Synthetic method of alpha, beta-unsaturated gamma-lactam

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a synthesis method of alpha, beta-unsaturated gamma-lactam. The synthesis method of the alpha, beta-unsaturated gamma-lactam comprises the following steps: in a protective atmosphere, taking an organic solvent as a reaction medium, and reacting carboxylic acid, isonitrile and propargyl ester under the action of alkalescent salt and a catalyst to obtain the alpha, beta-unsaturated gamma-lactam. The alpha, beta-unsaturated gamma-lactam has the following structure. The method is simple, and the raw materials are rich in variety, cheap and easy to obtain; the product functional group compatibility is wide, and the reaction atom economy is high. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for synthesizing α,β-unsaturated γ-lactam. Background Art

[0002] α,β-unsaturated γ-lactam structural fragments are widely present in the structure of natural products and are often used as intermediates in drug synthesis. For example, leprosy extract from Jatropha curcas with anti-tumor activity, bilirubin, the main component of bile, endothelin antagonists leucine and orthanycin (A Novel Biomimetic Route to the 3-Acyl-5-hydroxy-3-pyrrolin-2-one and 3-Acyl-3,4-epoxy-5-hydroxypyrrolidin-2-one Ring Systems. J. Org. Chem. 2004, 69, 8952.), marine actinomycete metabolite cyanamide (Cyanogramide with a New Spiro [indolinone-pyrroloimidazole] Skeleton from Actinoalloteichus Cyanogriseus. Org. Lett. 2014, 16, 3708.), anti-inflammatory drug irrexib (Synthesis and Anti-inflammatory Activity of the Major Metabolites of Imrecoxib. Bioorg. Med. Chem. Lett. 2009, 19, 2270.), antidiabetic drug glimepiride (Total Synthesis of Cis-and Trans-hydroxyglimepiride: Active Metabolite of Glimepiride. Tetrahedron Lett. 2003, 44, 4853.), etc.In addition, α,β-unsaturated γ-lactam compounds also show rich biological activities and are inhibitors of various enzymes or receptors, such as human mitotic kinesin (3D-QSAR Studies of Dihydropyrazole and Dihydropyrrole Derivatives as Inhibitors of Human Mitotic Kinesin Eg5 Based on Molecular Docking. Molecules 2012,17,2015.), cardiac cAMP phosphodiesterase (Imidazolylphenyl)pyrrol-2-one Inhibitors of Cardiac cAMP Phosphodiesterase. EJ Med. Chem. 1993,36,1041.), human immunodeficiency virus (HIV) integrase (3-Hydroxy-1,5-Dihydro-pyrrol-2-one Derivatives as Advanced Inhibitors of HIV Integrase. Bioorg. Med. Chem. 2007, 15, 5487.), protein tyrosine phosphatase (Efficient Total Synthesis of Pulchellalactam, a CD45 Protein Tyrosine Phosphatase Inhibitor. J. Org. Chem. 2002, 67, 470.), etc. As mentioned above, this skeleton structure is widely present in drugs and natural products, and therefore has received extensive attention from organic synthetic chemists.

[0003] Generally speaking, there are two main modes for constructing α,β-unsaturated γ-lactam skeletons: one is to use the amide fragment as a directing group, insert the unsaturated bond through directing CH bond activation, and then close the ring to obtain the corresponding lactam ring (Co(III)-Catalyzed[4+1]Annulation of Amides with Allenes via C-HActivation.Adv.Synth.Catal.2019,361,1140; Asymmetric Alkenyl C-HFunctionalization by Cp x R IIIforms 2H-Pyrrol-2-ones through[4+1]-Annulationof Acryl Amides and Allenes.Angew.Chem.Int.Ed.2019,58,18136.); the second is the addition of free radicals to olefinic amides, followed by intramolecular addition elimination to construct ɑ,β-unsaturated γ-lactams (Excited-State Copper-Catalyzed[4+1]Annulation Reaction Enables Modular Synthesis ofα,β-Unsaturated-γ-Lactams.J.Am.Chem.Soc.2022,144,20884.). Both of the above methods require the preparation of the corresponding amide substrate in advance, the substrate range is relatively limited, and the functional group compatibility is poor. Therefore, it is still a very meaningful research topic to develop a method with cheap and easy-to-obtain raw materials, simple operation, modularity and uniformity to obtain ɑ,β-unsaturated γ-lactams with diverse structures. Summary of the invention

[0004] In view of the problems and shortcomings of the prior art, the object of the present invention is to provide a method for synthesizing α,β-unsaturated γ-lactams. The present invention uses abundant and cheap carboxylic acids, commercially available isonitriles and easily prepared propargyl esters as raw materials to obtain a series of α,β-unsaturated γ-lactams with diverse structures with high yield, wide functional group compatibility and high atom economy.

[0005] The purpose of the present invention is achieved through the following technical solutions:

[0006] A method for synthesizing an ɑ,β-unsaturated γ-lactam comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, a carboxylic acid, an isonitrile and a propargyl ester react under the action of a weakly alkaline salt and a catalyst to obtain an ɑ,β-unsaturated γ-lactam.

[0007] The structure of the carboxylic acid is

[0008]

[0009] The structure of the isonitrile is

[0010]

[0011] The structure of the propargyl ester is

[0012] OBoc: -OC(O)-OC(CH3)3

[0013] In the formula, R1 is a C1-C12 straight or branched alkyl, cyclic alkyl, phenyl, substituted phenyl, heteroaryl, alkenyl, or substituted alkenyl;

[0014] The cyclic alkyl group is a three-membered, four-membered, five-membered, or six-membered cycloalkyl group;

[0015] The substituent in the substituted phenyl is one or two or three of methylamino (CH3-NH-), -NMe2, -CHO, -OAc, -OTs, -CF3, -F, -Cl, -Br, -I, -OH, -NH2, -SMe, -OMe, -Me; preferably 4-methylamino (4-CH3-NH-), 4-NMe2, 4-CHO, 4-OAc, 4-OTs, 4-CF3, 3-F, 3-Cl, 3-Br, 3-I, 3-OH, 3-NH2, 2-SMe, 2-OMe, 2-Me, 2-Br, 2-Cl, 3-OH-4-I, 2-Cl-4-Br, 2-Cl-4-OMe, 2-Cl-4-NH2, 1,2,3-trimethoxy;

[0016] The heteroaryl group is 3-quinolyl, 3-thienyl, 5-benzofuranyl, 5-pyrimidinyl;

[0017] The substituted alkenyl group is a 1-substituted alkenyl group or a 1,1- or 1,2-substituted alkenyl group, such as C6H5-CH=CH-.

[0018] R 2 It is a tertiary alkyl group, such as tert-butyl, adamantyl (structural formula is ).

[0019] R 3 It is a C1-C6 straight chain or branched alkyl group, phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furanyl, 2-furyl, dibenzo[b,d]furan-4-yl, 2-thienyl, 2-quinolyl, 2-quinoxalinyl, 4-pyridazinyl, etc.

[0020] R 3 In the above-mentioned, the substituents in the substituted phenyl group are 4-I, 4-Br, 4-Cl, 4-OMe, 4-SMe, 4-OCF3, 4-CO2Et, 4-CONMe2, and 3,4,5-trimethoxy.

[0021] The organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tert-butanol, and tert-amyl alcohol; preferably one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0022] The weak alkaline salt is one or more of potassium formate, sodium formate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, lithium phosphate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, cesium acetate, cesium fluoride, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium pivalate; preferably one or more of potassium carbonate, potassium bicarbonate, cesium carbonate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, and cesium acetate.

[0023] The catalyst is a transition metal nickel, palladium catalyst or cobalt catalyst;

[0024] The transition metal nickel is Ni(cod)2 (bis-(1,5-cyclooctadiene) nickel), Ni(acac)2 (nickel acetylacetonate), Ni(OTf)2 (nickel trifluoromethanesulfonate), NiCl2, NiCl 2· One or more of 6H2O, NiCl2(PPh3)2, NiCl2(dme)(nickel chloride dimethoxyethane), NiBr2, NiBr2(dme)(nickel bromide dimethoxyethane), NiBr2(PPh3)2, and NiI2.

[0025] The palladium catalyst is one or more of PdCl2, PdBr2, PdI2, Pd(OAc)2, Pd(TFA)2 (palladium trifluoroacetate), Pd(dba)2 (bis(dibenzylideneacetone)palladium), Pd(PPh3)4, Pd(PPh3)2Cl2, and Pd(DPPF)Cl2 (1,1'-bis(diphenylphosphinoferrocene)palladium dichloride).

[0026] The cobalt catalyst is one or more of CoCl2, CoBr2, CoI2, Co(acac)2 (cobalt acetylacetonate), and Co(OAc)2.

[0027] The catalyst is preferably a cobalt catalyst, specifically one or more of CoCl2, CoBr2, CoI2, and Co(acac)2.

[0028] The molar ratio of the carboxylic acid, isonitrile and propargyl ester is 1:(2.5-3.5):(1-1.5); the molar ratio of the carboxylic acid to the catalyst is 1:(0.05-0.15); and the molar ratio of the carboxylic acid to the weakly alkaline salt is 1:(1.5-2.5).

[0029] The reaction temperature is 80-130°C, preferably 115-125°C.

[0030] The reaction time is 6-12 hours, and the completion of the reaction is detected by thin layer chromatography.

[0031] After the reaction is completed, the mixture is cooled and quenched with a saturated aqueous ammonium chloride solution, then extracted with water and ethyl acetate, the organic phase is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent is removed by a reduced pressure rotary evaporator to obtain a crude product, which is then separated by column chromatography using an eluent.

[0032] Reaction equation of the present invention:

[0033]

[0034] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0035] The method of the present invention has abundant raw materials, which are cheap and easy to obtain; the product functional groups have wide compatibility and high reaction atom economy. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 The hydrogen spectrum of compound 4a ( 1 H NMR: 500MHz, CDCl3) graph;

[0037] Figure 2 The carbon spectrum of compound 4a is ( 13 C NMR: 126MHz, CDCl3) graph;

[0038] Figure 3 The hydrogen spectrum of compound 4b ( 1 H NMR: 500MHz, CDCl3) graph;

[0039] Figure 4 The carbon spectrum of compound 4b is ( 13 C NMR: 126MHz, CDCl3) graph;

[0040] Figure 5 The hydrogen spectrum of compound 4c ( 1 H NMR: 500MHz, CDCl3) graph;

[0041] Figure 6 The carbon spectrum of compound 4c is ( 13 C NMR: 126MHz, CDCl3) graph;

[0042] Figure 7 The hydrogen spectrum of compound 4d ( 1 H NMR: 500MHz, CDCl3) graph;

[0043] Figure 8 is the 4d carbon spectrum of the compound ( 13 C NMR: 126MHz, CDCl3) graph;

[0044] Fig. 9 The hydrogen spectrum of compound 4e ( 1 H NMR: 500MHz, CDCl3) graph;

[0045] Fig.10 The carbon spectrum of compound 4e is ( 13 C NMR: 126MHz, CDCl3) graph;

[0046] Fig.11 The hydrogen spectrum of compound 4f ( 1 H NMR: 500MHz, CDCl3) graph;

[0047] Fig.12 The carbon spectrum of compound 4f is ( 13 C NMR: 126MHz, CDCl3) graph;

[0048] Fig.13 The hydrogen spectrum of compound 4g is ( 1 H NMR: 500MHz, CDCl3) graph;

[0049] Fig.14 The carbon spectrum of compound 4g is ( 13 C NMR: 126MHz, CDCl3) graph;

[0050] Fig.15 The 4h hydrogen spectrum of compound ( 1 H NMR: 500MHz, CDCl3) graph;

[0051] Fig.16 The 4h carbon spectrum of the compound ( 13 C NMR: 126 MHz, CDCl3) chart. DETAILED DESCRIPTION

[0052] The present invention is further described in detail below in conjunction with specific examples, but the embodiments of the present invention are not limited thereto.

[0053] Example 1

[0054] Benzoic acid 1a (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester were used to prepare a 2-hydroxy-1-nitropropenyl ester. 3a (0.24 mmol) was used as the initial raw material, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added, and the mixture was heated and stirred in an oil bath at 120°C. After compound 1a was completely reacted (detected by thin layer chromatography spot plate), the reaction vessel was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether: ethyl acetate in a volume ratio of 5:1) to obtain compound 4a with a yield of 85%.

[0055]

[0056] Structural characterization data of 4a: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.29-7.19(m,3H),7.19-7.08(m,5H),7.08-7.01(m,2H),5.50(s,1H) ,2.24-2.17(m,3H),2.17-2.09(m,3H),2.04-1.98(m,3H),1.94(s,3H),1.67-1.55(m,6H); 13 C NMR (126MHz, CDCl3)δ173.5,152.5,139.3,133.2,129.7,128.5,128.4,128.3,128.2,127.6,66.1,57.2,40.3,29.8,9.8. The hydrogen and carbon spectra of compound 4a are shown in Figure 1 and 2 shown.

[0057] Example 2

[0058] 4-Methylaminobenzoic acid 1b (0.20mmol), adamantane isocyanide 2a (0.6mmol) and phenyl primary propargyl ester 3a (0.24mmol) were used as starting materials, cobalt chloride (0.020mmol) and sodium phosphate dodecahydrate (0.40mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After compound 1b was completely reacted, it was taken out, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4b with a yield of 65%.

[0059]

[0060] Structural characterization data of 4b: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.28-7.15(m,3H),7.12-7.01(m,2H),6.89(d,J=8.4Hz,2H),6.41(d,J=8.1Hz, 2H),5.41(s,1H),2.75(s,3H),2.25-2.11(m,6H),2.03-1.97(m,3H),1.94(s,3H),1.68-1.52(m,6H); 13 C NMR (126MHz, CDCl3) δ173.4, 152.6, 148.6, 133.6, 129.2, 128.5, 128.2, 128.0, 127.0, 112.5, 65.8, 57.0, 40.2, 36.5, 30.7, 29.8, 9.9. The hydrogen and carbon spectra of compound 4b are shown in Figure 3 and 4 shown.

[0061] Example 3

[0062] 2-Thiomethylbenzoic acid 1c (0.20 mmol), adamantane isonitrile 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as starting materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1c was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4c with a yield of 60%.

[0063]

[0064] Structural characterization data of 4c: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.25-7.15(m,4H),7.14-7.02(m,5H),6.30(s,1H),2.30 (s,3H),2.22-2.07(m,6H),2.04-1.96(m,3H),1.88(s,3H),1.67-1.54(m,6H); 13C NMR (126MHz, CDCl3) δ173.8,153.6,138.7,136.5,133.2,130.3,129.8,128.6,128.2,128.2,128.1,126.4,126.2,61.9,56.9,40.0,36.5,29.9,18.3,9.7. The hydrogen and carbon spectra of compound 4c are shown in Figure 5 and 6 shown.

[0065] Example 4

[0066] 3-Aminobenzoic acid 1d (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as starting materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1d was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4d with a yield of 67%.

[0067]

[0068] Structural characterization data of 4d: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.33-7.17(m,3H),7.06(d,J=7.3Hz,2H),6.93(t,J=7.7Hz,1H),6.57-6.47(m,1H),6.48 -6.38(m,2H),5.39(s,1H),3.56(s,2H),2.28-2.10(m,6H),2.08-1.97(m,3H),1.92(s,3H),1.70-1.54(m,6H); 13 C NMR (126MHz, CDCl3) δ173.5,152.5,146.5,140.3,133.3,129.6,129.3,128.5,128.2,128.2,114.6,66.1,57.2,40.2,36.4,29.8,9.8. The hydrogen and carbon spectra of compound 4d are shown in Figure 7 and 8 shown.

[0069] Example 5

[0070] Pyrimidine-5-carboxylic acid 1e (0.20 mmol), adamantane isonitrile 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as initial raw materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1e was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4e with a yield of 66%.

[0071]

[0072] Structural characterization data of 4e: yellow solid. 1 H NMR(500MHz, CDCl3)δ8.99(s,1H),8.49(s,2H),7.37-7.23(m,3H),7.19-7.10(m,2H) ,5.56(s,1H),2.20-2.09(m,6H),2.05(s,3H),2.02-1.97(m,3H),1.69-1.57(m,6H); 13 C NMR (126MHz, CDCl3) δ173.4, 158.0, 155.5, 151.2, 133.9, 131.9, 131.1, 129.1, 128.9, 128.2, 61.2, 57.7, 40.7, 36.2, 29.7, 9.9. The hydrogen and carbon spectra of compound 4e are shown in Fig. 9 and 10 shown.

[0073] Example 6

[0074] Cinnamic acid 1f (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as initial raw materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1f was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4f with a yield of 80%.

[0075]

[0076] Structural characterization data of 4f: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.39-7.33(m,2H),7.33-7.22(m,5H),7.21-7.16(m,3H),6.44(d,J=16.0Hz,1H),5.72(dd,J=1 6.0,8.6Hz,1H),5.18(dd,J=8.6,1.8Hz,1H),2.42-2.29(m,6H),2.14-2.06(m,3H),1.98(s,3H),1.75-1.63(m,6H); 13 C NMR (126MHz, CDCl3) δ172.6,149.6,136.6,133.2,132.6,131.1,129.4,128.7,128.6,128.6,128.4,127.8,126.4,64.3,56.9,40.7,36.5,29.9,10.2. The hydrogen and carbon spectra of compound 4f are shown in Fig.11 and 12 shown.

[0077] Example 7

[0078] Cyclopropanecarboxylic acid 1g (0.20mmol), adamantane isocyanide 2a (0.6mmol) and phenyl primary propargyl ester 3a (0.24mmol) were used as initial raw materials, cobalt chloride (0.020mmol) and sodium phosphate dodecahydrate (0.40mmol) were added, and finally 2ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1g was complete, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4g with a yield of 62%.

[0079]

[0080] Structural characterization data of 4g: yellow liquid. 1 H NMR (500MHz, CDCl3) δ7.43-7.37(m,2H),7.37-7.27(m,3H),4.52(dd,J=7.5,1.7Hz,1H),2.46-2.30(m,6H),2.17-2.0 9(m,3H),1.90(s,3H),1.80-1.68(m,6H),0.94-0.82(m,1H),0.44-0.33(m,1H),0.30-0.21(m,1H),0.14-0.02(m,2H); 13 C NMR (126MHz, CDCl3) δ172.7, 151.0, 135.2, 130.4, 128.6, 128.4, 128.2, 62.1, 56.3, 40.5, 36.7, 30.0, 16.5, 9.8, 7.3, 3.9. The hydrogen and carbon spectra of compound 4g are shown in Fig.13 and 14 shown.

[0081] Example 8

[0082] Benzoic acid 1a (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and 4-ethoxyphenyl primary propargyl ester 3b (0.24 mmol) were used as starting materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After the reaction of compound 1a was completed, the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4h with a yield of 73%.

[0083]

[0084] Structural characterization data of 4h: yellow solid. 1 H NMR (500MHz, CDCl3) δ7.97-7.84(m,2H),7.20-6.96(m,7H),5.51(s,1H),4.31(q,J=7.1Hz,2H) ,2.24-2.08(m,6H),2.02-1.95(m,3H),1.93(s,3H),1.63-1.54(m,6H),1.33(t,J=7.1Hz,3H); 13 CNMR (126MHz,CDCl3)δ173.0,166.2,151.4,138.8,137.7,131.0,130.1,129.5,128.6,128.4,127.7,66.0,61.1,57.3,40.2,36.3,29.7,14.4,9.9. The hydrogen and carbon spectra of compound 4h are shown in Fig.15 and 16 shown.

[0085] Example 9

[0086] Benzoic acid 1a (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as the initial raw materials, nickel chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After compound 1a was completely reacted (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4a with a yield of 3%.

[0087]

[0088] Example 10

[0089] Benzoic acid 1a (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as the starting materials, palladium chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After compound 1a was completely reacted (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4a with a yield of 5%.

[0090]

[0091] Embodiment 11

[0092] Benzoic acid 1a (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as the initial raw materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 100°C. After compound 1a was completely reacted (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4a with a yield of 36%.

[0093]

[0094] Comparative Example 1

[0095] 3-Pyridin-2-ylbenzoic acid 1h (0.20mmol), adamantane isocyanide 2a (0.6mmol) and phenyl primary propargyl ester 3a (0.24mmol) were used as starting materials, cobalt chloride (0.020mmol) and sodium phosphate dodecahydrate (0.40mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After compound 1h was completely reacted (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4i with a yield of 14%.

[0096]

[0097] Comparative Example 2

[0098] Diclofenac 1i (0.20 mmol), adamantane isocyanide 2a (0.6 mmol) and phenyl primary propargyl ester 3a (0.24 mmol) were used as starting materials, cobalt chloride (0.020 mmol) and sodium phosphate dodecahydrate (0.40 mmol) were added, and finally 2 ml of N,N-dimethylformamide was added. The mixture was heated and stirred in an oil bath at 120°C. After compound 1i was completely reacted (detected by thin layer chromatography spot plate), the reaction bottle was taken out from the oil bath, cooled to room temperature, quenched with saturated aqueous ammonium chloride solution, and then extracted with water and ethyl acetate. The organic phase was dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent was removed by a reduced pressure rotary evaporator to obtain a crude product. The crude product was further purified by column chromatography (the eluent was a mixed solvent of petroleum ether:ethyl acetate in a volume ratio of 5:1) to obtain compound 4j with a yield of 19%.

[0099]

[0100] It is easy for those skilled in the art to understand that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. Any modification, equivalent replacement or improvement made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for synthesizing α,β-unsaturated γ-lactam, characterized in that: The method comprises the following steps: in a protective atmosphere, with an organic solvent as a reaction medium, a carboxylic acid, an isonitrile and a propargyl ester react under the action of a weakly alkaline salt and a catalyst to obtain an α,β-unsaturated γ-lactam; The structure of the carboxylic acid is The structure of the isonitrile is The structure of the propargyl ester is In the formula, R 1 is a C1-C12 straight or branched alkyl, cyclic alkyl, phenyl, substituted phenyl, heteroaryl, alkenyl, or substituted alkenyl; The cyclic alkyl group is a three-membered, four-membered, five-membered, or six-membered cycloalkyl group; The substituents in the substituted phenyl are one, two or three of CH3-NH-, -NMe2, -CHO, -OAc, -OTs, -CF3, -F, -Cl, -Br, -I, -OH, -NH2, -SMe, -OMe, -Me; The heteroaryl group is 3-quinolyl, 3-thienyl, 5-benzofuranyl, 5-pyrimidinyl; The substituted alkenyl group is a 1-substituted alkenyl group or a 1,1- and 1,2-substituted alkenyl group; R 2 is a tertiary alkyl group; R 3 is a C1-C6 straight chain or branched alkyl group, phenyl, substituted phenyl, 2-pyridyl, 3-pyridyl, 6-chloro-3-pyridyl, 5-fluoro-2-pyridyl, 2-benzofuranyl, 2-furanyl, 3-furan, 2-furylvinyl, dibenzo[b,d]furan-4-yl, 2-thienylvinyl, 2-quinolyl, 2-quinoxalinyl, 4-pyridazinyl; The catalyst is a transition metal nickel, palladium catalyst or cobalt catalyst; The transition metal nickel is bis-(1,5-cyclooctadiene) nickel, nickel acetylacetonate, nickel trifluoromethanesulfonate, NiCl2, NiCl 2· One or more of 6H2O, NiCl2(PPh3)2, nickel chloride dimethoxyethane, NiBr2, nickel bromide dimethoxyethane, NiBr2(PPh3)2, NiI2; The palladium catalyst is one or more of PdCl2, PdBr2, PdI2, Pd(OAc)2, palladium trifluoroacetate, bis(dibenzylideneacetone)palladium, Pd(PPh3)4, Pd(PPh3)2Cl2, and 1,1'-bis(diphenylphosphinoferrocene)palladium dichloride; The cobalt catalyst is one or more of CoCl2, CoBr2, CoI2, cobalt acetylacetonate, and Co(OAc)2; The reaction temperature is 80-130°C; The structure of α,β-unsaturated γ-lactam:

2. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 1, characterized in that: R 1 wherein the substituent in the substituted phenyl is 4-CH3-NH-, 4-NMe2, 4-CHO, 4-OAc, 4-OTs, 4-CF3, 3-F, 3-Cl, 3-Br, 3-I, 3-OH, 3-NH2, 2-SMe, 2-OMe, 2-Me, 2-Br, 2-Cl, 3-OH-4-I, 2-Cl-4-Br, 2-Cl-4-OMe, 2-Cl-4-NH2, 1,2,3-trimethoxy; the 1-substituted alkenyl is C6H5-CH=CH-; R 2 is tert-butyl, adamantyl; R 3 wherein the substituent in the substituted phenyl is 4-I, 4-Br, 4-Cl, 4-OMe, 4-SMe, 4-OCF3, 4-CO2Et, 4-CONMe2, 3,4,5-trimethoxy; The reaction temperature is 115-125°C; The catalyst is a cobalt catalyst, specifically one or more of CoCl2, CoBr2, CoI2, and Co(acac)2.

3. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 1, characterized in that: The organic solvent is one or more of tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, methanol, tert-butyl alcohol, and tert-amyl alcohol; The weak alkaline salt is one or more of potassium formate, sodium formate, potassium carbonate, potassium bicarbonate, cesium carbonate, cesium bicarbonate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, sodium phosphate, lithium phosphate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, cesium acetate, cesium fluoride, sodium ethoxide, sodium methoxide, sodium tert-butoxide, and sodium pivalate.

4. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 3, characterized in that: The organic solvent is one or more of dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, and N,N-dimethylacetamide; The weakly alkaline salt is one or more of potassium carbonate, potassium bicarbonate, cesium carbonate, trisodium phosphate dodecahydrate, potassium acetate, sodium acetate, and cesium acetate.

5. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 1, characterized in that: The molar ratio of the carboxylic acid, isonitrile and propargyl ester is 1:(2.5-3.5):(1-1.5); the molar ratio of the carboxylic acid to the catalyst is 1:(0.05-0.15); and the molar ratio of the carboxylic acid to the weakly alkaline salt is 1:(1.5-2.5).

6. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 1, characterized in that: The reaction time is 6-12 hours, and the completion of the reaction is detected by thin layer chromatography.

7. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 1, characterized in that: After the reaction is completed, the mixture is cooled and quenched with a saturated aqueous ammonium chloride solution, then extracted with water and ethyl acetate, the organic phase is dried over anhydrous sodium sulfate or anhydrous magnesium sulfate, and the solvent is removed by a reduced pressure rotary evaporator to obtain a crude product, which is then separated by column chromatography using an eluent.

8. The method for synthesizing the α,β-unsaturated γ-lactam according to claim 7, characterized in that: The eluent is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of (4-6):1.

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