Method for synthesizing N-sulfonyl acetamidine compound by using calcium carbide and ammonium salt as acetylene and amine source and application of N-sulfonyl acetamidine compound

Abstract

The invention provides a method for synthesizing an N-sulfonyl acetamidine compound by taking calcium carbide and ammonium salt as acetylene and an amine source and application, and relates to the technical field of preparation of sulfonyl acetamidine, and the N-sulfonyl acetamidine compound is directly synthesized by taking the calcium carbide as a solid acetylene source, taking the ammonium salt as the amine source and carrying out multi-component one-pot room temperature reaction with a sulfonyl azide compound. The calcium carbide and the ammonium salt are cheap and easy to obtain, the preparation method is efficient and easy to operate, the substrate application range is wide, and the industrial application value is high.

Description

Technical Field

[0001] The invention relates to the technical field of preparation of sulfonylacetamidines, and in particular to a method and application of synthesizing N-sulfonylacetamidine compounds by using calcium carbide and ammonium salt as acetylene and amine sources. Background Art

[0002] N-sulfonylamidines are key components of a variety of natural and synthetic bioactive compounds and are widely used in organic synthesis, functional materials, and medicinal chemistry. The representative synthesis of N-sulfonylamidines is based on sulfonyl azide and terminal alkyne as starting reactants. (A) In 2008, Chang's group used copper salt to catalyze the three-component reaction of sulfonyl azide, ammonium chloride and terminal alkyne to synthesize N-sulfonylamidine, but unfortunately failed to synthesize N-sulfonylacetamidine; (B) In 2018, Bi's group reported the silver-catalyzed reaction of trimethylsilyl azide (TMSN3), terminal alkyne and sodium p-toluenesulfinate (TolSO2Na) to generate p-toluenesulfonyl enamine, which then reacted with sulfonyl azide to eliminate the equivalent by-product TolSO2CHN2 to obtain N-sulfonylamidine. Although the silver catalyst made the reaction activity and selectivity higher, the cost was also high; (C) In 2019, Yi's group reported the terminal alkyne-assisted copper-catalyzed reaction of sulfonyl azide, nitrile oxide generated in situ by hydroxyformyl chloride and water to synthesize N-sulfonylamidine. The preparation steps of hydroxyformyl chloride were cumbersome and time-consuming. The synthesis method of N-sulfonylamidine also includes the reaction of sulfonyl azide with thioamide (D) or enaminoketone (E), but the preparation process of the required starting reactants is cumbersome, and the formation of by-product diazoketone leads to low atom economy (the relevant equation is shown below). The reported synthesis methods of N-sulfonylamidine are of practical significance, but there are still some disadvantages, such as harsh reaction conditions, difficult to obtain starting materials, use of precious metal catalysts, generation of a large number of by-products, low industrial application value, etc., and only one literature reports the synthesis of N-sulfonylacetamidine. Therefore, it is crucial to develop a simpler method to directly synthesize N-sulfonylacetamidine compounds using cheap and readily available starting materials.

[0003] Summary of the invention

[0004] In view of this, the present invention provides a method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources.

[0005] It is also necessary to provide an application of the synthesized N-sulfonylacetamidine compounds.

[0006] The technical solution adopted by the present invention to solve its technical problem is:

[0007] S1: dissolving a sulfonyl azide compound 1, an ammonium salt, calcium carbide, an initiator, a copper salt catalyst, and a base in a solvent for a one-pot reaction to obtain a mixture containing an N-sulfonylacetamidine compound 2;

[0008] S2: Extract, wash, dry, concentrate and column chromatograph the mixture containing N-sulfonylacetamidine compound 2 to obtain pure N-sulfonylacetamidine compound 2. The synthetic route is as follows:

[0009]

[0010] Wherein: R is an aromatic group or a heterocyclic ring; X is an acid radical ion.

[0011] The N-sulfonylacetamidine compound synthesized by the above method is used to react with a halogenated hydrocarbon to obtain an N-alkyl-N'-sulfonylacetamidine compound.

[0012] Compared with the prior art, the present invention has the following beneficial effects:

[0013] The present invention uses calcium carbide as a solid acetylene source and ammonium salt as an amine source to directly synthesize N-sulfonylacetamidine compounds by a multi-component one-pot room temperature reaction with sulfonyl azide compounds; calcium carbide and ammonium salt are cheap and easy to obtain, the preparation method is efficient and easy to operate, the substrate has a wide range of adaptability, and the industrial application value is high. Figure 1 As shown, the present invention uses water as an initiator to partially hydrolyze calcium carbide into ethynyl calcium hydroxide A, and then I After coordination with sulfonyl azide 1 under catalysis, a triazole ring intermediate B is formed. Intermediate B is further hydrolyzed to open the ring and release nitrogen to obtain ketene imine intermediate C. Subsequently, intermediate C undergoes an addition reaction with ammonium salt to obtain the target product N-sulfonylacetamidine 2. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Schematic diagram for the synthesis of N-sulfonylacetamidine compounds using calcium carbide and ammonium salts as acetylene and amine sources.

[0015] Figure 2 This is the single crystal X-ray diffraction analysis diagram of the product obtained in Example 1 (CCDC: 2371279).

[0016] Figure 3 The product obtained in Example 1 1 H NMR spectrum.

[0017] Figure 4 The product obtained in Example 1 13 C NMR spectrum.

[0018] Figure 5 The product obtained in Example 10 1H NMR spectrum.

[0019] Figure 6 The product obtained in Example 10 13 C NMR spectrum.

[0020] Figure 7 The product obtained in Example 16 1 H NMR spectrum.

[0021] Figure 8 The product obtained in Example 16 13 C NMR spectrum.

[0022] Fig. 9 The product obtained in Example 22 1 H NMR spectrum.

[0023] Fig.10 The product obtained in Example 22 13 C NMR spectrum.

[0024] Fig.11 The product obtained in Example 25 1 H NMR spectrum.

[0025] Fig.12 The product obtained in Example 25 13 C NMR spectrum.

[0026] Fig.13 The product obtained in Example 33 1 H NMR spectrum.

[0027] Fig.14 The product obtained in Example 33 13 C NMR spectrum.

[0028] Fig.15 The product obtained in Example 46 1 H NMR spectrum.

[0029] Fig.16 The product obtained in Example 46 13 C NMR spectrum.

[0030] Fig.17 The product obtained in Example 48 1 H NMR spectrum.

[0031] Fig.18 The product obtained in Example 48 13 C NMR spectrum.

[0032] Fig.19The product obtained in Example 50 1 H NMR spectrum.

[0033] Fig. 20 The product obtained in Example 50 13 C NMR spectrum.

[0034] Fig.21 The product obtained in Example 53 1 H NMR spectrum.

[0035] Fig. 22 The product obtained in Example 53 13 C NMR spectrum. DETAILED DESCRIPTION

[0036] The technical solutions and technical effects of the embodiments of the present invention are further described in detail below in conjunction with the accompanying drawings of the present invention.

[0037] For ease of understanding, the present invention is further illustrated by the following examples:

[0038] Embodiment 1:

[0039] Materials: Calcium carbide was purchased from McLean Chemical Company (China, purity: 98%) and ground into powder (about 50-100 mesh) in a ceramic mortar before use. The reaction solvent was an ultra-dry solvent or distilled for more than one hour before use to remove moisture. All reagents required for the reaction were commercially available analytical grade reagents (purchased from Adamas, Aldrich and Energy Chemical) and were used without further purification unless otherwise specified. The reaction progress was monitored by thin layer chromatography (TLC) on silica gel GF-254 plates with a UV detector. Column chromatography was performed with silica gel (200-300 mesh) as the stationary phase and petroleum ether (60-90°C) and ethyl acetate as the eluent to purify the product.

[0040] Dissolve p-toluenesulfonyl azide 1a (1 mmol), ammonium salt (3 mmol), calcium carbide, copper salt catalyst, Et3N (1.5 mmol), KOH (1 mmol) and water in a solvent (3 mL) and stir at room temperature for 12 hours. Filter the resulting mixture to remove solids, extract the filtrate with dichloromethane (10 mL × 3), and wash the combined organic phases with saturated brine (10 mL × 3). The resulting organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is separated by column chromatography using petroleum ether and ethyl acetate (v / v = 3:1) as eluents to obtain N-sulfonylacetamidine 2a

[0041]

[0042] The above method was used to investigate the effects of copper salt catalyst, solvent, calcium carbide / water and ammonium salt on the synthesis yield. The experimental settings and results are shown in Table 1.

[0043] Table 1

[0044]

[0045]

[0046] As shown in Table 1, copper salt catalysts and their dosages were screened (experiments 1-17), and CuI (0.5mmol) was determined to be the best catalyst (experiment 3); the solvent also plays an important role in the reaction (experiments 3, 18-24), among which CH2Cl2 is the most effective solvent (experiment 3); further, the dosage of calcium carbide / water was screened (experiments 3, 25-28), and we found that calcium carbide / water had a higher yield when the dosage was 3mmol / 6mmol (experiment 3); finally, ammonium salts were screened, including NH4Cl, NH4Br, NH4I, NH3·H2O, NH4HCO3, (NH4)2SO4 (experiments 3, 29-33), and it was found that NH4HCO3 gave the highest yield of 88% (experiment 32). From the above experiments, it can be obtained that the reaction conditions shown in experiment 32 are the optimal conditions obtained by screening.

[0047] Embodiment 2 to Embodiment 49:

[0048] According to the synthesis method of Example 1 and the reaction conditions of Experiment 32 selected in Example 1, different sulfonyl azide compounds 1 were used to carry out the reaction.

[0049] The N-sulfonylacetamidine compounds 2 obtained in Example 1 to Example 49 and their yields are shown in Table 2.

[0050] Table 2

[0051]

[0052]

[0053]

[0054]

[0055]

[0056] pass 1 H NMR, 13 The products prepared in Examples 1 to 49 were characterized by C NMR, HRMS, single crystal X-ray diffraction analysis, etc., confirming that the product 2 shown in Table 2 was obtained. The characterization data are as follows (representative spectra are shown in Figure 2-Figure 18 shown).

[0057] Embodiment 1: 1 HNMR (500MHz, DMSO-d6) δ8.40(s,1H),7.98(s,1H),7.68(d,J=8.2Hz,2H),7.33(d,J=8.0Hz,2H),2.36(s,3H),2.03(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.5,141.8,140.4,129.2,125.9,21.5,20.9; HRMS(ESI)m / z:[M+H] + Calculate for C9H 13 N2O2S + 213.0692; found 213.0686.

[0058] Embodiment 2: 1 H NMR (500MHz, DMSO-d6) δ8.46(s,1H,),8.05(s,1H),7.81(d,J=7.9Hz,2H),7.58(t,J=7.3Hz,1H),7.53(t,J=7.3Hz,2H),2.06(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.8,143.2,131.7,128.8,125.9,21.5; HRMS(ESI)m / z:[M+H] + calculation for C8H 11 N2O2S + 199.0536; found 199.0535.

[0059] Embodiment three: 1 H NMR (500MHz, DMSO-d6) δ8.43(s,1H),8.02(s,1H),7.64-7.57(m,2H),7.45-7.35(m,2H),2.37(s,3H),2.06(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.6,143.1,138.4,132.3,128.6,126.2,123.1,21.5,20.8; HRMS(ESI)m / z:[M+H] + Calculate for C9H 13 N2O2S + 213.0692; found 213.0697.

[0060] Embodiment 4: 1 HNMR(500MHz,DMSO-d6)δ8.43(s,1H),8.01(s,1H),7.72(d,J=8.3Hz,2H),7.3 6(d,J=8.1Hz,2H),2.65(q,J=7.6Hz,2H),2.04(s,3H),1.18(t,J=7.6Hz,3H); 13 CNMR(126MHz,DMSO-d6)δ167.5,148.0,140.7,128.1,126.1,28.0,21.5,15.2; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 15 N2O2S + 227.0849; found 227.0843.

[0061] Embodiment five: 1 HNMR(500MHz,DMSO-d6)δ8.43(s,1H),8.01(s,1H),7.73(d,J=8.3Hz,2H),7 .39(d,J=8.3Hz,2H),3.05-3.00(m,1H),2.05(s,3H),1.20(d,J=7.0Hz,6H); 13 C NMR(126MHz,DMSO-d6)δ167.5,152.4,140.8,126.7,126.1,33.3,23.5,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 11 H 17 N2O2S + 241.1005; found 241.1000.

[0062] Embodiment six: 1 HNMR (500MHz, DMSO-d6) δ8.42(s,1H),8.00(s,1H),7.72(d,J=8.2Hz,2H),7.54(d,J=8.2Hz,2H),2.04(s,3H),1.29(s,9H); 13 C NMR(126MHz, DMSO-d6)δ167.5,154.6,140.4,125.8,125.6,34.7,30.8,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 12 H19 N2O2S + 255.1162; found 255.1158.

[0063] Embodiment seven: 1 HNMR(500MHz,DMSO-d6)δ8.26(s,1H),7.89(s,1H),6.95(s,2H),2.54(s,6H),2.23(s,3H),2.02(s,3H); 13 C NMR(126MHz, DMSO-d6)δ167.1,140.4,137.7,137.3,131.1,22.3,21.0,20.3; HRMS(ESI)m / z:[M+H] + calcdfor C 11 H 17 N2O2S + 241.1005; found 241.1002.

[0064] Embodiment eight: 1 H NMR (500MHz, DMSO-d6) δ8.24(s,1H),7.84(s,1H),7.19-7.11(m,2H),4.38-4.24(m,2H),2.97-2.91(m,1H),2.00(s,3H),1.17(d,J=8.2Hz,18H); 13 C NMR(126MHz, DMSO-d6)δ166.6,151.0,148.3,136.7,122.9,33.3,28.6,24.5,23.5,20.9; HRMS(ESI)m / z:[M+H] + Calculate for C 17 H 29 N2O2S + 325.1944; found 325.1939.

[0065] Embodiment nine: 1 HNMR(500MHz,DMSO-d6)δ8.41(s,1H),8.00(s,1H),7.71(d,J=8.1Hz,2H),7.37(d,J=8.1Hz,2H),2.61- 2.52(m,1H),2.04(s,3H),1.82-1.75(m,4H),1.73-1.67(m,1H),1.47-1.27(m,4H),1.28-1.17(m,1H); 13C NMR(126MHz, DMSO-d6)δ167.4,151.5,140.8,127.0,126.1,43.6,33.6,26.2,25.5,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 21 N2O2S + 281.1318; found 281.1312.

[0066] Embodiment ten: 1 H NMR(500MHz,DMSO-d6)δ8.39(s,1H),7.96(s,1H),7.64(s,1H),7.58(d,J=7.8Hz,1H ),7.34(d,J=7.9Hz,1H),2.89(q,J=7.0Hz,4H),2.04(s,3H),2.02(d,J=7.4Hz,2H); 13 C NMR(126MHz, DMSO-d6)δ167.3,148.1,144.5,141.2,124.3,124.2,121.8,32.2,32.1,25.0,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C 11 H 15 N2O2S + 239.0849; found 239.0842.

[0067] Embodiment eleven: 1 HNMR(500MHz,DMSO-d6)δ8.50(s,1H),8.10(s,1H),7.89(d,J=8.3Hz,2H),7.82(d,J=8.5 Hz,2H),7.71(d,J=7.5Hz,2H),7.50(t,J=7.5Hz,2H),7.42(t,J=7.2Hz,1H),2.09(s,3H); 13 CNMR(126MHz,DMSO-d6)δ167.8,143.4,142.0,138.8,129.1,128.3,127.1,127.0,126.6,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 15 N2O2S + 275.0849; found 275.0841.

[0068] Embodiment 12: 1 HNMR(500MHz,DMSO-d6)δ8.51(s,1H),8.48(s,1H),8.14-8.11(d,J=7.4Hz,2H),8.06(d,J =8.7Hz,1H),8.01(d,J=7.8Hz,1H),7.82(d,J=8.6Hz,1H),7.70-7.60(m,2H),2.09(s,3H); 13 C NMR(126MHz, DMSO-d6)δ167.9,140.2,133.9,131.7,129.1,128.9,128.3,127.7,127.3,126.1,122.5,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 12 H 13 N2O2S + 249.0692; found 249.0688.

[0069] Embodiment 13: 1 HNMR(500MHz,DMSO-d6)δ8.46(s,1H),8.41(d,J=8.5Hz,1H),8.36(d,J=8.7Hz,1H),8.19(d,J=7.2Hz,1H), 8.07(s,1H),7.60(t,J=7.9Hz,1H),7.55(t,J=8.1Hz,1H),7.20(d,J=7.5Hz,1H),2.80(s,6H),2.06(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.0,151.1,138.8,129.5,129.1,128.7,127.3,126.6,123.5,120.5,114.9,45.1,21.3; HRMS(ESI)m / z:[M+H] + Calculate for C 14 H 18 N3O2S + 292.1114; found 292.1110.

[0070] Embodiment 14: 1 H NMR (500MHz, DMSO-d6) δ8.39(s,1H),7.97(s,1H),7.73(d,J=8.8Hz,2H),7.04(d,J=8.8Hz,2H),3.81(s,3H),2.02(s,3H);13 C NMR(126MHz, DMSO-d6)δ167.3,161.7,135.2,128.0,113.9,55.6,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C9H 13 N2O3S + 229.0641; found 229.0638.

[0071] Embodiment 15: 1 H NMR (500MHz, DMSO-d6) δ8.40(s,1H),7.98(s,1H),7.39(d,J=8.4Hz,1H),7.28(s,1H),7.06(d,J=8.5Hz,1H),3.81(d,J=4.4Hz,6H),2.03(s,3H); 13 CNMR(126MHz,DMSO-d6)δ167.3,151.5,148.4,135.1,119.5,111.0,109.2,55.8,55.8,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 15 N2O4S + 259.0747; found 259.0741.

[0072] Embodiment 16: 1 H NMR (500MHz, DMSO-d6) δ8.29(s,1H),7.95(s,1H),7.68(d,J=8.7Hz,1H),6.66(s,1H),6.58(d,J=8.7Hz,1H),3.82(s,6H),2.03(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.3,163.5,158.1,129.7,123.5,104.3,99.3,56.0,55.7,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 15 N2O4S + 259.0747; found 259.0742.

[0073] Embodiment 17: 1H NMR(500MHz,DMSO-d6)δ8.35(s,1H),7.91(s,1H),7.65(s,1H),7.58(d,J=8.3Hz,1H ), 6.84 (d, J = 8.3Hz, 1H), 4.60 (t, J = 8.8Hz, 2H), 3.22 (t, J = 8.8Hz, 2H), 2.03 (s, 3H); 13 C NMR(126MHz, DMSO-d6)δ167.1,162.4,135.1,128.3,127.0,123.4,108.5,72.0,28.5,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 13 N2O3S + 241.0641; found 241.0636.

[0074] Embodiment 18: 1 H NMR (500MHz, DMSO-d6) δ8.40(s,1H),7.96(s,1H),7.27(d,J=10.2Hz,2H),6.97(d,J=8.2Hz,1H),4.29(q,J=5.2Hz,4H),2.03(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.4,146.3,143.0,135.9,119.4,117.2,115.1,64.3,64.1,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 13 N2O4S + 257.0591; found 257.0587.

[0075] Embodiment 19: 1 H NMR(500MHz,DMSO-d6)δ8.41(s,1H),7.98(s,1H),7.74(d,J=8.7Hz,2H),7.46(d,J=7.6Hz,2H) ,7.40(t,J=7.5Hz,2H),7.34(t,J=7.3Hz,1H),7.13(d,J=8.7Hz,2H),5.18(s,2H),2.03(s,3H); 13C NMR(126MHz, DMSO-d6)δ167.3,160.7,136.5,135.4,128.5,128.0,127.8,114.7,69.6,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 15 H 17 N2O3S + 305.0954; found 305.0954.

[0076] Embodiment 20: 1 HNMR (500MHz, DMSO-d6) δ8.50 (s, 1H), 8.08 (s, 1H), 7.86 (d, J = 8.8Hz, 2H), 7.51-7.19 (m, 3H), 2.06 (s, 3H); 13 C NMR (126MHz, DMSO-d6) δ167.9, 153.2 (t, J = 3.2Hz), 139.8, 128.3, 118.5, 116.1 (t, J = 258.9Hz), 21.5; HRMS (ESI) m / z: [M+H] + Calcd for C9H 11 F2N2O3S + 265.0453; found 265.0447.

[0077] Embodiment 21: 1 H NMR (500MHz, DMSO-d6) δ8.57(s,1H),8.15(s,1H),7.94(d,J=8.9Hz,2H),7.52(d,J=8.8Hz,2H),2.09(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.2,150.4(q,J=1.9Hz),142.3,128.5,121.2,120.4(q,J=258.2Hz),21.5; HRMS(ESI)m / z:[M+H] + Calculate for C9H 10 F3N2O3S + 283.0359; found 283.0354.

[0078] Embodiment 22: 1H NMR (500MHz, DMSO-d6) δ8.50(s,1H),8.07(s,1H),7.93(s,1H),7.79(d,J=8.6Hz,1H),7.23(d,J=8.7Hz,1H),3.92(s,3H),2.05(s,3H); 13 C NMR(126MHz,DMSO-d6)δ167.7,157.9,136.3,130.5,127.4,112.5,110.4,56.8,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C9H 12 BrN2O3S + 306.9747; found 306.9740.

[0079] Embodiment 23: 1 H NMR (500MHz, DMSO-d6) δ8.64(s,1H),8.20(s,1H),7.92(d,J=8.4Hz,1H),7.77(d,J=10.2Hz,1H),7.72(s,1H),2.09(s,3H); 13 C NMR (126MHz, DMSO-d6) δ168.5, 145.4, 134.8, 130.6, 130.5, 126.0, 123.8, 120.3 (q, J = 260.2Hz), 21.3; HRMS (ESI) m / z: [M+H] + Calcd for C9H9BrF3N2O3S + 360.9464; found 360.9457.

[0080] Embodiment 24: 1 H NMR (500MHz, DMSO-d6) δ8.50(s,1H),8.02(s,1H),7.94-7.88(m,1H),7.68-7.61(m,2H),7.57-7.50(m,1H),3.80(s,3H),2.06(s,3H); 13 C NMR(126MHz, DMSO-d6)δ167.9,167.7,140.5,131.8,131.5,130.5,128.1,127.6,52.7,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 12 N2O4S +256.0518; found 256.0583.

[0081] Embodiment 25: 1 H NMR (500MHz, DMSO-d6) δ8.57(s,1H),8.17(s,1H),8.08(d,J=8.2Hz,2H),7.93(d,J=8.2Hz,2H),2.62(s,3H),2.09(s,3H); 13 C NMR(126MHz, DMSO-d6)δ197.4,168.3,146.9,139.0,128.7,126.3,27.0,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H 13 N2O3S + 241.0641; found 241.0635.

[0082] Embodiment 26: 1 H NMR (500MHz, DMSO-d6) δ8.64(s,1H),8.24(s,1H),8.19(s,1H),8.11(d,J=7.9Hz,1H),8.06(d,J=7.8Hz,1H),7.76(t,J=7.9Hz,1H),2.10(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.4,144.4,135.4,130.5,130.4,129.5,117.7,112.1,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C9H 10 N3O2S + 224.0488; found 224.0482.

[0083] Embodiment 27: 1 H NMR (500MHz, DMSO-d6) δ8.64(s,1H),8.24(s,1H),8.01(d,J=8.3Hz,2H),7.97(d,J=8.2Hz,2H),2.10(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.6,147.2,133.1,126.8,117.9,114.3,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C9H 10 N3O2S+ 224.0488; found 224.0484.

[0084] Embodiment 28: 1 H NMR (500MHz, DMSO-d6) δ8.55(s,1H),8.18(s,1H),7.84(t,J=6.7Hz,1H),7.67-7.60(m,1H),7.40-7.30(m,2H),2.11(s,3H); 13 C NMR (126MHz, DMSO-d6) δ168.4, 158.4 (d, J = 253.4Hz), 134.4 (d, J = 8.3Hz), 130.8 (d, J = 14.7Hz), 128.6, 124.4 (d, J = 3.6Hz), 117.1 (d, J = 21.4Hz), 21.3; HRMS (ESI) m / z: [M+H] + Calculation for C8H 10 FN2O2S + 217.0442; found 217.0440.

[0085] Embodiment 29: 1 H NMR (500MHz, DMSO-d6) δ8.49 (s, 1H), 8.08 (s, 1H), 7.90-7.83 (m, 2H), 7.36 (t, J = 8.8Hz, 2H), 2.07 (s, 3H); 13 C NMR (126MHz, DMSO-d6) δ167.8, 163.7 (d, J = 250.2Hz), 139.6 (d, J = 3.2Hz), 128.8 (d, J = 9.3Hz), 115.8 (d, J = 22.5Hz), 21.5; HRMS (ESI) m / z: [M+H] + Calculation for C8H 10 FN2O2S + 217.0442; found 217.0439.

[0086] Embodiment 30: 1 H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.22(s,1H),7.54(d,J=9.0Hz,1H),7.49(d,J=5.0Hz,2H),2.10(s,3H); 13C NMR (126MHz, DMSO-d6) δ168.6, 163.0 (d, J = 12.3Hz), 161.0 (d, J = 12.4Hz), 146.7 (t, J = 8.2Hz ),109.8(d,J=7.1Hz),109.6(d,J=7.2Hz),107.5(t,J=25.8Hz),21.6; HRMS(ESI)m / z:[M+H] + Calcd for C8H9F2N2O2S + 235.0347; found 235.0346.

[0087] Embodiment 31: 1 H NMR (500MHz, DMSO-d6) δ8.60(s,1H),8.17(s,1H),7.97(d,J=7.0Hz,1H),7.82(s,1H),7.58(t,J=8.9Hz,1H),2.09(s,3H); 13 C NMR (126MHz, DMSO-d6) δ168.2, 158.9 (d, J = 252.6Hz), 140.7 (d, J = 3.9Hz), 128.4, 127. 2(d,J=8.7Hz),120.1(d,J=18.6Hz),117.6(d,J=22.3Hz),21.5; HRMS(ESI)m / z:[M+H] + Calcd for C8H9ClFN2O2S + 251.0052; found 251.0048.

[0088] Embodiment 32: 1 H NMR (500MHz, DMSO-d6) δ8.55(s,1H),8.16(s,1H),8.03(d,J=7.9Hz,1H),7.63-7.54(m,2H),7.49(t,J=6.7Hz,1H),2.11(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.3,140.3,133.2,131.5,131.1,129.0,127.3,21.6; HRMS(ESI)m / z:[M+H] + Calculate for C8H 10 ClN2O2S + 233.0146; found 233.0143.

[0089] Embodiment 33: 1H NMR (500MHz, DMSO-d6) δ8.53(s,1H),8.11(s,1H),7.81(d,J=8.6Hz,2H),7.60(d,J=8.6Hz,2H),2.07(s,3H); 13 C NMR(126MHz,DMSO-d6)δ168.1,142.1,136.6,128.9,127.9,21.5; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 ClN2O2S + 233.0146; found 233.0140.

[0090] Embodiment 34: 1 H NMR (500MHz, DMSO-d6) δ8.69(s,1H,),8.25(s,1H),7.84(s,1H),7.78(s,2H),2.11(s,3H); 13 C NMR(126MHz,DMSO-d6)δ168.6,146.3,134.7,131.4,124.6,21.6; HRMS(ESI)m / z:[M+H] + Calcd for C8H9Cl2N2O2S + 266.9756; found 266.9755.

[0091] Embodiment 35: 1 H NMR(500MHz,DMSO-d6)δ8.53(s,1H),8.12(s,1H),8.05(d,J=6.0Hz,1H),7.7 9(d,J=6.5Hz,1H),7.54(t,J=7.6Hz,1H),7.47(t,J=7.6Hz,1H),2.11(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.3,142.0,135.0,133.2,129.1,127.8,119.8,21.7; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 BrN2O2S + 276.9641; found 276.9639.

[0092] Embodiment 36: 1H NMR (500MHz, DMSO-d6) δ8.58(s,1H),8.17(s,1H),7.93(s,1H),7.83-7.76(2H,m),7.50(t,J=7.9Hz,1H),2.09(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.2,145.2,134.6,131.2,128.4,125.0,121.7,21.5; HRMS(ESI)m / z:[M+H] + calculation for C8H 10 BrN2O2S + 276.9641; found 276.9640.

[0093] Embodiment 37: 1 H NMR (500MHz, DMSO-d6) δ8.54(s,1H),8.11(s,1H),7.74(s,4H),2.07(s,3H); 13 CNMR(126MHz,DMSO-d6)δ168.1,142.5,131.9,128.0,125.4,21.5; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 BrN2O2S + 276.9641; found 276.9641.

[0094] Embodiment 38: 1 H NMR (500MHz, DMSO-d6) δ8.51(s,1H),8.07(s,1H),7.78(s,1H),7.73(d,J=8.3Hz,1H),7.54(d,J=8.3Hz,1H),2.40(s,3H),2.07(s,3H); 13 C NMR(126MHz, DMSO-d6)δ167.9,142.6,138.3,132.6,128.2,127.9,125.3,22.4,21.5; HRMS(ESI)m / z:[M+H] + Calculate for C9H 12 BrN2O2S + 290.9797; found 290.9793.

[0095] Embodiment 39: 1H NMR (500MHz, DMSO-d6) δ8.52(s,1H),8.09(s,1H),7.92(d,J=8.4Hz,2H),7.57(d,J=8.5Hz,2H),2.06(s,3H); 13 C NMR(126MHz,DMSO-d6)δ168.0,142.9,137.7,127.8,99.4,21.5; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 IN2O2S + 324.9502; found 324.9495.

[0096] Embodiment 40: 1 H NMR(500MHz,DMSO-d6)δ8.55(s,1H),8.21(d,J=7.9Hz,1H),8.13(s,1H),7.9 1(d,J=7.7Hz,1H),7.84(t,J=7.6Hz,1H),7.78(t,J=7.6Hz,1H),2.10(s,3H); 13 C NMR (126MHz, DMSO-d6) δ167.9,141.7,132.9,132.4,129.8,128.1(q,J=6.3Hz),125.9(q,J=32.6Hz),123.1(q,J=274.8Hz),21.4; HRMS(ESI)m / z:[M+H] + calculation for C9H 10 F3N2O2S + 267.0410; found 267.0405.

[0097] Embodiment 41: 1 H NMR (500MHz, DMSO-d6) δ8.62(s,1H),8.21(s,1H),8.02(d,J=8.1Hz,2H),7.91(d,J=8.2Hz,2H),2.10(s,3H); 13 C NMR (126MHz, DMSO-d6) δ168.5, 147.1, 131.7 (q, J = 32.2Hz), 127.0, 126.1 (q, J = 3.8Hz), 123.7 (q, J = 273.2Hz), 21.5; HRMS (ESI) m / z: [M+H] + Calculate for C9H 10 F3N2O2S +267.0410; found 267.0403.

[0098] Embodiment 42: 1 H NMR(500MHz,DMSO-d6)δ8.77(s,1H),8.38-8.36(m,4H),2.14(s,3H); 13 CNMR(126MHz,DMSO-d6)δ168.9,146.0,131.2(q,J=33.7Hz),126.6(q,J=4.0Hz),125.7,122.7(q,J=273.7Hz),21.7; HRMS(ESI)m / z:[M+H] + Calculate for C 10 H9F6N2O2S + 335.0283; found 335.0279.

[0099] Embodiment 43: 1 H NMR (500MHz, DMSO-d6) δ8.66 (s, 1H), 8.26 (s, 1H), 8.11-8.05 (m, 2H), 7.99 (d, J = 8.4Hz, 1H), 2.11 (s, 3H); 13 C NMR (126MHz, DMSO-d6) δ168.6, 143.3, 136.1, 131.4, 128.9 (q, J=31.4Hz), 125.1 (q, J=5.5Hz), 122.9, 122.3 (q, J=274.3Hz), 21.5; HRMS (ESI) m / z: [M+H] + Calcd for C9H9BrF3N2O2S + 344.9515; found 344.9507.

[0100] Embodiment 44: 1 H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.23(s,1H),8.06-8.04(m,1H),7.89-7.88(m,1H),7.87-7.79(m,2H),2.11(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.4,147.3,135.1,133.4,132.1,128.9,123.9,21.4; HRMS(ESI)m / z:[M+H] + calculation for C8H 10 N3O4S +244.0387; found 244.0385.

[0101] Embodiment 45: 1 H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.49(s,1H),8.42(d,J=7.3Hz,1H),8.30(s,1H),8.23(d,J=7.8Hz,1H),7.85(t,J=8.0Hz,1H),2.12(s,3H); 13 CNMR(126MHz,DMSO-d6)δ168.7,147.7,144.9,132.1,131.1,126.5,120.6,21.5; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 N3O4S + 244.0387; found 244.0384.

[0102] Embodiment 46: 1 H NMR (500MHz, DMSO-d6) δ8.67(s,1H),8.36(d,J=8.9Hz,2H),8.29(s,1H),8.05(d,J=8.8Hz,2H),2.12(s,3H); 13 C NMR(126MHz, DMSO-d6)δ168.7,149.2,148.7,127.5,124.3,21.4; HRMS(ESI)m / z:[M+H] + Calculation for C8H 10 N3O4S + 244.0387; found 244.0383.

[0103] Embodiment 47: 1 H NMR (500MHz, DMSO-d6) δ8.61(s,1H),8.14(s,1H),7.83(d,J=3.6Hz,1H),7.58(d,J=2.3Hz,1H),7.10(t,J=3.5Hz,1H),2.08(s,3H); 13 C NMR(126MHz,DMSO-d6)δ168.2,144.6,131.5,130.2,127.1,21.3; HRMS(ESI)m / z:[M+H] + Calcd for C6H9N2O2S2 + 205.0100; found 205.0096.

[0104] Embodiment 48: 1 H NMR (500MHz, DMSO-d6) δ8.72(s,1H),8.23(s,1H),7.42(d,J=2.9Hz,1H),7.26(d,J=4.8Hz,1H),2.10(s,3H); 13 C NMR(126MHz,DMSO-d6)δ168.6,145.7,130.7,117.1,21.3; HRMS(ESI)m / z:[M+H] + Calcd for C6H8BrN2O2S2 + 282.9205; found 282.9201.

[0105] Embodiment 49: 1 H NMR (500MHz, DMSO-d6) δ12.11(s,1H),8.44(s,1H),8.03(s,1H),7.98(s,1H),7.91(d,J=8.8Hz,1H),7.27(d,J=8.8Hz,1H),4.19( t,J=6.9Hz,2H),4.16(s,3H),2.78(t,J=7.5Hz,2H),2.08(s,3H),1.76-1.70(m,2H),1.34(t,J=6.9Hz,3H),0.94(t,J=7.4Hz,3H); 13 C NMR (126MHz, DMSO-d6) δ167.4,158.8,153.6,148.5,144.9,137.8,135.1,129.7,128. 4,124.3,122.9,112.7,64.7,37.8,27.1,21.7,21.5,14.2,13.7; HRMS(ESI)m / z:[M+H] + Calculate for C 19 H 25 N6O4S + 433.1653; found 433.1653.

[0106] It can be seen from Table 2 that aryl sulfonyl azide as a reactant, with an electron-donating group (alkyl, phenyl, alkoxy; Example 1-Example 23) or an electron-withdrawing group (ester, acyl, cyano, halogen, trifluoromethyl, nitro; Example 24-Example 46) attached to the aromatic ring, all give the corresponding products in good yields. Heteroaryl sulfonyl azide and complex aryl sulfonyl azide containing a pyrazolopyrimidinone structure (sildenafil sulfonyl azide) are used as reactants to obtain the corresponding products in moderate yields (Example 47-Example 49). Some aryl sulfonyl azides with large ortho-hindered substitutions or para-nitro substitutions give the corresponding products in lower yields (Example 8, Example 16, Example 24, Example 46). Unfortunately, when alkyl sulfonyl azide is used as a reactant, only trace amounts of products are generated. The exact structure of the product of Example 1 was confirmed by single crystal X-ray diffraction analysis (such as Figure 2 shown).

[0107] Embodiment 50 to 52:

[0108] Under argon atmosphere, the product 2 (1 mmol, 1 equiv) synthesized in Example 28 or Example 32 or Example 35, potassium carbonate (2 mmol, 2 equiv), cuprous iodide (0.05 mmol, 5 mol%), and N,N'-dimethylethylenediamine (0.1 mmol, 10 mol%) were dissolved in N,N-dimethylformamide (3 mL), stirred at 80°C for 8 hours, the solvent was removed under reduced pressure, the residue was dissolved in water, and acidified with hydrochloric acid to pH ≈ 1. The solid precipitate was filtered and dried to obtain 1,2,4-benzothiadiazine-1,1-dioxide 3; the synthetic route is as follows:

[0109]

[0110] pass 1 HNMR, 13 The products synthesized in Examples 50 to 52 were characterized by C NMR, confirming that product 3 was obtained. The characterization data are as follows (representative spectra are shown in Figure 19-20 shown):

[0111] Embodiment 50 (3): 1 H NMR (500MHz, DMSO-d6) δ11.99(s,1H),7.78(d,J=8.0Hz,1H),7.65(t,J=7.8Hz,1H),7.42(d,J=7.0Hz,1H),7.29(d,J=7.5Hz,1H),2.30(s,3H); 13 C NMR (126MHz, DMSO-d6) δ157.2,135.1,132.9,126.1,123.4,121.0,117.2,22.5.

[0112] Therefore, the synthesized N-sulfonylacetamidine compound 2 can be easily converted into 1,2,4-benzothiadiazine-1,1-dioxide 3 through intramolecular condensation cyclization of halogen and amino groups.

[0113] Furthermore, the synthesized N-sulfonylacetamidine compound 2 is used to react with a halogenated hydrocarbon to obtain an N-alkyl-N'-sulfonylacetamidine compound 4.

[0114]

[0115] Wherein: R is an aryl group or a heterocycle; R' is an alkyl group; X' is Br or I.

[0116] Embodiment 53:

[0117] The product 2a (1 mmol, 1 equiv) of Example 1, iodomethane (2 mmol, 2 equiv), and potassium carbonate (2 mmol, 2 equiv) were dissolved in acetone (3 mL) and stirred at 30° C. for 12 hours. The reaction mixture was extracted with dichloromethane (10 mL×3), and the combined organic phases were washed with saturated brine (10 mL×3). The organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by column chromatography using petroleum ether and ethyl acetate (v / v=3:1) as eluents to obtain N-alkyl-N'-sulfonylacetamidine compound 4a. The synthetic route is as follows:

[0118]

[0119] pass 1 H NMR, 13 The product synthesized in Example 53 was characterized by C NMR, confirming that product 4a was obtained. The characterization data are as follows (representative spectrum is shown in Figure 21-22 shown):

[0120] Embodiment 53 (4a): 1 HNMR (500MHz, CDCl3) δ7.74(d,J=7.9Hz,2H),7.24(d,J=7.8Hz,2H),7.01(s,1H),2.77(d,J=4.8Hz,3H),2.36(s,3H),2.24(s,3H); 13 C NMR (126MHz, CDCl3) δ167.0,142.3,140.5,129.3,126.2,28.7,21.4,20.4.

[0121] Therefore, the synthesized N-sulfonylacetamidine compound 2 can be converted into N-alkyl-N′-sulfonylacetamidine compound 4.

[0122] What is disclosed above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. A person skilled in the art can understand that all or part of the processes of the above embodiments and equivalent changes made according to the claims of the present invention still fall within the scope of the present invention.

Claims

1. A method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources, characterized in that: The following steps are involved: S1: dissolving a sulfonyl azide compound 1, an ammonium salt, calcium carbide, an initiator, a copper salt catalyst, and a base in a solvent for a one-pot reaction to obtain a mixture containing an N-sulfonylacetamidine compound 2; S2: Extract, wash, dry, concentrate and column chromatograph the mixture containing N-sulfonylacetamidine compound 2 to obtain pure N-sulfonylacetamidine compound 2. The synthetic route is as follows: Wherein: R is an aromatic group or a heterocyclic ring; X is an acid ion.

2. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: Said X is halogen or bicarbonate or carbonate or bisulfate or sulfate or bisulfite or sulfite.

3. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: In the step S1, the initiator is water, and the base is Et3N or KOH.

4. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: In the step S1, the copper salt catalyst is one of CuI, CuBr, CuCl, CuCN, Cu(OAc)2, Cu(OTf)2, Cu(acac)2, CuSCN, CuSO4, CuTc, Cu(MeCN)4BF4, Cu(MeCN)4PF6, and Cu(ClO4)2·6H2O.

5. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 4, characterized in that: The copper salt catalyst is CuI.

6. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: In the step S1, the solvent is CH2Cl2 or THF or MeCN or DMF or DMSO or C2H5OH or 1,4-Dioxane or CHCl3.

7. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 6, characterized in that: The solvent is CH2Cl2.

8. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: In the step S1, the reaction temperature is room temperature and the reaction time is 6 h-24 h.

9. The method for synthesizing N-sulfonylacetamidine compounds using calcium carbide and ammonium salt as acetylene and amine sources as claimed in claim 1, characterized in that: In the step S1, the volume of the solvent is 1-10 mL / mmol based on the amount of the sulfonyl azide compound, and the molar ratio of the sulfonyl azide compound to the initiator is 1:1-20; The molar ratio of the sulfonyl azide compound to the calcium carbide substance is 1:1-10, and the molar ratio of the sulfonyl azide compound to the ammonium salt substance is 1:1-12.

10. The use of the N-sulfonylacetamidine compound synthesized as claimed in claim 1, characterized in that: The N-sulfonylacetamidine compound reacts with a halogenated hydrocarbon to obtain an N-alkyl-N'-sulfonylacetamidine compound.

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