An n-acylsulfonamide compound, a preparation method and application thereof

Abstract

The application discloses an N-acyl sulfonamide compound and a preparation method and application thereof, and uses alkynyl sulfonamide and water as substrates, activates a carbon-carbon triple bond of the alkynyl sulfonamide by a gold catalyst, and selectively hydroxy hydrogenates water to synthesize N-acyl sulfonamide compounds in one step with high yield, and the hydroxyl group is selectively (100%) added to a nitrogen-substituted alkynyl carbon, and has the characteristics of high atom economy, mild reaction condition, high reaction region selectivity and the like. The synthesized N-acyl sulfonamide compound has antibacterial property on staphylococcus aureus, and the effect is equivalent to that of ciprofloxacin hydrochloride.

Description

(I) Technical Field

[0001] This invention relates to an N-acylsulfonamide compound, its preparation method, and its application in the preparation of antibacterial agents. (II) Background Technology

[0002] N-Acylsulfonamide compounds exhibit diverse pharmacological and biological activities, such as anti-leukemia, antiviral, anticancer, antibacterial, and antitumor effects, demonstrating their broad application potential in the pharmaceutical field. Furthermore, N-acylsulfonamide compounds possess excellent chemical hydrolysis and enzymatic stability, which allows them to maintain their activity in the in vivo environment, thus enabling them to exert their effects more effectively.

[0003] N-acylsulfonamide structures are found in many natural products, drug molecules, and bioactive molecules, such as the anti-HCV drugs asunaprevir and paritaprevir, and the anti-proliferative N-acylsulfonamide drug tacishuren.

[0004]

[0005] The conventional synthetic methods for N-ketosulfonamides can be summarized into several methods, such as... Figure 1 As shown. For example, Katritzky et al. (Katritzky AR, Hoffmann S and Suzuki K. Arkivoc., 2004, 14.) synthesized N-ketone sulfonamides via the reaction of N-acylbenzotriazole with sulfonamides, with yields of 70-95%. However, a significant drawback is that this reaction requires high temperatures and the use of sodium hydride, making it an energy-intensive reaction. Furthermore, the reaction also produces benzotriazole waste, reflecting poor atom economy. Figure 1 -Ia). The method reported by Raji Reddy C's group (Raji Reddy C, Mahipal Band Yaragorla S R. Tetrahedron Lett., 2007, 48, 7528.) avoids the use of strong bases, but requires the use of water-sensitive zinc chloride and phthalic anhydride reagents. The reaction system requires an anhydrous environment, and waste such as benzoic acid is generated during the reaction, resulting in low atom utilization efficiency. Figure 1 -Ib). Fu et al. reported (Fu S, Lian X, Ma T, et al. Tetrahedron Lett., 2010, 51, 5834.) that carboxylic acid esters can directly react with sulfonamides as acylation reagents in the presence of TiCl4-TCE to prepare N-ketosulfonamides. However, the reaction needs to be carried out at high temperatures and requires reagents such as titanium tetrachloride and trichloroethylene, which not only increases the difficulty of experimental operation but also affects the purity and yield of the product. Figure 1 -Ic).

[0006] As we all know, advocating for green chemistry is imperative in order to address the environmental challenges faced by traditional chemistry. The concept of "atom economy" in chemical reactions is one of the core elements of green chemistry. An ideal atom-economical reaction involves 100% conversion of atoms in the raw material molecules into products, producing no byproducts or waste, achieving "zero emissions." From the perspective of green chemistry, a significant drawback of the aforementioned synthetic methods is that they all generate waste and have poor atom economy.

[0007] Therefore, developing an atom-economical method for preparing N-ketosulfonamides remains an important research topic in green synthesis. Due to the absence of waste and the use of water as a reagent, the hydration of acetyleneamines prepares the corresponding carbonyl compounds (…). Figure 1 -II) is a sustainable and green chemical transformation model. However, a major challenge in the acetyleneamine hydration reaction is the complex regioselectivity control. This invention fills this gap, such as... Figure 1 As shown in -III, a series of novel N-ketosulfonamides with antibacterial activity were synthesized with 100% atom economy by using alkynylsulfonamides and water as substrates via a gold catalyst for highly regioselective (100%) hydration reactions. (III) Summary of the Invention

[0008] The purpose of this invention is to provide an N-acylsulfonamide compound, its preparation method, and its applications. This invention uses alkynylsulfonamide and water as substrates. A gold catalyst is used to activate the carbon-carbon triple bond of the alkynylsulfonamide, leading to a highly regioselective hydroxylation reaction with water. This results in the one-step, high-yield synthesis of N-acylsulfonamide compounds. The hydroxyl group adds to the nitrogen-substituted alkynyl carbon with high selectivity (100%), exhibiting high atom economy, mild reaction conditions, and high regioselectivity. The N-acylsulfonamide compound synthesized in this invention exhibits antibacterial activity against Staphylococcus aureus, with effects comparable to ciprofloxacin hydrochloride.

[0009] The technical solution adopted in this invention is:

[0010] This invention provides an N-acylsulfonamide compound of formula (II),

[0011]

[0012] In equation (II), R 1 It is aryl or alkyl, R 2 It is alkyl or aryl.

[0013] Furthermore, the R mentioned above 1It is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3-chlorophenyl, 3-methylphenyl, 2-methylphenyl, naphthyl, 3-thienyl, or pentyl; R 2 It is methyl or 4-methylphenyl.

[0014] Furthermore, the N-acylsulfonamide compound represented by formula (II) is one of the following:

[0015]

[0016] The present invention also provides a method for preparing the N-acylsulfonamide compound, the method comprising the following steps:

[0017] Using the compound shown in formula (I) as the reactant and IPrAuCl / AgNTf2 as the catalyst, the reaction was carried out in water and dichloroethane at 30-50°C (preferably 40°C). After the reaction was completed, the resulting reaction solution was post-treated to obtain the N-acylsulfonamide compound shown in formula (II).

[0018]

[0019] In equation (I), R 1 It is aryl or alkyl, R 2 R is alkyl or aryl; in formula (II) 1 R 2 In the same formula (I), R 1 R 2 .

[0020] Furthermore, the molar ratio of the compound shown in formula (I) to water is 1:2 to 1:2, preferably 1:2; the molar ratio of the compound shown in formula (I) to the catalyst is 1:0.003 to 0.05, preferably 1:0.01 to 0.04, wherein the molar ratio of IPrAuCl to AgNTf2 is 1:1; and the volumetric amount of dichloroethane used is 5-15 mL / mmol based on the molar amount of the compound shown in formula (I).

[0021] Furthermore, the post-treatment method of the reaction solution is as follows: after the reaction is completed, the reaction solution is filtered with diatomaceous earth, the filter residue is washed with dichloromethane, the filtrate and washing liquid are combined, and then washed with saturated NaCl aqueous solution. Then the organic phase is dried with anhydrous sodium sulfate. The solvent is evaporated, and the residue is purified by silica gel chromatography column. The eluent and developing solvent are both petroleum ether:ethyl acetate with a volume ratio of 3:1. The eluent with Rf of 0.4-0.6 is collected, and the solvent is evaporated under reduced pressure to obtain the N-acylsulfonamide compound shown in formula (II).

[0022] The present invention also provides the use of the N-acylsulfonamide compound in the preparation of an antibacterial agent, wherein the antibacterial agent includes an inhibitor of Staphylococcus aureus activity.

[0023] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0024] This invention provides a novel N-acylsulfonamide compound that uses alkynylsulfonamide and water as substrates to synthesize N-acylsulfonamide compounds in a one-step, high-yield manner. The hydroxyl group adds only to the nitrogen-substituted alkynyl carbon, exhibiting 100% regioselectivity and 100% atom economy. The reaction conditions are mild, and the yield is high. The N-acylsulfonamide compound synthesized in this invention exhibits antibacterial activity against Staphylococcus aureus, comparable to that of ciprofloxacin hydrochloride. (iv) Description of the attached drawings

[0025] Figure 1 A comparison of green chemistry methods (the methods of this invention) with traditional methods.

[0026] Figure 2 The reaction formula of the N-acylsulfonamide compounds of this invention.

[0027] Figure 3 Synthetic chemical reaction formula and crystal structure diagram of N-acylsulfonamide II-3. (V) Detailed Implementation

[0028] The present invention will be further described below with reference to specific embodiments, but the scope of protection of the present invention is not limited thereto:

[0029] Example 1: Preparation of N-acylsulfonamide II-1

[0030] The reaction formula is as follows:

[0031]

[0032] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. Stir the mixture at 40 °C for 1 hour and monitor the reaction by TLC (eluent: petroleum ether:ethyl acetate, v / v). After the reaction is complete, filter the reaction solution through diatomaceous earth, and wash the filter cake with dichloromethane. Combine the filtrate and washings, wash with saturated NaCl aqueous solution, and dry the organic phase with anhydrous sodium sulfate. Evaporate the solvent, and purify the residue by silica gel column chromatography using petroleum ether:ethyl acetate, v / v. Collect the eluent with an Rf of 0.4–0.6, evaporate the solvent under reduced pressure, and obtain N-acylsulfonamide II-1 in 96% molar yield.

[0033] The product is characterized as follows:

[0034] 1 H NMR (600MHz, Chloroform-d) δ7.73 (d, J = 8.4Hz, 2H), 7.39-7.24 (m, 5H), 7.16 (d, J = 6.8Hz, 2H), 4.07 (s, 2H), 3.31 (s, 3H), 2.45 (s, 3H). 13 C NMR(151MHz,Chloroform-d)δ171.27,144.99,136.08,133.51,129.90,129.40,128.59,127.56,127.17,43.07,33.30,21.63.GC-MS(EI):m / z 303[M+].

[0035] Example 2: Preparation of N-methyl-2-(p-tolyl)-N-toluenesulfonylacetamide II-2

[0036] The reaction formula is as follows:

[0037]

[0038] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 30.0 mg (0.1 mmol) alkynylsulfonamide (I-2), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 96%.

[0039] The product is characterized as follows:

[0040] 1 H NMR(500MHz,Chloroform-d)δ7.74(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),7.11( s,2H),7.03(d,J=8.0Hz,2H),4.01(s,2H),3.30(s,3H),2.46(s,3H),2.34(s,3H). 13 CNMR(126MHz,Chloroform-d)δ171.48,144.90,136.79,136.13,130.34,129.84,129.22,127.56,42.69,33.29,21.62,21.07.GC-MS(EI):m / z 317[M+].

[0041] Example 3: Preparation of 2-(4-fluorophenyl)-N-methyl-N-toluenesulfonylacetamide II-3

[0042] The reaction formula is as follows:

[0043]

[0044] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by 30.3 mg (0.1 mmol) of alkynylsulfonamide (I-3), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 95%. See the crystal diagram below. Figure 3 .

[0045] The product is characterized as follows:

[0046] 1 H NMR(500MHz,Chloroform-d)δ7.73(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),7.13 (d,J=8.7Hz,2H),6.98(t,J=8.7Hz,2H),4.04(s,2H),3.29(s,3H),2.46(s,3H). 13CNMR(126MHz,Chloroform-d)δ171.21,162.03(J=246.96Hz),145.10,136.01,131.08(J=8.19Hz ),129.96,129.26(J=3.02Hz),127.42,115.39(J=20.03Hz),42.12,33.27,21.61.GC-MS(EI):m / z 321[M+].

[0047] Example 4: Preparation of 2-(4-chlorophenyl)-N-methyl-N-toluenesulfonylacetamide II-4

[0048] The reaction formula is as follows:

[0049]

[0050] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 32.0 mg (0.1 mmol) alkynylsulfonamide (I-4), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 93%.

[0051] The product is characterized as follows:

[0052] 1H NMR(500MHz,Chloroform-d)δ7.72(d,J=8.3Hz,2H),7.34(d,J=8.1Hz,2H),7.26(d,J=8.4Hz,2H),7.08(d,J=8.4Hz,2H),4.04(s,2H),3.29(s,3H),2.46( s,3H).13CNMR(126MHz,Chloroform-d)δ170.92,145.15,135.94,133.14,132.00,130.85,129.98,128.66,127.40,42.31,33.30,21.64.GC-MS(EI):m / z 337[M+].

[0053] Example 5: Preparation of 2-(4-bromophenyl)-N-methyl-N-toluenesulfonylacetamide II-5

[0054] The reaction formula is as follows:

[0055]

[0056] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 36.4 mg (0.1 mmol) alkynylsulfonamide (I-5), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 90%.

[0057] The product is characterized as follows:

[0058] 1 H NMR (500MHz, Chloroform-d) δ7.72 (s, 2H), 7.38 (d, J = 30.7Hz, 4H), 7.04 (s, 2H), 4.03 (s, 2H), 3.29 (s, 3H), 2.47 (s, 3H). 13 C NMR(126MHz,Chloroform-d)δ170.83,145.14,135.94,132.51,131.62,131.19,129.98,127.38,42.39,33.29,21.64.GC-MS(EI):m / z 381[M+],383[M+2] + .

[0059] Example 6: Preparation of N-methyl-2-(m-tolyl)-N-toluenesulfonylacetamide II-6

[0060] The reaction formula is as follows:

[0061]

[0062] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 30.0 mg (0.1 mmol) alkynylsulfonamide (I-6), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 94%.

[0063] The product is characterized as follows:

[0064] 1 H NMR(500MHz,Chloroform-d)δ7.74(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),7.19(d,J=7.6Hz, 1H),7.09(s,1H),6.94(d,J=16.2Hz,2H),4.01(s,2H),3.31(s,3H),2.46(s,3H),2.31(s,3H).13 C NMR(126MHz,Chloroform-d)δ171.37,144.93,138.21,136.10,133.28,129.98,12 9.85,128.49,127.93,127.59,126.39,43.01,33.33,21.63,21.34.GC-MS(EI):m / z 317[M+].

[0065] Example 7: Preparation of 2-(3-chlorophenyl)-N-methyl-N-toluenesulfonylacetamide II-7

[0066] The reaction formula is as follows:

[0067]

[0068] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 32.0 mg (0.1 mmol) alkynylsulfonamide (I-7), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 92%.

[0069] The product is characterized as follows:

[0070] 1 H NMR(500MHz,Chloroform-d)δ7.73(d,J=8.3Hz,2H),7.33(d,J=8.1Hz,2H),7. 22(d,J=5.1Hz,2H),7.09-7.02(m,2H),4.02(s,2H),3.30(s,3H),2.44(s,3H). 13 CNMR(126MHz,Chloroform-d)δ170.65,145.22,135.92,135.47,134.20,130.03 ,129.76,129.52,127.79,127.42,127.34,42.49,33.32,21.64.GC-MS(EI):m / z 337[M+].

[0071] Example 8: Preparation of N-methyl-2-(o-tolyl)-N-tolylacetamide II-8

[0072] The reaction formula is as follows:

[0073]

[0074] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 30.0 mg (0.1 mmol) alkynylsulfonamide (I-8), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 96%.

[0075] The product is characterized as follows:

[0076] 1 HNMR(500MHz,Chloroform-d)δ7.79(d,J=8.3Hz,2H),7.36(d,J=8.0Hz,2H),7.21-7.15(m,2 H),7.12(s,1H),6.96(d,J=7.5Hz,1H),4.02(s,2H),3.36(s,3H),2.47(s,3H),2.10(s,3H). 13 C NMR(126MHz,Chloroform-d)δ171.15,136.76,136.22,132.47,130.34,129.93,129 .80,127.51,127.48,126.08,41.28,33.28,21.65,19.37.GC-MS(EI):m / z317[M+].

[0077] Example 9: Preparation of N-methyl-N-(methanesulfonyl)-2-phenylacetamide II-9

[0078] The reaction formula is as follows:

[0079]

[0080] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 20.9 mg (0.1 mmol) alkynylsulfonamide (I-9), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 85%.

[0081] The product is characterized as follows:

[0082] 1H NMR(500MHz,Chloroform-d)δ7.37(t,J=7.3Hz,2H),7.33–7.26(m,3H),4.02(s,2H),3.30(s,3H),3.09(s,3H).GC-MS(EI):m / z 227[M+].

[0083] Example 10: Preparation of N-methyl-N-(methanesulfonyl)-2-(4-nitrophenyl)acetamide II-10

[0084] The reaction formula is as follows:

[0085]

[0086] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by 25.4 mg (0.1 mmol) of alkynylsulfonamide (I-10), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 87%.

[0087] The product is characterized as follows:

[0088] 1H NMR(500MHz,Chloroform-d)δ8.31-8.16(m,2H),7.52-7.39(m,2H),4.14(s,2H),3.34(s,3H),3.21(s,3H).GC-MS(EI): m / z 272[M+].

[0089] Example 11: Preparation of 2-(2-chlorophenyl)-N-methyl-N-toluenesulfonylacetamide II-11

[0090] The reaction formula is as follows:

[0091]

[0092] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 32.0 mg (0.1 mmol) alkynylsulfonamide (I-11), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 93%.

[0093] The product is characterized as follows:

[0094] 1H NMR(500MHz,Chloroform-d)δ7.85(d,J=8.4Hz,2H),7.37(d,J=8.0Hz,2H),7.35–7.32 (m,1H),7.24–7.19(m,2H),7.18–7.12(m,1H),4.17(s,2H),3.36(s,3H),2.47(s,3H). 13 C NMR(126MHz,Chloroform-d)δ170.22,145.10,136.05,134.38,132.39,131.57 ,129.99,129.37,128.81,127.50,126.94,41.60,33.26,21.66.GC-MS(EI):m / z 337[M+].

[0095] Example 12: Preparation of N-methyl-N-toluenesulfonyl-2-(4-(trifluoromethyl)phenyl)acetamide II-12

[0096] The reaction formula is as follows:

[0097]

[0098] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 35.3 mg (0.1 mmol) alkynylsulfonamide (I-12), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 88%.

[0099] The product is characterized as follows:

[0100] 1 H NMR(500MHz,Chloroform-d)δ7.71(d,J=8.3Hz,2H),7.55(d,J=8.1Hz,2H),7.34(d,J=8.1 Hz,2H),7.28(d,J=8.0Hz,2H),4.15(s,2H),3.30(s,3H),2.45(s,3H).13CNMR(126MHz,Ch loroform-d)δ170.55,145.27,137.66,135.85,130.00(J=12.47Hz),129.44(J=12.47Hz) ,127.35,125.40(J=3.91Hz),124.14(J=227.00Hz),42.72,33.29,21.58.GC-MS(EI):m / z 371[M+].

[0101] Example 13: Preparation of N-methyl-N-toluenesulfonylheptamide II-13

[0102] The reaction formula is as follows:

[0103]

[0104] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by 28.0 mg (0.1 mmol) of alkynylsulfonamide (I-13), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 87%.

[0105] The product is characterized as follows:

[0106] 1 H NMR(500MHz,Chloroform-d)δ7.77(d,J=8.4Hz,2H),7.34(d,J=8.0Hz,2H),3.30(s,3H),2.67–2.61 (m,2H),2.44(s,3H),1.60–1.53(m,2H),1.26(d,J=6.0Hz,2H),1.22(s,2H),0.85(t,J=7.0Hz,3H). 13 C NMR(126MHz,Chloroform-d)δ173.39,144.77,136.49,129.84,127.38,36.44,32.99,31.44,28.63,24.58,22.4,21.58,13.96.GC-MS(EI):m / z 297[M+].

[0107] Example 14: Preparation of N-methyl-2-(naphth-2-yl)-N-toluenesulfonylacetamide II-14

[0108] The reaction formula is as follows:

[0109]

[0110] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by the sequential addition of 33.5 mg (0.1 mmol) alkynylsulfonamide (I-14), 3.6 mg (0.2 mmol) water, 0.31 mg (0.0005 mmol) IPrAuCl, and 0.19 mg (0.0005 mmol) AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 95%.

[0111] The product is characterized as follows:

[0112] 1 H NMR(500MHz,Chloroform-d)δ7.81(dd,J=19.9,7.3Hz,2H),7.72(d,J=8.3Hz,3H),7.54(s ,1H),7.47(d,J=9.5Hz,2H),7.28(d,J=8.2Hz,3H),4.23(s,2H),3.33(s,3H),2.43(s,3H). 13 C NMR(126MHz,Chloroform-d)δ129.85,127.62,127.48,127.39,126.14,125.89,43.22,33.38,21.60.GC-MS(EI):m / z 353[M+].

[0113] Example 15: Preparation of N-methyl-2-(thiophen-3-yl)-N-toluenesulfonylacetamide II-15

[0114] The reaction formula is as follows:

[0115]

[0116] Add 1 mL of dichloroethane (DCE) to the reaction flask, followed by 29.1 mg (0.1 mmol) of alkynylsulfonamide (I-15), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The following procedures were the same as in Example 1, with a molar yield of 91%.

[0117] The product is characterized as follows:

[0118] 1 H NMR(500MHz,Chloroform-d)δ7.69(d,J=8.4Hz,2H),7.33(d,J=8.0Hz,2H),7.28(s,1H ),7.05(d,J=1.8Hz,1H),6.95(d,J=4.9Hz,1H),4.10(s,2H),3.28(s,3H),2.46(s,3H). 13 C NMR(126MHz,Chloroform-d)δ170.83,145.00,135.94,133.11,129.92,128.58,127.45,125.73,123.21,37.80,33.24,21.64.GC-MS(EI):m / z 309[M+].

[0119] Example 16: Preparation of N-acylsulfonamide II-1

[0120] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1) and 3.6 mg (0.2 mmol) of water. The mixture was stirred at 40 °C for 10 hours, with the reaction monitored by TLC. No product II-1 was found to form, and the substrate I-1 did not decrease. The reaction temperature was then increased to 80 °C, and no product II-1 was formed after 5 hours of reaction.

[0121] Example 17: Preparation of N-acylsulfonamide II-1

[0122] 1.5 mL of dichloroethane (DCE) was added to the reaction flask, followed by the sequential addition of 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1), 3.6 mg (0.3 mmol) of water, 1.24 mg (0.002 mmol) of IPrAuCl, and 0.78 mg (0.002 mmol) of AgNTf2. The mixture was stirred at 40 °C for 0.5 hours, and other procedures were the same as in Example 1, yielding N-acylsulfonamide II-1 in 94% molar yield.

[0123] Example 18: Preparation of N-acylsulfonamide II-1

[0124] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by the sequential addition of 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1), 3.6 mg (0.2 mmol) of water, 0.62 mg (0.001 mmol) of IPrAuCl, and 0.39 mg (0.001 mmol) of AgNTf2. The mixture was stirred at 30 °C for 2 hours, and other procedures were the same as in Example 1, yielding N-acylsulfonamide II-1 in 93% molar yield.

[0125] Example 19: Preparation of N-acylsulfonamide II-1

[0126] 0.5 mL of dichloroethane was added to the reaction flask, followed by the sequential addition of 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The mixture was stirred at 50 °C for 0.5 hours, and other procedures were performed as in Example 1, yielding N-acylsulfonamide II-1 in 95% molar yield.

[0127] Example 20: Preparation of N-acylsulfonamide II-16

[0128] The reaction formula is as follows:

[0129]

[0130] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 34.7 mg (0.1 mmol) of alkynylsulfonamide (I-16), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The mixture was stirred at 40 °C for 1 hour, and the reaction was monitored by TLC (evolving solvent: petroleum ether:ethyl acetate, volume ratio 3:1). No reaction was observed, and the reaction was extended to 8 hours without product formation.

[0131] Example 21: Preparation of N-acylimidazolidine-2-one II-17

[0132] The reaction formula is as follows:

[0133]

[0134] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 18.6 mg (0.1 mmol) of N-alkynylimidazolidine-2-one (I-17), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The mixture was stirred at 40 °C for 1 hour. TLC monitoring showed that no reaction occurred, and the reaction was extended to 8 hours without product formation.

[0135] Example 22: Preparation of N-acylmorpholine II-18

[0136] The reaction formula is as follows:

[0137]

[0138] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 18.7 mg (0.1 mmol) of N-alkynylmorpholine (I-18), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The mixture was stirred at 40 °C for 1 hour. TLC monitoring showed that no reaction occurred, and the reaction was extended to 8 hours without product formation.

[0139] Example 23: Preparation of N-acylpiperidine II-19

[0140] The reaction formula is as follows:

[0141]

[0142] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 18.5 mg (0.1 mmol) of N-alkynylpiperidine (I-19), 3.6 mg (0.2 mmol) of water, 0.31 mg (0.0005 mmol) of IPrAuCl, and 0.19 mg (0.0005 mmol) of AgNTf2. The mixture was stirred at 40 °C for 1 hour. TLC monitoring showed that no reaction occurred. The reaction temperature was then increased to 60 °C, and the reaction time was extended to 8 hours, but no product was formed.

[0143] Example 24: Antibacterial activity assay of N-acylsulfonamides (II-1 to II-15)

[0144] The antibacterial activity of the above-mentioned synthetic compounds II-1 to II-15 and ciprofloxacin hydrochloride against Staphylococcus aureus was tested using the Oxford cup method.

[0145] (1) Test bacterial suspension: Staphylococcus aureus was inoculated into LB liquid medium and activated for 16 h at 37 ℃ and 120 r / min. The activated culture solution was then serially diluted with sterile water to a bacterial concentration of 10. 5 -10 6 mL -1 Prepare LB medium: Accurately weigh 0.5g tryptone, 0.25g yeast extract, and 0.5g NaCl and add them to 50mL of deionized water, stirring constantly until the solutes are completely dissolved. Adjust the pH to 7.0-7.2 with 1mol / L NaOH solution; sterilize the above LB liquid medium. For LB solid medium, weigh out 0.75g of agar powder for each.

[0146] (2) Working solutions of experimental compounds: 5 mg, 50 mg, 100 mg and 200 mg of compounds II-1 to II-15 prepared in Examples 1-15 were dissolved in 1 mL of DMSO, and then 9 mL of LB liquid culture medium was added to each of them to prepare working solutions of experimental compounds with concentrations of 0.5 mg / mL, 5 mg / mL, 10 mg / mL and 20 mg / mL.

[0147] (3) Positive control solution: Take 5mg, 50mg, 100mg and 200mg of ciprofloxacin hydrochloride and dissolve them in 1mL of DMSO. Then add 9mL of LB liquid culture medium to each solution to prepare positive control working solutions with concentrations of 0.5mg / mL, 5mg / mL, 10mg / mL and 20mg / mL.

[0148] (4) Blank working solution: LB liquid medium containing 10% DMSO by volume.

[0149] (5) Antibacterial test:

[0150] Preparation of agar plates: Cool the sterilized LB liquid medium to approximately 60°C and slowly pour it into the agar plates, about 15 mL per plate. Place the plates horizontally until completely solidified. Spread 0.1 mL of the test bacterial suspension evenly on each agar plate until no visible water droplets are visible on the surface. Using tweezers, vertically place five sterilized Oxford cups into each agar plate, evenly spaced apart. Gently press the Oxford cups to ensure they are in contact with the medium without gaps.

[0151] Detection: Accurately measure different concentrations (0.5 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL) of the experimental compound working solution, positive control working solution, and blank working solution into Oxford cups in petri dishes. Incubate at 37℃ for 12 hours, then measure the diameter of the inhibition zone with a ruler and record the results. The antibacterial activity of the compound is evaluated by the diameter of the inhibition zone in the Oxford cup. Based on the experimental results, generally, an inhibition zone diameter less than 6 mm indicates no antibacterial activity (marked "-"); between 6-10 mm indicates antibacterial activity (marked "+"); 11-15 mm indicates moderate sensitivity (marked "++"); and a diameter of 16 mm or more indicates high sensitivity (marked "+++").

[0152] Table 1. Results of antibacterial experiment

[0153]

[0154] Note: A=0.5mg / mL, B=5mg / mL, C=10mg / mL, D=20mg / mL, BG=0mg / mL

[0155] As shown in Table 1 above, when the dosage concentration is 0.5 mg / mL, compounds II-8, II-11, and II-12 exhibit antibacterial activity against Staphylococcus aureus. Among them, compounds II-8 and II-12 are moderately sensitive and have antibacterial activity comparable to that of ciprofloxacin hydrochloride. When the dosage concentration is 5 mg / mL, compounds II-1, II-2, II-3, II-4, II-7, II-8, II-11, II-12, II-14, and II-15 exhibit antibacterial activity against Staphylococcus aureus. Among them, compound II-8 has moderately sensitive antibacterial activity, and compound II-12 has highly sensitive antibacterial activity, which is comparable to that of ciprofloxacin hydrochloride. At a concentration of 10 mg / mL, compounds II-1 to II-5, II-7, II-8, and II-11 to II-15 exhibit antibacterial activity against Staphylococcus aureus. Compounds II-14 and II-15 show moderately sensitive antibacterial activity, while II-8 and II-12 show highly sensitive antibacterial activity, comparable to that of ciprofloxacin hydrochloride. At a concentration of 20 mg / mL, compounds II-1 to II-8 and II-10 to II-15 also exhibit antibacterial activity against Staphylococcus aureus. Compounds II-1, II-2, II-3, II-4, II-11, and II-15 show moderately sensitive antibacterial activity, while compounds II-8 to II-12 and II-14 show highly sensitive antibacterial activity, comparable to that of ciprofloxacin hydrochloride.

Claims

1. An N-acylsulfonamide compound of formula (II), characterized in that, The N-acylsulfonamide compound represented by formula (II) is one of the following: 。 2. A method for preparing the N-acylsulfonamide compound according to claim 1, characterized in that, The method includes the following steps: Using the compound shown in formula (I) as the reactant and IPrAuCl / AgNTf2 as the catalyst, the reaction was carried out in water and dichloroethane at 30-50°C. After the reaction was completed, the resulting reaction solution was post-treated to obtain the N-acylsulfonamide compound shown in formula (II). In equation (I), R 1 It is 4-trifluoromethylphenyl, 2-methylphenyl, R 2 It is 4-methylphenyl; R in formula (II) 1 R 2 In the same formula (I), R 1 R 2 .

3. The method as described in claim 2, characterized in that, The molar ratio of the compound shown in formula (I) to water is 1:2 to 3; the molar ratio of the compound shown in formula (I) to the catalyst is 1:0.003 to 0.05, wherein the molar ratio of IPrAuCl to AgNTf2 is 1:1; the volume of dichloroethane used is 5-15 mL / mmol based on the molar amount of the compound shown in formula (I).

4. The method as described in claim 2, characterized in that, The post-treatment method of the reaction solution is as follows: After the reaction is completed, the reaction solution is filtered with diatomaceous earth, the filter cake is washed with dichloromethane, the filtrate and washing liquid are combined, and then washed with saturated NaCl aqueous solution. The organic phase is then dried with anhydrous sodium sulfate. The solvent is evaporated, and the residue is purified by silica gel chromatography column. The eluent and developing solvent are both petroleum ether:ethyl acetate with a volume ratio of 3:

1. The eluent with Rf of 0.4-0.6 is collected, and the solvent is evaporated under reduced pressure to obtain the N-acylsulfonamide compound shown in formula (II).

5. The use of the N-acylsulfonamide compound of claim 1 in the preparation of an antibacterial agent, characterized in that, The antibacterial agent is an inhibitor of Staphylococcus aureus activity.

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