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CN-121990906-A - Method for preparing ester compounds and macrolide compounds

CN121990906ACN 121990906 ACN121990906 ACN 121990906ACN-121990906-A

Abstract

The invention discloses a method for preparing an ester compound and a macrolide compound, which belongs to the technical field of organic chemistry, wherein the preparation method of the ester compound is that an alpha-carbonyl alkenyl ester compound reacts with alcohol or phenol in an organic solvent under the catalysis of alkali, the preparation method of the macrolide compound is that the alpha-carbonyl alkenyl ester compound reacts with intramolecular hydroxyl in the organic solvent under the catalysis of alkali or acid, the method has the advantages of wide substrate range, high practicability, high yield, capability of inhibiting racemization of a carboxylic acid alpha-chiral center in the intermolecular esterification reaction and the macrolide reaction, mild reaction condition, simplicity, easiness in operation, wide substrate adaptability, non-racemization of a product and the like, and can be applied to complete synthesis of Brevicidine natural products containing a 13-membered cyclic ester peptide core structure.

Inventors

  • ZHAO JUNFENG
  • Lai Manting

Assignees

  • 广州医科大学

Dates

Publication Date
20260508
Application Date
20260306

Claims (10)

  1. 1. The method for preparing the ester compound is characterized in that in an organic solvent, an alkali is used as a catalyst, and the alpha-carbonyl alkenyl ester compound 1 reacts with alcohol or phenol compound 2 at the reaction temperature of-10-80 ℃ to generate an ester compound 3, wherein the reaction formula is shown in a formula (1): , R 1 in the formula (1) is selected from one of C1-C22 alkyl, C4-C10 aryl, substituted aryl, heterocyclic aryl, alkenyl, alkynyl, protected alpha-amino alkyl, protected beta-amino alkyl, protected gamma-amino alkyl and protected polypeptide chain alkyl; preferably one of 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, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthryl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyridyl, pyrrolyl, indolyl, indazolyl, furyl, benzofuranyl, thienyl, benzothienyl, quinolinyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α -aminoalkyl, protected β -aminoalkyl, protected γ -aminoalkyl, protected polypeptide chain alkyl; R 2 is selected from C1-C8 alkyl, C3-C10 cycloalkyl, aryl, substituted aryl, alkenyl, alkynyl, serine residue-containing polypeptide, tyrosine residue-containing polypeptide; preferably ethyl, n-hexyl, cyclohexyl, phenyl, naphthyl, benzyl, one of p-tolyl, p-methoxyphenyl, p-chlorophenyl, p-bromophenyl, 2-pyridyl, 2-thienyl, 2-furyl, serine residue-containing polypeptides having tyrosine residues; Wherein the molar ratio of the alpha-carbonyl alkenyl esters to the alcohol or the phenolic compound is 1 (1-10).
  2. 2. The method according to claim 1, wherein the organic solvent is selected from one or more of dichloromethane, acetonitrile, 1, 2-dichloroethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, N-dimethylformamide, acetone, preferably acetonitrile.
  3. 3. The method according to claim 1, wherein the base is selected from one or more of N, N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazole, pyridine, preferably 4-pyrrolidinylpyridine, and the amount of base is in the range of 0.1 to 1 equivalent, preferably 0.2 equivalent.
  4. 4. The method according to claim 1, wherein the reaction temperature is room temperature and the molar ratio of the alpha-carbonyl alkenyl esters to the alcohol or the phenolic compound is 1:1.1.
  5. 5. A method for preparing a macrolide compound is characterized in that in an organic solvent, an alkali or acid is used as a catalyst, and an alpha-carbonyl alkenyl ester compound 4 containing hydroxyl is subjected to intramolecular hydroxyl reaction at a reaction temperature of-10-80 ℃ to generate a macrolide compound 5, wherein the reaction formula is shown as a formula (2): , in the formula (2), the compound 4 represents an alpha-carbonyl alkenyl ester compound containing hydroxyl, the compound 5 represents a macrolide compound with a 6-24 membered ring, and the compound 6 represents a1, 3-dicarbonyl byproduct.
  6. 6. The method according to claim 5, wherein the organic solvent is selected from one or more of dichloromethane, acetonitrile, 1, 2-dichloroethane, chloroform, toluene, ethyl acetate, tetrahydrofuran, N-dimethylformamide, acetone, preferably 1, 2-dichloroethane.
  7. 7. The method according to claim 5, wherein the base is selected from one or more of N, N-diisopropylethylamine, triethylamine, sodium carbonate, potassium carbonate, 4-dimethylaminopyridine, 4-pyrrolidinylpyridine, cesium carbonate, sodium hydroxide, potassium hydroxide, imidazole, N-methylimidazole, pyridine, and the acid is selected from one or more of p-toluenesulfonic acid, methanesulfonic acid, copper (II) trifluoromethanesulfonic acid, dextromethorsulfonic acid, indium triflate, and p-chlorobenzenesulfonic acid.
  8. 8. The method of claim 7, wherein the base is 4-pyrrolidinylpyridine and the acid is p-toluenesulfonic acid.
  9. 9. The method of claim 5, wherein the reaction temperature is room temperature.
  10. 10. The process according to claim 5, wherein the base or acid is used in a catalytic range of 0.1 to 1 equivalent, preferably 0.2 equivalent.

Description

Method for preparing ester compounds and macrolide compounds Technical Field The invention relates to the technical field of organic chemistry, in particular to a method for preparing an ester compound and a macrolide compound. Background The esters and macrolide compounds are essential core intermediates and end products in the fields of medicines, pesticides, fragrances, high polymer materials and the like by virtue of the unique functional group structures and chemical activities thereof. In the medical field, macrolide antibiotics (such as erythromycin, azithromycin, clarithromycin) are first-line drugs for the treatment of bacterial infections, and their cyclic lactone structures impart excellent antibacterial activity and pharmacokinetic properties. In the perfume industry, macrolide compounds (such as cyclopentadecanolide and musk ketone analogues) are widely used for flavoring high-grade perfumes and cosmetics due to durable fragrance and good compatibility. In the field of high polymer materials, ester monomers can be used for preparing materials such as polyester, polyurethane and the like through polymerization reaction, and the performance of the materials directly determines key indexes such as mechanical strength, weather resistance and the like of a terminal product. Heretofore, numerous methods have been developed for the preparation of esters, including transition metal-catalyzed formation of C-O bonds, alkyne/alkene ring-closing metathesis, alkene coupling to build C-C bonds, and Nitrogen Heterocyclic Carbene (NHC) -catalyzed oxidative esterification of aldehydes. Among these methods, dehydration coupling reaction of carboxylic acid with alcohol or phenol starting material is an ideal strategy for preparing ester compounds because of easy availability of both. However, in order to remove water generated during the coupling process to push the equilibrium toward the esterification reaction, these reactions generally require high temperature, strong acid catalysts or dehydrating agents. Similar to the formation of amide bonds, the dehydration esterification reaction can be carried out under mild conditions by activating the carboxylic acid with a coupling agent. The use of conventional coupling agents (e.g., carbodiimides, phosphonium salts, ammonium/uronium salts) has a number of drawbacks, such as significant racemization of the alpha-chiral carboxylic acid, difficulty in product purification, and the like, and the high reaction temperature and limited substrate range are not suitable for later macrolide reactions, particularly in the total synthesis of natural products of complex macrolides. Among the macrolide preparation methods reported so far, the Yamaguchi reaction is the most common, but this method has some well-known problems including high sensitivity to moisture, racemization of the alpha-chiral containing hydroxy acid substrate, Z/E isomerization of the alpha, beta unsaturated hydroxy acid substrate, and very high temperature reaction conditions rendering it unsuitable for complex substrates. Furthermore, competing reactions involving dimerization in the intermolecular reactions of macrolides are also another concern in the industry, so macrolide reactions remain a laborious and challenging reaction. Therefore, searching for a mild, efficient and environment-friendly esterification method is a key problem focused by current scientific researchers. Disclosure of Invention The present invention has been made in view of the above problems, and an object of the present invention is to provide a method for producing an ester compound. In order to achieve the above purpose, the technical scheme adopted by the invention is as follows: the method for preparing the ester compound comprises the steps of reacting an alpha-carbonyl alkenyl ester compound 1 with alcohol or a phenolic compound 2 in an organic solvent by taking alkali as a catalyst, wherein the reaction temperature is-10-80 ℃, and an ester compound 3 is generated, and the reaction formula is shown as a formula (1): , In the formula (1), R1 is selected from one of C1-C22 alkyl, C4-C10 aryl, substituted aryl, heterocyclic aryl, alkenyl, alkynyl, protected alpha-amino alkyl, protected beta-amino alkyl, protected gamma-amino alkyl and protected polypeptide chain alkyl; preferably one of 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, phenylethynyl, phenyl, naphthyl, anthracenyl, phenanthryl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, pyridyl, pyrrolyl, indolyl, indazolyl, furyl, benzofuranyl, thienyl, benzothienyl, quinolinyl, styryl, phenylethynyl, benzyl, 11-hydroxyundecyl, pentadecyl, protected α -aminoalkyl, protected β -aminoalkyl, protected γ -aminoalk