N-acyl sulfonamide compound as well as preparation method and application thereof

Abstract

The invention discloses an N-acyl sulfonamide compound and a preparation method and application thereof.Alkynyl sulfonamide and water are used as substrates, carbon-carbon triple bonds of alkynyl sulfonamide are activated through a gold catalyst to be subjected to a selective hydroxyhydrogenation reaction with water, and the N-acyl sulfonamide compound is synthesized in a one-step and high-yield mode. Hydroxyl is added to nitrogen-substituted alkynyl carbon with high selectivity (100%), and the method has the characteristics of high atom economy, mild reaction conditions, high reaction region selectivity and the like. The N-acyl sulfonamide compound synthesized by the invention has an antibacterial property on staphylococcus aureus, and the effect is equivalent to the antibacterial property of ciprofloxacin hydrochloride.

Description

(I) Technical field

[0001] The invention relates to an N-acylsulfonamide compound and a preparation method thereof and application of the compound in preparing an antibacterial agent. (II) Background technology

[0002] N-acylsulfonamide compounds have shown their potential for wide application in the medical field due to their diverse pharmacological and biological activities, such as anti-leukemia, antiviral, anticancer, antibacterial and antitumor effects. In addition, N-acylsulfonamide compounds have excellent chemical hydrolysis and enzymatic stability, which enables these compounds to maintain their activity in the in vivo environment, thereby exerting their effects more effectively.

[0003] N-acylsulfonamide structures exist in many natural products, drug molecules and biologically active molecules, such as the anti-HCV drugs asunaprevir, paritaprevir, and the antiproliferative N-acylsulfonamide drug tasifirren.

[0004]

[0005] The conventional synthesis methods of 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-ketosulfonamide by reacting N-acylbenzotriazole with sulfonamide, with a yield of 70-95%. However, the obvious disadvantage is that the reaction needs to be carried out at high temperature and sodium hydride needs to be used, which is a high energy consumption reaction. At the same time, the reaction also produces benzotriazole waste, reflecting the 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 zinc chloride and phthalic anhydride reagents that are sensitive to water. The reaction system requires an anhydrous environment, and waste such as benzoic acid is produced during the reaction, resulting in low atomic utilization efficiency ( Figure 1 -Ib). Fu et al. reported (Fu S, Lian X, Ma T, et al. Tetrahedron Lett., 2010, 51, 5834.) that in the presence of TiCl4-TCE, carboxylic acid esters can be used as acylating agents to directly react with sulfonamides to prepare N-ketosulfonamides. However, the reaction needs to be carried out at high temperatures and requires the use of 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, in order to cope with the environmental challenges faced by traditional chemistry, it is imperative to advocate green chemistry. The concept of "atom economy" in chemical reactions is one of the core contents of green chemistry. The ideal atom economy reaction is that the atoms in the raw material molecules are 100% converted into products, without producing by-products or waste, achieving "zero emission" of waste. From the perspective of green chemistry, the obvious disadvantages of the above-mentioned synthesis methods are that they all produce waste and have poor atom economy.

[0007] Therefore, developing an atom-economical method for the preparation of N-ketosulfonamides remains an important research topic in green synthesis today. Due to the absence of waste and the use of water as a reagent, the hydration of acetyleneamine to prepare the corresponding carbonyl compounds ( Figure 1 -II) is a sustainable and green chemical transformation mode. However, the main problem faced by the hydration reaction of acetyleneamine is also the complex regioselectivity control. The present invention fills this gap, such as Figure 1 -III, using alkynylsulfonamide and water as substrates, a highly regioselective (100%) hydration reaction was completed by gold catalyst, and a series of new N-ketosulfonamides with antibacterial activity were synthesized with 100% atom economy. (III) Summary of the invention

[0008] The purpose of the present invention is to provide an N-acylsulfonamide compound and a preparation method and application thereof. The present invention uses alkynylsulfonamide and water as substrates, activates the carbon-carbon triple bond of alkynylsulfonamide with water through a gold catalyst, and undergoes a highly regioselective hydroxyl hydrogenation reaction, synthesizes N-acylsulfonamide compounds with high yield in one step, and highly selectively (100%) adds the hydroxyl group to the nitrogen-substituted alkyne carbon, which has the characteristics of high atom economy, mild reaction conditions, high reaction regioselectivity, etc. The N-acylsulfonamide compound synthesized by the present invention has antibacterial activity against Staphylococcus aureus, and the effect is equivalent to the antibacterial activity of ciprofloxacin hydrochloride.

[0009] The technical solution adopted by the present invention is:

[0010] The present invention provides an N-acylsulfonamide compound represented by formula (II),

[0011]

[0012] In formula (II), R 1 is an aryl group or an alkyl group, R 2 is an alkyl group or an aryl group.

[0013] Furthermore, the R 1is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 3-chlorophenyl, 3-methylphenyl, 2-methylphenyl, naphthyl, 3-thienyl or pentyl; R 2 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, which comprises the following steps:

[0017] The compound represented by formula (I) is used as a reaction raw material, IPrAuCl / AgNTf2 is used as a catalyst, and the reaction is carried out in water and dichloroethane at 30 to 50° C. (preferably 40° C.). After the reaction is completed, the obtained reaction solution is post-treated to obtain an N-acylsulfonamide compound represented by formula (II);

[0018]

[0019] In formula (I), R 1 is an aryl group or an alkyl group, R 2 is an alkyl or aryl group; in formula (II), R 1 , R 2 Same as R in formula (I) 1 , R 2 .

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

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

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

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

[0024] The present invention provides a new N-acylsulfonamide compound, which uses alkynylsulfonamide and water as substrates, synthesizes N-acylsulfonamide compounds with high yield in one step, and the hydroxyl group is only added to the nitrogen-substituted alkyne carbon, and has the characteristics of 100% regioselectivity and 100% atom economy, mild reaction conditions, high reaction yield, etc. The N-acylsulfonamide compound synthesized by the present invention has antibacterial activity against Staphylococcus aureus, which is equivalent to the antibacterial activity of ciprofloxacin hydrochloride. (IV) Description of the drawings

[0025] Figure 1 , comparison between green chemistry method (method of the present invention) and traditional method.

[0026] Figure 2 , the reaction formula of the N-acylsulfonamide compound of the present invention.

[0027] Figure 3 , synthetic chemical reaction formula and crystal structure diagram of N-acylsulfonamide II-3. (V) Specific implementation methods

[0028] The present invention is further described below in conjunction with specific embodiments, but the protection scope 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] 1 mL of dichloroethane (DCE) was added 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. The mixture was stirred at 40 °C for 1 hour, and the reaction was monitored by TLC (the developing solvent was petroleum ether: ethyl acetate in a volume ratio of 3:1). After the reaction was completed, the reaction solution was filtered through diatomaceous earth, and the filter cake was washed with dichloromethane. The filtrate and washings were combined, washed with a saturated aqueous NaCl solution, and then the organic phase was dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography, the eluent and developing solvent were both petroleum ether: ethyl acetate in a volume ratio of 3:1, and the effluent with Rf of 0.4-0.6 was collected, and the solvent was evaporated under reduced pressure to obtain N-acylsulfonamide II-1 with a molar yield of 96%.

[0033] The product characterization is 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-toluenesulfonyl acetamide II-2

[0036] The reaction formula is as follows:

[0037]

[0038] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 30.0 mg (0.1 mmol) of alkynylsulfonamide (I-2), 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 operations were the same as in Example 1, and the molar yield was 96%.

[0039] The product characterization is 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-toluenesulfonyl acetamide II-3

[0042] The reaction formula is as follows:

[0043]

[0044] 1 mL of dichloroethane (DCE) was added 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 operations were the same as in Example 1, and the molar yield was 95%. See the crystal diagram Figure 3 .

[0045] The product characterization is 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-toluenesulfonyl acetamide II-4

[0048] The reaction formula is as follows:

[0049]

[0050] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 32.0 mg (0.1 mmol) of alkynylsulfonamide (I-4), 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 operation was the same as in Example 1, and the molar yield was 93%.

[0051] The product characterization is 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-toluenesulfonyl acetamide II-5

[0054] The reaction formula is as follows:

[0055]

[0056] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 36.4 mg (0.1 mmol) of alkynylsulfonamide (I-5), 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 operation was the same as in Example 1, and the molar yield was 90%.

[0057] The product characterization is 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-toluenesulfonyl acetamide II-6

[0060] The reaction formula is as follows:

[0061]

[0062] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 30.0 mg (0.1 mmol) of alkynylsulfonamide (I-6), 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 operations were the same as in Example 1, and the molar yield was 94%.

[0063] The product characterization is 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-toluenesulfonyl acetamide II-7

[0066] The reaction formula is as follows:

[0067]

[0068] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 32.0 mg (0.1 mmol) of alkynylsulfonamide (I-7), 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 operation was the same as in Example 1, and the molar yield was 92%.

[0069] The product characterization is 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] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 30.0 mg (0.1 mmol) of alkynylsulfonamide (I-8), 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 operations were the same as in Example 1, and the molar yield was 96%.

[0075] The product characterization is 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-(methylsulfonyl)-2-phenylacetamide II-9

[0078] The reaction formula is as follows:

[0079]

[0080] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 20.9 mg (0.1 mmol) of alkynylsulfonamide (I-9), 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 operation was the same as in Example 1, and the molar yield was 85%.

[0081] The product characterization is 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-(methylsulfonyl)-2-(4-nitrophenyl)acetamide II-10

[0084] The reaction formula is as follows:

[0085]

[0086] 1 mL of dichloroethane (DCE) was added 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 operations were the same as in Example 1, and the molar yield was 87%.

[0087] The product characterization is 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-toluenesulfonyl acetamide II-11

[0090] The reaction formula is as follows:

[0091]

[0092] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 32.0 mg (0.1 mmol) of alkynylsulfonamide (I-11), 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 operation was the same as in Example 1, and the molar yield was 93%.

[0093] The product characterization is 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] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 35.3 mg (0.1 mmol) of alkynylsulfonamide (I-12), 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 operations were the same as in Example 1, and the molar yield was 88%.

[0099] The product characterization is 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-toluenesulfonylheptylamide II-13

[0102] The reaction formula is as follows:

[0103]

[0104] 1 mL of dichloroethane (DCE) was added 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 operation was the same as in Example 1, and the molar yield was 87%.

[0105] The product characterization is 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-(naphthalen-2-yl)-N-toluenesulfonyl acetamide II-14

[0108] The reaction formula is as follows:

[0109]

[0110] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 33.5 mg (0.1 mmol) of alkynylsulfonamide (I-14), 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 operation was the same as in Example 1, and the molar yield was 95%.

[0111] The product characterization is 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-toluenesulfonyl acetamide II-15

[0114] The reaction formula is as follows:

[0115]

[0116] 1 mL of dichloroethane (DCE) was added 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 operations were the same as in Example 1, and the molar yield was 91%.

[0117] The product characterization is 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, during which the reaction was monitored by TLC. It was found that no product II-1 was generated, and the reaction substrate I-1 did not decrease. The reaction temperature was then raised to 80 °C, and no product II-1 was generated 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 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 the other operations were the same as in Example 1 to obtain N-acylsulfonamide II-1 with a molar yield of 94%.

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

[0124] 1 mL of dichloroethane (DCE) was added to the reaction flask, followed by 28.5 mg (0.1 mmol) of alkynylsulfonamide (I-1), 3.6 mg (0.2 mmol) of water, 0.62 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 the other operations were the same as in Example 1 to obtain N-acylsulfonamide II-1 with a molar yield of 93%.

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

[0126] 0.5 mL of dichloroethane was added 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. The mixture was stirred at 50°C for 0.5 hours, and the other operations were the same as in Example 1 to obtain N-acylsulfonamide II-1 with a molar yield of 95%.

[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 (developing solvent was petroleum ether: ethyl acetate in a volume ratio of 3:1), and it was found that the reaction did not occur. The reaction was then extended to 8 hours and no product was generated.

[0131] Example 21: Preparation of N-acyl imidazolidin-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-alkynyl imidazolidin-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, and the reaction was monitored by TLC, and it was found that the reaction did not occur. The reaction was then extended to 8 hours, but no product was generated.

[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, and the reaction was monitored by TLC, which showed that no reaction occurred. The reaction was then extended to 8 hours, but no product was generated.

[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, and the reaction was monitored by TLC, and it was found that no reaction occurred. The reaction temperature was then raised to 60°C, and the reaction time was extended to 8 hours, but no product was generated.

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

[0144] The Oxford cup antibacterial test was used to detect the antibacterial effects of the above-mentioned synthetic compounds II-1 to II-15 and ciprofloxacin hydrochloride on Staphylococcus aureus.

[0145] (1) Test bacterial suspension: Staphylococcus aureus was inoculated into LB liquid culture medium and activated at 37°C and 120 rpm for 16 h. The activated culture medium was aspirated and diluted with sterile water to a bacterial concentration of 10 5 -10 6 mL -1 , set aside. Preparation of LB medium: Accurately weigh 0.5g of tryptone, 0.25g of yeast extract, and 0.5g of NaCl and add them to 50mL of deionized water, stirring continuously until the solute is completely dissolved. Use 1mol / L NaOH solution to adjust the pH value to 7.0-7.2; sterilize the above LB liquid medium. For LB solid medium, weigh 0.75g of agar powder each.

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

[0147] (3) Positive control solution: 5 mg, 50 mg, 100 mg, and 200 mg of ciprofloxacin hydrochloride were dissolved in 1 mL of DMSO, and 9 mL of LB liquid culture medium was added thereto to prepare positive control working solutions with concentrations of 0.5 mg / mL, 5 mg / mL, 10 mg / mL, and 20 mg / mL, respectively.

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

[0149] (5) Antibacterial test:

[0150] Preparation of flat culture dishes: Cool the sterilized LB liquid culture medium to about 60°C, slowly pour it into the culture dish, pour about 15mL of culture medium into each dish, and place it horizontally until it is completely solidified. Evenly apply 0.1mL of the test bacterial suspension to each culture dish until there are no visible water droplets on the surface. Use tweezers to vertically place the sterilized Oxford cup into the culture dish, place five Oxford cups at equal distances in each culture dish, and gently press the Oxford cup to make it contact with the culture medium without gaps.

[0151] Detection: Use a pipette to accurately measure different concentrations (0.5mg / mL, 5mg / mL, 10mg / mL, 20mg / mL) of the experimental compound working solution, the positive control working solution, and the blank working solution, and place them in the Oxford cup in the flat plate culture dish. After incubation in a 37℃ constant temperature incubator for 12 hours, use a millimeter ruler to measure the diameter of the inhibition zone and record the experimental results. The diameter of the Oxford cup inhibition zone is used to evaluate the antibacterial activity of the compound. According to the experimental results, it is generally believed that if the diameter of the inhibition zone is less than 6mm, it means that the substance has no antibacterial activity (recorded as "-"); between 6-10mm, it means that the substance has antibacterial activity (recorded as "+"); 11-15mm is moderately sensitive (recorded as "++"); and the diameter reaches 16mm or more, it is highly sensitive (recorded as "+++").

[0152] Table 1. Antibacterial test results

[0153]

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

[0155] It can be seen from Table 1 above that when the dosage concentration is 0.5 mg / mL, compounds II-8, II-11, and II-12 have antibacterial properties against Staphylococcus aureus, among which compounds II-8 and II-12 are moderately sensitive, which is equivalent to the antibacterial property 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 have antibacterial properties against Staphylococcus aureus, among which compound II-8 has moderately sensitive antibacterial property, and compound II-12 has highly sensitive antibacterial property, which is equivalent to the antibacterial property of ciprofloxacin hydrochloride. When the dosage concentration is 10 mg / mL, compounds II-1 to II-5, II-7, II-8, II-11 to II-15 all have antibacterial activity against Staphylococcus aureus, among which compounds II-14 and II-15 have moderately sensitive antibacterial activity, and II-8 and II-12 have highly sensitive antibacterial activity, which is equivalent to the antibacterial activity of ciprofloxacin hydrochloride. When the dosage concentration is 20 mg / mL, compounds II-1 to II-8, II-10 to II-15 all have antibacterial activity against Staphylococcus aureus, among which compounds II-1, II-2, II-3, II-4, II-11, and II-15 have moderately sensitive antibacterial activity, and compounds II-8 to II-12 and II-14 have highly sensitive antibacterial activity, which is equivalent to the antibacterial activity of ciprofloxacin hydrochloride.

Claims

1. An N-acylsulfonamide compound represented by formula (II), In formula (II), R 1 is an aryl group or an alkyl group, R 2 is an alkyl group or an aryl group.

2. The compound according to claim 1, characterized in that The R 1 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 Methyl or 4-methylphenyl.

3. The compound according to claim 1 The substance is characterized in that Place The N-acylsulfonamide compound represented by formula (II) is one of the following:

4. A method for preparing the N-acylsulfonamide compound according to claim 1, characterized in that: The method comprises the following steps: The compound represented by formula (I) is used as a reaction raw material, IPrAuCl / AgNTf2 is used as a catalyst, and the reaction is carried out in water and dichloroethane at 30 to 50° C. After the reaction is completed, the obtained reaction solution is post-treated to obtain an N-acylsulfonamide compound represented by formula (II); In formula (I), R 1 is an aryl group or an alkyl group, R 2 is an alkyl or aryl group; in formula (II), R 1 , R 2 Same as R in formula (I) 1 , R 2 .

5. The method according to claim 4, characterized in that The molar ratio of the compound represented by formula (I) to water is 1:2-3; the molar ratio of the compound represented by formula (I) to the catalyst is 1:0.003-0.05, wherein the molar ratio of IPrAuCl to AgNTf2 is 1:1; the volumetric amount of dichloroethane is 5-15 mL / mmol based on the molar amount of the compound represented by formula (I).

6. The method according to claim 4, 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 the washing liquid are combined, and then washed with a saturated NaCl aqueous solution, and then the organic phase is dried with anhydrous sodium sulfate; the solvent is evaporated, and the residue is purified by a silica gel chromatography column, the eluent and the developing solvent are both petroleum ether: ethyl acetate in a volume ratio of 3:1, and the effluent with an Rf of 0.4-0.6 is collected, and the solvent is evaporated under reduced pressure to obtain the N-acylsulfonamide compound represented by formula (II).

7. Use of the N-acylsulfonamide compound according to claim 1 in the preparation of an antibacterial agent.

8. The use according to claim 7, characterized in that The antimicrobial agents include inhibitors of Staphylococcus aureus activity.

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