A heterocyclic sulfonamide / sulfonate derivative, a preparation method and application thereof

Abstract

This invention discloses a heterocyclic sulfonamide / sulfonate derivative in the field of organic chemistry, its preparation, and its applications. The heterocyclic sulfonamide / sulfonate derivative has the general chemical formula III: where X is O or NH; R is one of the following rings: thiazole ring, isoxazole ring, quinoline ring, coumarin ring, benzothiadiazole ring, and benzofuran ring. The heterocyclic sulfonamide / sulfonate derivative exhibits significant antibacterial activity and can be used to prepare drugs for treating infectious diseases caused by *S. aureus*, *E. coli*, and MRSA. It can also be used in combination with other antibacterial active substances.

Description

Technical Field

[0001] This invention belongs to the field of organic chemistry, specifically a heterocyclic sulfonamide / sulfonate derivative and its preparation method and application. Background Technology

[0002] The widespread use of antibiotics has led to bacterial resistance and even the emergence of superbugs, severely impacting the efficacy of antimicrobial drugs. The successive emergence of multidrug-resistant and superbug-resistant bacteria poses a serious threat to human health, making many infectious diseases incurable. Therefore, developing novel antimicrobial drugs to address these worrying problems is of great significance. Summary of the Invention

[0003] The present invention aims to address the shortcomings of current antibiotic use by providing a series of heterocyclic sulfonamide / sulfonate derivatives that can replace antibiotics in clinical medicine.

[0004] The chemical structure of one heterocyclic sulfonamide / sulfonate derivative in this scheme is shown in general formula III:

[0005] Where X is O or NH; R is one of the following: thiazole ring, isoxazole ring, quinoline ring, coumarin ring, benzothiadiazole ring, and benzofuran ring.

[0006] Furthermore, the compounds include IIIb, IIId, IIIe, IIIf, IIIg, IIIh, IIIj, IIIl, IIIm, IIIn, IIIo, and IIIp, with the following structural formulas:

[0007]

[0008]

[0009] The heterocyclic sulfonamide / sulfonate derivatives described in this 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] The application of the heterocyclic sulfonamide / sulfonate derivatives in the preparation of antibacterial drugs for bacterial infectious diseases.

[0011] Among them, IIId, IIIe, IIIf, IIIg, IIIh, IIIl, IIIm, IIIn, IIIo, and IIIp have significant activity in the prevention of Staphylococcus aureus infection and can be used to prepare anti-Staphylococcus aureus drugs.

[0012] The aforementioned Ⅲb, Ⅲd, Ⅲe, Ⅲf, Ⅲg, Ⅲh, Ⅲj, Ⅲl, Ⅲm, Ⅲn, Ⅲo, and Ⅲp exhibit significant activity against Escherichia coli infection and can be used in the preparation of anti-Escherichia coli drugs.

[0013] The aforementioned IIId, IIIg, IIIh, IIIl, IIIn, IIIo, and IIIp exhibit significant activity against methicillin-resistant Staphylococcus aureus (MRSA) infections and can be used in the preparation of drugs against MRSA.

[0014] The synthetic route for the heterocyclic sulfonamide / sulfonate derivatives described in this invention is as follows:

[0015]

[0016] Specifically, the preparation of the heterocyclic sulfonamide / sulfonate derivative includes the following steps:

[0017] Preparation of Intermediate I: 3-fluoro-4-morpholinoaniline, NaHCO3, acetone, and distilled water were mixed. Benzyl chloroformate was slowly added dropwise at 0–5°C. After the reaction was complete at 0–50°C, the solvent (acetone) was concentrated, filtered, washed, dried, and added to a reaction flask along with tetrahydrofuran. Lithium tert-butoxide was added in portions at 0–5°C, followed by the slow addition of (R)-epoxychloropropane. After the reaction was complete at 0–50°C, the solvent was concentrated, ice water was added, and the mixture was stirred. The pH was adjusted to 7–8 with NH4Cl, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated. The mixture was then subjected to silica gel column chromatography (V...). 乙酸乙酯 V 石油醚 =1:3) Separation and purification yielded milky white crystals. The milky white crystals, sodium acetate, and 3 mL of dimethyl sulfoxide were added sequentially to a reaction flask. The reaction was carried out at 60–120°C until completion. Ice water was added, and the mixture was stirred to precipitate crystals. The crystals were filtered, dried, and a white solid was obtained. The white solid, distilled water, acetone, and Na₂CO₃ were added sequentially to a reaction flask. The reaction was carried out at 10–50°C until completion. The solvent was concentrated, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated. The mixture was then subjected to silica gel column chromatography (V) 乙酸乙酯 V 石油醚 =1:3) Separation and purification yielded intermediate I;

[0018] Preparation of Intermediate II: 3-fluoro-4-morpholinoaniline, lithium trifluoromethanesulfonate, (R)-epoxychloropropane, and isopropanol were added sequentially to a reaction flask. The reaction was carried out at 20–60 °C. The solvent was concentrated, dissolved in ethyl acetate, and then washed with saturated Na₂CO₃ and saturated NaCl solutions, dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated to obtain a yellow oily substance. This yellow oily substance, CaO, and 2-methyltetrahydrofuran were added to a reaction flask. Methyl chloroformate was slowly added at 0–5 °C, and the reaction was carried out at 0–50 °C. The mixture was filtered, washed sequentially with saturated NaHCO₃ and saturated NaCl solutions, dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated. The mixture was then subjected to silica gel column chromatography (V... 乙酸乙酯 V石油醚 =1:3) Separate and purify to obtain a pale yellow oily substance. Add the pale yellow oily substance, ammonia and methanol to the reaction flask. After the reaction is completed at 0-50℃, concentrate the solvent, add dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, recrystallize to obtain intermediate II.

[0019] Preparation of compound III: Intermediate I or intermediate II, sulfonyl chloride, anhydrous dichloromethane, and triethylamine were added sequentially to a reaction tube and reacted at 20–40 °C until completion. Thin-layer chromatography was used to monitor the reaction. After the reaction was completed, the solvent was concentrated and purified by silica gel column chromatography to obtain compound III. Detailed Implementation

[0020] The present invention will be further described below with reference to the embodiments. However, the present invention is not limited to the following embodiments. It is foreseeable that various changes may occur in the implementation when those skilled in the art combine it with the prior art.

[0021] The heterocyclic sulfonamide / sulfonate derivatives of general formula III of this invention Where X is O or NH; R is one of the following: thiazole ring, isoxazole ring, quinoline ring, coumarin ring, benzothiadiazole ring, and benzofuran ring.

[0022] This application exemplifies specific compounds as shown in Table 1:

[0023] Table 1

[0024]

[0025]

[0026]

[0027] The preparation route for the heterocyclic sulfonamide / sulfonate derivative is as follows:

[0028]

[0029] The preparation process is described in detail below using some compounds as examples:

[0030] Example 1: Preparation of compound III g

[0031] Add 2.45 g (12.5 mmol) of 3-fluoro-4-morpholinoaniline, 1.26 g (15 mmol) of NaHCO3, 15 mL of acetone and 5 mL of distilled water to a 50 mL reaction flask. Slowly add 2.39 mL (17.5 mmol) of methyl chloroformate at 0–5 °C. React at 30 °C. After completion, concentrate the solvent acetone, filter, wash, and dry. The solid can be used directly for the next reaction. Take 1.98 g (6 mmol) of the product from the previous step and 50 mL of tetrahydrofuran and add them to a 100 mL reaction flask. Add 0.96 g (12 mmol) of lithium tert-butoxide in three portions at 0–5 °C, stirring until dissolved. Then slowly add 1.13 mL (14.4 mmol) of (R)-epoxychloropropane. React at 30 °C. After completion, concentrate the solvent, add 50 mL of ice water and stir. Adjust the pH to 7–8 with NH4Cl, extract with ethyl acetate, combine the organic phases, wash with saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and perform silica gel column chromatography (V... 乙酸乙酯 V 石油醚 =1:3) Separation and purification yielded milky white crystals, which were used in the next reaction. In a 25 mL reaction flask, 0.21 g (0.67 mmol) of the milky white crystals obtained in the previous step, 0.08 g (1 mmol) of sodium acetate, and 3 mL of dimethyl sulfoxide (DMSO) were added sequentially. The reaction was carried out at 100 °C. After completion, 50 mL of ice water was added, the mixture was stirred, and crystals precipitated. The crystals were filtered, dried, and a white solid was obtained, which was directly used in the next reaction. In a 50 mL reaction flask, 0.62 g (0.18 mmol) of the white solid from the previous step, 5 mL of distilled water, 10 mL of acetone, and 0.14 g (1.25 mmol) of Na₂CO₃ were added sequentially. The reaction was carried out at 30 °C. After completion, the solvent was concentrated, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, the solvent was concentrated, and the mixture was subjected to silica gel column chromatography (V... 乙酸乙酯 V 石油醚 =1:1) Separation and purification yielded a white solid, namely intermediate I.

[0032] Weigh 0.45 mmol of intermediate I, 0.36 mmol of quinoline-8-sulfonyl chloride, 15 mL of anhydrous dichloromethane, and 0.32 mL (7.5 mmol) of triethylamine sequentially into a 50 mL reaction tube. React at 20 °C, monitored by thin-layer chromatography. After the reaction is complete, concentrate the solvent and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =3:1) Separation and purification yielded compound III g.

[0033] Example 2: Preparation of compound IIIn

[0034] In a 50 mL reaction flask, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) of (R)-epoxychloropropane and 25 mL of isopropanol were added sequentially. The reaction was carried out at 20 °C. After the reaction was completed, the solvent was concentrated, and 20 mL of ethyl acetate was added to dissolve the residue. The residue was then washed with saturated Na2CO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oily substance, which was used directly in the next reaction step. Take 5.6 g (19.6 mmol) of the product from the previous step, 2.24 g (40 mmol) of CaO, and 40 mL of 2-methyltetrahydrofuran and add them to a 100 mL reaction flask. Slowly add 2.1 g (22 mmol) of methyl chloroformate at 0–5 °C. React at 10 °C. After completion, filter, wash successively with saturated NaHCO3 solution and saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and perform silica gel column chromatography (V). 乙酸乙酯 V 石油醚 =1:3) Separation and purification yielded a pale yellow oily substance, which was used for the next reaction. 3.0 g (8.6 mmol) of the pale yellow oily substance obtained in the previous step, 6 mL of ammonia water, and 10 mL of methanol were added to a 50 mL reaction flask. The reaction was carried out at 10 °C. After completion, the solvent was concentrated, 20 mL of dichloromethane was added, and the mixture was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, the solvent was concentrated, and recrystallization yielded a white solid, i.e., intermediate II.

[0035] Weigh 0.45 mmol of intermediate II, 0.36 mmol of benzo(1,2,5)thiazole-4-sulfonyl chloride, 15 mL of anhydrous dichloromethane, and 0.32 mL (7.5 mmol) of triethylamine sequentially into a 50 mL reaction tube. React at 40 °C, monitored by thin-layer chromatography. After the reaction is complete, concentrate the solvent and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =3:1) Separation and purification yielded compound Ⅲn.

[0036] Example 3: Preparation of compound IIIo

[0037] In a 50 mL reaction flask, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) of (R)-epoxychloropropane and 25 mL of isopropanol were added sequentially. The reaction was carried out at 25 °C. After the reaction was completed, the solvent was concentrated, and 20 mL of ethyl acetate was added to dissolve the residue. The residue was then washed with saturated Na2CO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oily substance, which was directly used in the next reaction step. Take 5.6 g (19.6 mmol) of the product from the previous step, 2.24 g (40 mmol) of CaO, and 40 mL of 2-methyltetrahydrofuran and add them to a 100 mL reaction flask. Slowly add 2.1 g (22 mmol) of methyl chloroformate at 0–5 °C. React at 25 °C. After completion, filter, wash successively with saturated NaHCO3 solution and saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and perform silica gel column chromatography (V). 乙酸乙酯 V 石油醚 =1:3) Separate and purify to obtain a pale yellow oily substance, which is used for the next reaction. Add 3.0 g (8.6 mmol) of the pale yellow oily substance obtained in the previous step, 6 mL of ammonia water and 10 mL of methanol to a 50 mL reaction flask, react at 25 °C. After completion, concentrate the solvent, add 20 mL of dichloromethane, wash with saturated NaCl solution, dry with anhydrous Na2SO4, concentrate the solvent, recrystallize to obtain a white solid, i.e., intermediate II.

[0038] Weigh 0.45 mmol of intermediate II, 0.36 mmol of quinoline-8-sulfonyl chloride, 15 mL of anhydrous dichloromethane, and 0.32 mL (7.5 mmol) of triethylamine sequentially into a 50 mL reaction tube. React at 30 °C, monitored by thin-layer chromatography. After the reaction is complete, concentrate the solvent and perform silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =3:1) Separation and purification yielded compound IIIo.

[0039] Example 4: Preparation of compound IIIp

[0040] In a 50 mL reaction flask, 4.9 g (25 mmol) of 3-fluoro-4-morpholinoaniline, 3.9 g (25 mmol) of lithium trifluoromethanesulfonate, 2.30 g (30 mmol) of (R)-epoxychloropropane and 25 mL of isopropanol were added sequentially. The reaction was carried out at 20 °C. After the reaction was completed, the solvent was concentrated, and 20 mL of ethyl acetate was added to dissolve the residue. The residue was then washed with saturated Na2CO3 solution and saturated NaCl solution, dried over anhydrous Na2SO4, filtered, and the solvent was concentrated to obtain a yellow oily substance, which was used directly in the next reaction step. Take 5.6 g (19.6 mmol) of the product from the previous step, 2.24 g (40 mmol) of CaO, and 40 mL of 2-methyltetrahydrofuran and add them to a 100 mL reaction flask. Slowly add 2.1 g (22 mmol) of methyl chloroformate at 0–5 °C. React at 20 °C. After completion, filter, wash successively with saturated NaHCO3 solution and saturated NaCl solution, dry with anhydrous Na2SO4, filter, concentrate the solvent, and perform silica gel column chromatography (V). 乙酸乙酯 V 石油醚 =1:3) Separation and purification yielded a pale yellow oily substance, which was used for the next reaction. 3.0 g (8.6 mmol) of the pale yellow oily substance obtained in the previous step, 6 mL of ammonia water, and 10 mL of methanol were added to a 50 mL reaction flask. The reaction was carried out at 20 °C. After completion, the solvent was concentrated, 20 mL of dichloromethane was added, and the mixture was washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, and the solvent was concentrated again. Recrystallization yielded a white solid, i.e., intermediate II.

[0041] Finally, 0.45 mmol II, 0.36 mmol coumarin-6-sulfonyl chloride, 15 mL anhydrous dichloromethane, and 0.32 mL (7.5 mmol) triethylamine were weighed sequentially into a 50 mL reaction tube. The reaction was carried out at 40 °C, monitored by thin-layer chromatography. After the reaction was completed, the solvent was concentrated, and the mixture was subjected to silica gel column chromatography (V... 石油醚 V 乙酸乙酯 =3:1) Separation and purification yielded compound Ⅲp.

[0042] Antibacterial activity test of the present invention:

[0043] Using oxacillin as a control drug, the microdilution method was employed to determine the effect of compound of general formula III on Staphylococcus aureus (S.).

[0044] The minimum inhibitory concentrations (MICs) of *Staphylococcus aureus*, *Escherichia coli*, and methicillin-resistant *Staphylococcus aureus* (MRSA) are shown in Table 2.

[0045] Table 2

[0046]

[0047]

[0048] The experimental results clearly demonstrate that the compounds of formula III protected in this invention possess potential antibacterial activity. Some compounds exhibit superior or comparable antibacterial activity against *Escherichia coli* (E. coli), such as compounds IIIf, IIIg, IIIn, IIIo, and IIIp. Some compounds show inhibitory effects against *S. aureus* similar to those of oxacillin, such as compounds IIIo and IIIp. Most compounds demonstrate superior activity against methicillin-resistant *S. aureus* (MRSA), with compounds IIIn, IIIo, and IIIp showing significant anti-MRSA activity far exceeding that of the control drug. These compounds exhibit excellent antibacterial activity, showing good activity against Gram-positive bacteria, drug-resistant bacteria, and Gram-negative bacteria, exhibiting a broad antibacterial spectrum. Their potential antibacterial activity can be used to treat infectious diseases caused by *S. aureus*, *E. coli*, and MRSA. They can also be used in combination with other antibacterial active substances.

Claims

1. A heterocyclic sulfonamide / sulfonate derivative, characterized in that: The derivative has the chemical structural formula shown in general formula III: ， Specifically, the derivative is selected from any one of the following: 、 、 、 、 、 、 、 、 、 。 2. A drug, characterized in that: The drug includes the heterocyclic sulfonamide / sulfonate derivative of claim 1, wherein the heterocyclic sulfonamide / sulfonate derivative is the sole active ingredient or in combination with an antibacterial drug or other antibacterial active ingredients.

3. The use of a heterocyclic sulfonamide / sulfonate derivative according to claim 1 in the preparation of antibacterial drugs for bacterial infectious diseases.

4. The use of a heterocyclic sulfonamide / sulfonate derivative according to claim 1 in the preparation of a drug for treating and / or preventing Staphylococcus aureus infectious diseases, wherein the derivative is selected from any one of IIId, IIIe, IIIf, IIIh, IIIl, IIIm, IIIn, and IIIp.

5. The use of a heterocyclic sulfonamide / sulfonate derivative according to claim 1 in the preparation of a drug for treating and / or preventing infectious diseases of Escherichia coli, wherein the derivative is selected from any one of IIIb, IIId, IIIe, IIIf, IIIh, IIIj, IIIl, IIIm, IIIn, and IIIp.

6. The use of a heterocyclic sulfonamide / sulfonate derivative according to claim 1 in the preparation of a drug for treating and / or preventing methicillin-resistant Staphylococcus aureus infections, wherein the derivative is selected from any one of IIId, IIIh, IIIl, IIIn, and IIIp.

7. The method for preparing a heterocyclic sulfonamide / sulfonate derivative according to claim 1, characterized in that: The relevant chemical reactions of the heterocyclic sulfonamide / sulfonate derivatives are as follows: 。 8. The method for preparing a heterocyclic sulfonamide / sulfonate derivative according to claim 7, characterized in that: Includes the following steps: Preparation of Intermediate I: 3-fluoro-4-morpholinoaniline, NaHCO3, acetone, and distilled water were taken. Benzyl chloroformate was slowly added dropwise at 0–5 °C. After the reaction was complete at 0–50 °C, the solvent acetone was concentrated, filtered, washed, dried, and then added together with tetrahydrofuran to a reaction flask. Lithium tert-butoxide was added in multiple portions at 0–5 °C, followed by slow addition of… R Epichlorohydrin was reacted at 0-50 °C until complete. The solvent was concentrated, ice water was added and stirred, and the pH was adjusted to 7-8 with NH4Cl. The mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, the solvent was concentrated, and the mixture was purified by silica gel column chromatography to obtain milky white crystals. The above milky white crystals, sodium acetate, and dimethyl sulfoxide were added sequentially to the reaction flask, and the reaction was completed at 60-120 °C. Ice water was added, the mixture was stirred, and crystals precipitated. The crystals were filtered and dried to obtain a white solid. The white solid, distilled water, acetone, and Na2CO3 were added sequentially to the reaction flask, and the reaction was completed at 10-50 °C. The solvent was concentrated, the mixture was extracted with ethyl acetate, the organic phases were combined, washed with saturated NaCl solution, dried over anhydrous Na2SO4, filtered, the solvent was concentrated, and the mixture was purified by silica gel column chromatography to obtain intermediate I. Preparation of Intermediate II: 3-fluoro-4-morpholinoaniline, lithium trifluoromethanesulfonate, and ( R Epichlorohydrin and isopropanol were reacted at 20-60 °C until complete. The solvent was concentrated, and ethyl acetate was added to dissolve the residue. The residue was then washed with saturated Na₂CO₃ solution and saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated to obtain a yellow oily substance. The yellow oily substance, CaO, and 2-methyltetrahydrofuran were added to a reaction flask, and methyl chloroformate was slowly added at 0-5 °C until complete. The reaction was completed at 0-50 °C. The residue was filtered, washed with saturated NaHCO₃ solution and saturated NaCl solution, dried over anhydrous Na₂SO₄, filtered, and the solvent was concentrated. The residue was purified by silica gel column chromatography to obtain a pale yellow oily substance. The pale yellow oily substance, ammonia, and methanol were added to a reaction flask, and the reaction was completed at 0-50 °C. The solvent was concentrated, dichloromethane was added, washed with saturated NaCl solution, dried over anhydrous Na₂SO₄, the solvent was concentrated, and the residue was recrystallized to obtain intermediate II. Preparation of compound III: Intermediate I or intermediate II, sulfonyl chloride, anhydrous dichloromethane, and triethylamine were added sequentially to a reaction tube and reacted at 20-40 °C. After the reaction was completed, the solvent was concentrated and purified by silica gel column chromatography to obtain compound III.

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