CN107417594B

CN107417594B - Amide alcoholysis method

Info

Publication number: CN107417594B
Application number: CN201710317647.0A
Authority: CN
Inventors: 卢江平; 裴青蓝; 余金权; 张恩选
Original assignee: Kaileying Pharmaceutical Group (tianjin) Co Ltd
Current assignee: Kaileying Pharmaceutical Group (tianjin) Co Ltd
Priority date: 2017-05-08
Filing date: 2017-05-08
Publication date: 2020-03-27
Anticipated expiration: 2037-05-08
Also published as: CN107417594A

Abstract

The invention provides a method for alcoholysis of amides. The method comprises conducting alcoholysis of an amide-containing compound under basic conditions using an epoxy compound as an accelerator. The method is simple and easy to operate, the pure product can be obtained by simple conventional separation steps in the post-treatment, and meanwhile, the cost of the epoxy compound is low, so that the production operation cost and the risk and cost of three-waste treatment can be greatly reduced. When the method is used, the reaction conditions are mild, the method can be compatible with various different substituents and functional groups, good yield can be obtained for various amides with different structural types, and the application range of the substrate is wide. Namely, the invention provides an environment-friendly, economical and practical high-efficiency method for converting amide into more useful ester. The alcoholysis reaction is not influenced by impurities in a C-H activation reaction system in the previous step, intermediate purification steps are saved, and the C-H activation and amide alcoholysis two-step reaction can be carried out continuously.

Description

Amide alcoholysis method

Technical Field

The invention relates to the field of organic material synthesis, in particular to an amide alcoholysis method.

Background

Amide bonds, as a common functional group, are widely present in natural products such as proteins and synthetic compounds. It is generally believed that The resonance stability of The amide bond makes The amide a weaker electrophile (The structure of proteins: two hydrophilic configurations of The polypeptide in. Proc. Natl. Acad. Sci.1951,37,205) and that it is difficult to selectively open The C-N bond of The amide by chemical synthesis (Conversion of amides to esters by The key-catalyzed activity of amide C-N bonds. Nature 2015,524, 79).

-CONHAr_F(Ar_F＝p-CF₃C₆F₄) As an excellent amide directing group, it has very wide application in β -C-H activation reactions of various types, but has the disadvantage that it is difficult to remove 4(Ligand-Enabled β -C-H aryl of α -Amino Acids Using a Simple and practical Autoxiliary.J.Am.chem.Soc.2015, 137,3338) for some substrates, which greatly limits the further conversion and utilization of these C-H activated products, so it is necessary to develop a universal method for removing the directing group.

The existing methods for removing the directing group: 1. heating in strong base aqueous solution to hydrolyze the amide to carboxylic acid; 2. heating in a strong acid to hydrolyze the amide to the carboxylic acid; 3. adding NaNO₂At Ac₂Obtaining carboxylic acid in an O/AcOH mixed solvent; 4. using BF₃·Et₂Heating O in methanol to obtain; and 5, carrying out a step-by-step reaction of LiHMDS/MeOCOCl/MeONa to realize hydrolysis into ester.

The above-mentioned use of BF₃·Et₂The alcoholysis of the guide group is realized by the reaction of O at 100 ℃, and the method has the defects of high reagent price, complex operation and harsh reaction conditions. The other methods described above require strong acid or strong base conditions, under which many functional groups are not stable. And the above methods are obviously affected by the steric hindrance of the substrate, and the application range of the substrate is small.

Disclosure of Invention

The invention mainly aims to provide an amide alcoholysis method, which aims to solve the problems of complex operation and harsh reaction conditions of the amide alcoholysis method in the prior art.

In order to achieve the above object, according to one aspect of the present invention, there is provided a method for alcoholysis of an amide, the method comprising alcoholysis of an amide-containing compound under basic conditions using an epoxy compound as an alcoholysis promoter.

Further, the dosage ratio of the epoxy compound to the amide compound is 1-5: 1.

further, the amide-containing compound has the general formula I

R¹，R²Each independently selected from any one of alkyl, aryl, substituted alkyl and substituted aryl, preferably alkyl is selected from C₁～C₁₈Any of the alkyl groups in (1), preferably a substituted alkyl group having a main chain of carbon atoms of C₁～C₁₈Preferably, the substituent in the substituted alkyl group is selected from any one or more of aryl, heteroaromatic substituent, cyclane, heterocyclic alkane, alkenyl and alkynyl.

Further, the above epoxy compound has the general formula II

R³And R⁴Each independently selected from any one of H, alkyl and aryl, preferably alkyl is selected from C₁～C₁₈Any one of the alkyl groups of (1).

Further, the method comprises the following steps: mixing an amide-containing compound, an epoxy compound, a pH value regulator and a solvent to form an alkaline reaction system, wherein the pH value of the alkaline reaction system is preferably 7.5-9.5; the alkaline reaction system is reacted at 50 to 150 ℃ to carry out alcoholysis on the amide-containing compound.

Further, the pH regulator is weak acid or weak acidThe base, preferably the pH regulator, is selected from CF₃CO₂K、CF₃CO₂Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO₃、KHCO₃、NaHCO₃、LiHCO₃、CsF、KF、NaF、LiF、Cs₂CO₃、K₂CO₃、Na₂CO₃、Li₂CO₃、K₂HPO₄、Na₂HPO₄、Li₂HPO₄、K₃PO₄、Na₃PO₄Any one or more of sodium benzoate, tetramethyl ethylenediamine, N-N diisopropylethylamine and triethylamine.

Further, the solvent is selected from one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, ethylene glycol, glycerol, 1, 2-dimethoxyethane, ethylene glycol diethyl ether, 2-methoxyethyl ether, 2-ethoxyethyl ether and pyrrole.

Further, the above-mentioned amide compound is

The epoxy compound is methyl glycidyl ether, the pH value regulator is KOAc, and the solvent is ethanol.

Further, the alkaline reaction system is used for alcoholysis of the amide-containing compound by reaction at 80-100 ℃.

Further, after the alcoholysis is completed, the method further comprises: decompressing the alcoholysis product to remove the solvent to obtain a residue; mixing the residue with water to form a mixture; adjusting the pH value of the mixture to 3.5-4.5, and extracting by using n-hexane to obtain an organic phase; and drying and filtering the organic phase.

Further, after the alcoholysis is completed, the method further comprises: decompressing the alcoholysis product to remove the solvent to obtain a residue; the residue was purified by silica gel column chromatography.

By applying the technical scheme of the invention, the method is simple and easy to operate, the pure product can be obtained only by simple conventional separation steps in the post-treatment, and meanwhile, the cost of the epoxy compound is low, so that the production operation cost and the risk and cost of three-waste treatment can be greatly reduced. When the method is used, the reaction conditions are mild, the method can be compatible with various different substituents and functional groups, good yield can be obtained for various amides with different structural types, and the application range of the substrate is wide. Namely, the invention provides an environment-friendly, economical and practical high-efficiency method for alcoholysis of amide. The alcoholysis reaction is not influenced by impurities in a C-H activation reaction system in the previous step, intermediate purification steps are saved, and the C-H activation and acylamino alcoholysis reaction can be continuously carried out.

Detailed Description

It should be noted that the embodiments and features of the embodiments in the present application may be combined with each other without conflict. The present invention will be described in detail with reference to examples.

As analyzed in the background of the present application, there are several methods of amide-alcoholysis in the prior art, but each of these methods has different drawbacks, such as the use of BF₃·Et₂When the O reacts at 100 ℃ to realize the alcoholysis of the amide, the method has the defects of high reagent price, complex operation and harsh reaction conditions, and in order to solve the problem, the application provides a method for alcoholysis of the amide, which comprises the step of carrying out alcoholysis on a compound containing the amide under alkaline conditions by using an epoxy compound as an accelerator.

The inventor of the present application has surprisingly found that, in the research of targeted group removal on an amide compound, an alcohol solution of an epoxy compound is used under alkaline conditions to promote the conversion of amide into ester, amide N-H with certain acidity is subjected to nucleophilic attack on the ring opening of activated alkylene oxide under alkaline conditions to form an N-addition transition state product, the transition state is unstable, and after an oxygen anion generated in situ after the ring opening of the alkylene oxide is subjected to nucleophilic attack on a carbonyl group of the amide bond, a C-N bond of the amide group is broken to complete the amide alcoholysis reaction.

The method is simple and easy to operate, the pure product can be obtained by simple conventional separation steps in the post-treatment, and meanwhile, the cost of the epoxy compound is low, so that the production operation cost and the risk and cost of three-waste treatment can be greatly reduced. When the method is used, the reaction conditions are mild, the method can be compatible with various different substituents and functional groups, good yield can be obtained for various amides with different structural types, and the application range of the substrate is wide. Namely, the invention provides an environment-friendly, economical and practical high-efficiency method for alcoholysis of amide. The alcoholysis reaction is not influenced by impurities in a C-H activation reaction system in the previous step, intermediate purification steps are saved, and the C-H activation and amide alcoholysis two-step reaction can be carried out continuously.

In order to improve the conversion rate of amide as much as possible and ensure the utilization rate of the epoxy compound, the dosage ratio of the epoxy compound to the amide-containing compound is preferably 1-5: 1. of course, when the ratio of the epoxy compound to the amide-containing compound is greater than 5:1, alcoholysis can be achieved, but a large amount of epoxy compound does not participate in the reaction, resulting in waste of raw materials.

The method has the advantages that the reaction substrate has wide universality, the influence by the steric hindrance effect is not obvious, the amide substrates with almost all structures can smoothly react to obtain good yield, and preferably, the amide-containing compound has the general formula I

R¹，R²Each independently selected from any one of alkyl, aryl, substituted alkyl and substituted aryl, preferably alkyl is selected from C₁～C₁₈Any of the alkyl groups in (1), preferably a substituted alkyl group having a main chain of carbon atoms of C₁～C₁₈Preferably, the substituent in the substituted alkyl group is selected from any one or more of aryl, heteroaromatic substituent, cycloalkane, heterocyclic alkane, alkenyl and alkynyl, and the substituent in the substituted aryl group can be halogen, alkyl, substituted alkyl and the like, for example, R²Is composed of

The reaction temperature required in the reaction process of the amide-containing compound with the general formula structure is milder, the reaction time is shorter, and the method is more suitable for industrial large-scale application.

In order to further reduce the cost of carrying out the above process, it is preferred that the above epoxy compound has the general formula II

R³And R⁴Each independently selected from any one of H, alkyl and aryl, preferably the alkyl is selected from C₁～C₁₈Any one of the alkyl groups of (1).

When the alcoholysis is carried out by using the epoxy compound as the accelerator, the specific implementation process can refer to the alcoholysis process in the prior art, and the method preferably comprises the following steps: mixing an amide-containing compound, an epoxy compound, a pH value regulator and a solvent to form an alkaline reaction system; the alkaline reaction system is reacted at 50 to 150 ℃ to carry out alcoholysis on the amide-containing compound. Preferably, the pH value of the alkaline reaction system is 7.5-9.5.

Dispersing an amide-containing compound and an epoxy compound in a solvent, and then adjusting an alkaline reaction system by using a pH value regulator to enable subsequent alcoholysis to be carried out smoothly and efficiently, wherein the reaction rate is more ideal particularly when the pH value of the alkaline reaction system is 7.5-9.5; then the reaction system is carried out at a low temperature of 50-150 ℃. As can be seen from the above process, the method of the present application does not require special expensive reagents, has mild reaction conditions, and is applicable to a wide range of substrates and a wide range of applications.

The pH regulator for pH is not required to be strong acid or strong base, preferably weak acid or weak base, and more preferably selected from CF₃CO₂K、CF₃CO₂Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO₃、KHCO₃、NaHCO₃、LiHCO₃、CsF、KF、NaF、LiF、Cs₂CO₃、K₂CO₃、Na₂CO₃、Li₂CO₃、K₂HPO₄、Na₂HPO₄、Li₂HPO₄、K₃PO₄、Na₃PO₄Any one or more of sodium benzoate, tetramethyl ethylenediamine, N-N diisopropylethylamine and triethylamine. The materials are low in cost, and the formed pH system is mild.

The solvent of the present application may refer to the kind of solvent commonly used in amide alcoholysis in the prior art, and preferably the above solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isopentanol, ethylene glycol, glycerol, 1, 2-dimethoxyethane, ethylene glycol diethyl ether, 2-methoxyethyl ether, 2-ethoxyethyl ether and pyrrole.

The reaction principle is further illustrated below by using KOAc as a pH regulator and ethanol as a solvent: the method comprises the following steps of (1) nucleophilically attacking potassium ion activated alkylene oxide ring opening by amide N-H with certain acidity under the action of KOAc to form an N-addition transition state product, wherein the transition state is unstable, after oxygen anions generated in situ after the alkylene oxide ring opening are nucleophilically attacked by carbonyl of an amide bond, C-N bonds of amide groups are broken to form an esterification intermediate product, and then the esterification intermediate and an alcohol solvent are subjected to ester exchange reaction to generate a final amide alcoholysis product. See in particular the following chemical reaction processes:

in a preferred embodiment of the present application, the amide-containing compound is

When the method of the present application is applied to the above-mentioned alcoholysis of amide-containing compounds, the yield of the final target product is high.

In order to further increase the reaction rate and increase the yield, the alkaline reaction system is preferably reacted at 80 to 100 ℃ to alcoholyze the amide-containing compound.

In order to reduce the reaction cost, it is preferable to heat the reaction system with an oil bath.

After the alcoholysis is completed, the method preferably further comprises: decompressing the alcoholysis product to remove the solvent to obtain a residue; mixing the residue with water to form a mixture; adjusting the pH value of the mixture to 3.5-4.5, and extracting by using n-hexane to obtain an organic phase; and drying and filtering the organic phase. All substances adopted in the process are conventional materials, so that the implementation cost of the method is not increased; moreover, the process is a conventional operation in the purification process, and the complexity of the method can not be increased; further, during extraction, the pH value of the mixture is controlled to be 3.5-4.5, so that the extraction separation efficiency is improved, for example, the pH value is adjusted to be acidic, a secondary amine structure on a leaving group forms a salt, the water solubility of the leaving group is enhanced, and a leaving group byproduct is easier to wash and remove. If the acidity is stronger, other functional groups on the product may be deteriorated, and reagents may be wasted. Alternatively, after the alcoholysis is completed, the method preferably further comprises: decompressing the alcoholysis product to remove the solvent to obtain a residue; the residue was purified by silica gel column chromatography, a procedure suitable for product isolation in small laboratory runs.

The advantageous effects of the present application will be further described below with reference to examples and comparative examples.

The amide-containing compounds used in the following examples are as follows:

the epoxy compounds are as follows:

the product structure is as follows:

the reactants used in the following examples are as follows:

example 1

A25 mL dry clean Schlenck tube with a magnetic stir bar was charged with a1(87.5mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content <0.01 wt%), methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature by ceasing heating, and the solvent was removed under reduced pressure to give a residue, 2.0mL of purified water was added to the residue to form a mixture, and the pH of the mixture was adjusted to 4 with 3M hydrochloric acid with stirring, and then extracted with n-hexane (3mL × 3) to give an organic phase, the combined organic phases were dried over anhydrous sodium sulfate, filtered after completion of drying, and the filtrate was concentrated to give 45.5mg of pure product in 92% yield.

The chemical reaction of the alcoholysis process is shown in the following formula:

results of nuclear magnetic test of the product c1(Ethyl 2- (1, 3-dioxoindolin-2-yl) propanoate):

¹NMR(400MHz,CDCl₃)δ7.92–7.79(m,2H),7.77–7.60(m,2H),4.95(q,J＝7.5Hz,1H),4.19(td,J＝7.0,3.5Hz,2H),1.69(d,J＝7.5Hz,3H),1.22(t,J＝7.0Hz,3H)。¹³C NMR(125MHz,CDCl₃)δ169.75,167.47,134.20,131.99,123.49,61.90,47.66,15.28,14.12.

example 2

The difference from example 1 is that after the amount of each material in example 1 was increased by 100 times, alcoholysis reaction was carried out in a 500mL autoclave, and the filtrate was concentrated to obtain 4.648g of pure product with a yield of 94%, while the yield in example 2 was higher than that in example 1, because the adhesion loss was large in the small-scale reaction operation in example 1, and the yield was more accurate in the large-scale reaction.

Example 3

The difference from example 1 is that the molar ratio of the methyl glycidyl ether b1 to a1 is 5:1, and the yield is 93%.

Example 4

The difference from example 1 is that the molar ratio of the methyl glycidyl ether b1 to a1 is 1:1, and the yield is 69%.

Example 5

The difference from example 1 is that the molar ratio of the methyl glycidyl ether b1 to a1 is 8:1, and the yield is 94%.

Example 6

The difference from example 1 is that the Schlenck tube was placed in an oil bath at 80 ℃ and heated for 35 hours to give a product yield of 84%.

Example 7

The difference from example 1 is that the Schlenck tube was placed in a 100 ℃ oil bath and heated for 35 hours to give a 91% yield.

Example 8

The difference from example 1 is that the Schlenck tube was placed in a 150 ℃ oil bath and heated for 35 hours to react, resulting in a 82% yield.

Example 9

The difference from example 1 is that the Schlenck tube was placed in a 50 ℃ oil bath and heated for 35 hours to give a 48% yield.

Example 10

The difference from example 1 is that the Schlenck tube was placed in a 165 ℃ oil bath and heated for 35 hours to give a 74% yield.

Example 11

And embodiments thereof1 is distinguished in that the pH regulator used is CF₃CO₂K, product yield 93%.

Example 12

The difference from example 1 is that KHCO is used as pH regulator₃The product yield was 74%.

Example 13

The difference from example 1 is that the pH regulator used is K₂HPO₄The product yield was 51%.

Example 14

The difference from example 1 is that the pH regulator used is K₂CO₃The product yield was 22%.

Example 15

To a25 mL dry clean Schlenck tube with a magnetic stir bar were added a1(87.5mg,0.2mmol), NaHCO in that order₃(16.8mg,0.2mmol), absolute ethanol (2.0mL, water content. ltoreq.0.01 wt%), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give the pure product 36.1mg, 73% yield.

Example 16

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), LiOH (4.8mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 32.1mg of pure product in 65% yield. The LiOH used as the pH adjuster in this embodiment is a strong base, and not only has the effect of adjusting the pH, but also may be used as a metal ion to perform a complexing activation effect.

Example 17

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), NaOAc (16.4mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt%) and methylglycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give pure product 43.0mg, yield 87%.

Example 18

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), KCl (14.9mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 15.3mg of pure product in 31% yield.

Example 19

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), sodium trifluoroacetate (27.2mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 45 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give the pure product 46.0mg, 93% yield.

Example 20

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), potassium trifluoroacetate (30.4mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt%) and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 45 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 47.0mg of pure product in 95% yield. Although the yield is slightly improved, the reaction time is prolonged, and the cost of potassium trifluoroacetate is higher than that of potassium acetate.

Example 21

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a1(86.8mg,0.2mmol), triethylamine (20.2mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 35.6mg of pure product in 72% yield.

Example 22

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (1.0mL, water content 0.01 wt%) and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 38.6mg of pure product in 78% yield.

Example 23

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (3.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give the pure product 44.0mg, 89% yield.

Example 24

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a1(86.8mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (4.0mL, water content 0.01 wt%) and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give 20.3mg of pure product in 41% yield.

Example 25

The difference from example 1 is that methanol is used as solvent and the yield of the product is 91%.

Results of nuclear magnetic test of the product c2(Methyl 2- (1, 3-dioxoindolin-2-yl) propanoate):

¹NMR(400MHz,CDCl₃)δ7.82–7.75(m,2H),7.72–7.65(m,2H),4.91(q,J＝7.5Hz,1H),3.67(s,3H),1.63(d,J＝7.5Hz,3H).

example 26

The difference from example 1 is that isopropanol is used as solvent and the yield of the product is 95%.

Results of nuclear magnetic test of the product c3 (isoproyl 2- (1, 3-dioxoindolin-2-yl) propanoate):

¹NMR(400MHz,CDCl₃)δ7.83–7.76(m,2H),7.72–7.66(m,2H),5.09–4.95(m,1H),4.87(q,J＝7.5Hz,1H),1.63(d,J＝7.5Hz,1H),1.16(dd,J＝20.0,6.5Hz,6H).

example 27

The difference from example 1 is that isobutanol is used as the solvent and the product yield is 92%.

Results of nuclear magnetic test of the product c4(Isobutyl 2- (1, 3-dioxoindolin-2-yl) propanoate):

¹NMR(400MHz,CDCl₃)δ7.83–7.76(m,2H),7.73–7.65(m,2H),4.94(q,J＝7.5Hz,1H),3.93–3.83(m,2H),1.90–1.77(m,1H),1.67(d,J＝7.5Hz,3H),0.81(d,J＝7.0Hz,6H).

example 28

The difference from example 1 is that isoamyl alcohol is used as solvent and the product yield is 87%.

Results of nuclear magnetic test of the product c5(Isopentyl 2- (1, 3-dioxoindolin-2-yl) propanoate):

¹NMR(400MHz,CDCl₃)δ7.85–7.80(m,2H),7.74–7.67(m,2H),4.98–4.89(m,1H),4.14(t,J＝7.0Hz,2H),1.67(d,J＝7.5Hz,3H),1.59–7.50(m,1H),1.49–1.37(m,2H),0.84–0.75(m,6H).

example 29

The difference from example 1 is that the product system was cooled to room temperature after stopping heating, and the solvent was removed under reduced pressure to obtain a residue, 2.0mL of purified water was added to the residue to form a mixture, and the pH of the mixture was adjusted to 3.5 with 3M hydrochloric acid with stirring, followed by extraction with n-hexane (3 mL. times.3) to obtain an organic phase, and the combined organic phases were dried over anhydrous sodium sulfate and filtered after completion of drying in a yield of 91%.

Example 30

The difference from example 1 is that the product system was cooled to room temperature after stopping heating, and the solvent was removed under reduced pressure to obtain a residue, 2.0mL of purified water was added to the residue to form a mixture, and the pH of the mixture was adjusted to 4.5 with 3M hydrochloric acid with stirring, followed by extraction with n-hexane (3 mL. times.3) to obtain an organic phase, and the combined organic phases were dried over anhydrous sodium sulfate and filtered after completion of drying, with a yield of 89%.

Example 31

The difference from example 1 is that the product system was cooled to room temperature after stopping heating, and the solvent was removed under reduced pressure to give a residue, 2.0mL of purified water was added to the residue to form a mixture, and the pH of the mixture was adjusted to 5 with 3M hydrochloric acid with stirring, followed by extraction with n-hexane (3 mL. times.3) to give an organic phase, and the combined organic phases were dried over anhydrous sodium sulfate and filtered after completion of drying in a yield of 84%.

Example 32

The difference from example 1 was that the amide compound used was a2, and the yield was 96.

Results of nuclear magnetic tests of the product c6(Ethyl 3-phenylpropanoate):

^a8NMR(500MHz,CDCl₃)δ7.32–7.26(m,2H),7.24–7.17(m,3H),4.13(q,J＝7.0Hz,2H),2.96(t,J＝8.0Hz,2H),2.63(t,J＝8.0Hz,2H),1.24(t,J＝7.0Hz,3H)。

example 33

The difference from example 1 was that the amide compound used was a3, and the yield was 41%.

Example 34

The difference from example 1 was that the amide compound used was a4, and the yield was 97%.

Example 35

The difference from example 1 was that the amide compound used was a5, and the yield was 96%.

Example 36

The difference from example 1 was that the amide compound used was a6, and the yield was 93%.

Example 37

The difference from example 1 was that the amide compound used was a7, and the yield was 90%.

Example 38

The difference from example 1 was that the amide compound used was a8, and the yield was 62%.

Results of nuclear magnetic testing of product c7(Ethyl benzoate):

¹H NMR(500MHz,CDCl₃)δ8.13–7.97(m,2H),7.58–7.53(m,1H),7.47–7.38(m,2H),4.39(q,J＝7.0Hz,2H),1.42(t,J＝7.0Hz,3H)。

example 39

The difference from example 1 was that the amide compound used was a9, and the yield was 91%.

Nuclear magnetic test results for product c8(Ethyl 2-methyl-3-phenylacrylate):

¹H NMR(500MHz,CDCl₃)δ7.70(s,1H),7.43–7.36(m,4H),7.35–7.29(m,1H),4.28(q,J＝7.0Hz,2H),2.13(s,3H),1.36(t,J＝7.0Hz,3H).

example 40

The difference from example 1 was that the amide compound used was a10, and the yield was 97%.

EXAMPLE 41

The difference from example 1 was that the amide compound used was a11, and the yield was 94%.

Results of nuclear magnetic tests of the product c9(Ethyl 2, 2-dimethyl-3-phenylpropanoate):

¹H NMR(500MHz,CDCl₃)δ7.30–7.27(m,2H),7.25–7.20(m,a8),7.13(d,J＝7.0Hz,2H),4.13(q,J＝7.0Hz,2H),2.87(s,2H),1.25(t,J＝7.0Hz,4H),1.19(s,6H).¹³C NMR(125MHz,CDCl₃)δ177.62,138.10,130.30,128.06,126.52,60.52,46.41,43.61,25.09,14.31。

example 42

The difference from example 1 was that the amide compound used was a12, and the yield was 90%.

Results of nuclear magnetic tests of the product c10(Ethyl 2, 2-dimethyl-3-phenylpropanoate):

¹NMR(400MHz,CDCl₃)δ7.85–7.75(m,2H),7.74–7.67(m,2H),4.22(q,J＝7.0Hz,2H),1.83(s,6H),1.25(t,J＝7.0Hz,3H)。

example 43

The difference from example 1 was that 1m of the amide compound was used, and the yield was 89%.

Results of nuclear magnetic testing of product c11(Ethyl 1-benzoylpyrrolidine-2-carboxylate):

¹H NMR(500MHz,CDCl₃)δ7.55(d,J＝6.5Hz,2H),7.43–7.35(m,3H),4.69–4.59(m,1H),4.22(q,J＝7.0Hz,2H),3.64(dt,J＝14.0,7.0Hz,1H),3.56–3.47(m,1H),2.31(dd,J＝14.0,7.0Hz,1H),2.04–1.97(m,2H),1.92–1.82(m,1H),1.29(t,J＝7.0Hz,3H)。

ar in the structural formulae of the following examples 44 to 59_FIs p-CF₃C₅F₄And each amide-containing compound can be obtained by adopting the existing commodity in the prior art or carrying out C-H activation on the corresponding substrate, and simultaneously C-The product system obtained after H activation can be directly subjected to amidoalcoholysis as described in the following examples without purification.

Example 44

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a14(87.06mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), anhydrous methanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give the pure product 42.3mg, yield 90%.

Results of nuclear magnetic tests of the product c12(Methyl 4- (2- (methoxycarboxyl) cyclopropy) benzoate):

¹NMR(400MHz,CDCl₃)δ7.94(d,J＝8.0Hz,2H),7.33(d,J＝8.0Hz,2H),3.89(s,3H),3.43(s,3H),2.60(q,J＝8.0Hz,1H),2.18–2.13(m,1H),1.77–1.72(m,1H),1.43–1.37(m,1H)。

example 45

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a15(89.86mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), anhydrous methanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give the pure product in 93% yield.

Results of nuclear magnetic test of the product c13(Methyl 4- (2- (methoxycarbonyl) cyclobutyl) benzoate):

¹H NMR(400MHz,CDCl₃)δ7.98(d,J＝8.0Hz,2H),7.31(d,J＝8.0Hz,2H),3.91(s,3H),3.88–3.81(m,1H),3.71(s,3H),3.22(q,J＝8.0Hz,1H),2.38–2.31(m,2H),2.29–2.12(m,2H).¹³C NMR(125MHz,CDCl₃)δ174.66,167.13,148.93,129.86,128.39,126.50,52.16,51.94,45.07,43.10,25.33,21.90。

example 46

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a16(105.08mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), anhydrous methanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give the pure product in 95% yield.

Results of nuclear magnetic test of product c14(Dimethyl 4,4' - (2- (methoxycarboxyl) cyclobutane-1,3-diyl) dibenzoate):

¹H NMR(400MHz,CDCl₃)δ8.00(d,J＝8.0Hz,4H),7.34(d,J＝8.0Hz,4H),3.91(s,6H),3.84(q,J＝8.0Hz,2H),3.75(s,3H),3.32–3.28(m,1H),2.87–2.81(m,1H),2.34–2.26(m,1H).¹³C NMR(125MHz,CDCl₃)δ173.61,167.04,147.96,130.01,128.73,126.67,52.26,52.23,51.98,39.53,32.49,29.85。

example 47

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a17(95.47mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give 53.8mg of pure product in 93% yield.

Results of nuclear magnetic tests of the product c15(Ethyl 4- (2- (ethoxycarbonyl) cyclopentyl) benzoate):

¹H NMR(500MHz,CDCl₃)δ7.96(t,J＝8.0Hz,2H),7.29(d,J＝8.0Hz,2H),4.35(q,J＝7.0Hz,2H),4.05(q,J＝7.0Hz,2H),3.37(q,J＝9.0Hz,1H),2.81(q,J＝9.0Hz,1H),2.24–2.10(m,2H),2.02–1.93(m,1H),1.91–1.79(m,2H),1.79–1.69(m,1H),1.37(t,J＝7.0Hz,3H),1.14(t,J＝7.0Hz,3H).¹³C NMR(125MHz,CDCl₃)δ175.54,166.67,149.47,129.83,128.74,127.34,60.90,60.50,52.18,49.86,35.08,30.84,25.16,14.47,14.31。

example 48

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a18(98.28mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with heating discontinued and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give 54.1mg of pure product in 89% yield.

Results of nuclear magnetic test of the product c16(Ethyl 4- (2- (ethoxycarbonyl) cyclohexyl) benzoate:

¹H NMR(500MHz,CDCl₃)δ7.94(d,J＝8.0Hz,2H),7.26(d,J＝8.0Hz,2H),4.35(q,J＝7.0Hz,2H),3.90–3.80(m,2H),2.89–2.76(m,1H),2.63–2.53(m,1H),2.08–1.99(m,1H),1.92–1.78(m,3H),1.62–1.56(m,1H),1.50–1.42(m,2H),1.42–1.34(m,4H),0.94(t,J＝7.0Hz,3H).¹³C NMR(125MHz,CDCl₃)δ174.95,166.72,150.21,129.75,128.74,127.49,60.90,60.09,49.97,46.82,34.18,30.17,26.19,25.42,14.47,14.10.

example 49

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a19(113.90mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 25/1) to give the pure product in 95% yield.

Results of nuclear magnetic test of the product c17(Ethyl 4- (3-ethoxy-2- (4-isobutylphenyl) -3-oxopropy) benzoate):

¹H NMR(400MHz,CDCl₃)δ7.91(d,J＝8.0Hz,2H),7.21–7.17(m,4H),7.08(d,J＝8.0Hz,2H),4.35(q,J＝8.0Hz,2H),4.15–3.96(m,2H),3.83–3.76(m,1H),3.46–3.41(m,1H),3.08–3.03(m,1H),2.44(d,J＝8.0Hz,2H),1.89–1.79(m,1H),1.38(t,J＝8.0Hz,3H),1.12(t,J＝8.0Hz,3H),0.89(d,J＝8.0Hz,6H).¹³C NMR(125MHz,CDCl₃)δ173.30,166.65,144.65,141.00,135.66,129.63,129.47,129.08,128.70,127.65,60.91,53.05,45.11,39.95,30.26,22.44,14.42,14.14。

example 50

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a20(143.53mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 25/1) to give the pure product in 96% yield.

Results of nuclear magnetic test of the product c18(Diethyl 4,4' - (3-ethoxy-2- (4-isobutylphenyl) -3-oxopropan-1, 1-diyl) dibezoate):

¹H NMR(500MHz,CDCl₃)δ7.99(d,J＝8.0Hz,2H),7.73(d,J＝8.0Hz,2H),7.48(d,J＝8.0Hz,2H),7.15(d,J＝8.0Hz,2H),7.06(d,J＝8.0Hz,2H),6.94(d,J＝8.0Hz,2H),4.79(d,J＝12.0Hz,1H),4.40–4.33(m,3H),4.27(q,J＝7.0Hz,2H),4.02–3.96(m,1H),3.94–3.88(m,1H),2.35(d,J＝7.0Hz,2H),1.79–1.73(m,1H),1.37(t,J＝7.0Hz,3H),1.31(t,J＝7.0Hz,3H),1.01(t,J＝7.0Hz,3H),0.82–0.80(m,6H)。

example 51

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a21(99.49mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 50/1) to give the pure product in 96% yield.

Results of nuclear magnetic test of the product c19(Ehyl 2- (5-isobutylbiphenyl-2-yl) propanoate):

¹H NMR(500MHz,CDCl₃)δ7.47–7.40(m,2H),7.36(m,4H),7.15(d,J＝8.0Hz,1H),7.04(s,1H),4.17–4.05(m,2H),3.87(q,J＝7.0Hz,1H),2.49(d,J＝7.0Hz,2H),1.94–1.86(m,1H),1.37(d,J＝7.0Hz,3H),1.20(t,J＝7.0Hz,3H),0.94(d,J＝6.5Hz,6H).¹³C NMR(125MHz,CDCl₃)δ175.21,141.65,141.51,140.05,136.04,130.96,129.59,128.68,128.16,127.04,126.62,60.63,45.12,41.02,30.23,22.57,22.55,19.39,14.20。

example 52

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a22(104.88mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give the pure product in 93% yield.

Results of nuclear magnetic test of the product c20(Ethyl 2- (1, 3-dioxoindolin-2-yl) -3-p-tolypropanoate):

¹H NMR(500MHz,CDCl₃)δ7.82–7.74(m,2H),7.71–7.63(m,2H),7.04(d,J＝8.0Hz,2H),6.98(d,J＝8.0Hz,2H),5.15–5.08(m,1H),4.27–4.20(m,2H),3.58–3.46(m,2H),2.22(s,3H),1.25(t,J＝7.0Hz,3H)。

example 53

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a23(82.46mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 15/1) to give the pure product in 94% yield.

Results of nuclear magnetic measurements of product c21(Ethyl 2- ((2-fluoropyridin-4-yl) methyl) butanoate):

¹H NMR(500MHz,CDCl₃)δ8.09(d,J＝5.0Hz,1H),6.99(d,J＝5.0Hz,1H),6.74(s,1H),4.15–4.01(m,2H),2.96(dd,J＝14.0,9.5Hz,1H),2.77(dd,J＝14.0,6.0Hz,1H),2.65–2.55(m,1H),1.72–1.65(m,1H),1.63–1.53(m,1H),1.16(t,J＝7.0Hz,3H),0.94(t,J＝7.5Hz,3H).¹³CNMR(125MHz,CDCl₃)δ174.66,164.15(d,J＝237.5Hz,1H),154.76(d,J＝7.5Hz,1H),147.57(d,J＝15.0Hz,1H),122.07(d,J＝3.8Hz,1H),109.75(d,J＝36.3Hz,1H),60.65,48.01,37.14(d,J＝2.5Hz,1H),25.63,14.33,11.66.¹⁹F NMR(400MHz,CDCl₃)δ-69.29(S)。

example 54

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a24(120.10mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA-20/1) to give the pure product 62.3mg with a yield of 75%.

Results of nuclear magnetic test of the product c22(Ethyl 2- (1, 3-dioxoindolin-2-yl) -3-phenyl-3-p-tolypropanoate):

¹H NMR(500MHz,CDCl₃)δ7.83–7.69(m,2H),7.69–7.62(m,2H),7.50(d,J＝7.5Hz,1H),7.41(d,J＝7.5Hz,1H),7.33(t,J＝7.5Hz,1H),7.27(d,J＝9.0Hz,1H),7.22(t,J＝7.5Hz,0.5H),7.17(t,J＝7.0Hz,1H),7.11(t,J＝7.5Hz,1H),6.99(t,J＝7.5Hz,0.5H),6.93(d,J＝7.5Hz,1H),5.78–5.71(m,1H),5.33–5.23(m,1H),4.13–3.98(m,2H),2.32(s,1.5H),2.13(s,1.5H),1.06–0.98(m,3H).¹³C NMR(125MHz,CDCl₃)δ168.43,168.37,167.49,167.44,142.03,140.84,138.75,137.61,136.46,136.44,134.11,131.52,131.45,129.47,129.32,128.73,128.57,127.98,127.83,127.81,127.70,126.85,123.50,123.45,77.41,77.16,76.91,61.75,61.71,55.40,55.26,50.33,50.29,29.81,21.14,20.99,13.83。

example 55

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a25(118.89mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 10/1) to give the pure product in 91% yield.

Results of nuclear magnetic test of the product c23(Ethyl 4- (2- (1, 3-dioxoindolin-2-yl) -2- (ethoxycarbonyl) cyclopropy) benzoate):

¹H NMR(500MHz,CDCl₃)δ8.02(d,J＝8.0Hz,2H),7.92–7.91(m,2H),7.79–7.77(m,2H),7.68(d,J＝8.0Hz,2H),4.38(q,J＝7.0Hz,1H),3.84–3.76(m,2H),3.17(t,J＝9.5Hz,1H),2.51(dd,J₁＝6.5Hz,J₂＝9.0Hz,1H),1.94(dd,J₁＝6.5Hz,J₂＝9.0Hz,1H),1.40(t,J＝7.0Hz,3H),0.78(t,J＝7.0Hz,3H).¹³C NMR(125MHz,CDCl₃)δ168.22,167.65,166.66,140.20,134.56,131.87,129.91,129.46,123.76,61.74,61.07,38.21,33.48,19.24,14.50,13.84。

example 56

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a26(107.64mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 20/1) to give the pure product in 89% yield.

Results of nuclear magnetic test of the product c24(Ethyl 1-benzyl-4-p-tolylpiperidine-3-carboxylate):

¹H NMR(500MHz,CDCl₃)δ7.51–7.33(m,5H),7.18–7.01(m,2H),5.12–4.77(m,1H),4.08–3.70(m,3H),3.37–3.08(m,1H),3.04–2.55(m,3H),2.31(s,3H),1.89–1.60(m,2H),1.00–0.84(m,3H).

example 57

A25 mL dry clean Schlenck tube with a magnetic stirrer was charged with a27(78.26mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methyl glycidyl ether b1(52.9mg,0.6mmol) in that order to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 30/1) to give 38.7mg of pure product in 95% yield.

Results of nuclear magnetic testing of product c25(Ethyl 2-methyl-3-phenylbut-2-enoate):

¹H NMR(500MHz,CDCl₃)δ7.42–7.35(m,2H),7.32–7.28(m,1H),7.17(d,J＝7.0Hz,2H),4.34–4.24(m,2H),2.28(d,J＝1.5Hz,3H),1.78(d,J＝1.5Hz,3H),1.38(t,J＝7.0Hz,3H).

example 58

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a28(122.93mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 20/1) to give the pure product in 85% yield.

Results of nuclear magnetic test of the product c26(Ethyl 2- (1, 3-dioxoindolin-2-yl) -5- (trisisopropylphenyl) pent-4-ynoate):

¹H NMR(500MHz,CDCl₃)δ7.88–7.81(m,2H),7.76–7.69(m,2H),5.08(dd,J＝12.0,5.0Hz,1H),4.29–4.15(m,2H),3.36(dd,J＝17.5,12.0Hz,1H),3.11(dd,J＝17.5,5.0Hz,1H),1.23(t,J＝7.0Hz,3H),0.88–0.76(m,21H).¹³C NMR(125MHz,CDCl₃)δ168.05,167.31,134.21,132.02,123.59,102.79,83.66,62.28,50.91,20.86,18.43,18.42,14.19,11.11。

example 59

A25 mL dry clean Schlenck tube with a magnetic stirrer was sequentially charged with a29(120.34mg,0.2mmol), potassium acetate (19.6mg,0.2mmol), absolute ethanol (2.0mL, water content 0.01 wt% or less), and methylglycidyl ether b1(52.9mg,0.6mmol) to form a reaction system. And (3) placing the Schlenck tube in an oil bath at 90 ℃ for heating reaction for 35 hours, and displaying complete reaction of the raw materials by TLC to obtain a product system. The product system was cooled to room temperature with cessation of heating and the solvent was removed under reduced pressure to give a residue which was purified by silica gel column chromatography (hexane/EA ═ 50/1) to give the pure product in 93% yield.

Results of nuclear magnetic test of the product c27(Ethyl 2- (4-isobutyl-2- ((trioxypropylyl) Ethyl) phenyl) propanoate):

¹H NMR(500MHz,CDCl₃)δ7.27–7.25(m,1H),7.21(d,J＝8.0Hz,1H),7.11–7.04(m,1H),4.37(q,J＝7.0Hz,1H),4.21–4.03(m,2H),2.41(d,J＝7.0Hz,2H),1.85(dp,J＝14.0,7.0Hz,1H),1.47(d,J＝7.0Hz,3H),1.20(t,J＝7.0Hz,3H),1.14(s,18H),0.90(d,J＝7.0Hz,6H)。

example 60

The difference from example 1 is that b2 was used as the epoxy compound in a yield of 92%.

Example 61

The difference from example 1 is that b3 was used as the epoxy compound in 69% yield.

Example 62

The difference from example 1 is that b4 was used as the epoxy compound, and the yield was 21%.

Example 63

The difference from example 1 is that b5 was used as the epoxy compound in 68% yield.

Example 64

The difference from example 1 is that b6 was used as the epoxy compound in 87% yield.

Example 65

The difference from example 1 is that b7 was used as the epoxy compound in 89% yield.

Example 66

The difference from example 1 is that b8 was used as the epoxy compound in 47% yield.

From the results of the above examples, it can be seen that the method of the present application is applicable to a wide range of substrates and mild reaction conditions. The yield of some examples is somewhat lower, probably because the reaction conditions need to be adjusted or the solvent employed needs to be adjusted.

From the above description, it can be seen that the above-described embodiments of the present invention achieve the following technical effects:

the method provided by the application is simple and easy to operate, the pure product can be obtained only by simple conventional separation steps in the post-treatment, and meanwhile, the cost of the epoxy compound is low, so that the production operation cost and the risk and cost of three-waste treatment can be greatly reduced. When the method is used, the reaction conditions are mild, the method can be compatible with various different substituents and functional groups, good yield can be obtained for various amides with different structural types, and the application range of the substrate is wide. The invention provides an environment-friendly, economical and practical high-efficiency method for amide alcoholysis. The alcoholysis reaction is not influenced by impurities in a C-H activation reaction system in the previous step, intermediate purification steps are saved, and the C-H activation and amide alcoholysis two-step reaction can be carried out continuously.

The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for alcoholysis of an amide comprising conducting alcoholysis of an amide-containing compound under basic conditions using an epoxy compound as an accelerator, wherein the amide-containing compound has the formula I

R¹，R²Each independently selected from any one of alkyl, aryl, substituted alkyl, and substituted aryl, the method comprising:

mixing the amide-containing compound, the epoxy compound, a pH value regulator and a solvent to form an alkaline reaction system;

and reacting the alkaline reaction system at 50-150 ℃ to carry out alcoholysis on the amide-containing compound, wherein the pH value of the alkaline reaction system is 7.5-9.5, the pH value regulator is weak acid or weak base, and the solvent is selected from any one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, isoamylol, ethylene glycol, glycerol, 1, 2-dimethoxyethane, ethylene glycol diethyl ether, 2-methoxyethyl ether, 2-ethoxyethyl ether and pyrrole.

2. The method according to claim 1, wherein the epoxy compound and the amide-containing compound are used in a molar ratio of 1-5: 1.

3. the method of claim 1, wherein the alkyl group is selected from C₁～C₁₈Any one of the alkyl groups of (1).

4. The method of claim 1, wherein the substituted alkyl has a backbone carbonAtomic number of C₁～C₁₈Any one of them.

5. The method of claim 1, wherein the substituted alkyl group is a mono-substituted alkyl group or a poly-substituted alkyl group.

6. The method of claim 1, wherein the substituent in the substituted alkyl group is selected from the group consisting of aryl, heteroaromatic substituents, cycloalkane, heterocycloalkane, alkenyl, and alkynyl.

7. The method of claim 1, wherein the epoxy compound has the general formula II, wherein the general formula II is

The R is³And said R⁴Each independently selected from any one of H, alkyl and aryl, or R³And said R⁴One is H and the other is selected from-CH₂-O-CH₃、-CH₂-O-Ph-CH₃、-Cl、-OH、-CO₂Et.

8. The method of claim 7, wherein the alkyl group is selected from C₁～C₁₈Any one of the alkyl groups of (1).

9. The method of claim 1, wherein the pH adjusting agent is selected from CF₃CO₂K、CF₃CO₂Na、CsOAc、KOAc、NaOAc、LiOAc、CsHCO₃、KHCO₃、NaHCO₃、LiHCO₃、CsF、KF、NaF、LiF、Cs₂CO₃、K₂CO₃、Na₂CO₃、Li₂CO₃、K₂HPO₄、Na₂HPO₄、Li₂HPO₄、K₃PO₄、Na₃PO₄Any one or more of sodium benzoate, tetramethyl ethylenediamine, N-N diisopropylethylamine and triethylamine.

10. The method of claim 1, wherein the amide-containing compound is

11. The method of claim 10, wherein the alkaline reaction system is reacted at 80-100 ℃ to alcoholyze the amide-containing compound.

12. The process of claim 10, wherein after the alcoholysis is complete, the process further comprises:

decompressing the alcoholysis product to remove the solvent to obtain a residue;

mixing the residue with water to form a mixture;

adjusting the pH value of the mixture to 3.5-4.5, and extracting by using normal hexane to obtain an organic phase; and

and drying and filtering the organic phase.

13. The process of claim 10, wherein after the alcoholysis is complete, the process further comprises:

the residue was purified by silica gel column chromatography.