Internal sulfonamide compound and preparation method thereof

Abstract

The invention relates to an internal sulfonamide compound and a preparation method thereof. The invention relates to a preparation method of a sulfamide compound, which comprises the following steps: mixing an aminomalonic acid diethyl ester compound or an N-benzyl malonic acid monomethyl ester monoamide compound, a beta-aryl vinyl sulfonyl fluoride compound and MS, adding a solvent and a base catalyst, reacting at room temperature for 12-24 hours, separating and purifying to obtain the amide compound. The sulfamide compound and the preparation method thereof have the advantages of being simple in method, free of transition metal catalysis, wide in substrate range, mild in reaction condition, good in universality and the like.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology, specifically relating to a sulfonamide compound and its preparation method. Background Technology

[0002] In 1979, John A. Hyatt's research group (J. Org. Chem., 1979, 44(22): 3847-3858.) conducted a systematic study on vinyl sulfonyl fluoride (ESF). The study found that compared to sulfonyl chlorides, sulfonyl fluorides are more stable in certain situations and compatible with harsh reaction conditions, but exhibit excellent electrophilic reactivity to nucleophiles in specific environments. However, these studies did not attract widespread attention in the chemical community. It wasn't until 2014 that Professor K. Barry Sharpless, based on S... VI The unique stability of the -F bond has led to the development of a novel click reaction—the sulf(VI) fluoride exchange reaction (SuFEx) (Angew. Chem., Int. Ed. 2014, 53(36): 9430-9448.), which can be used to efficiently and reliably construct new compounds and has been widely applied in many fields in recent years (Chem. Soc. Rev., 2019, 48(17): 4731-4758., Chin. J. Org. Chem., 2025, 45, 1223-1238., Organic Chemistry, 2025, 45, 2245-2264.).

[0003] Sulfanamides are cyclic counterparts of sulfonamide compounds and have been extensively studied by scientists for decades due to their excellent applications in medicinal chemistry, synthetic organic chemistry and agricultural chemistry (Eur. J. Org. Chem. 2018, 2018(8), 933-956., Chem. Rev. 2011, 111(12), 7749-7773., Mini-Rev. Med. Chem. 2021, 20(20), 2193-2206.). In medicinal chemistry, they are the core heterocyclic scaffolds of many drugs and drug candidates, possessing activities such as antitumor (Mini-Rev. Med. Chem. 2013, 13(1), 70-86.), anti-HIV-1 (Bioorg. Med. Chem. Lett. 2006, 16(20), 5298-5302.), antiepileptic, antibacterial, and anti-inflammatory (Biochem. Pharmacol. 1965, 14(6), 961-970.). In organic synthetic chemistry, δ-lactamamides are important substrates for constructing new and efficient methodologies (J.Am.Chem.Soc.2013,135(3),971-974.,Org.Lett.2014,16(13),3468-3471.), preparing complex molecules (Org.Lett.2015,17(7),1688-1691.,Org.Lett.2016,18(5),1088-1091.), and for synthesis (ACSComb.Sci.2011,13(3),244-250.,ACS Comb.Sci.2012,14(4),268-272.). In agricultural chemistry, δ-lactamamides also exhibit strong herbicidal activity (Molecules 2016,21(7),861.). Therefore, these heterocyclic structures play a vital role in the fields of medicine, organic synthesis and agriculture, and have long attracted great attention from synthetic chemists (Org. Lett. 2024, 26(11), 2192-2196.).Therefore, various methods have been developed, especially using transition metals (such as Pd (Adv. Synth. Catal. 2016, 358(10), 1625-1638., Angew. Chem., Int. Ed. 2012, 51(26), 6471-6474., J. Org. Chem. 2013, 78(20), 10443-10451.), Rh (Angew. Chem ... 2016, 358(10), 1625-1638., Angew. Chem. 2016, Angew. Chem. 2016, Angew. Chem. 2016, Angew. Chem. 2016, Angew. Chem. 2016, Angew. Chem. 2016, Angew. Chem. 2016, m.,Int.Ed.2012,51(42),10610-10614.,Org.Chem.Front.2022,9(23),6592-6597.,Chem.Commun.2014,50(27),3616-3618.),Co(Org.Lett.2015,17(24),6118-6121.),Ag(Tetrahedron Lett.2012,53(48),6577-6583.),Au(Org.Lett.2021,23(20),7713-7717.),Ni(Org.Lett.2022,24(15),2915-2920.)) to obtain these sulfonamide skeletons. Furthermore, the sulfonamide skeleton can also be obtained through electrochemical methods (Tetrahedron Lett., 2024, 152, 155330., Org. Chem. Front., 2023, 10, 705-711.). Therefore, the synthetic methods of amide molecules are of great significance for drug discovery. However, current synthetic methods for amide compounds have drawbacks such as complex reactions, harsh conditions, the need for transition metal catalysis, and poor universality.

[0004] In view of this, the present invention proposes a new amide compound and its preparation method, which obtains the new amide compound through a simple intermolecular tandem Michael addition-intramolecular SuFEx reaction. Summary of the Invention

[0005] The purpose of this invention is to provide a method for preparing sulfonamide compounds. This method has the advantages of mild reaction conditions, good reaction selectivity, high yield, wide applicability and simple operation, and is expected to be used for large-scale preparation of various sulfonamide compounds.

[0006] To achieve the above objectives, the technical solution adopted is as follows:

[0007] A method for preparing a sulfonamide compound includes: reacting a diethyl aminomalonate compound or an N-benzylmalonate monomethyl ester monoamide compound, a β-arylethylenesulfonyl fluoride compound, etc. MS mixture was added, along with solvent and base catalyst, and reacted at room temperature for 12-24 hours. After separation and purification, the amide compound was obtained.

[0008] Furthermore, the molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound or the N-benzylmalonate monomethyl ester monoamide compound, and the base catalyst is 1:0.8-1.2;

[0009] The amount of the alkaline catalyst used is 10-20 mol% of the β-arylethylenesulfonyl fluoride compound.

[0010] Furthermore, the molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound or the N-benzylmalonate monomethyl ester monoamide compound, and the base catalyst is 1:1.

[0011] Furthermore, the structural formula of the β-arylethylenesulfonyl fluoride compound is as follows:

[0012] Among them, Ar 1 It is a phenyl, substituted phenyl, or aromatic heterocyclic compound.

[0013] Furthermore, the structural formula of the diethyl aminomalonic acid compound is as follows:

[0014] Among them, R 1 It can be phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl (Boc), or benzyloxycarbonyl (Cbz).

[0015] Furthermore, the N-benzylmalonic acid monomethyl ester monoamide compound has the following structural formula:

[0016] Among them, R 2 It is benzyl or substituted benzyl.

[0017] Furthermore, the alkaline catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), or potassium tert-butoxide (KO). t One of Bu, K2CO3, triethylamine, Na2CO3, and Cs2CO3.

[0018] Furthermore, the solvent is at least one selected from dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, toluene, and acetonitrile.

[0019] Another objective of this invention is to provide a sulfonamide compound prepared by the above-described method. This compound is a sulfonamide compound with diverse functional groups, and this series of compounds is characterized by functional group diversity and good tolerance.

[0020] To achieve the above objectives, the technical solution adopted is as follows:

[0021] A sulfonamide compound, wherein the amide compound is a γ-sulfonamide compound or a δ-sulfonamide compound;

[0022] The structural formula of the γ-lactamamide compound is as follows:

[0023] The structural formula of the δ-lactamamide compound is as follows:

[0024] Furthermore, in the aforementioned structural formula, Ar 1 It is a phenyl, a substituted phenyl, or an aromatic heterocyclic ring;

[0025] R 1 It is one of phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz);

[0026] R 2 It is benzyl or substituted benzyl.

[0027] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0028] Currently, there is no method for synthesizing sulfonamide compounds using diethyl aminomalonate or N-benzylmalonate monomethyl amide. Therefore, this invention innovatively constructs a method for synthesizing amide compounds and their synthesis under mild reaction conditions (no transition metal required, reaction can occur at room temperature), with a wide substrate applicability (tolerant to most functional groups), simple operation and good yield (all can obtain sulfonamides in excellent yield), simple and readily available starting materials (prepared according to (ACS Catal., 2016, 6, 6182-6190.; Org. Lett., 2018, 20, 4057-4061.)), and suitable for large-scale laboratory preparation.

[0029] The product obtained by the technical solution of this invention is a novel amide compound (γ-lactamamide and δ-lactamamide compound) obtained through a simple intermolecular tandem Michael addition-intramolecular SuFEx reaction. Studies have shown that compounds containing lactamamide structures exhibit a wide variety of biological activities, and this type of product is likely to possess certain biological activities and has potential pharmaceutical prospects. Attached Figure Description

[0030] Figure 1 Characterization of the single-crystal structure of product 3a;

[0031] Figure 2 The single-crystal structure of product 5a is characterized. Detailed Implementation

[0032] To further illustrate the sulfonamide compound and its preparation method according to the present invention, and to achieve the intended purpose of the invention, the following detailed description, in conjunction with preferred embodiments, details the specific implementation, structure, features, and effects of the sulfonamide compound and its preparation method according to the present invention. In the following description, different "an embodiment" or "an embodiment" do not necessarily refer to the same embodiment. Furthermore, specific features, structures, or characteristics in one or more embodiments can be combined in any suitable manner.

[0033] The following will provide a more detailed description of a sulfonamide compound and its preparation method according to the present invention, with reference to specific embodiments:

[0034] This invention provides a novel method for synthesizing γ-lactamamide and δ-lactamamide compounds, belonging to the field of organic synthesis technology. The preparation method of this compound includes the following steps: using β-arylethylenesulfonyl fluoride and monomethyl aminomalonic acid monoamide with different functional groups as raw materials, adding an alkaline catalyst... MS and solvent were mixed and reacted at room temperature for 12-24 h. The mixtures were then separated and purified to obtain γ-lactam and δ-lactam products. This method is simple, rapid, requires no transition metal catalysis, has a broad substrate range, mild reaction conditions, and good universality. Furthermore, it can obtain δ-lactam and γ-lactam compounds in excellent yields. Extensive literature review and research indicate that lactams are core heterocyclic scaffolds for many drugs and drug candidates, and are likely to possess certain biological activities and have potential pharmaceutical applications.

[0035] A method for preparing a sulfonamide compound includes: reacting a diethyl aminomalonate compound or an N-benzylmalonate monomethyl ester monoamide compound, a β-arylethylenesulfonyl fluoride compound, etc. MS mixture was added, along with solvent and base catalyst, and reacted at room temperature for 12-24 hours. After separation and purification, the amide compound was obtained.

[0036] Preferably, the molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound or the N-benzylmalonate monomethyl ester monoamide compound, and the base catalyst is 1:0.8-1.2;

[0037] The amount of the alkaline catalyst used is 10-20 mol% of the β-arylethylenesulfonyl fluoride compound.

[0038] More preferably, the molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound or the N-benzylmalonate monomethyl ester monoamide compound, and the base catalyst is 1:1.

[0039] Preferably, the structural formula of the β-arylethylenesulfonyl fluoride compound is:

[0040] Among them, Ar 1 It is a phenyl, substituted phenyl, or aromatic heterocyclic compound.

[0041] Preferably, the structural formula of the diethyl aminomalonic acid compound is:

[0042] Among them, R 1 It is one of phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0043] Preferably, the N-benzylmalonic acid monomethyl ester monoamide compound has the following structural formula:

[0044] Among them, R 2 It is benzyl or substituted benzyl.

[0045] Preferably, the alkaline catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), or potassium tert-butoxide (KO). t One of Bu, K2CO3, triethylamine Et3N, Na2CO3, and Cs2CO3.

[0046] Preferably, the solvent is at least one selected from dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, toluene, and acetonitrile.

[0047] A sulfonamide compound, wherein the amide compound is a γ-sulfonamide compound or a δ-sulfonamide compound;

[0048] The structural formula of the γ-lactamamide compound is as follows:

[0049] The structural formula of the δ-lactamamide compound is as follows:

[0050] Preferably, in the aforementioned structural formula, Ar 1 It is a phenyl, a substituted phenyl, or an aromatic heterocyclic ring;

[0051] R 1It is one of phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz);

[0052] R 2 It is benzyl or substituted benzyl.

[0053] In the embodiments, MS: Particle size is Molecular sieves.

[0054] I. Preparation method of γ-lactamamide:

[0055] Example 1.

[0056] The reaction formula is shown below:

[0057]

[0058] The reaction mechanism is as follows:

[0059]

[0060] The specific operating steps are as follows:

[0061] Add diethyl aminomalonate (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0062] Product: 1,1-dioxide of 2,4-diphenylisothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 81.7 mg, 98% yield. 1 H NMR(400MHz,Chloroform-d)δ7.43-7.36(m,2H),7.34-7.22(m,8H),4.94(dd,J=12.8,6.4Hz,1H),4.04-3.94(m,1H ),3.90-3.78(m,3H),3.57(dd,J=12.0,6.4Hz,1H),3.50-3.39(m,1H),0.80(t,J=7.2Hz,3H),0.71(t,J=6.8Hz,3H). 13 C NMR (100MHz, Chloroform-d)δ

[0063] 166.5,165.9,133.9,133.6,131.1,129.2,129.1,128.8,128.7,128.6,62.3,62.3,49.2,43.7,13.4,13.3.

[0064] Example 2.

[0065] The reaction formula is shown below:

[0066]

[0067] The specific steps are as follows:

[0068] Add diethyl 2-phenylaminomalonate (0.20 mmol, 1.0 equiv.) and β-arylethylenesulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0069] Product: 1,1-dioxide of 4-(4-fluorophenyl)-2-phenylisothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 85.3 mg, 98% yield. 1 H NMR(400MHz,Chloroform-d)δ7.61-7.54(m,2H),7.51-7.45(m,2H),7.44-7.34(m,5H),5.07(dd,J=12.8,6.8Hz,1H),4.15-4 .06(m,1H),4.01-3.88(m,3H),3.71(dd,J=12.4,6.8Hz,1H),3.61-3.51(m,1H),0.90(t,J=7.2Hz,3H),0.84(t,J=6.8Hz,3H). 13 CNMR(100MHz,Chloroform-d)δ166.4,165.9,150.1,135.2,133.4,131.3,131.1,129.5,129.3,121.4,62.7,62.6,49.2,43.2,13.4,13.4.

[0070] Example 3.

[0071] The reaction formula is shown below:

[0072]

[0073] The specific steps are as follows:

[0074] Add diethyl 2-phenylaminomalonate (0.20 mmol, 1.0 equiv.) and β-arylethylenesulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0075] Product: 1,1-dioxide of 2-phenyl-4-(p-tolyl)isothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 80.2 mg, 93% yield. 1 H NMR(400MHz,Chloroform-d)δδ

[0076] 7.53-7.44(m,2H),7.42-7.35(m,3H),7.31-7.27(m,2H),7.21-7.14(m,2H),4.99(dd,J=12.8,6.4Hz,1H),4.14 -4.05(m,1H),4.00-3.88(m,3H),3.68-3.56(m,2H),2.36(s,3H),0.90(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ166.6,166.0,138.8,133.7,131.1,130.8,129.4,129.2,129.2,128.6,62.4,62.3,49.4,43.5,21.2,13.4,13.4.

[0077] Example 4.

[0078] The reaction formula is shown below:

[0079]

[0080] The specific steps are as follows:

[0081] Add diethyl 2-phenylaminomalonate (0.20 mmol, 1.0 equiv.) and β-arylethylenesulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0082] Product: 1,1-dioxide of 2-phenyl-4-(thienyl)isothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 77.8 mg, 92% yield. 1 H NMR(400MHz,Chloroform-d)δ7.50-7.44(m,2H),7.40(q,J=3.8Hz,3H),7.36-7.29(m,2H),7.16-7.11(m,1H),5.06(d d,J=12.8,6.4Hz,1H),4.16-4.06(m,1H),4.02-3.86(m,3H),3.76-3.62(m,2H),0.96-0.93(m,3H),0.93-0.88(m,3H). 13 C NMR (100MHz, Chloroform-d) δ166.8,166.0,134.5,133.7,131.1,129.3,129.2,127.9,126.2,124.4,62.6,62.4,49.7,39.7,13.5,13.4.

[0083] Example 5.

[0084] The reaction formula is shown below:

[0085]

[0086] The specific steps are as follows:

[0087] Add diethyl aminomalonate (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0088] Product: 1,1-dioxide of 2-(4-chlorophenyl)-4-phenylisothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 89.3 mg, 99% yield. 1 H NMR(400MHz,Chloroform-d)δ7.48-7.43(m,2H),7.43-7.30(m,7H),4.99(dd,J=12.4,6.4Hz,1H),4.20-4.10(m,1H ),4.04-3.86(m,3H),3.69(dd,J=12.4,6.8Hz,1H),3.58-3.48(m,1H),0.99(t,J=7.2Hz,3H),0.80(t,J=7.2Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ166.4,165.9,135.4,134.0,132.7,132.2,129.4,129.0,128.8,128.7,62.6,62.4,49.4,43.8,13.6,13.4.

[0089] Example 6.

[0090] The reaction formula is shown below:

[0091]

[0092] The specific operating steps are as follows:

[0093] Add diethyl 2-alkylaminomalonate (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0094] Product: 1,1-dioxide of 2-butyl-4-phenylisothiazolidin-3,3-dicarboxylic acid diethyl ester. White solid, 51.6 mg, 65% yield. 1 H NMR(400MHz,Chloroform-d)δ7.44-7.39(m,2H),7.36-7.31(m,3H),4.67-4.58(m,1H),4.41-4.30(m,2H),3.96-3.85(m,1H),3.75-3 .56(m,3H),3.54-3.44(m,1H),3.26-3.15(m,1H),1.89-1.72(m,2H),1.42-1.32(m,5H),0.97(t,J=7.6Hz,3H),0.91(t,J=7.2Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ167.0,166.0,135.5,128.9,128.7,128.7,75.9,62.9,62.4,51.7,45.5,43.7,32.3,20.4,14.1,13.9,13.6.

[0095] Example 7.

[0096] The reaction formula is shown below:

[0097]

[0098] The specific operating steps are as follows:

[0099] Add diethyl 2-alkylaminomalonate (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (0.04 mmol, 20 mol%). The reaction mixture was stirred at room temperature for approximately 12 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure γ-lactamamide.

[0100] Product: 2-(tert-butyl)-3,3-diethyl-4-phenylisothiazolidin-2,3,3-tricarboxylic acid ester, 1,1-dioxide. White solid, 84.7 mg, 96% yield. 1H NMR(400MHz,Chloroform-d)δ7.31-7.24(m,3H),7.22-7.18(m,2H),4.32-4.20(m,2H),4.15(dd,J=12.8,6.4Hz, 1H),3.96-3.84(m,3H),3.47(dd,J=12.8,6.4Hz,1H),1.46(s,9H),1.24(t,J=7.2Hz,3H),0.95(t,J=7.2Hz,3H). 13 C NMR (100MHz, Chloroform-d) δ165.8,164.6,149.1,132.3,129.2,129.1,128.7,85.4,72.8,63.0,62.7,51.6,43.7,28.0,14.0,13.7.

[0101] Example 8.

[0102] The reaction formula is shown below:

[0103]

[0104] The specific operating steps are the same as in Example 1, the difference being that: in diethyl aminomalonate compounds and β-arylethylenesulfonyl fluoride compounds, Ar... 1 R 1 The selection of products is detailed in Table 1.

[0105] Table 1

[0106]

[0107]

[0108]

[0109]

[0110] II. Preparation method of δ-lactamamide:

[0111] Example 9.

[0112] The reaction formula is shown below:

[0113]

[0114] The reaction mechanism is as follows:

[0115]

[0116] The specific steps are as follows:

[0117] Add N-benzylmalonate monomethyl ester monoamide (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (6.9 mg, 0.04 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for approximately 24 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure δ-lactamamide with a diastereoselectivity greater than 20:1, predominantly trans-product.

[0118] Product: methyl 2-benzyl-3-oxo-5-phenyl-1,2-thiazinane-4-carboxylic acid ester, 1,1-dioxide. White solid, 73.9 mg, 99% yield. 1 H NMR(400MHz,Chloroform-d)δ7.55-7.41(m,2H),7.39-7.28(m,6H),7.27-7.24(m,2H), 4.95(dd,J=18.4,14.8Hz,2H),4.14-4.02(m,2H),3.81-3.72(m,1H),3.68-3.56(m,4H). 13 C NMR (100MHz, Chloroform-d) δ167.4,165.7,138.5,135.5,129.6,129.1,128.7,128.7,128.2,127.3,56.3,55.3,53.0,44.9,37.4.

[0119] Example 10.

[0120] The reaction formula is shown below:

[0121]

[0122] The specific steps are as follows:

[0123] Add N-benzylmalonate monomethyl ester monoamide (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (6.9 mg, 0.04 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for approximately 24 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure δ-lactamamide.

[0124] Product: Methyl 2-(4-bromophenyl)-3-oxo-5-phenyl-1,2-thiazinane-4-carboxylic acid ester, 1,1-dioxide. White solid, 80.3 mg, 89% yield. 1 H NMR (400MHz, Chloroform-d)δ

[0125] 7.48-7.43(m,2H),7.38-7.29(m,5H),7.27-7.23(m,2H),4.94-4.82(m,2H),4.11-4.02(m,2H),3.81-3.73(m,1H),3.67-3.56(m,4H). 13 C NMR (100MHz, Chloroform-d) δ167.3,165.6,138.3,134.5,131.9,131.0,129.6,128.8,127.2,122.4,56.3,55.3,53.0,44.2,37.4.

[0126] Example 11.

[0127] The reaction formula is shown below:

[0128]

[0129] The specific operating steps are as follows:

[0130] Add N-benzylmalonate monomethyl ester monoamide (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (6.9 mg, 0.04 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for approximately 24 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure δ-lactamamide.

[0131] Product: methyl 2-benzyl-3-oxo-5-(thienyl-2-yl)-1,2-thiazinane-4-carboxylic acid ester 1,1-dioxide. White solid, 64.4 mg, 85% yield. 1 H NMR (400MHz, Chloroform-d)δ

[0132] 7.47-7.40(m,2H),7.36-7.24(m,4H),6.98-6.90(m,2H),4.98-4.87(m,2H),4.49-4. 38(m,1H),4.05(d,J=11.2Hz,1H),3.81(dd,J=19.2,14.8Hz,1H),3.70-3.60(m,4H). 13 CNMR(100MHz,Chloroform-d)δ167.2,164.9,140.9,135.4,129.1,128.7,128.2,127.5,126.0,125.9,57.3,55.5,53.2,44.8,32.9.

[0133] Example 12.

[0134] The reaction formula is shown below:

[0135]

[0136] The specific operating steps are as follows:

[0137] Add N-benzylmalonate monomethyl ester monoamide (0.20 mmol, 1.0 equiv.) and β-arylvinyl sulfonyl fluoride (0.2 mmol, 1.0 equiv.) sequentially to a 25 mL Schlenk tube. MS and MeCN (2.0 mL) were added dropwise, followed by the addition of BTMG (6.9 mg, 0.04 mmol, 0.2 equiv.). The reaction mixture was stirred at room temperature for approximately 24 h. After the reaction was completed as monitored by TLC, the reaction mixture was diluted with dichloromethane and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (PE:EA = 5:1 (v:v)) to obtain pure δ-lactamamide.

[0138] Product: methyl 2-benzyl-3-oxo-5-(4-((fluorosulfonyl)oxy)phenyl)-1,2-thiazinane-4-carboxylic acid ester 1,1-dioxide. White solid, 88.5 mg, 94% yield. 1H NMR (400MHz, Chloroform-d) δ7.48-7.42(m,4H),7.38-7.31(m,5H),5.01-4.91(m,2H),4.19-4.10(m,2H),3.81-3.74(m,1H),3.67-3.57(m,4H). 13 C NMR (100MHz, Chloroform-d) δ167.2,165.3,149.8,139.9,135.4,129.7,129.1,128.8,128.4,122.2,55.8,55.2,53.2,45.4,36.5. 19 F NMR(376MHz,Chloroform-d)δ-63.9.

[0139] Example 13.

[0140] The reaction formula is shown below:

[0141]

[0142] The specific operating steps are the same as in Example 9, the difference being that: Ar in N-benzylmalonic acid monomethyl ester monoamide compounds and β-arylethylene sulfonyl fluoride compounds... 1 R 2 The selection of products is detailed in Table 2.

[0143] Table 2

[0144]

[0145]

[0146]

[0147] Note: For all products in the table above, the diastereoselectivity value dr > 20:1 indicates that the trans product is the major product.

[0148] Example 14.

[0149] Crystal structure analysis and single-crystal structure characterization were performed on products 3a and 5a. The results are as follows: Figure 1-2 As shown in Table 3-4.

[0150] Table 3 Crystal structure data

[0151]

[0152]

[0153] Table 4 Crystal structure data

[0154]

[0155]

[0156] As shown in Table 3-4, the crystal form of compound 3a is I, which is a triclinic crystal system with space group P-1 and cell parameters of [missing information]. α = 74.978(9)°, β=72.086(9)°, γ=73.527(9)°, The 5a compound has crystal form I, which is triclinic, space group P-1, and cell parameters of which are... α = 108.977(2)°, β=91.859(2)°, γ = 106.273(3)°,

[0157] Example 15.

[0158] The operation steps of Example 15 are the same as those of Example 1, except for the amount of alkaline catalyst used.

[0159] See Table 5 for details.

[0160] Table 5

[0161]

[0162] Example 16.

[0163] The operating steps of Example 16 are the same as those of Example 1, except for the ratio of β-arylethylenesulfonyl fluoride compounds and diethyl aminomalonic acid compounds. See Table 6 for details.

[0164] Table 6

[0165]

[0166] Example 17.

[0167] The operating steps of Example 17 are the same as those of Example 1, except for the selection of the alkaline catalyst. See Table 7 for details.

[0168] Table 7

[0169]

[0170] Example 18.

[0171] The operating steps of Example 18 are the same as those of Example 1, except for the choice of solvent. See Table 8 for details.

[0172] Table 8

[0173]

[0174] In summary, this invention is the first to propose the synthesis of γ- and δ-lactamamide compounds by reacting N-substituted diethyl aminomalonate or N-benzylmalonate monomethyl amide with alkenyl sulfonyl fluoride. The provided preparation method is simple, requires no transition metal catalyst, has a broad substrate range, good reaction selectivity, and high yield; it also boasts advantages such as simple process and mild reaction conditions. It holds promise for large-scale synthesis of lactamamides, research on their bioactivity, and applications in organic synthesis, medicinal chemistry, and other fields.

[0175] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Any simple modifications, equivalent changes, and alterations made to the above embodiments based on the technical essence of the present invention shall still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing a sulfonamide compound, characterized in that, The preparation method is as follows: diethyl aminomalonate or N-benzylmalonate monomethyl ester monoamide, β-arylethylenesulfonyl fluoride, ... MS mixture was added, along with solvent and base catalyst, and reacted at room temperature for 12-24 hours. After separation and purification, the amide compound was obtained.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound, or the N-benzylmalonate monomethyl ester monoamide compound to the base catalyst is 1:0.8-1.

2. The amount of the alkaline catalyst used is 10-20 mol% of the β-arylethylenesulfonyl fluoride compound.

3. The preparation method according to claim 2, characterized in that, The molar ratio of the β-arylethylenesulfonyl fluoride compound, the diethyl aminomalonate compound, or the N-benzylmalonate monomethyl ester monoamide compound to the base catalyst is 1:

1.

4. The preparation method according to claim 1, characterized in that, The structural formula of the β-arylethylenesulfonyl fluoride compound is: Among them, Ar 1 It is a phenyl, substituted phenyl, or aromatic heterocyclic compound.

5. The preparation method according to claim 1, characterized in that, The structural formula of the diethyl aminomalonic acid compound is: Among them, R 1 It is one of phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl, and benzyloxycarbonyl.

6. The preparation method according to claim 1, characterized in that, The N-benzylmalonic acid monomethyl ester monoamide compound has the following structural formula: Among them, R 2 It is benzyl or substituted benzyl.

7. The preparation method according to claim 1, characterized in that, The alkaline catalyst is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 2-tert-butyl-1,1,3,3-tetramethylguanidine (BTMG), or potassium tert-butoxide (KO). t One of Bu, K2CO3, triethylamine Et3N, Na2CO3, and Cs2CO3.

8. The preparation method according to claim 1, characterized in that, The solvent is at least one selected from dichloromethane, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane, toluene, and acetonitrile.

9. A sulfonamide compound, characterized in that, The amide compounds mentioned are γ-lactamamides and δ-lactamamides; The structural formula of the γ-lactamamide compound is as follows: The structural formula of the δ-lactamamide compound is as follows:

10. A sulfonamide compound according to claim 9, characterized in that, In the aforementioned structural formula, Ar 1 It is a phenyl, a substituted phenyl, or an aromatic heterocyclic ring; R 1 It is one of phenyl, substituted phenyl, alkyl, tert-butoxycarbonyl, and benzyloxycarbonyl; R 2 It is benzyl or substituted benzyl.

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