 5 mol / L hydrochloric acid was added, the reaction was allowed to proceed at 60°C. After completion, the product was extracted with dichloromethane and the solvent was concentrated to obtain a brown oil. This was recrystallized from acetone to obtain Intermediate I.

[0037] Next, 1 mmol of 2-bromo-1-(1,3-thiazol-2-yl)ethanone, 1.3 mmol of thiourea, and 10 mL of anhydrous ethanol were added to a 50 mL reaction flask in sequence and reacted at 50°C until completion, monitored by thin-layer chromatography. After completion of the reaction, the solvent was concentrated, distilled water was added for recrystallization, filtered, and dried to obtain intermediate II1.

[0038] Finally, 0.45 mmol of intermediate I, 0.3 mmol of intermediate II and 15 mL of dichloromethane were weighed into a 50 mL flask, and then 0.45 mmol of HOBT, 0.45 mmol of EDCI and 0.15 mmol of DMAP were added, and 0.4 mmol of DIPEA was slowly added dropwise. The reaction was carried out at 20°C. After completion, thin layer chromatography was performed. After the reaction was completed, the product was washed with saturated NaCl solution, extracted with dichloromethane, dried over anhydrous MgSO4, filtered, and the solvent was concentrated. The product was separated and purified by thin layer chromatography on silica gel to obtain compound III1.

[0039] Example 3: Preparation of Compound IIIm

[0040] First, 20 mmol of 1,3-diethyl 2,2-dihydroxymethylmalonate, 60 mmol of Et3N, and 60 mL of dichloromethane were weighed into a 250 mL reaction flask. 42 mmol of methanesulfonyl chloride was slowly added at 0-5°C. The reaction was allowed to proceed at 30°C. After completion, the solvent was concentrated, dried, and used directly in the next reaction. Separately, 10 mmol of the product from the previous step, 11 mmol of diphenylmethylamine, 30 mL of toluene, and 30 mmol of Et3N were weighed into a 100 mL reaction flask. The reaction was allowed to proceed at 90°C. The solid was filtered off, the organic layer was washed with water, the solvent was concentrated, dried, and used directly in the next reaction. 3 mmol of the product from the previous step was weighed into a 50 mL reaction flask. 12 mL of 5 mol / L hydrochloric acid was added, the reaction was allowed to proceed at 50°C. After completion, the product was extracted with dichloromethane and the solvent was concentrated to obtain a brown oil. This was recrystallized from acetone to obtain Intermediate I.

[0041] Next, 1 mmol of 1-cyclopropyl-2-bromoethanone, 1.3 mmol of thiourea, and 10 mL of anhydrous ethanol were added to a 50 mL reaction flask in sequence and reacted at 60°C until completion, monitored by thin-layer chromatography. After completion of the reaction, the solvent was concentrated, and distilled water was added for recrystallization, filtered, and dried to obtain intermediate IIm.

[0042] Finally, 0.45 mmol of intermediate I, 0.3 mmol of intermediate II and 15 mL of dichloromethane were weighed into a 50 mL flask, and then 0.45 mmol of HOBT, 0.45 mmol of EDCI and 0.15 mmol of DMAP were added, and 0.4 mmol of DIPEA was slowly added dropwise. The reaction was carried out at 10°C and completed. Thin layer chromatography was used for tracking. After the reaction was completed, the product was washed with saturated NaCl solution, extracted with dichloromethane, dried over anhydrous MgSO4, filtered, and the solvent was concentrated. The product was separated and purified by thin layer chromatography on silica gel to obtain compound IIIm.

[0043] Example 4: Preparation of Compound IIIn

[0044] First, 20 mmol of 1,3-diethyl 2,2-dihydroxymethylmalonate, 60 mmol of Et3N, and 60 mL of dichloromethane were weighed into a 250 mL reaction flask. 42 mmol of methanesulfonyl chloride was slowly added at 0-5°C. The reaction was allowed to proceed at 20°C. After completion, the solvent was concentrated, dried, and used directly in the next reaction. Separately, 10 mmol of the product from the previous step, 11 mmol of diphenylmethane, 30 mL of toluene, and 30 mmol of Et3N were weighed into a 100 mL reaction flask. The reaction was allowed to proceed at 100°C. After completion, the solid was filtered off, the organic layer was washed with water, the solvent was concentrated, dried, and used directly in the next reaction. 3 mmol of the product from the previous step was weighed into a 50 mL reaction flask. 12 mL of 5 mol / L hydrochloric acid was added, the reaction was allowed to proceed at 60°C. After completion, the product was extracted with dichloromethane and the solvent was concentrated to obtain a brown oil. This was recrystallized from acetone to obtain Intermediate I.

[0045] Next, 1 mmol of 1-bromo-2-butanone, 1.3 mmol of thiourea, and 10 mL of anhydrous ethanol were added to a 50 mL reaction flask in sequence and reacted at 70°C until completion, monitored by thin-layer chromatography. After completion of the reaction, the solvent was concentrated, and distilled water was added for recrystallization, filtered, and dried to obtain intermediate IIn.

[0046] Finally, 0.45 mmol of intermediate I, 0.3 mmol of intermediate II and 15 mL of dichloromethane were weighed into a 50 mL flask, and then 0.45 mmol of HOBT, 0.45 mmol of EDCI and 0.15 mmol of DMAP were added, and 0.4 mmol of DIPEA was slowly added dropwise. The reaction was carried out at 10°C and completed. Thin layer chromatography was used for tracking. After the reaction was completed, the product was washed with saturated NaCl solution, extracted with dichloromethane, dried over anhydrous MgSO4, filtered, and the solvent was concentrated. The product was separated and purified by thin layer chromatography on silica gel to obtain compound IIIn.

[0047] Antimicrobial activity test of the present invention:

[0048] Using oxacillin as the control drug, the microdilution method was used to determine the activity of the compound of formula III against Staphylococcus aureus (S.

[0049] aureus), Escherichia coli (E. coli), and methicillin-resistant Staphylococcus aureus (MRSA).

[0050] Table 2

[0051]

[0052] From the above experimental results, it can be clearly seen that the compounds of general formula III to be protected by the present invention have potential antibacterial activity. Most compounds have better antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) than the control drug oxacillin. For example, compounds IIIf, IIIl, IIIm, and IIIn have much lower MICs against MRSA than the control drug oxacillin, demonstrating significant anti-MRSA activity. Some compounds, such as compounds IIIl and IIIm, have similar antibacterial activity against Staphylococcus aureus (S. aureus) as the control drug oxacillin. Some compounds, such as compounds IIIf, IIIl, IIIm, and IIIn, have better or equivalent antibacterial activity against Escherichia coli (E. coli). This class of compounds exhibits significant inhibitory effects against Gram-positive bacteria, drug-resistant bacteria, and Gram-negative bacteria, and has a broad antibacterial spectrum. Their potential antibacterial activity can be used to prepare drugs for treating S. aureus, E. coli, and MRSA infections. They can also be used in combination with other antibacterial active substances.

Claims

1. An azetidine derivative, characterized in that Its chemical structure is shown in formula III: ， Among them, R 1 is one of methyl, ethyl, cyclopropyl, phenyl, and thiazolyl; R 2 It is one of hydrogen, methyl and ethyl.

2. An azetidine derivative, characterized in that: Its structural formula is as follows: 、 、 、 、 、 、 、 、 、 、 。 3. A drug, characterized in that: The azetidine derivative according to claim 1 or 2 is included, wherein the azetidine derivative in the medicine serves as the sole active ingredient.

4. Use of an azetidine derivative according to claim 1 or 2 in the preparation of antibacterial drugs for bacterial infectious diseases.

5. Use of an azetidine derivative in the preparation of a drug for treating and / or preventing Staphylococcus aureus infectious diseases, characterized in that: The azetidine derivative is selected from IIIc, IIId, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, and IIIo according to claim 2.

6. Use of an azetidine derivative in the preparation of a medicament for treating and / or preventing Escherichia coli infectious diseases, characterized in that: The azetidine derivative is selected from IIIc, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp according to claim 2.

7. Use of an azetidine derivative in the preparation of a medicament for treating and / or preventing methicillin-resistant Staphylococcus aureus infections, characterized in that: The azetidine derivative is selected from IIIc, IIIf, IIIh, IIIi, IIIl, IIIm, and IIIn according to claim 2.

8. The method for preparing an azetidine derivative according to claim 1, wherein: The reaction scheme of the method is as follows: 。 9. The method for preparing an azetidine derivative according to claim 8, wherein: The following steps are involved: Preparation of Intermediate I: Mix 1,3-diethyl 2,2-dihydroxymethylmalonate, Et3N, and dichloromethane, slowly add methanesulfonyl chloride at 0-5°C, complete the reaction at 0-40°C, concentrate the solvent, dry the mixture, react with dibenzylamine, toluene, and Et3N at 90-110°C, filter to remove the solid, wash the organic layer with water, concentrate the solvent, dry the mixture, add hydrochloric acid, complete the reaction at 50-100°C, extract with dichloromethane, and concentrate the solvent to obtain a brown-yellow oil, which is recrystallized from acetone to obtain Intermediate I. Preparation of intermediate II: α -Bromoketone, thiourea and anhydrous ethanol were added to the reaction flask and the reaction was completed at 50-80 °C. Thin layer chromatography was used for tracking. After the reaction was completed, the solvent was concentrated and distilled water was added for recrystallization. The product was filtered and dried to obtain intermediate II. Preparation of compound III: Mix intermediate I, intermediate II and dichloromethane, then add 1-hydroxybenzotriazole, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride and 4-dimethylaminopyridine, and slowly add N,N-diisopropylethylamine dropwise. The reaction is completed at 0-30°C and monitored by thin-layer chromatography. After the reaction is completed, wash with saturated NaCl solution, extract with dichloromethane, dry over anhydrous MgSO4, filter, concentrate the solvent, and separate and purify by thin-layer chromatography on silica gel to obtain compound III.

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