An amide derivative and a process for its preparation

Abstract

The application belongs to the technical field of compound synthesis, and particularly relates to an amide derivative and a preparation method thereof, wherein the preparation method of the amide derivative comprises the following steps: S1, graphite carbon rod electrodes and platinum sheet electrodes are respectively arranged on two sides of a 10mL three-port glass bottle; S2, a magnet is added to the three-port glass bottle, the bottle mouth is sealed, and then the three-port glass bottle is transferred to a glove box for feeding, and benzoylformic acid, morpholine, 10mol% ferrocene, tetrabutylammonium iodide, 75mg molecular sieves and 4mL anhydrous acetonitrile are sequentially added; S3, after the feeding is completed, the bottle mouth of the three-port glass bottle is tightly wrapped with sealing film, and argon is introduced into the three-port glass bottle. The application utilizes the oxidation capacity of electrochemistry, uses ferrocene as a redox medium, performs decarboxylation activation on alpha-keto acid, and is combined with an amine compound to synthesize an amide derivative, so that the construction of a C-N bond is realized. The method is not only suitable for aromatic alpha-keto acid, but also suitable for aliphatic alpha-keto acid, and can be compatible with primary amine and secondary amine compounds.

Description

Technical Field

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

[0002] Nitrogen-containing organic compounds are widely present in natural products, active pharmaceutical ingredients, and synthetic chemistry, so the construction of C-N bonds is of great significance. Carboxylic acids are abundant and inexpensive, making them one of the ideal reaction substrates. Carboxylic acid amidation is one of the most common strategies for constructing C-N bonds (amide bonds). However, direct amination of carboxylic acids is a very challenging reaction: 1. Carboxylic acids may undergo acid-base neutralization competition with amine compounds; 2. Multi-step synthesis results in low value; 3. Direct amination of carboxylic acids requires overcoming a very high energy barrier, and generally only harsh reaction conditions (such as high temperature and high pressure) can provide sufficient energy; 4. Unstable intermediates are produced, resulting in poor safety.

[0003] One of the most common methods is to use an acid chloride intermediate to undergo amination reaction. Common intermediates also include anhydrides and esters. However, these intermediates are extremely unstable and require the use of highly toxic dichlorothionyl (SOCl2) to prepare them. At the same time, the preparation process releases toxic gas sulfur dioxide (SO2). In industrial production, the general strategy is to activate the carboxylic acid by adding a condensation reagent to the system to increase its activity to generate the corresponding intermediate, and then react with the intermediate to achieve carboxylic acid amination. However, in addition to considering the toxicity and cost of the condensation reagent, the use of the condensation reagent can also lead to diastereoisomerization at the α position of the complex compound.

[0004] In addition, there are four other commercially available methods for constructing C-N bonds (amide bonds): boron-catalyzed amidation, oxidative amination, ester amidation, and carbonyl amidation. However, these methods generally suffer from low atom economy, high safety risks, and high costs. Specifically, some methods are limited to structurally simple amine compounds and are unable to achieve amidation of some sterically hindered amine compounds (such as adamantaneamine). For example, transition metal-catalyzed ester transamidation strategies, in addition to the use of expensive precious metals (such as iridium catalysts), also have low reaction efficiency. Currently reported amidation strategies generally only functionalize specific substrates, lacking universal applicability.

[0005] Therefore, in order to solve the above technical problems, it is necessary to provide an amide 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 amide 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 amide derivative with the structural formula:

[0010]

[0011] A method for preparing an amide derivative comprises the following steps:

[0012] S1. Assemble 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 a three-necked glass bottle, seal both sides of the bottle and transfer it to a glove box for feeding, add benzoylformic acid, morpholine, 10 mol% ferrocene, tetrabutylammonium iodide, 75 mg of molecular sieves and 4 mL of anhydrous acetonitrile;

[0014] S3. After the feeding is completed, the mouths of the three-necked glass bottles are tightly wrapped with sealing film, argon gas is introduced into the three-necked glass bottles, and a constant current of 10 mA is passed through the bottles for electrolysis;

[0015] S4, after 12 hours of reaction, perform thin layer chromatography monitoring until new compounds are produced;

[0016] S5. Separate the compound in S4 by column chromatography to obtain an amide derivative.

[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 a stirring mechanism is installed at the bottom of the three-necked glass bottle body, and the stirring mechanism is used to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, Molecular sieves and anhydrous acetonitrile allow various substances to be fully mixed, thereby improving the subsequent electrolysis effect;

[0018] The stirring mechanism includes a base, in which a motor and a power supply are installed. The motor is electrically connected to the power supply, the power supply is used to supply power to the motor, and the motor is used to provide driving force.

[0019] In one or more embodiments of the present invention, the output shaft of the motor is connected to a rotating shaft, one end of the rotating shaft is arranged in the main body of the three-necked glass bottle, the end of the rotating shaft away from the motor is fixedly connected to a fixed sleeve, and a plurality of first stirring rods are fixedly connected to the fixed sleeve. When the motor is running, the motor drives the rotating shaft to rotate, and then drives the fixed sleeve and the first stirring rods to rotate in the main body of the three-necked glass bottle, so as to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, molecular sieves and anhydrous acetonitrile.

[0020] In one or more embodiments of the present invention, the side wall of the rotating shaft is fixedly connected to a limit plate for mounting the movable sleeve;

[0021] A movable sleeve is provided on the upper side of the limit plate, and the diameter of the movable sleeve is larger than the diameter of the rotating shaft so that the movable sleeve will not rotate with the rotating shaft;

[0022] The movable sleeve is connected to a plurality of second stirring rods, the second stirring rods corresponding to the first stirring rods, and the second stirring rods can play a role of auxiliary stirring.

[0023] In one or more embodiments of the present invention, a linkage mechanism is connected between the first stirring rod and the second stirring rod, and the linkage mechanism can increase the linkage effect between the first stirring rod and the second stirring rod;

[0024] The linkage mechanism includes a first rotating sleeve, which is fixedly connected to the second stirring rod. A first rotating ball is rotatably provided in the first rotating sleeve, and an inner rod is connected to the first rotating ball. Through the mutual cooperation of the first rotating sleeve and the first rotating ball, the inner rod can be tilted at a certain angle.

[0025] In one or more embodiments of the present invention, an outer rod is slidably provided on the outer side of the inner rod, and the outer rod is used to protect the metal rod, the controller and the heating wire;

[0026] A second rotating ball is fixedly connected to the outer rod, and a second rotating sleeve is rotatably connected to the outer side of the second rotating ball. The second rotating sleeve is fixedly connected to the second stirring rod. Through the cooperation of the second rotating ball and the second rotating sleeve, the outer rod can be tilted at a certain angle. When the first stirring rod rotates, under the action of the second rotating ball and the second rotating sleeve, the outer rod connected to the first stirring rod is tilted by the force of the first stirring rod, thereby causing the outer rod and the inner rod to be relatively displaced. At this time, the metal rod and the heating wire are not protected by the outer rod, and the inner rod can drive the second stirring rod to move and rotate around the rotating shaft, which can play a role in auxiliary stirring.

[0027] In one or more embodiments of the present invention, one end of the inner rod located inside the outer rod is connected to a metal rod, and the metal rod is used to fix the heating wire;

[0028] The metal rod is connected to a controller, and the controller is electrically connected to a heating wire. The heating wire is arranged outside the metal rod. When the controller is operated, the heating wire is heated, thereby increasing the temperature of the liquid in the three-necked glass bottle body, so that various substances can be better mixed;

[0029] An elastic rope is connected between the controller and the inner wall of the outer rod. When the second rotating sleeve is not subjected to the force of the first stirring rod, the metal rod and the heating wire re-enter the outer rod under the action of the elastic rope and are protected by the outer rod.

[0030] In one or more embodiments of the present invention, in S4, the time when the new compound is generated is when the ratio shift value (Rf) is 0.3.

[0031] 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.

[0032] Compared with the existing technology, the present invention provides an amide derivative and a preparation method thereof. By utilizing the electrochemical oxidation ability and using ferrocene as the redox medium of the system, α-keto acid is decarboxylated and activated, and reacted with an amine compound to synthesize an amide derivative, thereby realizing the construction of a CN bond. This method is applicable not only to aromatic α-keto acids, but also to fatty α-keto acids, and is compatible with primary amine and secondary amine compounds. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] 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.

[0034] Figure 1 This is a flow chart of a method for preparing an amide derivative according to one embodiment of the present invention;

[0035] Figure 2 This is a cross-sectional view of a three-necked glass bottle in one embodiment of the present invention;

[0036] Figure 3 for Figure 2 Schematic diagram of the structure at A in the middle;

[0037] Figure 4 for Figure 2 Schematic diagram of the structure at B in the middle;

[0038] Figure 5 A schematic diagram of a portion of the structure of a stirring mechanism in one embodiment of the present invention;

[0039] Figure 6 This is a three-necked glass bottle perspective view of an embodiment of the present invention;

[0040] Figure 7 4-1c in one embodiment of the present invention 1 H-NMR spectrum;

[0041] Figure 8 4-1c in one embodiment of the present invention 13 CNMR spectrum.

[0042] Description of main reference numerals:

[0043] 1-three-necked glass bottle body, 2-stirring mechanism, 201-base, 202-motor, 203-power supply, 204-rotating shaft, 205-fixed sleeve, 206-first stirring rod, 207-limiting plate, 208-movable sleeve, 209-second stirring rod, 3-linkage mechanism, 301-first rotating sleeve, 302-first rotating ball, 303-inner rod, 304-outer rod, 305-second rotating ball, 306-second rotating sleeve, 307-metal rod, 308-controller, 309-heating wire, 310-elastic rope. DETAILED DESCRIPTION

[0044] 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.

[0045] Example 1

[0046] An amide derivative in one embodiment of the present invention has the structural formula:

[0047]

[0048] like Figure 1 As shown, a method for preparing an amide derivative comprises the following steps:

[0049] S1. Assemble a graphite carbon rod electrode (φ = 6 mm) and a platinum sheet electrode (10 × 10 × 0.2 mm, below the liquid level = 10 mm) on both sides of a 10 mL three-necked glass bottle;

[0050] S2, add a magnetic particle to a three-necked glass bottle, seal both sides of the bottle and transfer it to a glove box for feeding, add benzoylformic acid 4-1a (0.4 mmol, 1 equiv), morpholine 4-1b (1.2 mmol, 3 equiv), 10 mol% ferrocene, tetrabutylammonium iodide (0.02 mol / L), 75 mg of molecular sieves and 4 mL of anhydrous acetonitrile;

[0051] S3. After the feeding is completed, the mouths of the three-necked glass bottles are tightly wrapped with sealing film, argon gas is introduced into the three-necked glass bottles, and a constant current of 10 mA is passed through the bottles for electrolysis;

[0052] S4. After 12 hours of reaction, thin layer chromatography was performed to monitor the reaction, and a new compound was observed to be generated at a relative shift value (Rf) of about 0.3;

[0053] S5. Separate the compound in S4 by column chromatography (volume ratio of eluent: petroleum ether: ethyl acetate = 3:1) to obtain amide derivative 4-1c.

[0054] like Figures 2 to 6 As shown, the three-necked glass bottle includes a three-necked glass bottle body 1, and a stirring mechanism 2 is installed at the bottom of the three-necked glass bottle body 1. The stirring mechanism 2 is used to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, Molecular sieves and anhydrous acetonitrile allow various substances to be fully mixed, thereby improving the subsequent electrolysis effect.

[0055] The stirring mechanism 2 includes a base 201 , in which a motor 202 and a power supply 203 are installed. The motor 202 is electrically connected to the power supply 203 . The power supply 203 is used to supply power to the motor 202 , and the motor 202 is used to provide driving force.

[0056] In addition, the output shaft of the motor 202 is connected to a rotating shaft 204, one end of the rotating shaft 204 is arranged in the three-necked glass bottle body 1, and the end of the rotating shaft 204 away from the motor 202 is fixedly connected to a fixing sleeve 205, and a plurality of first stirring rods 206 are fixedly connected to the fixing sleeve 205. When the motor 202 is running, the motor 202 drives the rotating shaft 204 to rotate, and then drives the fixing sleeve 205 and the first stirring rods 206 to rotate in the three-necked glass bottle body 1, so as to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, molecular sieves and anhydrous acetonitrile.

[0057] Specifically, the side wall of the rotating shaft 204 is fixedly connected with a limiting plate 207, which is used for mounting a movable sleeve 208. The movable sleeve 208 is arranged on the upper side of the limiting plate 207, and the diameter of the movable sleeve 208 is greater than that of the rotating shaft 204, so that the movable sleeve 208 cannot rotate with the rotating shaft 204.

[0058] In addition, the movable sleeve 208 is connected with a plurality of second stirring rods 209, which correspond to the first stirring rods 206. The second stirring rods 209 can play an auxiliary stirring role.

[0059] As shown in Figures 2 to 6 , the first stirring rods 206 and the second stirring rods 209 are connected with a linkage mechanism 3. The linkage mechanism 3 can increase the linkage effect between the first stirring rods 206 and the second stirring rods 209.

[0060] The linkage mechanism 3 comprises a first rotating sleeve 301, which is fixedly connected with the second stirring rods 209. A first rotating ball 302 is rotatably arranged in the first rotating sleeve 301. An inner rod 303 is connected with the first rotating ball 302. Through the cooperation of the first rotating sleeve 301 and the first rotating ball 302, the inner rod 303 can be inclined at a certain angle.

[0061] In addition, an outer rod 304 is slidably arranged on the outer side of the inner rod 303. The outer rod 304 is used for protecting a metal rod 307, a controller 308 and an electric heating wire 309. A second rotating ball 305 is fixedly connected with the outer rod 304. A second rotating sleeve 306 is rotatably connected with the outer side of the second rotating ball 305. The second rotating sleeve 306 is fixedly connected with the second stirring rods 209.

[0062] Through the cooperation of the second rotating ball 305 and the second rotating sleeve 306, the outer rod 304 can be inclined at a certain angle. When the first stirring rods 206 rotate, under the action of the second rotating ball 305 and the second rotating sleeve 306, the outer rod 304 connected with the first stirring rods 206 is inclined under the action force of the first stirring rods 206, and then the outer rod 304 and the inner rod 303 are relatively displaced. At this time, the metal rod 307 and the electric heating wire 309 are not protected by the outer rod 304. The inner rod 303 can drive the second stirring rods 209 to move and rotate around the rotating shaft 204, which can play an auxiliary stirring role.

[0063] Specifically, one end of the inner rod 303, located within the outer rod 304, is connected to a metal rod 307, which is used to secure a heating wire 309. Metal rod 307 is connected to a controller 308, which is electrically connected to the heating wire 309, which is located outside the metal rod 307. When the controller 308 is activated, the heating wire 309 heats up, thereby increasing the temperature of the liquid within the three-necked glass bottle body 1 and enabling better mixing of the various substances.

[0064] In addition, an elastic rope 310 is connected between the controller 308 and the inner wall of the outer rod 304. When the second rotating sleeve 306 is not subjected to the force of the first stirring rod 206, under the action of the elastic rope 310, the metal rod 307 and the heating wire 309 re-enter the outer rod 304 and are protected by the outer rod 304.

[0065] When it is used specifically, when it is necessary to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, When the molecular sieve and anhydrous acetonitrile are added, the motor 202 is operated, the motor 202 drives the rotating shaft 204 to rotate, and the rotating shaft 204 drives the fixed sleeve 205 and the first stirring rod 206 to rotate, and is used to stir the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, molecular sieves and anhydrous acetonitrile for stirring.

[0066] When the first stirring rod 206 rotates, the outer rod 304 connected to the first stirring rod 206 is subjected to the force of the first stirring rod 206 and tilts under the action of the second rotating ball 305 and the second rotating sleeve 306. At the same time, the outer rod 304 and the inner rod 303 also move relative to each other. At this time, the metal rod 307 and the heating wire 309 are not protected by the outer rod 304. The outer rod 304 can drive the second stirring rod 209 to rotate around the rotating shaft 204 through the inner rod 303, the first rotating ball 302 and the first rotating sleeve 301, which can play a role in auxiliary stirring, greatly improving the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, Stirring effect of molecular sieves and anhydrous acetonitrile.

[0067] In addition, when the metal rod 307 and the heating wire 309 are not protected by the outer rod 304, the controller 308 operates, so that the heating wire 309 generates heat, thereby heating the benzoylformic acid, morpholine, ferrocene, tetrabutylammonium iodide, The molecular sieve and anhydrous acetonitrile are heated so that the substances in the three-necked glass bottle body 1 can be better mixed, which is convenient for subsequent electrolysis.

[0068] Synthesis of 4-1c:

[0069]

[0070] The molecular mass of 4-1c was identified by gas chromatography-mass spectrometry: the charge-to-mass ratio of 4-1c was m / z = 191.09, which was consistent with the target product. 1 H-NMR, 13 The chemical structure of 4-1c was identified by C-NMR technology.

[0071] 4-1c 1 H-NMR spectrum Figure 7 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 is: 1 H-NMR (400MHz, Chloroform-d) δ7.41-7.37 (m, 5H), 3.75-3.43 (m, 8H).

[0072] The extracted data were analyzed: the multiple peaks in the aliphatic region δ = 3.43-3.75 (m, 8H) are derived from the aliphatic nitrogen heterocycle of substrate 4-1b. The nitrogen heterocycle contains 4 methylene groups, which are coupled with adjacent methylene groups, resulting in the original triplet peak being further split into multiple peaks. The multiple peaks at δ = 7.37-7.41, with an integrated area of ​​5, are attributed to the monosubstituted benzene ring. 1 The HNMR spectrum was compared with the previously reported standard spectrum, and it was found that the two were consistent in key parameters such as chemical shift, coupling constant, and integral number, so 4-1c was determined to be the target product.

[0073] 4-1c 13 CNMR spectrum Figure 8 As shown, CDCl3 is used as the solvent to dissolve the sample to be tested, and the solvent peak is calibrated to δ = 77.23 ppm. The extracted data is: 13 CNMR (101MHz, CDC l3 )δ170.57, 135.36, 130.01, 128.68, 127.18, 66.99, 48.33, 42.66.

[0074] For 4-1c 13The CNMR data were analyzed: there were a total of 8 groups of signals in different chemical environments: 3 groups in the aliphatic region, δ = 42.66 and δ = 48.33 were carbon atoms connected to the nitrogen atom on the nitrogen heterocycle; δ = 66.99 was the carbon atom connected to the oxygen atom on the nitrogen heterocycle, among which the other carbon atom connected to the oxygen atom on the morpholine ring did not emit a peak due to rotational hindrance; the peak intensities of the two carbon atoms with chemical shift values ​​of δ = 42.66 and δ = 48.33 were relatively weak, also due to a certain degree of rotational hindrance; the four peaks of δ = 127.18-135.36 were attributed to the monosubstituted benzene ring; δ = 170.57 ppm was the characteristic peak of the carbonyl group, indicating the successful construction of the amide bond (-CONH-).

[0075] By converting 4-1c 1 H-NMR, 13 The CNMR spectrum was 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, thus confirming that 4-1c was the target product.

[0076] Example 2

[0077] The preparation method of the amide derivative in Example 2 is the same as that in Example 1. The synthesis experiment is carried out using a secondary aliphatic heterocyclic amine amide. The structural formula and abbreviation of the synthesized amide derivative are as follows:

[0078]

[0079] As shown above, this chemical system has good compatibility with secondary heterocyclic amines, with product isolation yields ranging from 40% to 83%. The chiral cis-2,6-dimethylmorpholine (4-2c) was successfully amidated, maintaining its chirality and achieving an 83% isolation yield.

[0080] The spiro ring structure is a polycyclic structure connected by the same atom (C, N, O, S, Si, etc.), so it has a larger three-dimensional space than the structure of the planar compound, which increases the sp 3 The proportion of the components in the electrochemical reaction was significantly increased, thereby improving the solubility of the spirocyclic compound for organic compounds. The spiroamine 4-piperidone ethylene glycol acetal (4-4c) was amidated as expected under these electrochemical conditions, with an isolated yield of 60%.

[0081] Furthermore, piperazines containing protecting groups (Boc and Cbz) successfully achieved amide bond formation under neutral conditions (4-5c-4-6c). For piperidine compounds, in addition to being compatible with electron-donating groups such as methoxy (4-3c), electron-withdrawing groups were also compatible. Secondary aliphatic amines linked to trifluoromethyl (4-7c), cyano (4-8c), and ester (4-9c) groups were all successfully converted, with product isolation yields ranging from 57% to 73%. Under these conditions, piperazines containing unsaturated functional groups (4-10c) were also successfully amidated, with no addition or polymerization of the double bond occurring.

[0082] Example 3

[0083] The preparation method of the amide derivative in Example 3 is the same as that in Example 1. N-benzylamide is used for the synthesis experiment. The structural formula and abbreviation of the synthesized amide derivative are as follows:

[0084]

[0085] As can be seen from the above, this method is beneficial for the amidation of N-benzyl amine compounds, especially N-methylbenzylamine compounds (4-11c-4-13c). Product yields generally exceed 60%, and the N-methylbenzylamine compound containing a halogen substituent (4-13c) achieved an isolated yield of 80%. In addition to being compatible with halogen functional groups that are sensitive in electrochemical environments, it also has a good reaction effect on N-methylbenzylamine compounds containing electron-donating substituents, with the product 4-12c achieved an isolated yield of 62%. The heavily hindered dibenzylamine (4-14c) was also successfully converted under these conditions.

[0086] Therefore, this electrochemical strategy is not only applicable to the amidation of secondary amines but also has the potential to synthesize complex amide derivatives.

[0087] Example 4

[0088] The preparation method of the amide derivative in Example 4 is the same as that in Example 1. The synthesis experiment is carried out using a primary amide. The structural formula and abbreviation of the synthesized amide derivative are as follows:

[0089]

[0090] As shown above, small molecules such as n-propylamine (4-15c), the heavily hindered tert-amylamine (4-16c) and tert-amylamine (4-17c), and 2-methoxyethylamine (4-18c) with an electron-donating group were successfully amidated. In addition to small primary aliphatic amines, the larger molecular weight 3-phenyl-1-propylamine (4-19c) also underwent corresponding conversion under electrochemical conditions, achieving moderate isolated yields.

[0091] Small cyclic amines such as cyclopropylamine (4-20c), cyclobutylamine (4-21c), cyclopentylamine (4-22c), cyclohexylamine (4-23c), and cycloheptylamine (4-24c) were all subjected to amidation with yields ranging from 30% to 68%. The integrity of the strained ring was maintained, and no ring-opening byproducts were produced. 4-Aminotetrahydropyran (4-25c) was also amidated under these conditions with an isolated yield of 80%. During substrate expansion, it was discovered that amine compounds containing a protecting group (Boc) could form C-N bonds under neutral conditions (4-26c-4-27c).

[0092] In addition to the above molecules, the electrochemical system is also compatible with 4-methoxybenzylamine (4-28c) and 1,2,3,4-tetrahydro-1-naphthylamine (4-29c) containing electron-donating groups, improving the application of the two compounds as synthetic building blocks in pharmaceutical intermediates.

[0093] This application also achieves the amidation conversion of polyfluoro-substituted cyclobutylamines. The amide fragment in product 4-30c is a key precursor of ivosidenib, a drug used to treat acute myeloid leukemia. Therefore, the electrochemical amidation method enhances the application of 4-30c as a pharmaceutical intermediate. Furthermore, the electrochemical amidation method is also compatible with alkenyl (4-31c) and dimethylsilyl functional groups (4-32c), successfully converting alkenyl-substituted and silicon-substituted fatty amines into their corresponding amide derivatives.

[0094] Example 5

[0095] The preparation method of the amide derivatives in Examples 4 and 5 is the same as that in Example 1. Aromatic heterocyclic amides are used for the synthesis experiments. The structural formulas and abbreviations of the synthesized amide derivatives are as follows:

[0096]

[0097] As can be seen from the above, under electrochemical conditions, the substrate 3-(2-aminoethyl)pyridine (4-33c) was successfully functionalized, but the product had an isolated yield of only 35%. In addition to the pyridine heterocycle, electron-rich and electron-deficient thiopheneamine compounds (4-34c-4-35c) were amidated, respectively, broadening the application of thiopheneamine compounds as synthetic building blocks in organic synthesis and pharmaceutical intermediates. In addition to the two types of heterocyclic amines, pyridine and thiophene, this method is also applicable to pyrimidineamine compounds. This application successfully converted 2-aminopyrimidine (4-36c) into the corresponding amide derivative, and the isolated yield of the product 4-36c was 38%.

[0098] Example 6

[0099] The preparation method of the amide derivative in Example Six is the same as that of the amide derivative in Example One, and the synthesis experiment is carried out using an α-keto acid. The structural formula and abbreviation of the synthesized amide derivative are as follows:

[0100]

[0101] As can be seen from the above, the benzoyl formic acid connected with various electron-donating groups is successfully converted into the corresponding amide derivative in the system, wherein the electron-donating groups are methyl (4-37c), tert-butyl (4-39c), n-pentyl (4-40c), and cyclohexyl (4-41c), and the yield of the amide product ranges from 40% to 67%. The amide reaction of 3,4-methylenedioxybenzoyl formic acid and 3-benzyloxybenzoyl formic acid with the substrate 4-1b under the electrochemical conditions obtains the corresponding amide products 4-42c and 4-43c, respectively, with separation yields of 45% and 53%.

[0102] Exploring the scope of α-keto acids, it is found that the system can be compatible with various types of functional groups (including electron-withdrawing groups and electron-donating groups), such as sulfides (4-44c) and cyano groups (4-45c). α-Keto acids containing two benzene ring structures, such as biphenyl (4-46c), 2-naphthyl (4-47c), or 1-naphthyl α-keto acid (4-48c), also complete the construction of amide bonds under the electrochemical conditions and achieve moderate yields (50%-56%).

[0103] Notably, in addition to the amide conversion of α-keto acids containing benzene ring structures, furan-type α-keto acid (4-49c) and thiophene-type α-keto acid (4-50c) also achieve amide under the electrochemical conditions.

[0104] In summary, the exploration of the substrate scope of α-keto acids proves that the electrochemical method has good universality, realizes the conversion of various types of α-keto acids into high-value-added amide derivatives, and improves the application scenarios of heterocyclic amide molecules as pharmaceutical intermediates.

[0105] Comparative Example One

[0106] The preparation method is the same as that of Example One, except for the difference in electrode materials. The specific results are as follows:

[0107] Entry Electrode <![CDATA[Yield of 4-lc(%) b ]]> 1 C / Pt 75 2 C / C 16 3 C / Ni ＜10 4 Fe / Pt trace 5 Cu / Pt NR 6 Pt / Pt trace 7 Pt / C trace

[0108] As can be seen from the table above, the target product 4-1c was only detected when the graphite carbon rod was used as the anode (entrie81-3), and the yield of the product was between 10% and 75%. Continuing to keep the graphite carbon rod as the anode, the cathode materials were replaced with graphite carbon rod electrodes and nickel sheet electrodes (entries 2, 3), and it was found that only a small amount of 4-1c was produced (10%-16%). Keeping the platinum sheet electrode as the cathode, we continued to try to use different anodes for the reaction and found that the iron sheet and copper sheet electrodes were not effective, and almost no product was observed (entries 5, 6), proving that the two did not act as sacrificial electrodes. When the electrodes were paired with a platinum sheet electrode (anode) and a graphite carbon rod electrode (cathode), only a trace amount of product was produced (entry 7).

[0109] Therefore, a graphite carbon rod electrode (φ=6 mm) was determined as the anode of the battery, and a platinum sheet (10×10×0.2, mm) was determined as the cathode of the battery.

[0110] Comparative Example 2

[0111] The preparation method is the same as that of Example 1, except that the electrolyte is different. The specific results are as follows:

[0112] Entry Electrolyte <![CDATA[Yield of4-lc(%) b ]]> 1 <![CDATA[nBu4NCl]]> 75 2 <![CDATA[nBu4NBF4]]> trace 3 <![CDATA[nBu4NI]]> trace 4 <![CDATA[nBu4NBr]]> 45 5 <![CDATA[nBu4NClO4]]> 20 6 <![CDATA[nBu4NAc]]> 39 7 <![CDATA[LiBF4]]> 32 8 LiCl 36 9 -- 34

[0113] As can be seen from the table above, the present application responds poorly to the conventional tetrabutylammonium tetrafluoroborate (nBu4NBF4) electrolyte, and the product is only obtained in trace yields (entry 2). Continuing to change the anion of the electrolyte, it is found that the effects of tetrabutylammonium iodide (nBu4NI) and tetrabutylammonium bromide (nBu4NBr) are completely different (entries 3, 4). When tetrabutylammonium perchlorate (nBu4NC1O4) is used as the electrolyte, the yield of 4-1c only reaches 20% (entry 5), which is 55% lower than the yield when tetrabutylammonium chloride (nBu4NCl) is used as the electrolyte. When the electrolyte is tetrabutylammonium acetate (nBu4OAc), the yield of 4-1c is 39% (entry 6), which proves that the acetate ion (Ac - ) had no promoting effect on the system. Using lithium salts as electrolytes, the yield of 4-1c ranged from 32% to 36% (entries 7-8), which was inferior to that of tetrabutylammonium salts. Without the addition of electrolyte, 4-1c also achieved a 34% yield (entry 9). Therefore, nBu4NCl was selected as the electrolyte for the electrochemical amidation reaction.

[0114] After determining nBu4NC1 as the optimal electrolyte for the electrochemical α-ketoacid amination reaction, the addition amount of electrolyte nBu4NC1 was screened.

[0115] Entry 4-la:4-lb <![CDATA[the equivalent of nBu4NCl(mol%)]]> <![CDATA[Yield of4-lc(%) b ]]> 1 1∶3 10 36 2 1∶3 20 75 3 1∶3 40 49 4 1∶3 50 48 5 1∶3 100 50 6 1∶3 200 36

[0116] As can be seen from the table above, when the addition amount of electrolyte is 10 mol%, the yield of 4-1c is only 36% (entry 1). When the addition amount is increased to 20 mol%, the reaction yield increases by about 40% (entry 2). Continuing to increase the addition amount of electrolyte, it is found that when the addition amount of nBu4NCl is 40 mol%, 50 mol%, 100 mol% and 200 mol%, the separation yield of 4-1c is 49%, 48%, 50% and 36% respectively (entries 3-6). The increase in the addition amount of electrolyte does not increase the yield of the reaction, but inhibits the formation of product 4-1c. At the same time, the addition of excessive electrolyte also causes atomic waste, which is not in line with the concept of green chemistry.

[0117] Comparative Example 3

[0118] The preparation method is the same as that of Example 1, except that the solvent is different. The specific results are as follows:

[0119] Entry Solvents <![CDATA[Yield of4-lc(%) b ]]> 1 MeCN 75 2 DMF 58 3 DMA 40 4 NMP 62 5 DMSO 55 6 DME 12 7 DCM 30 8 THF 32 9 1,4-Dioxane:MeCN=4:1 10 10 MeCN:MeOH=4:1 32 11 <![CDATA[MeCN:H2O=4:1]]> trace 12 MeCN:TFA=4:1 NR

[0120] As shown in the table above, using acetonitrile (MeCN) as the solvent, product 4-1c achieved a 75% isolated yield. Based on this, screening of conventional polar aprotic solvents revealed unsatisfactory results (entries 2-8), with isolated yields of product 3-1c ranging from 12% to 62%. To further improve the yield of the target product, a mixed solvent of 1,4-dioxane and acetonitrile at a 4:1 volume ratio was added to the reaction. However, the yield of target product 4-1c dropped sharply, to only 10% (entry 9).

[0121] The protic solvents methanol (CH3OH), water (H2O), and trifluoroacetic acid (TFA) were prepared with acetonitrile in a 4:1 volume ratio to form a mixed solvent. The introduction of protons actually inhibited the formation of the target product 4-1c, resulting in a maximum isolated yield of only 32% (entries 10-12). These results suggest that the reaction does not represent a paired electrolysis reaction. The introduction of protons may disrupt the original electronic redox balance in the system or hinder the dissociation of the active hydrogen in benzoylformic acid. Therefore, acetonitrile was determined to be the solvent of choice for the electrochemical amidation reaction.

[0122] Comparative Example 4

[0123] The preparation method is the same as that of Example 1, except that the base is different. The specific results are as follows:

[0124] Entry Base <![CDATA[Yield of 4-lc(%) b ]]> 1 -- 75 2 K2CO3 50 3 <![CDATA[Cs2CO3]]> 45 4 DMAP 22 5 KO f Bu]]> 12

[0125] As can be seen from the table above, unlike common carboxylic acid amination reactions, the addition of a base does not promote the reaction. Product 4-1c, on the other hand, achieved a 75% isolated yield (entry 1) without the addition of a base. Potassium carbonate (K2CO3) and cesium carbonate (Cs2CO3), both of which are currently used frequently in the industrial production of amide compounds, were selected for screening inorganic bases. Product 4-1c achieved isolated yields of 50% and 45%, respectively (entries 2, 3), representing a 30% decrease compared to the yield without the addition of a base.

[0126] As organic bases, 4-dimethylaminopyridine (DMAP) and potassium tert-butoxide, which are frequently used in the production process, were also selected, but the yield of the target product 4-1c was only 12% (entries 4, 5). Therefore, it was determined that the electrochemical amidation process does not require the participation of a base.

[0127] Comparative Example 5

[0128] The preparation method is the same as that of Example 1, except that the redox medium is different. The specific results are as follows:

[0129] Entry Addivtive 10 mol% <![CDATA[Yield of4-lc(%) b ]]> 1 ferrocene 75 2 tribenzylamine trace 3 1,4-benzoquinone 20 4 N-hydroxyphthalimide trace 5 <![CDATA[PPh3]]> 15 6 -- 25

[0130] As shown in the table above, the optimal reaction was achieved when ferrocene was used as the redox mediator for the amidation reaction, with the target product 4-1c isolated in a 75% yield (entry 1). When triphenylamine was used as the mediator, only trace amounts of 4-1c were produced (entry 2), demonstrating its incompatibility with this system.

[0131] Further screening of redox mediators revealed that conventional redox mediators, such as 1,4-p-benzoquinone, N-hydroxyphthalimide, and triphenylphosphine (PPh3), failed to promote the reaction and instead inhibited product formation, resulting in a maximum yield of only 20% (entries 3, 4, and 5). Even without the addition of a redox mediator, product 4-1c was isolated in a 25% yield (entry 6).

[0132] Analysis of the above results revealed that the yield of 4-1c was still 25% even without the addition of a redox mediator, indicating that benzoylformic acid can undergo oxidative decarboxylation under electrochemical oxidation conditions alone. With the addition of ferrocene as the mediator, the yield of the target product 4-1c increased to 75%, demonstrating that ferrocene promotes the decarboxylation of benzoylformic acid, significantly shifting the reaction equilibrium toward the product. Therefore, ferrocene was determined to be the redox mediator for the electrochemical amidation reaction.

[0133] Comparative Example 6

[0134] The preparation method is the same as that of Example 1, except for the different molecular sieves. The specific results are as follows:

[0135]

[0136] From the above table, it can be seen that adding 75 mg of Molecular sieves, the separation yield of product 4-1c increased by 15% (entry 2), indicating that the reaction system is sensitive to water. When adding materials, it is necessary to ensure the dryness of each raw material (the reagents for the reaction can be stored in a dry glove box in advance) to avoid the introduction of protons to reduce the yield of the reaction. However, when the amount of molecular sieve added continued to increase, the separation yield of product 4-1c began to decrease (entry 3). This may be because the excess molecular sieve covered the electrode surface, hindering the electron transfer between the electrode and the ferrocene medium; it may also be that the excess molecular sieve is incompatible with the acetonitrile solvent, reducing the contact efficiency between the substrate molecules or between the benzoylformic acid molecules and the ferrocene medium. Therefore, it was determined The amount of molecular sieve added was 75 mg.

[0137] Comparative Example 7

[0138] The preparation method is the same as that of Example 1, except for the difference in current and time. The specific results are as follows:

[0139] Entry Time / h Current / mA Yield of 4-1c (%)b 1 12 10 75 2 12 15 10 3 12 20 5 4 6 10 12 5 9 10 58 6 12 0 NR

[0140] As can be seen from the table above, under the same conditions, increasing the reaction current (15mA and 20mA) resulted in a sharp decrease in the yield of the target product 4-1c (entries 2, 3). The reaction was carried out under constant current conditions. According to Ohm's law, under the premise of constant resistance, the potential increases with increasing current. Therefore, it is possible that the high potential generated under high current conditions oxidatively decomposed 4-1c, leaving only a small amount of undecomposed product 4-1c in the system. During the condition screening process, it was found that after 6 hours of reaction at 10mA constant current, only 12% yield of the target product was generated (entry 4); further extending the current application time, after 9 hours of reaction at 10mA constant current, the target product yield was 58% (entry 5), which was significantly improved compared to the product yield under 6 hours of current application.

[0141] Combined with the results of experiments (entries 4 and 5), it is speculated that the reaction is a two-step process: first, sufficient time is required to generate the intermediate, which is the rate-determining step of the reaction; second, the intermediate reacts with another amine molecule and migrates toward the product. When the current is 0 mA, no target molecule is detected, confirming that the amidation under these conditions is an electrochemically driven process. Therefore, the amidation reaction current is determined to be a constant current of 10 mA, and the reaction time is determined to be 12 hours.

[0142] In summary, the standard conditions for the electrochemical amidation reaction were determined as follows: substrate 4-1a (0.4 mmol), substrate 4-1b (1.2 mmol, 3 equiv), ferrocene (10 mol%), MS (75 mg), nBu4NCl (0.02 mol / L) electrolyte, anhydrous acetonitrile (MeCN, 4 mL) solvent, a graphite carbon rod (φ = 6 mm) as anode, a platinum sheet (10 × 10 × 0.2 mm) as cathode, argon (Ar) atmosphere, and a constant current (10 mA) at room temperature for 12 hours. Under standard conditions, the isolated yield of the desired product 4-1c was 75%.

[0143] Application Examples

[0144] Some amine compounds with pharmaceutical value were derivatized under standard conditions. The specific results are as follows:

[0145]

[0146] Amantadine, an antiviral drug commonly used to combat influenza and treat Parkinson's disease (PD), was successfully synthesized using amantadine and benzoylformic acid under standard conditions to yield the amide derivative 4-e, achieving a one-step derivatization of the sterically hindered amantadine under mild conditions.

[0147] By replacing adamantane with 4-[2-(dimethylamino)ethoxy]benzylamine, the trimethobenzamide analog 4-f was obtained for antiemetic use.

[0148] Furthermore, the study found that the system exhibited excellent reactivity with amino alcohols, successfully synthesizing the β-amino alcohol derivative 4-g with a 78% yield. This derivative is primarily used as an antimicrobial agent against various bacteria and fungi. In addition to the derivatization of primary amines, secondary amines were also explored. Under standard conditions, the amidation product 4-h was synthesized in a single step, an analog of the antiseptic drug moclobemide.

[0149] Furthermore, product 4-i, a precursor of donepezil, used to treat Alzheimer's disease, was synthesized under these conditions in a 48% yield. Desloratadine, used to treat allergic rhinitis, was also amidated with a 41% isolated yield.

[0150] 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.

[0151] 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 amide derivative, characterized in that: The following steps are involved: S1. Assemble 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 a three-necked glass bottle, seal both sides of the bottle, and transfer it to a glove box for feeding. Add benzoylformic acid, morpholine, 10 mol% ferrocene, tetrabutylammonium iodide, 75 mg of 5Å molecular sieves, and 4 mL of anhydrous acetonitrile in this order. S3. After the feeding is completed, the mouths of the three-necked glass bottles are tightly wrapped with sealing film, argon gas is introduced into the three-necked glass bottles, and a constant current of 10 mA is passed through the bottles for electrolysis; S4, after 12 hours of reaction, perform thin layer chromatography monitoring until new compounds are produced; S5. Separate the compound in S4 by column chromatography to obtain an amide derivative. .

2. The method for preparing an amide derivative according to claim 1, characterized in that: In S1, the three-necked glass bottle includes a three-necked glass bottle body, a stirring mechanism is installed at the bottom of the three-necked glass bottle body, the stirring mechanism includes a base, a motor and a power supply are installed in the base, and the motor is electrically connected to the power supply.

3. The method for preparing an amide derivative according to claim 2, characterized in that: The output shaft of the motor is connected to a rotating shaft, one end of the rotating shaft is arranged in the main body of the three-necked glass bottle, and the end of the rotating shaft away from the motor is fixedly connected to a fixing sleeve, and a plurality of first stirring rods are fixedly connected to the fixing sleeve.

4. The method for preparing an amide derivative according to claim 3, characterized in that: The side wall of the rotating shaft is fixedly connected to a limit plate, and a movable sleeve is provided on the upper side of the limit plate. The diameter of the movable sleeve is larger than the diameter of the rotating shaft, and a plurality of second stirring rods are connected to the movable sleeve, and the second stirring rods correspond to the first stirring rods.

5. The method for preparing an amide derivative according to claim 4, characterized in that: A linkage mechanism is connected between the first stirring rod and the second stirring rod, and the linkage mechanism includes a first rotating sleeve, the first rotating sleeve is fixedly connected to the second stirring rod, a first rotating ball is rotatably provided in the first rotating sleeve, and the first rotating ball is connected to the inner rod.

6. The method for preparing an amide derivative according to claim 5, characterized in that: An outer rod is slidably provided on the outer side of the inner rod, a second rotating ball is fixedly connected to the outer rod, a second rotating sleeve is rotatably connected to the outer side of the second rotating ball, and the second rotating sleeve is fixedly connected to the second stirring rod.

7. The method for preparing an amide derivative according to claim 6, characterized in that: One end of the inner rod located inside the outer rod is connected to a metal rod, the metal rod is connected to a controller, the controller is electrically connected to a heating wire, the heating wire is arranged outside the metal rod, and an elastic rope is connected between the controller and the inner wall of the outer rod.

8. The method for preparing an amide derivative according to claim 1, characterized in that: In S4, the new compound is generated when the ratio shift value is 0.

3.

9. The method for preparing an amide 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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