Method for preparing ester compound and macrolide compound

Abstract

The invention discloses a method for preparing an ester compound and a macrolide compound, and belongs to the technical field of organic chemistry, the preparation method of the ester compound is as follows: in an organic solvent, an alpha-carbonyl alkenyl ester compound reacts with alcohol or phenol under the catalytic condition of alkali to obtain the ester compound; the preparation method of the macrolide compound comprises the following step: in an organic solvent, carrying out intramolecular hydroxyl reaction on an alpha-carbonyl alkenyl ester compound under the catalysis condition of alkali or acid, thereby obtaining the macrolide compound. The method is wide in substrate range, high in practicability and high in yield, racemization of a carboxylic acid alpha-chiral center can be inhibited in intermolecular esterification reaction and macrocyclic lactonization reaction, and the method can be applied to total synthesis of a Brevicidine natural product containing a 13-membered cyclic ester peptide core structure; the method disclosed by the invention has the advantages of mild reaction conditions, simplicity, easiness in operation, wide substrate adaptability, no racemization of the product and the like.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and in particular to a method for preparing ester compounds and macrocyclic lactone compounds. Background Technology

[0002] Esters and macrolides, with their unique functional group structures and chemical activities, have become indispensable core intermediates and end products in the fields of pharmaceuticals, pesticides, fragrances, and polymer materials. In the pharmaceutical field, macrolide antibiotics (such as erythromycin, azithromycin, and clarithromycin) are first-line drugs for treating bacterial infections; their cyclic lactone structure endows them with excellent antibacterial activity and pharmacokinetic properties. In the fragrance industry, macrolides (such as cyclopentadecanolactone and muscone analogs) are widely used in the blending of high-end perfumes and cosmetics due to their long-lasting aroma and good compatibility. In the field of polymer materials, ester monomers can be polymerized to prepare materials such as polyesters and polyurethanes; their properties directly determine key indicators such as the mechanical strength and weather resistance of the end products.

[0003] To date, numerous methods for ester preparation have been developed, including transition metal-catalyzed CO bond formation, alkyne / alkene ring-closing metathesis, alkene coupling reactions to construct C / C bonds, and nitrogen-heterocyclic carbene (NHC)-catalyzed oxidative esterification of aldehydes. Among these methods, the dehydration coupling reaction of carboxylic acids with alcohols or phenols is an ideal strategy for ester preparation due to the readily available availability of these starting materials. However, to remove the water generated during coupling and drive the equilibrium towards esterification, these reactions typically require high temperatures, strong acid catalysts, or dehydrating agents. Similar to amide bond formation, dehydration esterification can be carried out under mild conditions by activating carboxylic acids with coupling agents. The use of traditional coupling agents (such as carbodiimides, phosphonium salts, and ammonium / ureonium salts) has several drawbacks, such as significant racemization of α-chiral carboxylic acids, difficulty in product purification, and unsuitability of high reaction temperatures and limited substrate range for later macrolide reactions, especially in the total synthesis of complex natural macrolide products.

[0004] Among the currently reported methods for preparing macrolides, the Yamaguchi reaction is the most common. However, this method suffers from several well-known problems, including high sensitivity to moisture, racemization of α-chiral hydroxy acid substrates, Z / E isomerization of α,β-unsaturated hydroxy acid substrates, and the very high reaction temperatures required, making it unsuitable for complex substrates. Furthermore, the competing dimerization reactions involved in intermolecularization of macrolides are another concern in the field. Therefore, macrolide esterification remains a challenging and demanding process. Consequently, finding a mild, efficient, and environmentally friendly esterification method is a key issue of concern for researchers. Summary of the Invention

[0005] One of the objectives of this invention is to provide a method for preparing ester compounds to solve the above-mentioned problems.

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

[0007] A method for preparing ester compounds, wherein the method comprises: in an organic solvent, using a base as a catalyst, reacting α-carbonyl alkenyl ester compound 1 with an alcohol or phenol compound 2 at a reaction temperature of -10 to 80°C to generate ester compound 3, the reaction formula of which is shown in formula (1):

[0008] ,

[0009] In formula (1), R1 is selected from one of the following: C1~C22 alkyl, C4~C10 aryl, substituted aryl, heterocyclic aryl, alkenyl, alkynyl, protected α-aminoalkyl, protected β-aminoalkyl, protected γ-aminoalkyl, and protected polypeptide chain alkyl; preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, adamantyl, vinyl, 1-propynyl, 2-propynyl, 1-butenyl, 2-butenyl, 3-butenyl, styryl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, phenylethynyl, phenyl, naphthyl, anthraceneyl, phenanthrene, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyridyl, pyrroleyl, indole R1 is selected from one of the following: alkyl, indolemethyl, indazole, furanyl, benzofuranyl, thiophene, benzothiophene, quinolinyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α-aminoalkyl, protected β-aminoalkyl, protected γ-aminoalkyl, and protected polypeptide chain alkyl; R2 is selected from one of the following: C1-C8 alkyl, C3-C10 cycloalkyl, aryl, substituted aryl, alkenyl, alkynyl, polypeptide containing serine residues, and polypeptide containing tyrosine residues; preferably ethyl, n-hexyl, cyclohexyl, phenyl, naphthyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl, 2-pyridyl, 2-thiophene, 2-furanyl, polypeptide containing serine residues, and polypeptide containing tyrosine residues; wherein the molar ratio of α-carbonyl alkenyl esters to alcohols or phenolic compounds is 1:(1-10).

[0010] As a preferred technical solution, the organic solvent is selected from one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, trichloromethane, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetone, with acetonitrile being preferred. Choosing acetonitrile results in a higher yield.

[0011] As a preferred technical solution, the alkali is selected from one or more of N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazolium, and pyridine; preferably 4-pyrrolylpyridine; the amount of alkali used ranges from 0.1 to 1 equivalent, preferably 0.2 equivalent. Higher yield is achieved when 4-pyrrolylpyridine is selected.

[0012] As a preferred technical solution, the reaction temperature is room temperature; the molar ratio of α-carbonyl alkenyl esters to alcohols or phenolic compounds is 1:1.1.

[0013] The second objective of this invention is to provide a method for preparing macrocyclic lactone compounds. The technical solution adopted is that, in an organic solvent, with a base or acid as a catalyst, α-carbonyl alkenyl ester compound 4 undergoes an intramolecular hydroxyl reaction at a reaction temperature of -10 to 80°C to generate macrocyclic lactone compound 5, as shown in formula (2).

[0014] ,

[0015] In formula (2), compound 4 represents an α-carbonyl alkenyl ester compound containing hydroxyl groups; compound 5 represents a macrocyclic lactone compound with 6-24 member rings; and compound 6 represents a 1,3-dicarbonyl byproduct.

[0016] As a preferred technical solution, the organic solvent is selected from one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetone; preferably 1,2-dichloroethane.

[0017] As a preferred technical solution, the alkali is selected from one or more of N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazolium, and pyridine; the acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, copper(II) trifluoromethanesulfonate, dextrorotatory camphorsulfonic acid, indium trifluoromethylcarbonate, and p-chlorobenzenesulfonic acid.

[0018] As a further preferred technical solution, the base is 4-pyrrolidinylpyridine; the acid is p-toluenesulfonic acid.

[0019] As a preferred technical solution, the reaction temperature is room temperature.

[0020] As a preferred technical solution, the catalytic range of the alkali or acid is 0.1-1 times equivalent, and the preferred amount of alkali or acid is 0.2 times equivalent.

[0021] Through extensive research, the inventors discovered that alkenyl esters can be applied to esterification and macrocyclic lactone reactions in the presence of specific catalysts. The inventors developed a novel method for preparing esters and macrocyclic lactones using allenones as condensing agents by employing an addition reaction of carboxylic acids with allenones under mild and simple conditions.

[0022] Compared with existing technologies, the advantages of this invention are as follows: This invention develops a novel method for allenone-mediated esterification reactions. In an organic solvent, α-carbonyl alkenyl esters react with alcohols or phenols under alkaline catalysis to obtain ester compounds. The amount of alcohol or phenol used is only 1.1 equivalents. The substrate range of carboxylic acids, alcohols, and phenols has been verified: aromatic, aliphatic, and heterocyclic carboxylic acids can all yield esterification products in high yields. No Z / E isomerization was detected in the esterification products of α,β-unsaturated carboxylic acids, and α-amino acids can yield chiral-retained esterification products. Long-chain fatty alcohols, α,β-unsaturated alcohols, alcohols substituted with electron-withdrawing or electron-donating groups, phenols, and naphthols can all participate in the reaction. This invention also develops a novel method for allenone-mediated macrocyclic esterification reactions. In organic solvents, α-carbonyl alkenyl esters undergo intramolecular hydroxyl reactions under alkaline or acidic catalysis to generate macrocyclic lactones. This method can prepare various macrocyclic lactones with ring sizes of 6-24 members in good to excellent yields, and high-resolution mass spectrometry confirms that dimer lactone byproducts are minimal or absent. Furthermore, the method of this invention can also construct cyclic ester peptides. In both intermolecular esterification and macrocyclic lactide reactions, racemization of the α-chiral center of the carboxylic acid is suppressed, successfully applying this method to the total synthesis of Brevicidine, a natural product containing a 13-membered cyclic ester peptide core structure. The method of this invention has advantages such as mild reaction conditions, simplicity, ease of operation, broad substrate adaptability, and racemic products. Attached Figure Description

[0023] Figure 1 The proton NMR spectrum of the compound in Example 7;

[0024] Figure 2 The carbon spectrum of the compound in Example 7;

[0025] Figure 3 The proton NMR spectrum of the compound in Example 13;

[0026] Figure 4 The carbon spectrum of the compound in Example 13;

[0027] Figure 5 The proton NMR spectrum of the compound in Example 16;

[0028] Figure 6 The carbon spectrum of the compound in Example 16;

[0029] Figure 7This is the proton NMR spectrum of the compound in Example 23; that is, the proton NMR spectrum of the core structure of the natural product Brevicidine 13-membered cyclic ester peptide.

[0030] Figure 8 This is the carbon spectrum of the compound in Example 23; that is, the carbon spectrum of the core structure of the natural product Brevicidine 13-membered cyclic ester peptide. Detailed Implementation

[0031] To explain the technical content, objectives, and effects of the present invention in detail, the following specific embodiments are provided to further illustrate the content of the present invention. However, the content of the present invention is far more than the following examples.

[0032] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available.

[0033] Examples 1-5 below describe the preparation of α-carbonyl alkenyl ester compounds.

[0034] Example 1

[0035] A method for preparing α-carbonyl alkenyl ester compounds with the following structure:

[0036]

[0037] Allenone (0.22 mmol) and p-chlorobenzoic acid (0.2 mmol) were added to a clean 4 mL reaction flask, and 2 mL of CH2Cl2 was added as solvent. The reaction was carried out at room temperature for 24 h, and the reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain a pure product, a yellow solid, with a yield of 94%.

[0038] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.95 (d, J = 7.2 Hz, 2H), 7.55 (d, J = 7.4 Hz, 1H), 7.50 – 7.45 (m, 4H), 6.94(s, 1H), 2.53 (s, 3H);

[0039] 13 C NMR (101 MHz, CDCl3) δ 190.3, 163.9, 163.3, 140.6, 138.7, 133.1,131.6, 129.2, 128.8, 128.3, 127.7, 114.1, 19.2;

[0040] HRMS m / z (ESI) calculated for C17 H 14 ClO3+ (M+) + : 301.0626, found: 301.0621.

[0041] Example 2

[0042] A method for preparing α-carbonyl alkenyl ester compounds with the following structure:

[0043]

[0044] Allenone (0.22 mmol) and 10-hydroxydecenoic acid (0.2 mmol) were added to a clean 4 mL reaction flask, and 2 mL of CH2Cl2 was added as solvent. The reaction was carried out at room temperature for 24 h, and the reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product, a white solid, with a yield of 88%.

[0045] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ7.83 (d, J = 7.1 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.09 – 6.99 (m, 1H), 6.76 (s,1H), 5.82 (d, J = 15.6 Hz, 1H), 3.52 (d, J = 2.7 Hz, 2H), 2.67 (s, 1H), 2.35(s, 3H), 2.16 (q, J = 6.9, 6.5 Hz, 2H), 1.43 (d, J = 29.3 Hz, 4H), 1.24 (s,6H);

[0046] 13 C NMR (101 MHz, CDCl3) δ190.3, 164.0, 163.7, 152.7, 138.5, 132.7,128.4, 128.0, 120.0, 113.2, 62.4, 32.5, 32.2, 29.0, 28.9, 27.6, 25.5, 18.9;

[0047] HRMS m / z (ESI) calculated for C 20 H 27 O4+(M+) + :331.1904, found:331.1900.

[0048] Example 3

[0049] A method for preparing α-carbonyl alkenyl ester compounds with the following structure:

[0050]

[0051] Allenone (0.20 mmol) and 10-hydroxyalkanoic acid (0.2 mmol) were added to a clean 4 mL reaction flask, and 2 mL of CH2Cl2 was added as solvent. The reaction was carried out at room temperature for 24 h, and the reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain a pure product, a white solid, with a yield of 91%.

[0052] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ7.91 (d, J = 7.5 Hz, 2H), 7.54(t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 6.77 (s, 1H), 3.63 (t, J = 6.6Hz, 2H), 2.47 (t, J = 7.5 Hz, 2H), 2.39 (s, 3H), 1.73 – 1.66 (m, 2H), 1.57 –1.53 (m, 2H), 1.30 (d, J = 15.1 Hz, 10H);

[0053] 13 C NMR (101 MHz, CDCl3) δ190.6, 171.4, 164.1, 138.8, 133.0, 128.7,128.3, 113.6, 63.2, 34.6, 32.9, 29.7, 29.6, 29.5, 29.2, 25.9, 24.9, 19.2;

[0054] HRMS m / z (ESI) calculated for C 20 H 29 O4+(M+) + :333.2060, found :333.2055.

[0055] Example 4

[0056] A method for preparing α-carbonyl alkenyl ester compounds with the following structure:

[0057]

[0058] Add 0.20 mmol of acetylacetamide and 0.2 mmol of (8-((2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutamido)octanoic acid to a clean 4 mL reaction flask, add 2 mL of CH2Cl2 as solvent, react at room temperature for 24 h, and detect by TLC. After the reaction is completed, concentrate the solvent and precipitate by column chromatography to obtain the pure product, a white solid, with a yield of 88%.

[0059] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ7.90 (d, J = 7.3 Hz, 2H), 7.54(t, J = 7.3 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 7.33 (d, J = 3.8 Hz, 5H), 6.77(s, 1H), 6.65 (s, 1H), 5.88 (d, J = 7.9 Hz, 1H), 5.17 – 5.07 (m, 2H), 4.34 (d, J = 6.1 Hz, 1H), 4.12 – 4.02 (m, 1H), 3.67 (s, 1H), 3.29 – 3.15 (m, 2H),2.45 (t, J = 7.5 Hz, 2H), 2.38 (s, 3H), 1.76 – 1.63 (m, 2H), 1.55 – 1.44 (m,2H), 1.33 (s, 4H), 1.15 (d, J = 6.4 Hz, 3H);

[0060] 13 C NMR (101 MHz, CDCl3) δ 190.5, 171.2, 171.0, 171.0, 163.9, 157.1,138.7, 136.1, 132.9, 128.7, 128.7, 128.4, 128.2, 128.1, 113.6, 67.4, 66.8,58.5, 39.5, 34.5, 28.9, 28.9, 26.6, 24.7, 19.1, 18.3;

[0061] HRMS m / z (ESI) calculated for C 30 H 39 N₂O₇⁺(M⁺) + :539.2752, found :539.2747.

[0062] Example 5

[0063] A method for preparing α-carbonyl alkenyl ester compounds with the following structure:

[0064]

[0065] Allenone (0.20 mmol) and (12-hydroxydodecanoyl)-L-phenylalanine (0.2 mmol) were added to a clean 4 mL reaction flask, and 2 mL of CH2Cl2 was added as solvent. The reaction was carried out at room temperature for 20 h, and the reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product, a white solid, with a yield of 90%.

[0066] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 7.8 Hz, 2H), 7.55 (t, J = 7.3 Hz, 1H), 7.46 (t, J = 7.6 Hz, 2H), 7.35 – 7.27 (m, 3H), 7.21(d, J = 7.4 Hz, 2H), 6.64 (s, 1H), 6.08 (d, J = 7.5 Hz, 1H), 4.98 (q, J = 6.7Hz, 1H), 3.62 (t, J = 6.6 Hz, 2H), 3.20 (d, J = 6.5 Hz, 2H), 2.33 (s, 3H),2.21 (t, J = 7.5 Hz, 2H), 1.84 (s, 1H), 1.65 – 1.58 (m, 2H), 1.57 – 1.50 (m, 2H), 1.32 – 1.23 (m, 14H);

[0067] 13 C NMR (101 MHz, CDCl3) δ 190.2, 173.2, 169.7, 163.3, 138.5, 135.5,133.1, 129.4, 128.9, 128.7, 128.3, 127.5, 113.9, 63.0, 53.3, 37.9, 36.5,32.8, 29.6, 29.5, 29.5, 29.4, 29.4, 29.2, 25.8, 25.6, 18.8;

[0068] HRMS m / z (ESI) calculated for C 31 H 42 NO5+(M+)+ :508.3057, found :508.3051.

[0069] Examples 6-14 below describe the preparation of ester compounds.

[0070] Example 6

[0071] A method for preparing ester compounds with the following structure:

[0072]

[0073] In a clean 4 mL reaction flask, add activated p-chlorobenzoic acid ester (0.20 mmol), phenol (0.22 mmol), and 4-pyrrolylpyridine (0.04 mmol); add 2 mL of MeCN (i.e., acetonitrile) as solvent, react at room temperature for 2 h, and detect by TLC. After the reaction is complete, concentrate the solvent and precipitate by column chromatography to obtain the pure product, a pale yellow solid, with a yield of 95%.

[0074] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ 8.16 – 8.11 (d, 2H), 7.52 –7.47 (d, 2H), 7.43 (t, J = 7.9 Hz, 2H), 7.32 – 7.26 (t, 1H), 7.23 – 7.18 (d,2H);

[0075] 13 C NMR (100 MHz, CDCl3) δ 164.34, 150.80, 140.14, 131.55, 129.55, 128.96, 128.06, 126.04, 121.62;

[0076] HRMS m / z (ESI) calculated for C 13 H 10 ClO2+(M+)+:233.0364, found:233.0358.

[0077] Based on Example 6 above, only the solvent was replaced with dichloromethane, while the other conditions remained unchanged, and the yield was 80%.

[0078] Based on Example 6 above, only the solvent was replaced with toluene, while the other conditions remained unchanged, and the yield was 74%.

[0079] Based on Example 6 above, only the solvent was replaced with tetrahydrofuran, while the other conditions remained unchanged, and the yield was 70%.

[0080] Based on Example 6 above, only the solvent was replaced with acetone, while the other conditions remained unchanged, and the yield was 60%.

[0081] Based on Example 6 above, only the solvent was replaced with N,N-dimethylformamide, and the other conditions remained unchanged, resulting in a yield of 88%.

[0082] Based on Example 6 above, only the catalyst was replaced with triethylamine, and the other conditions remained unchanged, resulting in a yield of 90%.

[0083] Based on Example 6 above, only the catalyst was replaced with N,N-diisopropylethylamine, and the other conditions remained unchanged, resulting in a yield of 91%.

[0084] Based on Example 6 above, only the substrate amount was replaced with activated p-chlorobenzoic acid ester (0.20 mmol) and phenol (0.15 mmol), while the other conditions remained unchanged, and the yield was 56%.

[0085] Based on Example 6 above, only the substrate amounts were replaced with activated p-chlorobenzoic acid ester (0.20 mmol) and phenol (0.20 mmol), while all other conditions remained unchanged. The resulting yield was 82%.

[0086] Example 7

[0087] A method for preparing ester compounds with the following structure:

[0088]

[0089] In a clean 4 mL reaction flask, add activated p-chlorobenzoic acid ester (0.20 mmol), N-CBZ-L-tyrosine methyl ester (0.22 mmol), and 4-pyrrolidine pyridine (0.04 mmol); add 2 mL of MeCN (i.e., acetonitrile) as solvent, react at room temperature for 1 h, and detect by TLC. After the reaction is complete, concentrate the solvent to obtain the pure product, a white solid, with a yield of 85%.

[0090] Its structure confirms the data, such as Figure 1 and Figure 2 As shown: 1H NMR (400 MHz, CDCl3) δ 8.12 (d, J =8.5 Hz, 2H), 7.48 (d, J = 8.5 Hz, 2H), 7.38 – 7.30 (m, 5H), 7.18 – 7.11 (m,4H), 5.36 (s, 1H), 5.15 – 5.07 (m, 2H), 4.74 – 4.59 (m, 1H), 3.73 (s, 3H), 3.21 – 3.05 (m, 2H);

[0091] 13 C NMR (101 MHz, CDCl3) δ 171.9, 164.3, 155.7, 149.9, 140.3, 136.3,133.7, 131.6, 130.5, 129.1, 128.6, 128.3, 128.2, 128.0, 121.8, 67.1, 54.9,52.5, 37.7;

[0092] HRMS m / z (ESI) calculated for C 25 H 23 ClNO6+(M+) + :468.1208, found:468.1211.

[0093] Example 8

[0094] A method for preparing ester compounds with the following structure:

[0095]

[0096] In a clean 4 mL reaction flask, add activated p-chlorobenzoic acid ester (0.20 mmol), diacetone galactose (0.22 mmol), and 4-pyrrolylpyridine (0.04 mmol); add 2 mL of MeCN as solvent, react at room temperature for 8 h, and detect by TLC. After the reaction is complete, concentrate the solvent and column chromatography to obtain the pure product, a colorless oily liquid, with a yield of 93%.

[0097] Its structural confirmation data: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.0 Hz, 2H),7.41 (d, J = 6.9 Hz, 2H), 5.57 (d, J = 3.8 Hz, 1H), 4.66 (d, J = 7.8 Hz, 1H),4.56 – 4.48 (m, 1H), 4.47 – 4.39 (m, 1H), 4.38 – 4.30 (m, 2H), 4.21 – 4.13(m, 1H), 1.51 (s, 3H), 1.48 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H);

[0098] 13 C NMR (101 MHz, CDCl3) δ 165.7, 139.6, 131.2, 128.8, 128.6, 109.8,108.9, 96.4, 71.2, 70.8, 70.6, 66.2, 64.3, 26.1, 26.1, 25.1, 24.6;

[0099] HRMS m / z (ESI) calculated for C 19 H 24 ClO7+(M+) + :399.1205, found:399.1201.

[0100] Example 9

[0101] A method for preparing ester compounds with the following structure:

[0102]

[0103] In a clean 4 mL reaction flask, add activated p-chlorobenzoic acid ester (0.20 mmol), 2-thiophene methanol (0.22 mmol), and 4-pyrrolylpyridine (0.04 mmol); add 2 mL MeCN as solvent, react at room temperature for 2 h, and detect by TLC. After the reaction is complete, concentrate the solvent and precipitate by column chromatography to obtain the pure product, a white solid, with a yield of 85%.

[0104] Its structural confirmation data: 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 8.6 Hz, 1H), 7.44 – 7.32 (m, 2H), 7.18 (d, J = 3.3 Hz, 1H), 7.01 (dd, J = 5.1, 3.5 Hz,1H), 5.51 (s, 2H);

[0105] 13 C NMR (101 MHz, CDCl3) δ 165.5, 139.7, 137.8, 131.3, 128.9, 128.5,128.5, 127.1, 127.0, 61.4;

[0106] HRMS m / z (ESI) calculated for C 12 H 10 ClO2S+(M+) + :253.0085, found:253.0079.

[0107] Example 10

[0108] A method for preparing ester compounds with the following structure:

[0109]

[0110] In a clean 4 mL reaction flask, add activated p-chlorobenzoic acid ester (0.20 mmol), trifluoroethanol (0.22 mmol), and 4-pyrrolylpyridine (0.04 mmol); add 2 mL MeCN as solvent, react at room temperature for 30 min, and detect by TLC. After the reaction is complete, concentrate the solvent and precipitate by column chromatography to obtain the pure product, a white solid, with a yield of 87%.

[0111] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δ 8.04 – 7.99 (m, 2H), 7.49 – 7.43 (m, 2H), 4.70 (q, J = 8.4 Hz, 2H);

[0112] 13 C NMR (101 MHz, CDCl3) δ 164.3, 140.7, 131.5, 129.2, 127.3, 127.0,124.5, 121.8, 119.0, 61.6, 61.3, 60.9, 60.5. (J C-F= 277.2 Hz), 61.6 (J C-F =36.8 Hz);

[0113] HRMS m / z (ESI) calculated for C9H7ClF3O2+(M+) + :239.0081, found:239.0075.

[0114] Example 11

[0115] A method for preparing ester compounds with the following structure:

[0116]

[0117] Activated 2-naphthoic acid ester (0.20 mmol), p-hydroxybenzonitrile (0.22 mmol), and 4-pyrrolidinylpyridine (0.04 mmol) were added to a clean 4 mL reaction flask. 2 mL of MeCN was added as solvent, and the reaction was carried out at room temperature for 2 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product, a white solid, with a yield of 83%.

[0118] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δ 8.78 (s, 1H), 8.16 (dd, J = 8.6, 1.7 Hz, 1H), 8.04 – 7.90 (m, 3H), 7.80 – 7.72 (m, 2H), 7.70 –7.56 (m, 2H), 7.42 (d, J = 8.8 Hz, 2H);

[0119] 13 C NMR (101 MHz, CDCl3) δ 164.5, 154.4, 136.0, 133.8, 132.5, 132.3,129.5, 129.0, 128.7, 127.9, 127.1, 125.8, 125.3, 123.0, 118.3, 109.9;

[0120] HRMS m / z (ESI) calculated for C 18 H 12 NO2+(M+) + :274.0863, found:274.0858.

[0121] Example 12

[0122] A method for preparing ester compounds with the following structure:

[0123]

[0124] In a clean 4 mL reaction flask, add 0.20 mmol of activated phenylpropynic acid ester, 0.22 mmol of p-hydroxybenzonitrile, and 0.04 mmol of 4-pyrrolidinylpyridine; add 2 mL of MeCN as solvent, react at room temperature for 1 h, and detect by TLC. After the reaction is complete, concentrate the solvent and precipitate by column chromatography to obtain the pure product, a white solid, with a yield of 83%.

[0125] Its structural confirmation data: 1 H NMR (400 MHz, CDCl3) δ7.72 (d, J = 8.5 Hz, 2H),7.64 (d, J = 8.3 Hz, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 7.5 Hz, 2H),7.34 (d, J = 8.6 Hz, 2H);

[0126] 13 C NMR (101 MHz, CDCl3) δ 153.3, 151.2, 133.9, 133.8, 133.4, 133.3,131.5, 128.9, 128.8, 122.7, 122.7, 118.9, 118.1, 110.4, 89.9, 79.8;

[0127] HRMS m / z (ESI) calculated for C 16 H 10 NO2+(M+) + :248.0706, found:248.0703.

[0128] Example 13

[0129] A method for preparing ester compounds with the following structure:

[0130]

[0131] In a clean 4 mL reaction flask, N-benzyloxycarbonyl-L-phenylalanine activated ester (0.20 mmol), p-methoxyphenol (0.22 mmol), and 4-pyrrolidinylpyridine (0.04 mmol) were added; 2 mL of MeCN was added as solvent, and the reaction was carried out at room temperature for 1 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product as a white solid with a yield of 87%.

[0132] Its structure confirms the data, such as Figure 3 and Figure 4 As shown: 1 H NMR (400 MHz, Chloroform-d) δ 7.28 –7.19 (m, 8H), 7.13 (d, J = 6.5 Hz, 2H), 6.85 – 6.73 (m, 4H), 5.26 (d, J = 7.2Hz, 1H), 5.04 (s, 2H), 4.86 – 4.74 (m, 1H), 3.70 (s, 3H), 3.17 (d, J = 5.9Hz, 2H);

[0133] 13 C NMR (101 MHz, CDCl3) δ 170.6, 157.6, 155.8, 143.9, 136.3, 135.6,129.6, 128.9, 128.7, 128.3, 128.2, 127.5, 122.1, 114.6, 67.2, 55.7, 55.1,38.4;

[0134] HRMS m / z (ESI) calculated for C 24 H 24 NO5+(M+) + :406.1649, found:406.1644.

[0135] Example 14

[0136] A method for preparing ester compounds with the following structure:

[0137]

[0138] In a clean 4 mL reaction flask, N-benzyloxycarbonyl-L-alanine-L-phenylalanine activated ester (0.20 mmol), p-methoxyphenol (0.22 mmol), and 4-pyrrolidinylpyridine (0.04 mmol) were added; 2 mL of MeCN was added as solvent, and the reaction was carried out at room temperature for 12 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product as a white solid with a yield of 85%.

[0139] Its structural confirmation data: 1H NMR (400 MHz, Chloroform-d) δ 7.38 – 7.28 (m,8H), 7.21 (d, J = 6.8 Hz, 2H), 6.92 – 6.85 (m, 4H), 6.78 (d, J = 6.8 Hz, 1H), 5.44 (d, J = 7.1 Hz, 1H), 5.12 – 5.03 (m, 3H), 4.40 – 4.18 (m, 1H), 3.78 (s, 3H), 3.23 (d, J = 5.9 Hz, 2H), 1.35 (d, J = 6.9 Hz, 3H);

[0140] 13 C NMR (101 MHz, CDCl3) δ172.2, 170.4, 157.5, 156.0, 143.8, 136.2,135.6, 129.5, 128.8, 128.6, 128.3, 128.1, 127.4, 122.1, 114.5, 67.1, 55.7,53.5, 50.5, 37.9, 18.5;

[0141] HRMS m / z (ESI) calculated for C 27 H 29 N₂O₆⁺(M⁺) + :477.2020, found:477.2018.

[0142] Based on Example 14 above, only the solvent was replaced with dichloromethane, and the other conditions remained unchanged, resulting in a yield of 65%.

[0143] Based on Example 14 above, only the solvent was replaced with tetrahydrofuran, and the other conditions remained unchanged, resulting in a yield of 55%.

[0144] Based on Example 14 above, only the solvent was replaced with ethyl acetate, and the other conditions remained unchanged, resulting in a yield of 50%.

[0145] Based on Example 14 above, only the catalyst p-toluenesulfonic acid was replaced with p-chlorobenzenesulfonic acid, while the other conditions remained unchanged, and the yield was 73%.

[0146] Based on Example 14 above, only the catalyst p-toluenesulfonic acid was replaced with methanesulfonic acid, while the other conditions remained unchanged, and the yield was 58%.

[0147] Based on Example 14 above, only the amount of the catalyst p-toluenesulfonic acid was replaced with 0.1 mol, while all other conditions remained unchanged, resulting in a yield of 60%.

[0148] Based on Example 14 above, only the amount of the catalyst p-toluenesulfonic acid was replaced with 0.3 mol, while the other conditions remained unchanged, and the yield was 52%.

[0149] Examples 15-23 below describe the preparation of macrocyclic lactone compounds.

[0150] Example 15

[0151] A method for preparing macrocyclic lactone compounds with the following structure:

[0152]

[0153] Activated 10-hydroxydecanoic acid ester (0.10 mmol) and p-toluenesulfonic acid (0.02 mmol) were added to a clean 50 mL round-bottom flask. 20 mL of 1,2-dichloroethane was added as solvent, and the reaction was carried out at room temperature for 48 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product, a white solid, with a yield of 80%.

[0154] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δ 4.10 (t, J = 5.8 Hz, 2H), 2.30 (t, J = 7.0 Hz, 2H), 1.67 – 1.59 (m, 4H), 1.32 – 1.25 (m, 10H);

[0155] 13 C NMR (101 MHz, CDCl3) δ 174.1, 64.2, 35.0, 29.6, 29.3, 29.2, 29.1,28.8, 26.2, 25.5;

[0156] HRMS m / z (ESI) calculated for C 10 H 19 O2+(M+) + :171.1380, found: 171.1375.

[0157] Example 16

[0158] A method for preparing macrocyclic lactone compounds with the following structure:

[0159]

[0160] Activated 10-hydroxydecenoic acid ester (0.10 mmol) and p-toluenesulfonic acid (0.02 mmol) were added to a clean 50 mL round-bottom flask. 20 mL of 1,2-dichloroethane was added as solvent, and the reaction was carried out at room temperature for 48 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product, a white solid, with a yield of 52%.

[0161] Its structure confirms the data, such as Figure 5 and Figure 6 As shown: 1 H NMR (400 MHz, Chloroform-d) δ 6.90 (dt, J = 15.3, 7.1 Hz, 1H), 5.78 (d, J = 15.7 Hz, 1H), 4.19 – 4.13 (m, 2H), 2.19 (q, J = 7.5 Hz, 2H), 1.66 – 1.58 (m, 2H), 1.48 – 1.40 (m, 2H), 1.36 –1.27 (m, 6H);

[0162] 13 C NMR (101 MHz, CDCl3) δ166.8, 149.3, 121.8, 64.0, 32.0, 28.8, 28.8,28.5, 27.5, 25.8;

[0163] HRMS m / z (ESI) calculated for C 10 H 17 O2+(M+) + :169.1223, found: 169.1220.

[0164] Example 17

[0165] A method for preparing macrocyclic lactone compounds with the following structure:

[0166]

[0167] In a clean 50 mL round-bottom flask, add 0.10 mmol of (12-hydroxydodecanoyl)-L-phenylalanine activated ester and 0.02 mmol of p-toluenesulfonic acid. Add 20 mL of 1,2-dichloroethane as solvent and react at room temperature for 48 h. Detect the reaction by TLC. After the reaction is complete, concentrate the solvent and perform column chromatography to obtain the pure product as a white solid, with a yield of 55%.

[0168] Its structural confirmation data: 1H NMR (400 MHz, Chloroform-d) δ7.29 (d, J = 6.9 Hz,1H), 7.25 (dd, J = 7.4, 4.9 Hz, 2H), 7.15 – 7.12 (m, 2H), 5.83 (d, J = 8.4Hz, 1H), 4.94 (dt, J = 8.5, 6.1 Hz, 1H), 4.29 – 4.22 (m, 1H), 4.02 (d, J =14.8 Hz, 1H), 3.10 (dd, J = 6.0, 4.2 Hz, 2H), 2.31 – 2.25 (m, 1H), 2.12 –2.03 (m, 1H), 1.60 – 1.41 (m, 4H), 1.26 (d, J = 12.2 Hz, 14H);

[0169] 13 C NMR (101 MHz, CDCl3) δ 172.7, 171.6, 136.2, 129.5, 128.7, 127.2, 65.4, 53.4, 38.4, 36.8, 28.3, 27.2, 27.1, 26.7, 26.7, 26.4, 25.3, 25.0, 24.3;

[0170] HRMS m / z (ESI) calculated for C 21 H 32 NO3+(M+) + :346.2377, found:346.2375.

[0171] Example 18

[0172] A method for preparing macrocyclic lactone compounds with the following structure:

[0173]

[0174] In a clean 50 mL round-bottom flask, add 0.10 mmol of activated ester of (8-((2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutamido) acid 12-((2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutamido)dodecanoic acid and 0.02 mmol of p-toluenesulfonic acid. Add 20 mL of 1,2-dichloroethane as solvent, and react at room temperature for 48 h. Detect the reaction by TLC. After the reaction is complete, concentrate the solvent and perform column chromatography to obtain a pure product as a white solid, with a yield of 52%.

[0175] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δ7.38 – 7.34 (m, 5H), 6.13 – 6.07 (m, 1H), 5.63 (d, J = 8.1 Hz, 1H), 5.45 – 5.41 (m, 1H), 5.14 (s,2H), 4.32 – 4.25 (m, 1H), 3.36 – 3.22 (m, 2H), 2.26 (t, J = 7.3 Hz, 2H), 1.62– 1.44 (m, 4H), 1.33 – 1.28 (m, 14H), 1.23 (d, J = 6.5 Hz, 3H);

[0176] 13 C NMR (101 MHz, CDCl3) δ172.0, 168.5, 156.5, 136.0, 128.8, 128.6,128.4, 70.1, 67.6, 58.1, 39.6, 34.1, 29.1, 27.2, 26.8, 26.6, 26.6, 26.2,26.0, 25.5, 23.9, 16.2;

[0177] HRMS m / z (ESI) calculated for C 24 H 37 N₂O₅⁺(M⁺) + :433.2697, found:433.2695.

[0178] Example 19

[0179] A method for preparing macrocyclic lactone compounds with the following structure:

[0180]

[0181] In a clean 50 mL round-bottom flask, add (6S,9S,12S,15S)-6-benzyl-15-hydroxy-9,12-diisobutyl-17-methyl-5,8,11,14-tetraoxo-10-oxa-4,7,13-triazaoctadecanoic acid activated ester (0.10 mmol) and 4-pyrrolidinylpyridine (0.02 mmol). Add 20 mL of 1,2-dichloroethane as solvent, react at room temperature for 1 h, and detect the reaction by TLC. After the reaction is complete, concentrate the solvent and perform column chromatography to obtain a pure product as a white solid, with a yield of 80%.

[0182] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δδ 7.30 – 7.19 (m, 6H),7.13 (d, J = 7.9 Hz, 1H), 7.03 – 6.88 (m, 1H), 5.29 – 5.12 (m, 1H), 5.00 –4.88 (m, 1H), 4.83 – 4.65 (m, 1H), 4.52 – 4.24 (m, 1H), 3.89 – 3.63 (m, 1H), 3.59 – 3.47 (m, 1H), 3.47 – 3.36 (m, 1H), 3.26 (dd, J = 13.7, 4.4 Hz, 1H),2.98 (dd, J = 13.5, 9.9 Hz, 1H), 1.78 – 1.63 (m, 6H), 1.56 – 1.39 (m, 3H), 1.02 – 0.95 (m, 9H), 0.93 (d, J = 5.3 Hz, 3H), 0.86 – 0.80 (m, 6H);

[0183] 13 C NMR (101 MHz, CDCl3) δ 171.9, 171.8, 171.8, 171.7, 170.6, 137.0,129.3, 128.6, 127.0, 74.9, 73.3, 54.4, 51.9, 40.5, 40.5, 39.6, 38.0, 35.2,34.0, 25.1, 24.6, 24.5, 23.2, 23.1, 22.9, 22.0, 21.9, 21.6;

[0184] HRMS m / z (ESI) calculated for C 30 H 46 N3O7+(M+) + :560.3330, found:560.3325.

[0185] Example 20

[0186] A method for preparing macrocyclic lactone compounds with the following structure:

[0187]

[0188] Add N²-((benzyloxy)carbonyl)-D-altothreonyl-L-valine-L-valine-D-threonyl-N to a clean 50 mL round-bottom flask. 4 Triphenylmethyl-D-asparaginyl-D-alanine activated ester (0.10 mmol), p-toluenesulfonic acid (0.02 mmol). 20 mL of 1,2-dichloroethane was added as solvent, and the reaction was carried out at room temperature for 24 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product as a white solid with a yield of 50%.

[0189] Its structural confirmation data: 1 H NMR (400 MHz, Chloroform-d) δ8.50 (s, 1H), 8.30 –8.20 (m, 2H), 8.20 – 8.10 (m, 1H), 7.36 – 7.30 (m, 5H), 7.25 – 7.17 (m, 15H),7.06 – 6.93 (m, 2H), 5.35 – 5.24 (m, 1H), 5.14 – 5.00 (m, 2H), 4.54 – 4.45(m, 1H), 4.38 – 4.31 (m, 1H), 4.29 – 4.23 (m, 1H), 4.22 – 4.13 (m, 3H), 4.00– 3.93 (m, 1H), 3.18 – 3.04 (m, 1H), 2.65 – 2.53 (m, 1H), 2.05 – 1.98 (m,1H), 1.87 – 1.71 (m, 1H), 1.26 – 1.23 (m, 2H), 1.21 – 1.15 (m, 6H), 1.12 (s,9H), 1.06 (d, J = 6.2 Hz, 3H), 0.90 – 0.86 (m, 6H), 0.81 (d, J = 6.5 Hz, 3H), 0.72 (d, J = 6.7 Hz, 3H);

[0190] 13C NMR (101 MHz, CDCl3) δ172.4, 170.5, 170.3, 170.2, 169.9, 169.8,168.5, 156.7, 144.9, 136.9, 128.7, 128.4, 127.9, 127.6, 127.4, 126.3, 73.6,70.0, 69.5, 66.0, 65.9, 59.9, 59.5, 56.8, 56.7, 50.3, 47.6, 37.6, 31.8, 29.1,28.2, 19.4, 19.0, 18.0, 17.5, 16.7;

[0191] HRMS m / z (ESI) calculated for C 52 H 64 N7O 11 +(M+) + :962.4658, found:962.4657.

[0192] Example 21

[0193] A method for preparing macrocyclic lactone compounds with the following structure:

[0194]

[0195] In a clean 50 mL round-bottom flask, add 0.10 mmol of activated ester of (S)-4-(2-((S)-1-(((benzyloxy)carbonyl)-L-threonyl-L-alanyl-L-leucyl)pyrrolidine-2-formamido)acetamyl)-5-(tert-butoxy)-5-oxovalerate and 0.02 mmol of 4-pyrrolylpyridine. Add 20 mL of 1,2-dichloroethane as solvent, and react at room temperature for 1 h. Detect the reaction by TLC. After the reaction is complete, concentrate the solvent and perform column chromatography to obtain a pure product as a white solid, with a yield of 88%.

[0196] Its structural confirmation data: 1H NMR (400 MHz, Chloroform-d) δ8.82 – 8.69 (m, 1H), 8.53 – 8.38 (m, 1H), 7.40 – 7.35 (m, 4H), 7.34 – 7.31 (m, 1H), 7.26 (d, J =5.9 Hz, 1H), 7.00 (d, J = 8.6 Hz, 1H), 6.39 (d, J = 7.5 Hz, 1H), 5.64 – 5.45(m, 1H), 5.06 (s, 2H), 4.60 – 4.46 (m, 1H), 4.39 – 4.32 (m, 1H), 4.21 – 4.14(m, 2H), 4.04 – 3.99 (m, 1H), 3.91 – 3.84 (m, 2H), 3.57 – 3.49 (m, 2H), 3.17 – 3.04 (m, 1H), 2.68 – 2.58 (m, 1H), 2.18 – 1.85 (m, 7H), 1.80 – 1.54 (m,4H), 1.39 (s, 9H), 1.28 – 1.24 (m, 3H), 0.94 – 0.87 (m, 6H);

[0197] 13 C NMR (101 MHz, CDCl3) δ172.2, 171.9, 171.7, 170.7, 170.2, 169.3,169.1, 156.5, 136.7, 128.3, 127.8, 127.6, 80.6, 70.1, 65.7, 60.2, 57.5, 52.3,48.8, 47.2, 45.7, 42.1, 38.8, 30.0, 28.8, 27.6, 25.4, 24.9, 24.0, 22.9, 21.3,17.7, 16.6;

[0198] HRMS m / z (ESI) calculated for C 37 H 55 N6O 11 +(M+) + :759.3923, found:759.3921.

[0199] Example 22

[0200] A method for preparing macrocyclic lactone compounds with the following structure:

[0201]

[0202] In a clean 50 mL round-bottom flask, add (S)-4-(2-((S)-1-(((S)-2-((2S,3R)-2-(((benzyloxy)carbonyl)amino)-3-hydroxybutamido)propyl)-L-phenylalanyl-L-leucyl)pyrrolidine-2-carboxamido)acetamyl)-5-(tert-butoxy)-5-oxovalerate activated ester (0.10 mmol) and 4-pyrrolidinylpyridine (0.02 mmol); add 20 mL of 1,2-dichloroethane as solvent, react at room temperature for 1 h, and detect by TLC. After the reaction is complete, concentrate the solvent and precipitate by column chromatography to obtain the pure product as a white solid with a yield of 92%.

[0203] Its structural confirmation data: 1H NMR (400 MHz, Chloroform-d) δ8.70 – 8.52 (m, 1H),8.28 (d, J = 6.5 Hz, 1H), 7.91 (d, J = 7.3 Hz, 1H), 7.47 (d, J = 6.4 Hz, 1H),7.38 – 7.32 (m, 4H), 7.29 – 7.25 (m, 2H), 7.23 – 7.19 (m, 3H), 5.41 – 5.27(m, 1H), 5.13 – 5.04 (m, 2H), 4.77 – 4.48 (m, 1H), 4.37 – 4.30 (m, 2H), 4.21– 4.16 (m, 1H), 4.15 – 4.07 (m, 1H), 4.07 – 4.01 (m, 1H), 3.87 (dd, J = 17.2,7.3 Hz, 1H), 3.75 – 3.68 (m, 1H), 3.53 – 3.41 (m, 2H), 3.37 – 3.28 (m, 2H),3.21 (dd, J = 13.9, 4.5 Hz, 1H), 3.00 (dd, J = 13.9, 9.7 Hz, 1H), 2.48 – 2.30(m, 1H), 2.27 – 2.08 (m, 2H), 2.05 – 1.82 (m, 5H), 1.81 – 1.71 (m, 1H), 1.61– 1.53 (m, 1H), 1.39 (s, 9H), 1.37 – 1.31 (m, 2H), 1.17 (d, J = 6.4 Hz, 3H),1.02 (d, J = 7.1 Hz, 3H), 0.89 (d, J = 6.5 Hz, 3H), 0.82 (d, J = 6.6 Hz, 3H);

[0204] 13C NMR (101 MHz, CDCl3) δ 172.3, 172.0, 171.9, 170.7, 170.6, 170.0,169.1, 168.8, 156.7, 138.1, 136.8, 129.2, 128.4, 128.2, 127.9, 127.8, 126.3,80.7, 69.9, 65.8, 60.5, 57.2, 54.5, 52.5, 48.7, 47.1, 42.1, 35.5, 30.2, 28.7,27.7, 27.6, 26.2, 25.1, 23.7, 23.3, 21.1, 18.0, 16.3;

[0205] HRMS m / z (ESI) calculated for C 46 H 66 N7O 11 +(M+) + :892.4815, found:892.4812.

[0206] Example 23

[0207] A method for preparing macrocyclic lactone compounds with the following structure:

[0208]

[0209] Add NN to a clean 50mL round-bottom flask α -(((9H-fluorene-9-yl)methoxy)carbonyl)-1-(tert-butoxycarbonyl)-L-tryptophanyl-L-threonyl-L-isoleucylglycyl)-O-(tert-butyl)-L-serine activated ester (0.10 mmol), 4-pyrrolidinylpyridine (0.01 mmol); 20 mL of 1,2-dichloromethane was added as solvent, and the reaction was carried out at room temperature for 8 h. The reaction was detected by TLC. After the reaction was completed, the solvent was concentrated and column chromatography was performed to obtain the pure product as a white solid with a yield of 48%.

[0210] Its structure confirms the data, such as Figure 7 and Figure 8 As shown: 1H NMR (400 MHz, DMSO-d6) δ 8.60 (t, J= 5.7 Hz, 1H), 8.31 (dd, J = 16.3, 8.7 Hz, 2H), 8.03 (d, J = 8.0 Hz, 1H),7.85 (d, J = 7.5 Hz, 2H), 7.76 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.8 Hz, 3H),7.53 (d, J = 8.4 Hz, 1H), 7.35 (dt, J = 13.6, 7.5 Hz, 3H), 7.23 (dt, J =15.6, 7.5 Hz, 3H), 5.09 – 4.91 (m, 1H), 4.69 – 4.52 (m, 2H), 4.43 (dt, J =9.0, 4.7 Hz, 1H), 4.26 – 4.08 (m, 4H), 3.99 (dd, J = 14.8, 6.6 Hz, 1H), 3.67– 3.52 (m, 2H), 3.15 – 2.90 (m, 2H), 1.82 (d, J = 7.7 Hz, 1H), 1.56 (s, 10H),1.48 (dd, J = 11.7, 6.2 Hz, 1H), 1.14 (s, 13H), 1.03 – 0.96 (m, 1H), 0.81 (t,J = 7.1 Hz, 6H);

[0211] 13 C NMR (101 MHz, DMSO-D6) δ 171.7, 171.6, 169.3, 168.7, 167.2, 155.9,155.9, 149.1, 143.7, 140.7, 134.7, 130.4, 127.7, 127.1, 125.3, 125.2, 124.4,124.2, 122.5, 120.2, 119.6, 116.7, 114.7, 83.5, 73.2, 70.0, 65.8, 61.5, 58.6,54.5, 54.4, 53.9, 53.1, 46.6, 43.5, 34.3, 27.7, 27.3, 24.5, 15.4, 14.1, 10.5.

[0212] HRMS m / z (ESI) calculated for C 50 H 63N6O 11 +(M+)+:923.4549, found:923.4541.

[0213] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for preparing ester compounds, characterized in that, The method is as follows: In an organic solvent, using an alkali as a catalyst, α-carbonyl alkenyl ester compound 1 reacts with alcohol or phenol compound 2 at a reaction temperature of -10 to 80°C to generate ester compound 3, the reaction formula of which is shown in formula (1): ， In equation (1), R 1 The compound is selected from one of the following: C1-C22 alkyl groups, C4-C10 aryl groups, substituted aryl groups, heterocyclic aryl groups, alkenyl groups, alkynyl groups, protected α-aminoalkyl groups, protected β-aminoalkyl groups, protected γ-aminoalkyl groups, and protected polypeptide chain alkyl groups; preferably methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, cyclohexyl, adamantyl, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, styryl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl. One of the following: alkyl, phenylethynyl, phenyl, naphthyl, anthraceneyl, phenanthryl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyridyl, pyrroleyl, indoleyl, indolemethyl, indazole, furanyl, benzofuranyl, thiopheneyl, benzothiopheneyl, quinolinyl, styrylyl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α-aminoalkyl, protected β-aminoalkyl, protected γ-aminoalkyl, protected polypeptide chain alkyl; R 2 Selected from C1-C8 alkyl groups, C3-C10 cycloalkyl groups, aryl groups, substituted aryl groups, alkenyl groups, alkynyl groups, polypeptides containing serine residues, and polypeptides containing tyrosine residues; preferably ethyl, n-hexyl, cyclohexyl, phenyl, naphthyl, benzyl, p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl, 2-pyridyl, 2-thiophenyl, 2-furanyl, polypeptides containing serine residues, and polypeptides containing tyrosine residues; The molar ratio of α-carbonyl alkenyl esters to alcohols or phenols is 1:(1 to 10).

2. The method according to claim 1, characterized in that, The organic solvent is selected from one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetone, with acetonitrile being preferred.

3. The method according to claim 1, characterized in that, The alkali is selected from one or more of N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazolium, and pyridine; preferably 4-pyrrolylpyridine; the amount of alkali used ranges from 0.1 to 1 equivalent, preferably 0.2 equivalent.

4. The method according to claim 1, characterized in that, The reaction temperature is room temperature; the molar ratio of α-carbonyl alkenyl esters to alcohols or phenols is 1:1.

1.

5. A method for preparing macrocyclic lactone compounds, characterized in that, The method is as follows: In an organic solvent, with a base or acid as a catalyst, α-carbonyl alkenyl ester compound 4 containing hydroxyl groups undergoes an intramolecular hydroxyl reaction at a reaction temperature of -10 to 80°C to generate macrocyclic lactone compound 5, as shown in formula (2). ， In formula (2), compound 4 represents an α-carbonyl alkenyl ester compound containing hydroxyl groups; compound 5 represents a macrocyclic lactone compound with 6-24 member rings; and compound 6 represents a 1,3-dicarbonyl byproduct.

6. The method according to claim 5, characterized in that, The organic solvent is selected from one or more of dichloromethane, acetonitrile, 1,2-dichloroethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and acetone; preferably 1,2-dichloroethane.

7. The method according to claim 5, characterized in that, The base is selected from one or more of N,N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazolium, and pyridine; the acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, copper(II) trifluoromethanesulfonate, dextrorotatory camphorsulfonic acid, indium trifluoromethylcarbonate, and p-chlorobenzenesulfonic acid.

8. The method according to claim 7, characterized in that, The base is 4-pyrrolidinylpyridine; the acid is p-toluenesulfonic acid.

9. The method according to claim 5, characterized in that, The reaction temperature is room temperature.

10. The method according to claim 5, characterized in that, The catalytic range of the base or acid is 0.1-1 equivalent, preferably 0.2 equivalent.

Images