Alpha-ketoamide derivatives and processes for their preparation

Abstract

The application belongs to the technical field of compound synthesis, and particularly relates to an alpha-ketoamide derivative and a preparation method thereof, wherein the preparation method of the alpha-ketoamide derivative comprises the following steps: S1, first, a graphite carbon rod electrode and a platinum sheet electrode are respectively assembled on two sides of a 10mL three-port glass bottle; S2, then, a magnetic son is added into the three-port glass bottle, the bottle mouths on two sides are sealed, the three-port glass bottle is transferred to a glove box for feeding, and benzoylformic acid, morpholine and 10mol% of ferrocene in 4mL hexafluoroisopropanol are sequentially added; S3, after the feeding is completed, the last bottle mouth of the three-port glass bottle is sealed, and a constant current of 3mA is introduced for electrolysis. The application realizes the amination reaction of alpha-keto acid by using an electrocatalytic decarboxylation strategy, selectively synthesizes alpha-ketoamide derivatives, and the reaction is suitable for primary amine compounds, secondary amine compounds, is also suitable for aromatic and aliphatic alpha-keto acids, and excellent functional group tolerance is exhibited.

Description

Technical Field

[0001] The present invention belongs to the technical field of compound synthesis, and particularly relates to an α-ketoamide derivative and a preparation method thereof. Background Art

[0002] The backbones of organic molecules are primarily composed of carbon-carbon (C-C) bonds, but the functionality of these molecules often derives from the presence of heteroatoms such as nitrogen (N), oxygen (O), and sulfur (S), which are anchored in these molecules via carbon-hetero (C-X) atom bonds. Heterocyclic compounds containing C-N, C-O, or C-S bonds are widely found in pharmaceutical molecules. Furthermore, useful synthetic intermediates often contain C-B or C-Si bonds, which are then converted into C-C, C-O, or C-N bonds.

[0003] Based on the high added value of carbon-heteroatom bond construction, chemists have mainly developed the following strategies for carbon-heteroatom bond construction: (1) construction of carbon-heteroatom bonds through nucleophilic substitution reactions and transition metal-catalyzed cross-coupling reactions; (2) construction of intermolecular carbon-heteroatom bonds initiated by decarboxylation; and (3) photochemical strategies to induce carbon-heteroatom bond construction. Currently, the above strategies have problems such as the high cost of the metal catalysts used, the need for functional group preactivation, the narrow substrate range, and the limited number of activated chemical bonds.

[0004] Compared with traditional synthesis methods, organic electrochemical synthesis utilizes clean electrons to replace traditional redox reagents, and has the advantages of mild reaction conditions and green sustainability. It is particularly suitable for the synthesis and production of high-value-added fine chemicals and has practical economic value and development significance. Among them, for the construction of CN bonds (amide bonds), general strategies include: (1) boron-based compound catalytic amidation; (2) ester amidation; (3) aldehyde oxidative amidation; (4) carbonyl amidation. However, the boron-based compound catalytic method has the problem of low atom economy, resulting in a huge waste of atoms; the ester amidation strategy is essentially similar to the condensation amidation strategy. At present, relatively green and efficient synthetic methods have been developed, but they have not yet gotten rid of the selective regulation of the reaction by the metal-coordinated ligand effect; the aldehyde oxidative amidation method is one of the more common strategies, and there is still room for breakthroughs in the substrate range; the biggest challenge of the carbonyl amidation method is safety. The use of CO cannot be avoided. Although it can be solved by using dicarbonyl compounds such as α-keto acids, it is difficult to control the activity of dicarbonyl compounds or amine compounds.

[0005] Therefore, in order to solve the above technical problems, it is necessary to provide an α-ketoamide derivative and a preparation method thereof.

[0006] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the Invention

[0007] The object of the present invention is to provide an α-ketoamide derivative and a preparation method thereof, which can solve the problems in the above-mentioned background technology.

[0008] In order to achieve the above object, a specific embodiment of the present invention provides the following technical solutions:

[0009] An α-ketoamide derivative with the structural formula:

[0010]

[0011] A method for preparing the α-ketoamide derivative comprises the following steps:

[0012] S1. First, install a graphite carbon rod electrode and a platinum sheet electrode on both sides of a 10 mL three-necked glass bottle;

[0013] S2. Add a magnet to the three-necked glass bottle, seal both sides of the bottle, and transfer the three-necked glass bottle to a glove box for feeding. Add benzoylformic acid, morpholine, and 10 mol% ferrocene dissolved in 4 mL of hexafluoroisopropanol in sequence;

[0014] S3. After the feeding is completed, the last bottle mouth of the three-necked glass bottle is sealed and a constant current of 3 mA is passed through for electrolysis;

[0015] S4. After 12 hours of reaction, thin layer chromatography was performed to monitor the reaction. A new spot was observed at a shift value of 0.3.

[0016] S5. Separate and separate the product α-ketoamide compound by column chromatography.

[0017] In one or more embodiments of the present invention, in S1, the three-necked glass bottle includes a three-necked glass bottle body, and the three-necked glass bottle body is provided with three bottle mouths, each of which is equipped with a sealing mechanism, and the bottle mouth is sealed by the sealing mechanism to prevent the gas in the three-necked glass bottle body from overflowing.

[0018] In one or more embodiments of the present invention, the sealing mechanism includes a first sealing member and a second sealing member, the first sealing member corresponds to the second sealing member, and the first sealing member and the second sealing member are both connected to a snap ring, and the first sealing member and the second sealing member are fixed to the bottle mouth by cooperating with the snap ring to ensure a sealing effect on the bottle mouth;

[0019] The bottle mouth is sealed by a first seal, a second seal and a clamping ring. The second seal is fixedly connected to a fixing seat, and the first seal is fixedly connected to a hinge seat. The hinge seat is rotatably connected to the fixing seat. The first seal and the second seal can be connected into one piece through the mutual cooperation between the fixing seat and the hinge seat.

[0020] In one or more embodiments of the present invention, one end of the first sealing member away from the hinge seat is connected to a snap-fit ​​seat, a snap-fit ​​member is rotatably connected in the snap-fit ​​seat, and a nut is threadedly connected to the snap-fit ​​member.

[0021] In one or more embodiments of the present invention, a snap-fit ​​seat is fixedly connected to the second sealing member, and the snap-fit ​​seat corresponds to the snap-fit ​​member and the nut. Through the mutual cooperation of the snap-fit ​​member, the nut and the snap-fit ​​seat, the first sealing member and the second sealing member can be closed to ensure the sealing effect of the sealing mechanism on the bottle mouth.

[0022] In one or more embodiments of the present invention, air bags are installed on the opposite sides of the first sealing member and the second sealing member to facilitate the passage of the graphite carbon rod electrode and the platinum sheet electrode through the sealing mechanism, thereby being able to seal different bottle openings;

[0023] The first sealing member and the second sealing member are both equipped with gas pipes, and the pair of gas pipes are respectively connected to a pair of air bags. Gas can be injected into the air bags through the gas pipes to expand the air bags. When the graphite carbon rod electrode and / or platinum sheet electrode passes through the sealing mechanism, the air bags can be in close contact with the side walls of the graphite carbon rod electrode or platinum sheet electrode, thereby ensuring the sealing effect of the sealing mechanism on the bottle mouth.

[0024] The sides of the pair of air bags that are close to each other are both connected with magnetic strips, and the pair of magnetic strips attract each other, which can further improve the sealing effect of the sealing mechanism on the bottle mouth.

[0025] In one or more embodiments of the present invention, in S1, the diameter of the graphite carbon rod electrode is 6 mm, the size of the platinum sheet electrode is 10×10×0.2 mm, and the distance of the platinum sheet electrode below the liquid surface is 10 mm.

[0026] In one or more embodiments of the present invention, in S2, the concentration of the benzoylformic acid is 1.2 mmol, and the concentration of the morpholine is 0.4 mmol.

[0027] In one or more embodiments of the present invention, in S5, the eluent in the column chromatography separation method includes petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is 3:1.

[0028] Compared with the existing technology, the α-ketoamide derivative and preparation method of the present invention utilize an electrocatalytic decarboxylation strategy to achieve the amination reaction of α-ketoacid and selectively synthesize α-ketoamide derivatives. The reaction is applicable to primary amine compounds, secondary amine compounds, and aromatic and aliphatic α-keto acids, and exhibits excellent functional group tolerance. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments recorded in the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0030] Figure 1 This is a flow chart of a method for preparing an α-ketoamide derivative according to one embodiment of the present invention;

[0031] Figure 2 A three-necked glass bottle in accordance with an embodiment of the present invention is shown from a first angle;

[0032] Figure 3 for Figure 2 Schematic diagram of the structure at A in the middle;

[0033] Figure 4 A perspective view of a three-necked glass bottle from a second angle according to an embodiment of the present invention;

[0034] Figure 5 for Figure 4 Schematic diagram of the structure at B in the middle;

[0035] Figure 6 This is a cross-sectional view of a three-necked glass bottle in one embodiment of the present invention;

[0036] Figure 7 for Figure 6 Schematic diagram of the structure at C in the middle;

[0037] Figure 8 for Figure 6 Schematic diagram of the structure at D in the middle;

[0038] Figure 9 is the product 4-1d in one embodiment of the present invention 1 HNMR spectrum;

[0039] Figure 10 is the product 4-1d in one embodiment of the present invention 13 CNMR spectrum.

[0040] Description of main reference numerals:

[0041] 1-three-necked glass bottle body, 2-sealing mechanism, 201-first sealing member, 202-second sealing member, 203-fixing seat, 204-hinge seat, 205-engaging seat, 206-engaging member, 207-nut, 208-engaging seat, 209-snapping ring, 210-air bag, 211-air pipe, 212-magnetic strip. DETAILED DESCRIPTION

[0042] In order to enable those skilled in the art to better understand the technical solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the accompanying drawings of the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts should fall within the scope of protection of the present invention.

[0043] Example 1

[0044] An α-ketoamide derivative with the structural formula:

[0045]

[0046] A method for preparing an α-ketoamide derivative comprises the following steps:

[0047] S1. First, install a graphite carbon rod electrode (6 mm in diameter) and a platinum sheet electrode (10 × 10 × 0.2 mm in size, 10 mm below the liquid surface) on both sides of a 10 mL three-necked glass bottle.

[0048] S2. Add a magnet to the three-necked glass bottle, seal both sides of the bottle, and transfer the three-necked glass bottle to a glove box for feeding. Add benzoylformic acid (4-1a, 1.2 mmol), morpholine (4-1b, 0.4 mmol), and 10 mol% ferrocene dissolved in 4 mL of hexafluoroisopropanol (HFIP) in sequence;

[0049] S3. After the feeding is completed, the last bottle mouth of the three-necked glass bottle is sealed and a constant current of 3 mA is passed through for electrolysis;

[0050] S4. After 12 hours of reaction, thin layer chromatography (TLC) monitoring was performed, and a new spot was observed at a relative shift value (Rf) of 0.3;

[0051] S5. The product α-ketoamide compound (4-1d) was obtained by column chromatography (volume ratio of eluent: petroleum ether (PE): ethyl acetate (EA) = 3:1).

[0052] In S1, as Figures 2 to 8As shown, the three-necked glass bottle includes a three-necked glass bottle body 1, which is provided with three bottle openings. A sealing mechanism 2 is installed on each bottle opening to seal the bottle opening to prevent the gas in the three-necked glass bottle body 1 from overflowing.

[0053] Among them, the sealing mechanism 2 includes a first sealing member 201 and a second sealing member 202. The first sealing member 201 corresponds to the second sealing member 202. The first sealing member 201 and the second sealing member 202 are both connected with a snap ring 209. The first sealing member 201 and the second sealing member 202 are respectively fixed on the bottle mouth by cooperating with the snap ring 209 to ensure the sealing effect on the bottle mouth.

[0054] In addition, the bottle mouth is sealed by the first sealing member 201, the second sealing member 202 and the retaining ring 209. The second sealing member 202 is fixedly connected to the fixing seat 203, and the first sealing member 201 is fixedly connected to the hinge seat 204. The hinge seat 204 is rotatably connected to the fixing seat 203. The first sealing member 201 and the second sealing member 202 can be connected into one piece through the mutual cooperation between the fixing seat 203 and the hinge seat 204.

[0055] like Figures 2 to 8 As shown, one end of the first sealing member 201 away from the hinge seat 204 is connected to a snap-fit ​​seat 205 , a snap-fit ​​member 206 is rotatably connected in the snap-fit ​​seat 205 , and a nut 207 is threadedly connected to the snap-fit ​​member 206 .

[0056] Among them, the second sealing member 202 is fixedly connected to a snap-fit ​​seat 208, which corresponds to the snap-fit ​​member 206 and the nut 207. Through the mutual cooperation of the snap-fit ​​member 206, the nut 207 and the snap-fit ​​seat 208, the first sealing member 201 and the second sealing member 202 can be closed to ensure the sealing effect of the sealing mechanism 2 on the bottle mouth.

[0057] In addition, air bags 210 are installed on the opposite sides of the first sealing member 201 and the second sealing member 202 to facilitate the graphite carbon rod electrode and the platinum sheet electrode to pass through the sealing mechanism 2, thereby being able to seal different bottle openings.

[0058] like Figures 2 to 8 As shown, a gas pipe 211 is installed on the first sealing member 201 and the second sealing member 202. A pair of gas pipes 211 are respectively connected to a pair of airbags 210. Gas can be injected into the airbags 210 through the gas pipes 211 to expand the airbags 210. When the graphite carbon rod electrode and / or platinum sheet electrode passes through the sealing mechanism 2, the airbags 210 can be in close contact with the side walls of the graphite carbon rod electrode or the platinum sheet electrode, thereby ensuring the sealing effect of the sealing mechanism 2 on the bottle mouth.

[0059] The sides of the pair of air bags 210 that are close to each other are both connected with magnetic strips 212 , and the pair of magnetic strips 212 attract each other, which can further improve the sealing effect of the sealing mechanism 2 on the bottle mouth.

[0060] In specific use, when the mouth of the three-necked glass bottle body 1 needs to be sealed, the first sealing member 201 or the second sealing member 202 is rotated so that the first sealing member 201 can fit the second sealing member 202, the nut 207 is loosened, the engaging member 206 is engaged with the engaging seat 208, and then locked and fixed with the nut 207. Gas is injected into the airbag 210 through the air pipe 211, and the gas causes the airbag 210 to expand. The expanded airbag 210 can contact the graphite carbon rod electrode or the platinum sheet electrode, thereby sealing the bottle mouth.

[0061] At the same time, the magnetic strips 212 in the pair of air bags 210 will attract each other, thereby avoiding the presence of a gap between the pair of air bags 210, thereby further improving the sealing effect on the bottle mouth.

[0062] Synthesis of 4-1d:

[0063]

[0064] Among them, 4-1a is benzoylformic acid (1.2 mmol), and 4-1b is morpholine (0.4 mmol).

[0065] The α-ketoamide compound 4-1d prepared above was 1 H-NMR, 13 C-NMR technology was used for molecular structure and mass identification.

[0066] 4-1d 1 HNMR spectrum Figure 9 As shown, CDCl3 was selected as the solvent to dissolve the sample to be tested, and the solvent peak was calibrated to δ = 7.26 ppm. The extracted data was: 1 HNMR (400MHz, Chloroform-d) δ7.95 (d, J=8Hz, 2H), δ7.64 (t, J=8Hz, 1H), δ7.51 (t, J=8Hz, 2H), δ3.78 (m, 4H), δ3.64 (t, J=8Hz, 2H), δ3.37 (t, J=8Hz, 2H).

[0067] The extracted data were analyzed: the triplet peaks of δ=3.36-3.88 in the aliphatic region, the triplet peak of δ=3.63-3.65, and the multiplet peak of δ=3.78 were attributed to the nitrogen heterocycle in the product 4-1d, wherein the multiplet peak of δ=3.78 was formed by the coupling of the methylene of the aliphatic nitrogen heterocycle with the adjacent methylene; the multiplet peak of δ=7.49-7.96, with an integrated area of ​​5, was attributed to the monosubstituted benzene ring. 1 The HNMR spectrum was compared with the spectrum of α-ketoamide compounds reported in the literature, and it was found that the two were consistent in key parameters such as chemical shift and coupling constant, so 4-1d was determined to be the target product.

[0068] 4-1d 13 CNMR spectrum Figure 10 As shown, CDCl3 was selected as the solvent to dissolve the sample to be tested, and the solvent peak was calibrated to: δ = 77.23ppm. 13 CNMR (101MHz, CDCl3) δ191.33, 165.51, 135.14, 133.14, 129.81, 129.27, 66.86, 66.79, 46.39, 41.75.

[0069] For 4-1d 13 CNMR data analysis revealed 10 groups of signals with different chemical environments: four in the aliphatic region, and six at chemical shifts greater than 100 ppm. In the aliphatic region, δ = 41.75 and δ = 46.39 correspond to carbon atoms attached to nitrogen atoms in the nitrogen heterocycle; δ = 66.79 and δ = 66.86 belong to carbon atoms attached to oxygen atoms in the nitrogen heterocycle; four groups of signals at chemical shifts of δ = 129-136 (δ = 129.27, 129.81, 133.14, and 135.14) indicate the presence of carbon atoms in the same chemical environment on the benzene ring, corresponding to a benzene ring with only one substituent; δ = 165.51 and δ = 191.33 are characteristic peaks for carbonyl groups, indicating that product 4-1d contains at least two carbonyl groups.

[0070] Therefore, by converting the product 4-1d 1 HNMR, 13 The CNMR spectrum data were compared with the data reported in the literature, and it was found that the two were consistent in key parameters such as chemical shift, integrated area, and coupling constant, so 4-1d was confirmed to be an α-ketoamide compound.

[0071] Example 2

[0072] The preparation method of the α-ketoamide derivative in Example 2 is the same as that in Example 1. The structural formula and abbreviation of the prepared α-ketoamide derivative are as follows:

[0073]

[0074]

[0075] As shown above, benzoylformic acids containing electron-donating substituents such as methyl (4-2d), tert-butyl (4-3d), cyclohexyl (4-4d), and benzyloxy (4-5d) all underwent amidation under these electrochemical conditions, transforming into the corresponding α-ketoamide derivatives (45%-70% isolated yield). 2-(Naphth-1-yl)-2-oxoacetic acid, containing two benzene rings, was also successfully converted to the target α-ketoamide product (4-6d) in 73% isolated yield.

[0076] In addition, the preparation method of the α-ketoamide derivatives in this application is also compatible with relatively sensitive halogen functional groups (4-7d and 4-8d). It is worth mentioning that in addition to aromatic α-keto acids, alkyl α-keto acids such as adamantane-1-ylglyoxylic acid (4-9d) also have the ability to be converted into α-ketoamides.

[0077] Secondly, the target molecules (4-10d, 4-11d) were successfully synthesized under electrochemical conditions from the fatty chain small molecule n-propylamine and 2-methoxyethylamine with an electron-donating group, with isolation yields of 53% and 63%, respectively. Aminopyran was successfully converted into an α-ketoamide derivative (4-12d) with an isolation yield of 75%, further improving its application as a pharmaceutical intermediate. In addition to the amidation of the above three types of primary amines, the corresponding conversions of primary spirocyclic amine compounds (4-13d), benzylamine compounds (4-14d), and 2-(tert-butyldimethylsilyloxy)ethylamine (4-15d) were also achieved under the electrochemical system.

[0078] Specifically, the preparation method of the α-ketoamide derivatives disclosed herein is also compatible with piperidine derivatives containing chiral (4-16d) and spirocyclic (4-17d) structures, but is less effective for piperidine derivatives containing electron-withdrawing groups (4-18d) and macromolecular piperidine derivatives (4-21d). This method can also electrochemically amidate piperazine compounds containing protecting groups (4-19d, 4-20d) under neutral conditions.

[0079] Therefore, the preparation method of the α-ketoamide derivatives disclosed in this application has good compatibility with α-keto acids and can be used to promote the synthesis of some complex-structured α-ketoamide bioactive molecules. The derivatization of primary and secondary amine compounds and the exploration of the universality of α-keto acid substrates demonstrate the practicality of constructing C-N bonds under the organic electrochemical synthesis strategy.

[0080] Comparative Example 1

[0081] The preparation method is the same as that of Example 1, except that different reaction electrodes are used. The specific results are as follows:

[0082]

[0083] As shown in the table above, a graphite carbon rod paired with a platinum sheet electrode as the anode and cathode, respectively, achieved the best electrochemical synthesis of product 4-1d with a 70% isolation yield (entry 1). While the cathode (platinum sheet electrode) remained unchanged, replacing the graphite carbon rod electrode with an iron sheet electrode and a copper sheet electrode, respectively, no product 4-1d was produced (entries 2, 3). Even when both the cathode and anode electrodes were replaced with platinum sheets, no production of the target product 4-1d was detected (entry 4).

[0084] Comparative Example 2

[0085] The preparation method is the same as that of Example 1, except that a different solvent is used. The specific results are as follows:

[0086]

[0087] As can be seen from the table above, hexafluoroisopropanol (HFIP) can promote the reaction, and the target product 4-1d can reach an isolated yield of 70% (entry 1). Since hexafluoroisopropanol (HFIP) is a typical protic solvent, based on this idea, the same type of protic solvent methanol (MeOH) was tried for the reaction, but it was found that only 35% of the isolated yield of 4-1d was produced (entry 2). Later, methanol (MeOH) and trifluoroacetic acid (TFA) were tried to be prepared into a mixed solvent with hexafluoroisopropanol (HFIP) at a volume ratio of 1:4 for the reaction. The isolated yield of the target product 4-1d decreased to 32% and 30%, respectively (entries 3, 4). The preparation method of the α-ketoamide derivative adopted in this application has a very poor reaction effect in trifluoroethanol (TFE), which is also a protic solvent, and the isolated yield of 4-1d is only 12%. In order to improve the isolation yield of the target product, acetonitrile was added to hexafluoroisopropanol (HFIP) as a mixed solvent, and a 50% isolation yield was achieved in 4-1d (entry 5).

[0088] Therefore, mixed solvents have no facilitating effect on the preparation of α-ketoamide derivatives. Screening the reaction using aprotic solvents revealed that they were less effective than protic solvents. The target product 4-1d was isolated in acetonitrile with a yield of only 30%, and was virtually undetectable in methyl tert-butyl ether (MTBE), acetone, and 1,2-dichloroethane (DCE) (entries 7-10). Therefore, hexafluoroisopropanol (HFIP) was identified as the preferred solvent for the electrochemical synthesis of α-ketoamides from α-keto acids.

[0089] Comparative Example 3

[0090] The preparation method is the same as that of Example 1, except that a different electrolyte is used. The specific results are as follows:

[0091]

[0092] As can be seen from the table above, by screening conventional electrolytes used in organic electrochemical synthesis, it was found that the addition of electrolytes did not improve the activity of the reaction, but inhibited the forward movement of the reaction. When 0.02 mol / L of tetrabutylammonium salt electrolytes nBu4NBF4 and nBu4NPF6 were added to the system, the isolated yield of product 4-1d was less than 30% (entries 1, 3). Continuing to change the anion of the electrolyte, it was found that acetate ion (Ac - ), perchlorate ion (ClO4 - ), bromide anion (Br - ) and other tetrabutylammonium salts reduced the isolated yield of product 4-1d (entries 4-6). Surprisingly, without the addition of any electrolyte, a very good result was achieved, with product 4-1d reaching an isolated yield of 70%.

[0093] Therefore, it was determined that the reaction of α-keto acid to α-ketoamide under electrochemical conditions does not require the addition of electrolyte.

[0094] Comparative Example 4

[0095] The preparation method is the same as that of Example 1, except that different redox media and gas atmospheres are used. The specific results are as follows:

[0096]

[0097] As can be seen from the table above, in order to explore whether the reaction requires the addition of a redox medium and whether it is necessary to conduct the reaction in an inert gas atmosphere, the following control experiments were conducted using the controlled variable method. Through the comparative experiments, it was found that under the same gas atmosphere, the addition of ferrocene medium is conducive to the formation of product 4-1d, and the isolation yield of product 4-1d is increased by 5% and 15% respectively (entries 1, 2 and entries 3, 5). Through the comparative experiments, it was found that the atmosphere of inert gas protection can promote the formation of product 4-1d, and the isolation yield of product 4-1d is increased by 9% and 27% respectively (entries 1, 3 and entries 2, 5).

[0098] Therefore, ferrocene was determined to be an additive, and 10 mol % of ferrocene was selected to be added in the reaction as a redox medium. The reaction was carried out in an inert gas argon (Ar) atmosphere.

[0099] In summary, through optimization of key parameters for the electrochemical synthesis of α-ketoamides, the standard conditions were determined: 4-1a (1.2 mmol, 3 equiv), 4-1b (0.4 mmol, 1 equiv), ferrocene (10 mol%), HFIP (4 mL) solvent, a graphite carbon rod as anode (φ = 6 mm), a platinum sheet as a cathode (10 × 10 × 0.2 mm), an argon (Ar) atmosphere, and a constant current (3 mA) at room temperature for 12 hours. Under these standard conditions, the target product 4-1d was isolated in a yield of 70%.

[0100] This application utilizes the electrochemical oxidation capacity, using ferrocene as the redox mediator, to decarboxylate and activate α-keto acids. This decarboxylation reaction then reacts with amine compounds to selectively synthesize α-ketoamide derivatives, achieving the construction of C-N bonds. This method is applicable not only to aromatic α-keto acids but also to fatty α-keto acids, and is compatible with both primary and secondary amine compounds.

[0101] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above and that the invention can be embodied in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as illustrative and non-restrictive, and the scope of the invention is defined by the appended claims, not the foregoing description, and all variations within the meaning and range of equivalents of the claims are intended to be included therein. Any reference sign in a claim should not be construed as limiting the claim to which it relates.

[0102] In addition, it should be understood that although this specification is described in terms of implementation methods, not every implementation method contains only one independent technical solution. This narrative method of the specification is only for the sake of clarity. Those skilled in the art should regard the specification as a whole. The technical solutions in each embodiment can also be appropriately combined to form other implementation methods that can be understood by those skilled in the art.

Claims

1. A method for preparing an α-ketoamide derivative, characterized in that: The following steps are involved: S1. First, install a graphite carbon rod anode and a platinum sheet cathode on both sides of a 10 mL three-necked glass bottle; S2. Add a magnet to the three-necked glass bottle, seal both sides of the bottle, and transfer the three-necked glass bottle to a glove box for feeding. Add benzoylformic acid, morpholine, and 10 mol% ferrocene dissolved in 4 mL of hexafluoroisopropanol in sequence; S3. After the feeding is completed, the last bottle mouth of the three-necked glass bottle is sealed and a constant current of 3 mA is passed through for electrolysis; S4. After 12 hours of reaction, thin layer chromatography was performed to monitor the reaction. A new spot was observed at a shift value of 0.

3. S5. Obtaining the product α-ketoamide compound by column chromatography separation chromatography .

2. The method for preparing an α-ketoamide derivative according to claim 1, characterized in that: In S1, the three-necked glass bottle includes a three-necked glass bottle body, the three-necked glass bottle body is provided with three bottle openings, and each of the bottle openings is installed with a sealing mechanism.

3. The method for preparing an α-ketoamide derivative according to claim 2, characterized in that: The sealing mechanism includes a first sealing member and a second sealing member, the first sealing member corresponds to the second sealing member, and the first sealing member and the second sealing member are both connected with a snap ring. The bottle mouth is sealed by the first sealing member, the second sealing member and the snap ring. The second sealing member is fixedly connected to a fixing seat, and the first sealing member is fixedly connected to a hinge seat, and the hinge seat is rotatably connected to the fixing seat.

4. The method for preparing an α-ketoamide derivative according to claim 3, characterized in that: One end of the first sealing member away from the hinge seat is connected to a clamping seat, a clamping member is rotatably connected in the clamping seat, and a nut is threadedly connected on the clamping member.

5. The method for preparing an α-ketoamide derivative according to claim 4, characterized in that: A snap-fit ​​seat is fixedly connected to the second sealing member, and the snap-fit ​​seat corresponds to the snap-fit ​​member and the nut.

6. The method for preparing an α-ketoamide derivative according to claim 5, characterized in that: Airbags are installed on the opposite sides of the first seal and the second seal, and air pipes are installed on the first seal and the second seal. A pair of air pipes are respectively connected to a pair of airbags, and a magnetic strip is connected to the side of the pair of airbags close to each other.

7. The method for preparing an α-ketoamide derivative according to claim 1, characterized in that: In S1, the diameter of the graphite carbon rod electrode is 6 mm, the size of the platinum sheet electrode is 10×10×0.2 mm, and the distance below the liquid surface of the platinum sheet electrode is 10 mm.

8. The method for preparing an α-ketoamide derivative according to claim 1, characterized in that: In S2, the concentration of the benzoylformic acid is 1.2 mmol, and the concentration of the morpholine is 0.4 mmol.

9. The method for preparing an α-ketoamide derivative according to claim 1, characterized in that: In S5, the eluent in the column chromatography separation method includes petroleum ether and ethyl acetate, and the volume ratio of the petroleum ether to ethyl acetate is 3:1.

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