Azetidine derivative as well as preparation method and application thereof

Abstract

The invention discloses an azetidine derivative and preparation and application thereof in the field of organic chemistry, the chemical structural general formula III of the azetidine derivative is # imgabs0 #, R1 is one of methyl, ethyl, cyclopropyl, phenyl, substituted phenyl and thiazolyl; r2 is one of hydrogen, methyl and ethyl. According to the present invention, the azetidine derivative has significant antibacterial activity, and can be used for preparation of drugs for treatment of S.aureus, E.coli and MRSA infectious diseases. And meanwhile, the antibacterial agent can also be combined with other antibacterial active substances for use.

Description

Technical Field

[0001] The 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 extensive use of antimicrobial drugs has led to bacterial resistance and even the emergence of super bacteria, which has seriously affected the efficacy of antimicrobial drugs. The emergence of multi-drug resistant and super-resistant bacteria has seriously threatened human health and caused many infectious diseases to be unable to be completely cured clinically. Therefore, it is of great significance to develop novel antimicrobial drugs to address these worrying issues. 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] Further, 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 drug 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 in the preparation of 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 in the preparation of 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, react at 0-40°C, concentrate the solvent, dry and react with dibenzhydrylamine, toluene and Et3N at 90-110°C, filter to remove solid, wash the organic layer with water, concentrate the solvent, dry and add hydrochloric acid, react at 50-100°C, extract with dichloromethane, concentrate the solvent to obtain a brown oil, add acetone for recrystallization to obtain intermediate I;

[0017] Preparation of Intermediate II: α-bromoketone, thiourea and anhydrous ethanol are added to a reaction bottle in sequence, and the reaction is completed at 50-80°C, and thin layer chromatography is used for tracking. After the reaction is completed, the solvent is concentrated, distilled water is added for recrystallization, suction filtration is performed, and drying is performed to obtain Intermediate II;

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

[0019] The present invention is further described below in conjunction with embodiments, but the present invention is not limited to the following embodiments. It can be foreseen that those skilled in the art may make various changes in the implementation 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 20mmol 2,2-dihydroxymethylmalonic acid-1,3-diethyl ester, 60mmol Et3N and react at 25℃. After completion, concentrate the solvent, dry it, and use it directly in the next reaction. Weigh 10mmol of the product obtained in the previous step, 11mmol diphenylmethylamine, 30mL toluene and 30mmol Et3N in a 100mL reaction bottle, react at 110℃, after completion, filter to remove the solid, wash the organic layer with water, concentrate the solvent, dry it, and use it directly in the next reaction. Weigh 3mmol of the product obtained in the previous step in a 50mL reaction bottle, add 12mL of 5mol / L hydrochloric acid, react at 50℃, after completion, extract with dichloromethane, concentrate the solvent, and obtain a brown oil. Add acetone for recrystallization to obtain intermediate I.

[0033] Next, 1 mmol 2-bromo-3'-fluoroacetophenone, 1.3 mmol thiourea and 10 mL anhydrous ethanol were added to a 50 mL reaction bottle in sequence and reacted at 60°C until completion, with thin layer chromatography tracking. After completion of the reaction, the solvent was concentrated, distilled water was added for recrystallization, suction 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 and followed by thin layer chromatography. After the reaction was completed, the mixture was washed with saturated NaCl solution, extracted with dichloromethane, dried over anhydrous MgSO4, filtered, and the solvent was concentrated. The mixture was separated and purified by thin layer chromatography on silica gel plate to obtain compound IIIf.

[0035] Example 2: Preparation of Compound III1

[0036] First, weigh 20mmol 2,2-dihydroxymethylmalonic acid-1,3-diethyl ester, 60mmol Et3N and 60mL dichloromethane in a 250mL reaction bottle, slowly add 42mmol methanesulfonyl chloride at 0-5℃, react at 10℃, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 10mmol of the product obtained in the previous step, 11mmol diphenylmethylamine, 30mL toluene and 30mmol Et3N in a 100mL reaction bottle, react at 90℃, and filter to remove the solid. Wash the organic layer with water, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 3mmol of the product obtained in the previous step in a 50mL reaction bottle, add 12mL of 5mol / L hydrochloric acid, react at 60℃, extract with dichloromethane, concentrate the solvent, and obtain a brown oil. Add acetone for recrystallization to obtain intermediate I.

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

[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 and followed by thin layer chromatography. 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 plate to obtain compound IIIl.

[0039] Example 3: Preparation of Compound IIIm

[0040] First, weigh 20mmol 2,2-dihydroxymethylmalonic acid-1,3-diethyl ester, 60mmol Et3N and 60mL dichloromethane in a 250mL reaction bottle, slowly add 42mmol methanesulfonyl chloride at 0-5℃, react at 30℃, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 10mmol of the product obtained in the previous step, 11mmol diphenylamine, 30mL toluene and 30mmol Et3N in a 100mL reaction bottle, react at 90℃, and filter to remove the solid. Wash the organic layer with water, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 3mmol of the product obtained in the previous step in a 50mL reaction bottle, add 12mL of 5mol / L hydrochloric acid, react at 50℃, and extract with dichloromethane. Concentrate the solvent to obtain a brown oil, add acetone for recrystallization, and obtain intermediate I.

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

[0042] Finally, 0.45mmol intermediate I, 0.3mmol intermediate II and 15mL dichloromethane were weighed into a 50mL flask, and then 0.45mmol HOBT, 0.45mmol EDCI and 0.15mmol DMAP were added, and 0.4mmol DIPEA was slowly added dropwise. The reaction was carried out at 10°C. After completion, 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 plate to obtain compound IIIm.

[0043] Example 4: Preparation of Compound IIIn

[0044] First, weigh 20mmol 2,2-dihydroxymethylmalonic acid-1,3-diethyl ester, 60mmol Et3N and 60mL dichloromethane in a 250mL reaction bottle, slowly add 42mmol methanesulfonyl chloride at 0-5℃, react at 20℃, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 10mmol of the product obtained in the previous step, 11mmol diphenylmethylamine, 30mL toluene and 30mmol Et3N in a 100mL reaction bottle, react at 100℃, complete, filter to remove the solid, wash the organic layer with water, concentrate the solvent, dry, and use it directly in the next reaction. Weigh 3mmol of the product obtained in the previous step in a 50mL reaction bottle, add 12mL of 5mol / L hydrochloric acid, react at 60℃, complete, extract with dichloromethane, concentrate the solvent, and obtain a brown oily substance. Add acetone for recrystallization to obtain intermediate I.

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

[0046] Finally, 0.45mmol intermediate I, 0.3mmol intermediate II and 15mL dichloromethane were weighed into a 50mL flask, and then 0.45mmol HOBT, 0.45mmol EDCI and 0.15mmol DMAP were added, and 0.4mmol DIPEA was slowly added dropwise. The reaction was carried out at 10°C. After completion, 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 plate 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), and the data are shown in Table 2.

[0050] Table 2

[0051]

[0052] It can be clearly seen from the above experimental results 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, the MIC of compounds IIIf, IIIl, IIIm and IIIn against MRSA is much lower than that of the control drug oxacillin, and the anti-MRSA activity is significant; some compounds are close to the control drug oxacillin against Staphylococcus aureus (S.aureus), such as compounds IIIl and IIIm; some compounds have better or equivalent antibacterial activity against Escherichia coli (E.coli), such as compounds IIIf, IIIl, IIIm and IIIn. This type of compound shows a significant inhibitory effect on Gram-positive bacteria, drug-resistant bacteria, and Gram-negative bacteria, and has a wide antibacterial spectrum. Its potential antibacterial activity can be used to prepare drugs for treating S.aureus, E.coli and MRSA infectious diseases. At the same time, it 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, substituted phenyl, and thiazolyl; R 2 It is one of hydrogen, methyl and ethyl.

2. An azetidine derivative according to claim 1, characterized in that: The compounds include IIIc, IIId, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp, and their structural formulas are as follows:

3. A drug, characterized in that: The azetidine derivative according to claim 1 is included, wherein the azetidine derivative is used as the sole active ingredient or is combined with an antibacterial drug or an antibacterial active ingredient.

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

5. Use of IIIc, IIId, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, and IIIo according to claim 2 in the preparation of drugs for treating and / or preventing Staphylococcus aureus infectious diseases.

6. Use of IIIc, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm, IIIn, IIIo and IIIp according to claim 2 in the preparation of drugs for treating and / or preventing Escherichia coli infectious diseases.

7. Use of IIIc, IIIf, IIIh, IIIi, IIIj, IIIl, IIIm and IIIn according to claim 2 in the preparation of drugs for treating and / or preventing methicillin-resistant Staphylococcus aureus infectious diseases.

8. The method for preparing an azetidine derivative according to claim 1, characterized in that: The relevant chemical reaction of the azetidine derivative is as follows:

9. The method for preparing an azetidine derivative according to claim 8, characterized in that: 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, react at 0-40°C, concentrate the solvent, dry and react with dibenzhydrylamine, toluene and Et3N at 90-110°C, filter to remove solid, wash the organic layer with water, concentrate the solvent, dry and add hydrochloric acid, react at 50-100°C, extract with dichloromethane, concentrate the solvent to obtain a brown oil, add acetone for recrystallization to obtain intermediate I; Preparation of Intermediate II: α-bromoketone, thiourea and anhydrous ethanol are added to a reaction bottle in sequence, and the reaction is completed at 50-80°C, and thin layer chromatography is used for tracking. After the reaction is completed, the solvent is concentrated, distilled water is added for recrystallization, suction filtration is performed, and drying is performed to obtain Intermediate II; Preparation of compound III: Mix intermediate I, intermediate II and dichloromethane, 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 tracked by thin layer chromatography. After the reaction is completed, wash with saturated NaCl solution, extract with dichloromethane, dry with anhydrous MgSO4, filter, concentrate the solvent, and separate and purify by thin layer chromatography on silica gel plate to obtain compound III.

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