Preparation method of medium-to-large-ring lactone compound

Abstract

The invention relates to a preparation method of medium-to-large-ring lactone compounds, and belongs to the field of organic synthesis. According to the method, alpha, beta-unsaturated cyclic ketone and alkynyl phenol which are simple and easy to obtain are adopted as reactants, and under the catalytic action of a transition metal catalyst, synthesis of medium-to-macrolide is achieved through an aromatization-driven palladium catalysis beta-carbon elimination strategy. Various reaction factors (such as palladium pre-catalyst, temperature, phosphine ligand, alkali and solvent) are evaluated through the system, and optimal conditions are determined. Subsequently, the universality and limitation of the method are investigated by researching the substrate range. The process exhibits good functional group tolerance and can prepare a series of middle and large ring lactones in medium to good yields.

Description

Technical Field

[0001] The invention relates to a derivative of a meso- to macro-cyclic lactone skeleton, and in particular to a method for preparing a meso- to macro-cyclic lactone compound. Background Art

[0002] Medium to macrocyclic lactones (medium rings are usually 8-11 members) are the core skeletons of many biologically active natural products, pesticides and drug molecules. Due to their wide range of biological activities, they have always attracted the attention of medicinal chemists. For example, cephalosporins are a group of naturally occurring eight-membered lactones isolated from fermenting fungi. [1] Cehalosporolide D is composed of two chiral centers (C-4 and C-8) and a saturated eight-membered lactone ring. It is one of the important compounds in the saturated eight-membered lactone ring of natural products. Diplodialide D is a ten-membered lactone first isolated by Wada and Ishida from the plant pathogenic fungus Diplodialide, which can effectively inhibit the activity of steroid hydroxylase. [2] ; (-)-apicularen A isolated from various strains of the myxobacterium Chondroitinibacterium in 1998 has strong anticancer activity [3] Studies have shown that it has a high inhibitory effect on a variety of human cancer cell lines such as ovarian cancer, prostate cancer, lung cancer, kidney cancer, cervical cancer, leukemia and tissue cells; Decarestrictine is a highly oxidized decalactone compound formed during the fermentation of Penicillium. Experimental studies have found that this type of compound has an important inhibitory effect on cholesterol biosynthesis [4] ; Branimycin has good antibacterial activity against Bacillus subtilis, Micrococcus luteus, etc. [5] . [1] G. Redyd,R. Kumar, E. Sreedhar, et al. Stereoselective synthesis (+)-cephalosporolideD. Tetrahedron Lett. 2010, 51, 1723-1726. [2] N. Chebolu, Total Synthesis of Diplodialide C and D. ARKIVOC , 2018,7, 332-340. [3] Q. Su, J. Panek, TotalSynthesis of -Apicularen A. J. Am. Chem. Soc.2004, 126, 2425-2430. [4] A.Khan, L. Yang, J. Xu, et al. Palladium-Catalyzed Asymmetric DecarboxylativeCycloaddition of Vinylethylene Carbonates with Michael Acceptors:Construction of Vicinal Quaternary Stereocenters. Angew. Chem. Int. Ed .2014,53, 11257-11260. [5] (a) A. Braa, A. Sarmiento-Vizcaíno, I. Pérez-Victoria,et al. Branimycins B and C, Antibiotics Produced by the AbyssalActinobacterium Pseudonocardia carboxydivorans. J. Nat. Prod .2017, 80, 569-573; (b) S. Marchart, A. Gromov and J. Mulzer. Total Synthesis of theAntibiotic Branimycin. Angew. Chem. Int. Ed .2010, 49, 2050-2053.

[0003] The construction of medium-ring compounds is considered to be the most difficult type of cyclization reaction. The adverse entropic effects (the frequency of encounters between chain end groups and the additional loss of torsional freedom) and enthalpy effects (ring strain caused by unfavorable bond angles and torsion) caused by the interaction between ring strain and cross-rings make it very challenging to efficiently construct medium-ring lactones. Currently, the available methods are limited, among which the two most widely used strategies are end-to-end lactonization and ring-closing metathesis. However, there are side reactions of intermolecular dimerization or polymerization during intramolecular cyclization, so synthetic chemists use conditions such as high dilution or slow addition to suppress intermolecular competitive reactions. This method has unpredictable results in terms of substrate universality and reaction efficiency. Therefore, further developing new synthetic strategies and preparing medium-ring lactone compounds in a diverse manner has long been a goal pursued by organic chemists.

[0004] The present invention aims to construct medium to macrocyclic lactone compounds by alkyne bridging and utilizing a palladium-catalyzed non-strained ring opening strategy. The method of the present invention has good compatibility with various groups such as halogen (fluorine, chlorine), cyano, ester, methoxy and the like, and these groups themselves have good reactivity, so the obtained product can be further transformed by other organic chemical reactions, thereby introducing more functional groups on the medium to macrocyclic lactone skeleton, and other compounds of novel structures can also be constructed. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing medium to macrocyclic lactone compounds, which has readily available raw materials, wide substrate applicability, simple operation, etc.

[0006] The present invention uses aryl bromide alkenyl cyclopentanone and ortho-acetylenic phenol as reaction substrates, and reacts at a certain temperature for a period of time under the catalytic action of a transition metal catalyst to obtain a macrolide compound as a product. The general reaction formula is as follows:

[0007] Where R 1 and R 3 For various substituents, R 2 are various alkyl, alkenyl and aryl substituents.

[0008] The organic solvent is tetrahydrofuran, 1, 4-dioxane, acetone, dimethyl ether and acetonitrile, among which 1, 4-dioxane is the best. The palladium catalyst is palladium trifluoroacetate, palladium dichloride, allyl palladium chloride, palladium acetate, tetrakistriphenylphosphine palladium and bistriphenylphosphine palladium dichloride, among which palladium acetate is the best. The ligands are tricyclohexylphosphine, triphenylphosphine, diphenylcyclohexylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, tri(p-methoxyphenyl)phosphine, tri(m-methoxyphenyl)phosphine, tri(pentafluorophenyl)phosphine, tri(4-fluorophenyl)phosphine, 2-(di-tert-butylphosphine)biphenyl (JohnPhos), 2-dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (S-phos), 1,1'-bis(diphenylphosphino)ferrocene (DPPF), 1,1'-bis(dicyclohexylphosphino)ferrocene (CyDPPF), bis(dicyclohexylphosphinophenyl)ether (CyDPEPhos), 2-dicyclohexylphosphino-2'-( N , N-dimethylamine)-biphenyl (DavePhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), etc., among which n-butyldi(1-adamantyl)phosphine is the best. The base is potassium carbonate, cesium carbonate, cesium acetate, sodium acetate, sodium phosphate, potassium phosphate, dipotassium hydrogen phosphate, sodium methoxide, sodium hydroxide, potassium tert-butoxide and triethylamine, among which dipotassium hydrogen phosphate is the best. The solvent is ethylene glycol dimethyl ether, tetrahydrofuran, trifluorotoluene, 1, 4-dioxane, acetone, dichloroethane, acetonitrile, N, N -dimethylformamide and toluene, among which 1, 4-dioxane is the best.

[0009] The reaction temperature was 130 o C, the reaction time is 7 hours.

[0010] The reaction was carried out under argon protection.

[0011] In the method for preparing the macrolide compound molecule by the above method, the R 2 and R 3 The group has good compatibility with various substituents, and can produce good yields whether it is an alkyl, electron-rich aromatic or electron-deficient aromatic group. This method is simple to operate, the substrate is easily available, and gram-scale scale-up experiments can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 This is the single crystal structure diagram of 3a. DETAILED DESCRIPTION

[0012] The following examples are provided to further illustrate the present invention, but are not intended to limit the scope of the present invention. Embodiment 1:

[0013]

[0014] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3a with a yield of 70%. The following is the nuclear magnetic resonance experimental data of product 3a: 1H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.80 (dd, J = 11.0, 8.2 Hz,2H), 7.71 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.2 Hz, 2H),7.43 (t, J = 7.5 Hz, 1H), 7.39 – 7.28 (m, 3H), 7.20 (d, J = 7.7 Hz, 2H), 6.94 –6.80 (m, 3H), 6.67 (dd, J = 7.8, 1.9 Hz, 1H), 4.08 (d, J = 14.3 Hz, 1H), 3.94 (d, J = 14.2 Hz, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 168.6, 150.1, 142.2, 140.2, 136.6, 136.2,136.1, 133.8, 133.6, 133.0, 132.8, 132.5, 132.1, 131.6, 131.2, 130.7, 130.4,129.4, 129.1, 128.4, 128.0, 127.8, 127.4, 127.1, 126.9, 126.2, 125.7, 124.5,119.0, 39.6, 21.3. Embodiment 2:

[0015]

[0016] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 oC for 7 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3b with a yield of 59%. The following is the nuclear magnetic resonance experimental data of product 3b: 1 H NMR (500 MHz, CDCl3): δ 8.02 (s, 1H), 7.83 (dd, J = 12.6, 8.2 Hz,2H), 7.73 (d, J = 7.7 Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.4, 5.3 Hz,2H), 7.51 (d, J = 7.6 Hz, 1H), 7.43 (dt, J = 19.0, 7.4 Hz, 2H), 7.34 (dt, J = 14.8,7.6 Hz, 2H), 7.23 (q, J = 7.8 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H), 6.92 (d, J = 7.6Hz, 1H), 6.90 – 6.78 (m, 2H), 4.10 (d, J = 14.2 Hz, 1H), 3.96 (d, J = 14.2 Hz,1H). 13 C NMR (126 MHz, CDCl3): δ 168.5, 150.1, 142.1, 140.1, 139.7, 136.2,133.8, 133.6, 133.0, 132.8, 132.5, 131.9, 131.8, 131.2, 130.5, 130.5, 129.4,128.5, 128.4, 128.1, 127.4, 127.0, 126.9, 126.7, 126.2, 125.8, 124.4, 119.1,39.5. Embodiment three:

[0017]

[0018] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The crude product was directly separated and purified by silica gel column to obtain the desired product 3c with a yield of 56%. The following is the nuclear magnetic resonance experimental data of product 3c: 1 H NMR (500 MHz, CDCl3): δ 8.02 (s, 1H), 7.90 – 7.83 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.74– 7.55 (m, 5H), 7.47 (dd, J = 8.0, 5.9 Hz, 2H), 7.34 (q, J =6.9 Hz, 3H), 7.23 (ddd, J = 8.6, 6.3, 2.8 Hz, 1H), 6.94 (d, J = 8.0 Hz, 1H), 6.90– 6.81 (m, 2H), 4.10 (d, J = 14.3 Hz, 1H), 3.97 (d, J = 14.3 Hz, 1H). 13 C NMR (126 MHz, CDCl3): δ 165.4, 147.2, 140.8, 139.1, 135.6, 133.3,131.0, 130.5, 130.1, 129.7, 129.6, 129.1, 128.5, 128.2, 128.0, 127.0, 126.4,126.0, 125.9 (q, J C-F = 33.1 Hz), 125.9, 124.7, 124.1, 123.5, 123.3, 122.4 (q, J C-F = 2.5 Hz), 121.7, 121.4(q,J C-F = 272.3 Hz), 121.1 (q, J C-F = 3.6 Hz), 116.4,36.6. Embodiment 4:

[0019]

[0020] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3e with a yield of 50%. The following is the nuclear magnetic resonance experimental data of the product 3e: 1 H NMR (500 MHz, CDCl3): δ 8.10 (dd, J = 8.0, 1.9 Hz, 1H), 8.01 (s,1H), 7.83 (d, J = 8.2 Hz, 1H), 7.77 (td, J = 5.8, 2.9 Hz, 2H), 7.71 (d, J = 7.8 Hz,1H), 7.67 – 7.63 (m, 1H), 7.59 (ddd, J = 12.4, 6.5, 4.0 Hz, 2H), 7.46 (t, J = 9.2Hz, 2H), 7.33 (dt, J = 15.3, 7.6 Hz, 2H), 7.24 – 7.17 (m, 1H), 6.95 – 6.76 (m,3H), 4.09 (d, J = 14.4 Hz, 1H), 3.95 (d, J = 14.3 Hz, 1H), 3.92 (s, 3H). 13C NMR (126 MHz, CDCl3): δ 168.3, 167.1, 150.1, 145.0, 142.0, 138.9,136.2, 133.8, 133.5, 133.0, 132.7, 132.5, 131.8, 131.4, 131.1, 130.7, 130.1,129.7, 129.4, 128.9, 128.6, 128.4, 128.4, 127.6, 127.0, 126.5, 126.3, 126.1,124.6, 119.2, 52.1, 39.4. Embodiment five:

[0021]

[0022] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The crude product was directly separated and purified by silica gel column to obtain the desired product 3g with a yield of 56%. The following is the nuclear magnetic resonance experimental data of product 3g: 1 H NMR (500 MHz, DMSO- d 6):δ 8.17 (s, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.86(d, J = 7.7 Hz, 1H), 7.63 (td, J = 7.6, 1.5 Hz, 1H), 7.60 – 7.48 (m, 5H), 7.45 –7.34 (m, 3H), 7.29 (ddd, J = 8.4, 7.2, 2.1 Hz, 1H), 7.21 (dd, J = 8.2, 2.3 Hz,1H), 7.10 – 6.93 (m, 2H), 6.75 (dd, J= 8.3, 2.1 Hz, 1H), 4.26 (d, J = 14.6 Hz,1H), 3.78 (d, J = 14.5 Hz, 1H). 13 C NMR (126 MHz, DMSO): δ 168.4, 150.2, 141.5, 138.5, 138.5, 136.2, 134.2, 133.9, 133.8, 133.1, 132.9, 132.4, 132.1, 131.8, 131.5, 131.5, 130.6,129.5, 129.2, 128.9, 128.7, 128.1, 127.9, 127.4, 127.0, 126.9, 126.3, 125.4,119.9, 39.0. Embodiment six:

[0023]

[0024] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3i with a yield of 63%. The following is the nuclear magnetic resonance experimental data of the product 3i: 1 H NMR (500 MHz, CDCl3): δ 8.01 (s, 1H), 7.84 (d, J = 8.1 Hz, 1H), 7.73(d, J = 7.6 Hz, 1H), 7.69 – 7.63 (m, 2H), 7.61 – 7.56 (m, 2H), 7.52 (dt, J = 7.7,1.6 Hz, 1H), 7.48 – 7.40 (m, 2H), 7.37 – 7.29 (m, 2H), 7.23 (tt, J= 7.5, 1.4Hz, 1H), 7.11 (td, J = 7.6, 1.4 Hz, 1H), 7.00 (dd, J = 8.3, 2.3 Hz, 1H), 6.81(dt, J = 7.7, 1.6 Hz, 1H), 6.71 (d, J = 2.2 Hz, 1H), 4.09 (d, J = 14.1 Hz, 1H),3.98 (d, J = 14.1 Hz, 1H), 2.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 168.7, 148.0, 142.1, 140.2, 139.8, 136.2,134.4, 133.9, 133.0, 132.9, 132.4, 131.8, 131.8, 131.1, 130.4, 130.0, 129.2,128.8, 128.4, 128.1, 127.4, 127.0, 126.9, 126.8, 126.6, 126.1, 125.8, 118.8,39.5, 20.5. Embodiment seven:

[0025]

[0026] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3l with a yield of 53%. The following is the nuclear magnetic resonance experimental data of the product 3l: 1 H NMR (500 MHz, CDCl3): δ 7.90 (s, 1H), 7.77 (dd, J= 8.3, 1.1 Hz,1H), 7.72 (d, J = 9.0 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.63 (dd, J = 7.6, 1.5 Hz,1H), 7.56 (td, J = 7.6, 1.5 Hz, 1H), 7.38 (dd, J = 7.7, 1.9 Hz, 1H), 7.33 (td, J =7.6, 1.1 Hz, 1H), 7.20 (ddd, J = 10.0, 7.6, 1.9 Hz, 2H), 7.12 (dd, J = 9.0, 2.5Hz, 1H), 6.93 – 6.79 (m, 4H), 6.67 (dd, J = 7.7, 1.9 Hz, 1H), 4.04 (d, J = 14.2Hz, 1H), 3.91 (d, J = 14.3 Hz, 1H), 3.66 (s, 3H), 2.32 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 168.6, 157.5, 150.1, 142.2, 138.9, 136.7,136.1, 134.1, 133.7, 133.5, 133.1, 132.7, 132.4, 131.3, 131.1, 130.9, 130.4,129.3, 129.2, 129.0, 128.6, 128.3, 127.8, 127.7, 126.8, 124.4, 119.0, 118.7,105.5, 55.2, 39.4, 21.3. Embodiment eight:

[0027]

[0028] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3r with a yield of 48%. The following is the nuclear magnetic resonance experimental data of the product 3r: 1 H NMR (500 MHz, CDCl3): δ 7.95 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.80(dd, J = 8.3, 1.1 Hz, 1H), 7.67 (dd, J = 8.5, 5.8 Hz, 1H), 7.58 (d, J = 8.6 Hz,1H), 7.48 – 7.41 (m, 2H), 7.37 (dd, J = 7.7, 1.9 Hz, 1H), 7.31 (ddd, J = 8.4,6.8, 1.3 Hz, 1H), 7.24 – 7.19 (m, 2H), 7.04 (td, J = 8.2, 2.5 Hz, 1H), 6.88(dtd, J = 19.0, 7.6, 1.5 Hz, 3H), 6.65 (dd, J = 7.8, 1.9 Hz, 1H), 4.03 (d, J = 14.2Hz, 1H), 3.95 (d, J = 14.1 Hz, 1H), 2.33 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 167.5, 164.9(d, J C-F = 253.9 Hz), 150.0,145.4 (d, J C-F = 8.2 Hz), 140.3, 136.5, 136.2, 135.4, 133.7, 133.6, 132.9,132.1, 131.9 (d, J C-F= 9.1 Hz), 131.6, 130.3, 129.1, 129.0 (d, J C-F = 3.2 Hz),128.5, 127.9, 127.8, 127.4, 127.1, 126.3, 125.9, 124.5, 118.6, 118.3 (d, J =21.8 Hz), 114.0 (d, J C-F = 21.8 Hz), 39.5, 21.3. Embodiment nine:

[0029]

[0030] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3s with a yield of 53%. The following is the NMR experimental data of the product 3s: 1 H NMR (500 MHz, CDCl3): δ 8.00 (s, 1H), 7.84 (t, J = 8.0 Hz, 2H), 7.59(dd, J = 11.5, 8.2 Hz, 2H), 7.53 (s, 1H), 7.44 (t, J = 7.4 Hz, 1H), 7.39 (dd, J =7.7, 2.0 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 7.22 (qd, J = 4.7, 2.1 Hz, 2H), 7.16(d, J = 7.8 Hz, 1H), 6.99 – 6.82 (m, 3H), 6.68 (dd, J= 7.7, 1.9 Hz, 1H), 4.02(d, J = 14.0 Hz, 1H), 3.93 (d, J = 14.0 Hz, 1H), 2.51 (s, 3H), 2.34 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 168.6, 150.1, 143.2, 142.3, 140.1, 136.6,136.3, 136.1, 133.8, 133.6, 132.9, 132.1, 132.0, 131.6, 130.5, 130.4, 130.0,129.7, 129.1, 128.4, 127.8, 127.7, 127.7, 127.4, 127.1, 126.1, 125.7, 124.3,118.6, 39.6, 21.8, 21.3. Embodiment ten:

[0031]

[0032] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3t with a yield of 63%. The following is the nuclear magnetic resonance experimental data of the product 3t: 1 H NMR (500 MHz, CDCl3): δ 7.98 (s, 1H), 7.84 (dd, J = 8.2, 5.7 Hz,2H), 7.62 (dd, J = 12.5, 8.5 Hz, 2H), 7.45 (t, J = 7.5 Hz, 1H), 7.40 (dd, J = 7.7,1.9 Hz, 1H), 7.31 (td, J= 7.2, 6.8, 3.6 Hz, 1H), 7.25 – 7.20 (m, 2H), 7.19 (d, J = 2.8 Hz, 1H), 7.13 (dd, J = 8.4, 2.9 Hz, 1H), 6.99 – 6.85 (m, 3H), 6.69 (dd, J = 7.7, 1.9 Hz, 1H), 4.03 (d, J = 14.3 Hz, 1H), 3.88 (d, J = 14.3 Hz, 1H), 3.84(s, 3H). 13 C NMR (126 MHz, CDCl3): δ 168.4, 158.3, 150.0, 140.1, 136.7, 136.6,136.1, 134.5, 133.6, 133.5, 133.0, 132.3, 132.0, 131.6, 130.6, 130.4, 129.1,128.4, 127.8, 127.8, 127.4, 127.1, 126.1, 125.7, 124.5, 118.9, 118.8, 113.7,77.4, 77.1, 76.8, 55.6, 38.7, 21.3. Embodiment eleven:

[0033]

[0034] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3ab with a yield of 64%. The following is the nuclear magnetic resonance experimental data of the product 3ab: 1H NMR (500 MHz, CDCl3): δ 7.91 – 7.82 (m, 2H), 7.62 (d, J = 8.6 Hz,1H), 7.49 (t, J = 7.5 Hz, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.38 – 7.28 (m, 3H), 7.16 (q, J = 7.5 Hz, 2H), 7.05 (t, J = 7.6 Hz, 1H), 6.85 – 6.73 (m, 3H), 2.93 –2.80 (m, 1H), 2.67 (dt, J = 13.6, 4.2 Hz, 1H), 2.50 – 2.29 (m, 3H), 1.93 (t, J =12.5 Hz, 1H), 1.79 (qd, J = 12.9, 5.1 Hz, 1H), 1.61 (dq, J = 15.8, 5.8, 5.3 Hz,1H). 13 C NMR (126 MHz, CDCl3): δ 172.5, 148.2, 140.2, 139.9, 137.8, 136.2,134.6, 133.1, 131.6, 131.3, 131.3, 130.5, 128.1, 127.3, 127.2, 127.0, 126.9,126.5, 126.3, 126.0, 125.4, 124.8, 123.3, 35.2, 28.6, 28.3, 20.6. Embodiment 12:

[0035]

[0036] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 oC for 7 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3ad with a yield of 50%. The following is the nuclear magnetic resonance experimental data of the product 3ad: 1 H NMR (500 MHz, CDCl3): δ 7.92 – 7.86 (m, 2H), 7.72 (dd, J = 8.4, 1.1Hz, 1H), 7.54 – 7.45 (m, 2H), 7.34 (ddd, J = 8.3, 6.7, 1.3 Hz, 1H), 7.24 (ddd, J = 9.6, 4.4, 2.4 Hz, 1H), 7.15 (tt, J = 5.0, 2.7 Hz, 4H), 7.05 (td, J = 4.3, 2.0Hz, 1H), 6.93 (td, J = 7.4, 1.2 Hz, 1H), 6.88 (dd, J = 7.6, 1.9 Hz, 1H), 2.69(dt, J = 15.5, 4.4 Hz, 1H), 2.50 (ddd, J = 15.9, 12.8, 3.3 Hz, 1H), 2.35 – 2.28(m, 2H), 2.27 – 2.18 (m, 1H), 1.83 – 1.73 (m, 1H), 1.62 (tt, J = 11.0, 3.8 Hz,1H), 1.50 – 1.41 (m, 1H), 1.36 (dtt, J = 12.0, 9.2, 4.5 Hz, 3H), 1.25 (tt, J =10.6, 3.9 Hz, 1H). 13C NMR (126 MHz, CDCl3): δ 171.6, 148.7, 139.6, 139.6, 138.1, 136.6,133.1, 132.4, 131.6, 131.2, 130.7, 129.7, 127.9, 127.7, 127.5, 127.1, 126.8,126.5, 125.8, 125.4, 125.3, 124.4, 120.2, 33.6, 29.8, 26.9, 25.6, 25.1, 24.0. Embodiment 13:

[0037]

[0038] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3ae with a yield of 65%. The following is the nuclear magnetic resonance experimental data of the product 3ae: 1 H NMR (500 MHz, CDCl3): δ 7.89 (d, J = 8.3 Hz, 1H), 7.82 (s, 1H), 7.53– 7.45 (m, 2H), 7.36 – 7.31 (m, 1H), 7.25 – 7.22 (m, 1H), 7.21 – 7.11 (m,5H), 7.06 (q, J = 3.7, 2.8 Hz, 2H), 7.01 (dt, J = 6.8, 2.0 Hz, 1H), 2.53 (td, J =7.4, 2.7 Hz, 2H), 2.30 (td, J = 7.6, 5.7 Hz, 2H), 1.79 (q, J = 7.3, 6.7 Hz, 1H),1.56 (ddt, J= 19.8, 13.7, 7.0 Hz, 3H), 1.39 – 1.16 (m, 12H). 13 C NMR (126 MHz, CDCl3): δ 171.4, 148.2, 139.3, 139.0, 139.0, 135.1,133.2, 132.6, 132.0, 131.1, 130.8, 130.4, 127.9, 127.5, 127.5, 127.4, 126.8,126.7, 126.1, 125.8, 125.2, 124.5, 121.7, 34.2, 33.0, 28.2, 27.0, 26.8, 26.5,26.3, 25.6, 25.5, 23.6. Embodiment 14:

[0039]

[0040] In a dry 25 mL Schlenk tube, add a small magnetic particle, replace with argon three times, weigh 1a (0.2 mmol), 2a (0.3 mmol), Pd (OAc) 2 (2.3 mg, 5 mol%), phosphine ligand (10 mol%) and base (2 equiv.) was placed in a Schlenk tube under argon protection, 4 mL of 1, 4-dioxane was added via a syringe, and the mixture was heated at 130 o C for 7 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, filtered through diatomaceous earth, and the solvent was removed under reduced pressure. The resulting crude product was directly separated and purified by a silica gel column to obtain the desired product 3af with a yield of 59%. The following is the nuclear magnetic resonance experimental data of the product 3af: 1 H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 7.6 Hz,1H), 7.48 (d, J = 11.4 Hz, 2H), 7.40 – 7.27 (m, 6H), 7.25 – 7.19 (m, 2H), 7.19– 7.11 (m, 4H), 6.87 –6.79 (m, 2H), 3.82 (ddd, J = 14.8, 8.8, 6.1 Hz, 1H), 3.28(ddd, J= 14.6, 8.9, 6.1 Hz, 1H), 3.15 (ddd, J = 14.2, 8.9, 4.8 Hz, 1H), 2.85(ddd, J = 13.9, 8.8, 4.8 Hz, 1H). 13 C NMR (126 MHz, CDCl3): δ 168.0, 151.2, 140.8, 139.9, 139.5, 137.0,134.6, 133.4, 133.0, 131.9, 131.8, 131.7, 131.5, 131.4, 130.9, 130.2, 129.9,128.7, 128.4, 128.0, 127.2, 127.1, 126.8, 126.7, 126.2, 126.0, 125.4, 124.6,121.4, 77.4, 77.1, 76.8, 34.9, 31.2 。

Claims

1. A method for preparing a medium to macrocyclic lactone compound, comprising the following steps: In an organic solvent, a compound having a structure as shown in Formula I is used. α，β -unsaturated cyclic ketone and alkynylphenol of structure as formula II are used as reaction substrates, under transition metal catalyst and ligand catalysis, certain temperature conditions and inert gas protection, react for a period of time to obtain medium to macrocyclic lactone compounds of structure as formula III, 。 2. According to claim 1, the compound of formula I α，β - unsaturated cyclic ketone, characterized in that: The substituted R 1 The groups include but are not limited to methyl, methoxy, fluoro and chloro groups; X includes but is not limited to Cl, Br, I, OTf and other groups.

3. The substrate alkynylphenol of structure II according to claim 1, characterized in that: The R 2 The group includes but is not limited to phenyl, alkyl, naphthyl and alkenyl, etc.; the R 3 The group includes, but is not limited to, methyl, methoxy, and fluoro groups, and the like.

4. The method for preparing medium to macrocyclic lactone compounds according to claim 1, characterized in that: The organic solvent includes but is not limited to tetrahydrofuran, 1,4-dioxane, acetone, N, N -Dimethylformamide, dimethyl ether, acetonitrile, dichloroethane and toluene, etc.

5. The method for preparing medium to macrocyclic lactone compounds according to claim 1, characterized in that: The temperature is 90 o C-150 o C, the time is 7h, and the protective gas includes but is not limited to N2 and Ar.

6. The method for preparing medium to macrocyclic lactone compounds according to claim 1, characterized in that: The palladium catalyst includes but is not limited to Pd(TFA)2, [Pd(allyl)Cl]2, PdCl2, PdCl2(PPh3)2, Pd(OAc)2, Pd2(dba)3, and Pd(PPh3)4.

7. The method for preparing medium to macrocyclic lactone compounds according to claim 1, characterized in that: The ligands include but are not limited to PPh3, PCy3, SPhos, Cydppf, DPEHos and DPPF.

8. The method for preparing medium to macrocyclic lactone compounds according to claim 1, characterized in that: The base includes but is not limited to CsOAc, NaOAc, Na3PO4, Na2CO3, NaOCH3 and NEt3.

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