Synthesis method and application of beta-sulfamide

Abstract

The invention belongs to the field of organic synthesis, and relates to a method for synthesizing beta-sulfamide. According to the method, primary amine and alkenyl sulfonyl fluoride are used as raw materials, silica gel is used as a catalyst, and a reaction is carried out in a solvent to generate the beta-sulfamide compound. Compared with a traditional method for synthesizing beta-sulfamide through a multi-step reaction, the beta-sulfamide synthesis method is easy and convenient to operate, mild in condition, low in reagent cost, easy to obtain, high in reaction yield and wide in substrate application range. The invention also discloses an application of beta-sulfamide compounds synthesized from primary amine and alkenyl sulfonyl fluoride under a silica gel catalysis condition in drug modification.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and specifically relates to a chemical synthesis method of β-lactam sulfonamide and application of its product. Background Art

[0002] β-lactam is an analog of β-lactam antibiotics and a cyclic derivative of taurine, with a variety of physiological and pharmacological activities. For example, because its SN bond can be attacked by the nucleophilic serine active site of elastase, β-lactam can be used as an elastase inactivator, showing antibacterial and anti-inflammatory biological activities (Mini. Rev. Med. Chem. 2020, 20 (20), 2193-2206). In addition, the four-membered ring structure of β-lactam contains three different types of hetero single bonds: CN, CS and NS bonds, which are considered to be common synthetic elements and are important molecular building blocks for the synthesis of other heterocyclic compounds (Angew. Chem. Int. Ed. Engl. 2011, 50 (39), 9104-9107).

[0003] At present, the method for synthesizing β-internal sulfonamide mainly includes intramolecular cyclization synthesis using β-aminosulfonyl chloride. However, the β-aminosulfonyl chloride used in this method is highly toxic, difficult to synthesize, and difficult to store for a long time (Monatsh.Chem.2004,135(8),979-999). Another common method is to introduce a leaving group at the β-position of sulfonamide, then deprotonate the sulfonamide part and attack the β-position under strong alkaline conditions (such as NaH), and synthesize β-internal sulfonamide by the formation of CN bonds (Tetrahedron 2018,74(13),1355-1421). However, the precursor compounds required for these methods are usually not directly available, and often require complex chemical synthesis steps. In order to overcome the above-mentioned technical defects, the present invention provides a novel synthesis method of β-internal sulfonamide. This method uses easily available primary amines and alkenyl sulfonyl fluorides as raw materials, and can efficiently synthesize β-internal sulfonamide under mild reaction conditions catalyzed by silica gel. Summary of the invention

[0004] The purpose of the present invention is to provide a novel synthesis method of β-lactamide, so that primary amine can react with alkenyl sulfonyl fluoride under silica gel catalysis to efficiently synthesize β-lactamide. The raw materials used in the method are all commercial reagents, and a cumbersome multi-step precursor synthesis process is not required. In addition, the reaction has the advantages of simple operation, mild conditions, atom economy, and a wide range of substrate applications.

[0005] The technical solution of the present invention is as follows:

[0006] The present invention provides a chemical reaction method for synthesizing β-lactamide, which is characterized in that: the method uses primary amine (1) and alkenyl sulfonyl fluoride (2) as raw materials, adds silica gel as a catalyst, and generates β-lactamide compounds represented by formula (3) in an aprotic solvent:

[0007]

[0008] Where R 1 is one of alkyl, alkenyl, alkynyl and aralkyl; R 2 is one of hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, alkaryl, aryl, and heteroaryl; R 3 It is one of hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, alkaryl, aryl and heteroaryl.

[0009] The aprotic solvent is at least one of dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and diethyl ether.

[0010] Furthermore, R 1 represents one of a substituted or unsubstituted straight-chain or branched alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, or a substituted or unsubstituted aralkyl group, and R 2 , R 3 Can be the same or different.

[0011] Preferably, R 1 C4-C 20 A linear or branched substituted or unsubstituted alkyl group, a C3-C7 substituted or unsubstituted cycloalkyl group, a C5-C 10 A substituted or unsubstituted aralkyl group.

[0012] Preferably, R 2 is substituted or unsubstituted alkyl, hydrogen; more preferably, R 2 For hydrogen.

[0013] Preferably, R 3 is substituted or unsubstituted alkyl, hydrogen; more preferably, R 3 For hydrogen.

[0014] Furthermore, formula (1) is an amino compound with various functions; preferably, formula (1) is amlodipine, dehydroabietinamine, tryptamine, dopamine, C4-C 20 Straight-chain or branched substituted or unsubstituted alkylamine, C3-C7 substituted or unsubstituted cycloalkylamine, C5-C 10 A substituted or unsubstituted arylalkylamine.

[0015] The present invention provides a method for synthesizing β-sulfonamide using silica gel catalysis, which is characterized in that: a primary amine (1) shown in formula II and an olefin sulfonyl fluoride (2) are subjected to an addition reaction to obtain a β-aminoethanesulfonyl fluoride compound, and then a silica gel catalyzed intramolecular SuFEx reaction is performed to obtain a β-sulfonamide compound.

[0016]

[0017] Furthermore, the primary amine (1) and the alkenylsulfonyl fluoride (2) are added in a functional group molar ratio of 1:0.9-2.5.

[0018] Furthermore, silica gel is used as a catalyst, and the amount of silica gel used per millimole of the primary amine substrate is 5-300 mg.

[0019] Furthermore, the reaction of the primary amine (1) and the alkenyl sulfonyl fluoride (2) is carried out in an aprotic solvent, and the aprotic solvent is at least one of dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and diethyl ether; preferably, the aprotic solvent is dichloromethane.

[0020] Furthermore, the aprotic solvent is used to provide a reaction environment for the reaction of the primary amine (1) and the alkenylsulfonyl fluoride (2), and the amount of the aprotic solvent can be selected according to actual conditions.

[0021] Furthermore, the reaction temperature is 0-100° C. Preferably, the primary amine (1) and the alkenyl sulfonyl fluoride (2) can be mixed in a solvent at room temperature. After the primary amine (1) and the alkenyl sulfonyl fluoride (2) have reacted completely, the reaction can be stopped.

[0022] Furthermore, after the reaction is completed, the process further comprises the step of post-treating the reaction solution to obtain the β-internal sulfonamide shown in the general formula (3). The post-treatment of the reaction comprises the step of removing the solvent, the catalyst and other impurities, and purifying the product by column chromatography. The main component of the impurities is the unreacted raw material. The catalyst can be removed by filtering, the solvent can be removed by rotary evaporation, and then the impurities can be removed by column chromatography to obtain the β-internal sulfonamide shown in the general formula (3).

[0023] On the other hand, the present invention provides a method for synthesizing a class of β-lactam sulfonamide compounds and its application in drug modification.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The method of the present invention overcomes many defects in the prior art of synthesizing β-lactamide compounds, and provides a method for synthesizing β-lactamide compounds, using cheap silica gel as a catalyst to realize the reaction of converting commercial primary amines and alkenyl sulfonyl fluorides into β-lactamides. Compared with the prior art, the present invention has the following advantages: (1) No excess base is required in the intramolecular SuFEx reaction process, the conditions are milder, and the cost is saved; (2) The silica gel catalyst can be removed by simple filtration, and the operation is simple; (3) The raw materials are easily available; (4) The synthesis efficiency is high, the application range is wide, and it can be suitable for a variety of substrates. (5) The synthesis steps are simple, the side reactions are few, the target product yield is high, and it has a high promotion value. (6) The synthesized β-lactamide compounds have a wide range of application value in the field of drug modification. In summary, the synthesis method of β-lactamide based on silica gel catalysis proposed by the present invention is simple to operate, low cost, mild reaction conditions, and is a new technology with a wide range of applications. DETAILED DESCRIPTION

[0026] The technical solution of the present invention is described clearly and completely below in conjunction with specific embodiments, but it is obvious that the present invention is not limited to the described embodiments.

[0027] Several preferred embodiments of the present invention are listed below to further illustrate the advantages of the present invention. However, the following description is only used to explain the present invention and does not limit its content.

[0028] Example 1

[0029]

[0030] Add 14.6 mg (0.200 mmol) of n-butylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 78%). 1 H NMR (500MHz, CDCl3) δ4.05(t,J=6.6Hz,2H),3.16(t,J=6.6Hz,2H),3.02(t,J=7.3Hz,2H),1.60-1.52(m,2H),1.43-1.35(m,2H),0.92(t,J=7.4Hz,3H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ57.3,46.8,35.9,29.7,20.4,13.8.

[0031] Example 2

[0032]

[0033] Add 25.9 mg (0.200 mmol) of n-octylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 hours. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 96%). 1 H NMR (500MHz, CDCl3) δ4.05(t,J=6.6Hz,2H),3.15(t,J=6.6Hz,2H),3.00(t,J=7.3Hz, 2H),1.61-1.52(m,2H),1.39-1.31(m,2H),1.31-1.19(m,8H),0.86(t,J=6.9Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ57.3,47.1,35.8,31.9,29.2,29.2,27.7,27.1,22.7,14.2.HRMS(ESI)m / z:calculated for C 10 H 21 NO2S+Na + :242.1191[M+Na] + ; found:242.1195.

[0034] Example 3

[0035]

[0036] Add 37.1 mg (0.200 mmol) of dodecylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 85%). 1 H NMR (500MHz, CDCl3) δ4.04(t,J=6.7Hz,2H),3.16(t,J=6.7Hz,2H),3.00(t,J=7.4Hz, 2H),1.59-1.53(m,2H),1.38-1.31(m,2H),1.31-1.19(m,16H),0.86(t,J=6.9Hz,3H). 13 C{ 1H}NMR(126MHz, CDCl3)δ57.3,47.1,35.8,32.0,29.7(×3),29.6,29.4,29.3,27.7,27.1,22.8,14.2.

[0037] Example 4

[0038]

[0039] Add 53.9 mg (0.200 mmol) of octadecylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 95%). 1 H NMR (500MHz, CDCl3) δ4.05(t,J=6.6Hz,2H),3.16(t,J=6.6Hz,2H),3.01(t,J=7.4Hz, 2H),1.62-1.53(m,2H),1.39-1.31(m,2H),1.31-1.19(m,28H),0.87(t,J=6.9Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ57.3,47.2,35.9,32.1,29.8,29.8,29.8,29.7,29.6,29.5,29.3,27.7,27.2,22.8,14.2.HRMS(ESI)m / z:calculated for C 20 H 41 NO2S+Na + :382.2756[M+Na] + ; found:382.2760.

[0040] Example 5

[0041]

[0042] Add 23.2 mg (0.200 mmol) of 4-dimethylaminobutylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 91%). 1H NMR (500MHz, CDCl3) δ4.03(t,J=6.7Hz,2H),3.14(t,J=6.7Hz,2H),3.04-2.99(m,2H),2.37-2.30(m,2H),2.25(s,6H),1.62-1.52(m,4H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ59.0,57.3,46.8,45.2,35.8,25.5,24.8.HRMS(ESI)m / z:calculated for C8H 18 N2O2S+H + :207.1167[M+H] + ; found:207.1171.

[0043] Example 6

[0044]

[0045] 89.1 mg (1.000 mmol) of 4-amino-1-butanol and 5 mL of dichloromethane were added to a 25 mL single-necked flask, mixed, and then 110.1 mg (1.00 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel were added thereto, and stirred at room temperature for 16 h. After the reaction was completed, the silica gel was removed by filtration, the solvent was removed by rotary evaporation, and the target product was purified by flash column chromatography (yield was 85%). 1 HNMR (500MHz, CDCl3) δ4.05(t,J=6.7Hz,2H),3.64(q,J=5.3Hz,2H),3.16(t,J=6.7Hz,2H),3.05(t,J=6.7Hz,2H),1.69-1.59(m,4H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ62.2,57.4,46.9,35.9,30.2,24.2.

[0046] Example 7

[0047]

[0048] Add 33.1 mg (0.200 mmol) of 2-aminoethyl methacrylate hydrochloride and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 81%).1 H NMR (500MHz, CDCl3) δ6.18 (s, 1H), 5.61 (t, J = 1.7Hz, 1H), 4.30 (t, J = 5.3Hz, 2H), 4.12(t,J=6.7Hz,2H),3.35(t,J=5.2Hz,2H),3.28(t,J=6.7Hz,2H),1.95(s,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ167.1,135.9,126.6,62.4,58.0,45.6,36.6,18.4.HRMS(ESI)m / z:calculated for C8H 13 NO4S+Na + :242.0463[M+Na] + ; found:242.0467.

[0049] Example 8

[0050]

[0051] 23.9 mg (0.200 mmol) of 4-pentyn-1-amine hydrochloride and 1 mL of dichloromethane were added to a 10 mL single-necked flask, mixed, and then 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel were added, and stirred at room temperature for 16 h. After the reaction was completed, the silica gel was removed by filtration, the solvent was removed by rotary evaporation, and the target product was purified by flash column chromatography (yield was 74%). 1 H NMR (500MHz, CDCl3) δ4.08(t,J=1.7Hz,2H),3.21-3.15(m,4H),2.35-2.30(m,2H),1.98(t,J=2.7Hz,1H),1.83-1.77(m,2H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ82.9,69.5,57.5,45.8,36.1,26.6,16.1.

[0052] Example 9

[0053]

[0054] 27.0 mg (0.200 mmol) of 3-phenyl-1-propylamine and 1 mL of dichloromethane were added to a 10 mL single-necked flask, and after mixing, 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel were added thereto, and stirred at room temperature for 16 h. After the reaction was completed, the silica gel was removed by filtration, the solvent was removed by rotary evaporation, and the target product was purified by flash column chromatography (yield was 93%). 1 HNMR (500MHz, CDCl3) δ7.32-7.27(m,2H),7.22-7.17(m,3H),4.07(t,J=6.7Hz,2H),3 .16(t,J=6.7Hz,2H),3.04(t,J=7.2Hz,2H),2.72(t,J=7.5Hz,2H),1.95-1.88(m,2H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ141.1,128.6,126.2,57.4,46.4,35.9,33.1,29.3.HRMS(ESI)m / z:calculated for C 11 H 15 NO2S+Na + :248.0721[M+Na] + ;found:248.0725

[0055] Example 10

[0056]

[0057] Add 27.0 mg (0.200 mmol) of 4-methyl-phenylethylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 95%). 1 HNMR (500MHz, CDCl3) δ7.12(s,4H),4.05(t,J=6.7Hz,2H),3.28(t,J=7.5Hz,2H),3.08(t,J=6.7Hz,2H),2.87(t,J=7.5Hz,2H),2.32(s,3H). 13 C{ 1H}NMR(126MHz, CDCl3)δ136.4,135.5,129.4,128.7,57.6,48.7,36.2,34.1,21.2.HRMS(ESI)m / z:calculated forC 11 H 15 NO2S+Na + :248.0721[M+Na] + ; found:248.0725.

[0058] Embodiment 11

[0059]

[0060] 17.4 mg (0.200 mmol) of 2-aminopentane and 1 mL of dichloromethane were added to a 10 mL single-necked flask, mixed, and then 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel were added, and stirred at room temperature for 16 h. After the reaction was completed, the silica gel was filtered off, the solvent was removed by rotary evaporation, and the target product was purified by flash column chromatography (yield was 94%). 1 HNMR(500MHz, CDCl3)δ3.98(t,J=6.6Hz,2H),3.35-3.29(m,1H),3.19-3.13(m,2H), 1.64-1.52(m,1H),1.49-1.28(m,3H),1.20(d,J=6.5Hz,3H),0.92(t,J=7.1Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ56.4,53.0,36.6,33.5,18.5,17.6,14.1.HRMS(ESI)m / z:calculated forC7H 15 NO2S+Na + :200.0721[M+Na] + ; found:200.0721.

[0061] Example 12

[0062]

[0063] Add 11.4 mg (0.200 mmol) of cyclopropylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 36 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 67%). 1 H NMR (500MHz, CDCl3) δ4.02(t,J=6.7Hz,2H),3.23(t,J=6.7Hz,2H),2.50-2.45(m,1H),0.76-0.71(m,2H),0.71-0.65(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ57.3,36.6,26.7,5.3.HRMS(ESI)m / z:calculated for C5H9NO2S+Na + :170.0252[M+Na] + ; found:170.0255.

[0064] Example 13

[0065]

[0066] Add 14.2 mg (0.200 mmol) of cyclobutylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 79%). 1 H NMR (500MHz, CDCl3) δ4.01(t,J=6.6Hz,2H),3.86-3.78(m,1H),3.17(t,J=6.6Hz,2H),2.23-2.11(m,4H),1.90-1.72(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ57.0,50.8,32.7,27.3,16.3.HRMS(ESI)m / z:calculated for C6H 11 NO2S+Na + :184.0408[M+Na] + ; found:184.0410.

[0067] Embodiment 14

[0068]

[0069] Add 17.0 mg (0.200 mmol) of cyclopentylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 87%). 1 H NMR (500MHz, CDCl3) δ4.00(t,J=6.7Hz,2H),3.62-3.56(m,1H),3.13(t,J=6.7Hz,2H),1.85-1.65(m,6H),1.64-1.55(m,2H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ59.0,56.6,34.8,30.9,23.6.HRMS(ESI)m / z:calculated for C7H 13 NO2S+Na + :198.0565[M+Na] + ; found:198.0566.

[0070] Embodiment 15

[0071]

[0072] Add 19.8 mg (0.200 mmol) of cyclohexylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 97%). 1 H NMR (500MHz, CDCl3) δ3.99(t,J=6.6Hz,2H),3.19-3.12(m,3H),1.91-1.84(m,2H),1.78-1.70(m,2H),1.61-1.54(m,1H),1.46-1.20(m,5H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ56.6,56.3,33.7,30.7,25.7,23.7.

[0073] Example 16

[0074]

[0075] Add 22.6 mg (0.200 mmol) of cycloheptylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 97%). 1 H NMR (500MHz, CDCl3) δ3.96(t,J=6.6Hz,2H),3.34-3.27(m,1H),3.14(t,J=6.6Hz,2H),1.95-1.86(m,2H),1.74-1.64(m,2H),1.64-1.39(m,8H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ59.1,56.1,34.3,32.4,28.0,23.6.HRMS(ESI)m / z:calculated for C9H 17 NO2S+Na + :226.0878[M+Na] + ; found:226.0883.

[0076] Embodiment 17

[0077]

[0078] Add 14.6 mg (0.200 mmol) of tert-butylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 99%). 1 H NMR (500MHz, CDCl3) δ3.97 (t, J = 6.4Hz, 2H), 3.20 (t, J = 6.4Hz, 2H), 1.32 (s, 9H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ56.5,55.3,30.2,27.1.

[0079] Embodiment 18

[0080]

[0081] Add 30.3 mg (0.200 mmol) of adamantane amine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 99%). 1 HNMR (500MHz, CDCl3) δ3.96(t,J=6.4Hz,2H),3.22(t,J=6.4Hz,2H),2.13-2.06(m,3H),1.95-1.92(m,6H),1.70-1.62(m,6H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ56.5,55.9,40.3,36.3,29.1,28.8.HRMS(ESI)m / z:calculated for C 12 H 19 NO2S+Na + :264.1034[M+Na] + ; found:264.1033.

[0082] Embodiment 19

[0083]

[0084] Add 21.4 mg (0.200 mmol) of benzylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 91%). 1 H NMR (500MHz, CDCl3) δ7.39-7.29 (m, 5H), 4.24 (s, 2H), 4.10 (t, J = 6.7Hz, 2H), 3.13 (t, J = 6.7Hz, 2H). 13 C{ 1 H}NMR (126MHz, CDCl3) δ134.4,128.9,128.7,128.2,57.5,50.6,35.5.

[0085] Embodiment 20

[0086]

[0087] Add 22.6 mg (0.200 mmol) of 2-thiophenemethylamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 91%). 1 HNMR (500MHz, CDCl3) δ7.30-7.28(m,1H),7.06-7.04(m,1H),6.99-6.96(m,1H),4.42(s,2H),4.09(t,J=6.7Hz,2H),3.17(t,J=6.7Hz,2H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ136.6,127.7,127.2,126.4,57.5,45.3,35.3.HRMS(ESI)m / z:calculated for C7H9NO2S+Na + :225.9972[M+Na] + ; found:225.9974.

[0088] Embodiment 21

[0089]

[0090] Add 21.6 mg (0.200 mmol) of 3-aminomethylpyridine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 95%). 1 HNMR(500MHz, CDCl3)δ8.60(d,J=2.2Hz,1H),8.58-8.55(m,1H),7.76-7.73(m,1 H),7.32-7.29(m,1H),4.29(s,2H),4.13(t,J=6.7Hz,2H),3.16(t,J=6.7Hz,2H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ149.9,149.7,136.4,130.2,123.8,57.7,48.3,35.8.HRMS(ESI)m / z:calculated for C8H 10 N2O2S+H +:199.0541[M+H] + ; found:199.0543.

[0091] Embodiment 22

[0092]

[0093] Add 34.5 mg (0.200 mmol) of 1,10-diaminodecane and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 44.0 mg (0.400 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 hours. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 85%). 1 H NMR (500MHz, CDCl3) δ4.04 (d, J = 6.6 Hz, 4H), 3.14 (t, J = 6.6 Hz, 4H), 2.99 (t, J = 7.3 Hz, 4H), 1.59-1.51 (m, 4H), 1.37-1.29 (m, 4H), 1.29-1.22 (m, 8H). 13 C{ 1 H}NMR(126MHz,CDCl3)δ57.3,47.0,35.8,29.3,29.1,27.6,27.0.HRMS(ESI)m / z:calculated forC 14 H 28 N2O4S+Na + :375.1388[M+Na] + ; found:375.1392.

[0094] Embodiment 23

[0095]

[0096] Add 32.0 mg (0.200 mmol) of tryptamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 87%). 1H NMR (500MHz, CDCl3) δ8.09(s,1H),7.61(d,J=7.9Hz,1H),7.36(d,J=8.1Hz,1H),7.21(t,J=7.4Hz,1H),7.1 4(t,J=7.4Hz,1H),7.07(d,J=2.3Hz,1H),4.03(d,J=6.7Hz,2H),3.38(t,J=7.4Hz,2H),3.12-3.03(m,4H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ136.3,127.2,122.3,122.2,119.6,118.7,112.7,111.4,57.6,47.6,36.0,24.1.HRMS(ESI)m / z:calculated forC 12 H 14 N2O2S+Na + :273.0674[M+Na] + ; found:273.0677.

[0097] Embodiment 24

[0098]

[0099] Add 57.1 mg (0.200 mmol) of dehydroabietinamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield 77%). 1 HNMR(500MHz, CDCl3)δ7.19(d,J=8.1Hz,1H),7.02-6.99(m,1H),6.91(d,J=2.0Hz,1H),4.17-4.05(m,2H),3.31-3.26(m,1H),3.26-3.21(m,1H) ,2.99(d,J=15.0Hz,1H),2.95-2.89(m,2H),2.88-2.80(m,2H),2.33-2. 28(m,1H),1.82-1.67(m,4H),1.66-1.62(m,1H),1.49-1.38(m,3H),1.27 -1.20(m,9H),0.94(s,3H). 13 C{ 1H}NMR (126MHz, CDCl3) δ147.2,145.7,134.6,127.0,124.3,124.0,58.8,57.9,44.8,39.5,38. 3,37.4,37.3,37.0,33.5,33.0,25.4,24.1(×2),18.9,18.8,18.7.HRMS(ESI)m / z:calculated for C 22 H 33 NO2S+Na + :398.2130[M+Na] + ; found:398.2135.

[0100] Embodiment 25

[0101]

[0102] Add 36.2 mg (0.200 mmol) of dopamine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 76%). 1 H NMR (500MHz, CDCl3) δ6.81-6.73 (m, 3H), 4.04 (t, J = 6.7Hz, 2H), 3.85 (d, J = 10. 0Hz, 6H), 3.27 (t, J = 7.5Hz, 2H), 3.08 (t, J = 6.7Hz, 2H), 2.84 (t, J = 7.5Hz, 2H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ149.0,147.8,131.1,120.7,112.1,111.4,57.6,56.0(d,J=1.6Hz),48.7,36.2,34.1.HRMS(ESI)m / z:calculated for C 12 H 17 NO4S+Na + :294.0776[M+Na] + ; found:294.0781.

[0103] Embodiment 26

[0104]

[0105] Add 81.8 mg (0.200 mmol) of amlodipine and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride and 30.0 mg of silica gel, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product (yield is 78%). 1 HNMR (500MHz, CDCl3) δ7.69 (s, 1H), 7.40 (dd, J=7.9, 1.7Hz, 1H), 7.19 (dd, J=7.9 ,1.3Hz,1H),7.13-7.10(m,1H),7.03-6.98(m,1H),5.38(s,1H),4.83(d,J=15.7 Hz,1H),4.71(d,J=15.7Hz,1H),4.11(t,J=6.8Hz,2H),4.07-3.96(m,2H),3.71- 3.63(m,2H),3.59(s,3H),3.32-3.21(m,4H),2.35(s,3H),1.16(t,J=7.1Hz,3H). 13 C{ 1 H}NMR(126MHz, CDCl3)δ168.3,167.4,146.3,145.4(×2),132.2,131.7,129.1,127.3,127.1,103 .6,101.3,68.8,68.7,59.8,57.3,50.8,47.4,37.0,35.9,18.8,14.4.HRMS(ESI)m / z:calculated forC 22 H 27 ClN2O7S+Na + :521.1125[M+Na] + ; found:521.1129.

[0106] It can be seen from Examples 1 to 26 that the synthesis method provided by the present invention has simple reaction operation, a wide substrate range, an economical and practical synthesis process, and has strong use value and broad application prospects.

[0107] In order to compare and illustrate the catalytic effect of silica gel on the synthesis of β-lactam sulfonamide, we set up a comparative experiment:

[0108] Comparative Example 1

[0109]

[0110] Add primary amine (0.200 mmol) and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add 22.0 mg (0.200 mmol) of ethylenesulfonyl fluoride, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product. The yield is shown in Table 1.

[0111] Comparative Example 2

[0112]

[0113] Add primary amine (0.200 mmol) and 1 mL of dichloromethane to a 10 mL single-necked flask, mix well, add ethylenesulfonyl fluoride 22.0 mg (0.200 mmol) and silica gel 30.0 mg, and stir at room temperature for 16 h. After the reaction is completed, filter to remove the silica gel, concentrate by rotary evaporation to remove the solvent, and purify by flash column chromatography to obtain the target product. The yield is shown in Table 1.

[0114] Table 1. Effect of silica gel on the yield of β-sulfonamide

[0115]

[0116] As can be seen from Table 1, the silica gel proposed in the present invention as a catalyst can greatly improve the synthesis yield of β-lactamide, and plays an important catalytic role in converting the primary amine (1) and alkenyl sulfonyl fluoride (2) shown in Formula I into β-lactamide.

[0117] The above is only a preferred embodiment of the present invention, and does not limit the present invention in other forms. Any technician familiar with the profession may use the technical content disclosed above to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment according to the technical essence of the present invention without departing from the content of the technical solution of the present invention still belongs to the protection content of the technical solution of the present invention.

Claims

1. A chemical reaction method for synthesizing β-lactam sulfonamide, characterized in that: The method uses primary amine (1) and alkenyl sulfonyl fluoride (2) as raw materials, adds silica gel as a catalyst, and generates a β-internal sulfonamide compound represented by formula (3) in an aprotic solvent: Where R 1 is one of alkyl, alkenyl, alkynyl and aralkyl; R 2 is one of hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, alkaryl, aryl, and heteroaryl; R 3 is one of hydrogen, halogen, alkyl, alkenyl, alkynyl, aralkyl, alkaryl, aryl, and heteroaryl; The aprotic solvent is at least one of dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and ether.

2. The method for synthesizing β-lactam by silica gel catalysis according to claim 1, characterized in that: The primary amine (1) shown in formula II and olefin sulfonyl fluoride (2) undergo addition reaction to obtain β-aminoethanesulfonyl fluoride compound (4), which is then subjected to silica gel-catalyzed intramolecular SuFEx reaction to obtain β-internal sulfonamide compound (3). 。 3. The method for synthesizing the β-lactam sulfonamide compound according to any one of claims 1 to 2, characterized in that: Primary amine (1) and alkenyl sulfonyl fluoride (2) are added according to a functional group molar ratio of 1:0.9-2.5; silica gel is used as a catalyst, and the amount of silica gel corresponding to each millimole of primary amine substrate is 5-300 mg; the reaction is carried out in an aprotic solvent, and the aprotic solvent is at least one of dichloromethane, acetonitrile, acetone, tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, and diethyl ether; the reaction temperature is 0-100°C.

4. Use of the synthesis method of the β-lactam sulfonamide compound according to any one of claims 1 to 2 in drug modification.

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