Preparation method of amide compound

Abstract

The invention discloses a preparation method of an amide compound, which comprises the following steps: mixing an amine compound, an organic halide, a photocatalyst and an additive in a molar ratio of 1.0: (0.5-2.0): (0.001-0.3): (0-3.0) with a solvent to prepare a mixed solution of the amine compound with the molar concentration of 0.02-0.8 M, and reacting for 4-30 hours at 20-50 DEG C in a CO gas atmosphere and under visible light irradiation, and after the reaction is finished, purifying to obtain the amide compound. Wherein the photocatalyst is a perovskite material. The reaction is performed at normal temperature and normal pressure, no transition metal catalyst participates, and the method is simple and efficient.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical engineering, and particularly relates to a method for preparing amide compounds. Background Art

[0002] Amide bonds are important structural units in the fields of medicinal chemistry and biochemistry, and are widely present in many natural products and drug molecules. For example, penicillin and aminoamide local anesthetics both contain amide bonds. From the perspective of atom economy, carbon monoxide (CO), as a widely available and low-cost "one-carbon" resource, is directly used as a carbonyl source in carbonylation reactions for the efficient synthesis of amide compounds.

[0003] The three-component carbonylation reaction between organic halides, organic amines, and CO is one of the effective ways to construct amide bonds. Since Heck proposed using palladium catalysts to promote the aminocarbonylation process of aryl halides in 1974, traditional transition metal-catalyzed aminocarbonylation reactions have always been one of the effective ways to synthesize amide compounds. However, this method has limitations in the synthesis of amides: on the one hand, competitive β-H elimination limits its application in alkyl halides; on the other hand, the coordination inactivation phenomenon of transition metal catalysts with CO leads to a high energy barrier in the oxidative addition process, making the reaction usually require relatively harsh conditions such as high temperature and high pressure.

[0004] Compared with transition metal-catalyzed aminocarbonylation reactions, the radical carbonylation reaction proposed by Ryu et al. can well solve the problems of slow oxidative addition and reactivity such as β-H elimination when using alkyl halides as substrates. However, it usually requires the use of toxic and dangerous radical initiators or high-energy light radiation to initiate radicals, or requires the combination of transition metal catalysis and photocatalysis to promote the reaction, and most reactions still have the limitation of high CO partial pressure. Chinese Patent Publication No. CN108276234A disclosed a method for preparing amides by a carbonylation reaction involving CO on July 13, 2018. This method uses haloarenes, organic amines, and CO as substrates. Under light irradiation, the haloarenes homolyze to generate radicals, and then amide compounds are obtained through a radical addition process. Although it does not require any metal catalyst and can react under normal pressure, it requires high-energy light to initiate radicals, and there are problems such as high energy consumption, high cost, and low yield.

[0005] Both transition metal-catalyzed aminocarbonylation and radical carbonylation reactions have different limitations: either they require the participation of transition metal catalysts and reaction conditions such as high temperature and high pressure, or they introduce radical initiators or high-energy light, which greatly increases the production and equipment costs in practical applications, and it is difficult to ensure the safety of the process, thus limiting their applications. Summary of the Invention

[0006] The object of the present invention is to overcome the above-mentioned drawbacks and provide a method for preparing amide compounds that reacts under normal temperature and pressure, without the participation of transition metal catalysts, and is simple and efficient.

[0007] The object of the present invention and the solution to its main technical problems are achieved through the following technical solutions:

[0008] A method for preparing an amide compound of the present invention includes the following steps:

[0009] (1) According to the molar ratio of amine compound, organic halide, photocatalyst, and additive being 1.0:0.5 - 2.0:0.001 - 0.3:0 - 3.0, mix with a solvent to prepare a mixed solution of amine compound with a molar concentration of 0.02 - 0.8 M, and react at 20 - 50 °C for 4 - 30 h under a CO gas atmosphere and visible light irradiation;

[0010] (2) After the reaction is completed, purify to obtain the amide compound.

[0011] The amine compound is: aromatic amine, aliphatic amine (preferably primary amine and secondary amine).

[0012] The organic halide is: primary alkyl iodide, secondary alkyl iodide, tertiary alkyl iodide.

[0013] The photocatalyst is a perovskite material, and the perovskite material is MAPbBr3, FAPbBr3, CsPbBr3, MAPbI3, FAPbI3, CsPbI3, CsSnBr3, BiFeO3, or LaFeO3, etc.

[0014] The additive is an organic base or inorganic base such as Et3N, DMAP, DIPEA, Na2CO3, K2CO3, or Cs2CO3, etc.

[0015] The solvent is dichloromethane, toluene, tetrahydrofuran, ethyl acetate, or dioxane, etc.

[0016] For the above-mentioned method for preparing an amide compound, the purification method in step (2) is to filter with an organic filter membrane to obtain a clear solution, use GC-MS and a nuclear magnetic resonance instrument to qualitatively judge the presence or absence of the target product, and then separate and purify the crude product by silica gel column chromatography: a. Column packing: Wet packing of silica gel; b. Dry loading: Rotary evaporation and mixing of the sample, with the ratio of silica gel to sample usage being 1:1. After mixing the sample well, evenly spread it on top of the silica gel column; c. Elution: The eluent is n-hexane / ethyl acetate or dichloromethane / methanol or toluene / ethyl acetate; d. Monitoring: TCL tracking of the product spots; e. Collection: Fractional collection and rotary evaporation for concentration; f. Determination of the product: Use GC-MS and a nuclear magnetic resonance instrument to determine the purity of the target product to obtain a pure amide compound.

[0017] Compared with the prior art, the present invention has obvious advantages and beneficial effects. As can be seen from the above technical solutions, the present invention uses a perovskite material as a photocatalyst to directly carry out a three-component reaction with CO as a carbonyl source under light irradiation conditions, avoiding the introduction of excessive toxic reagents and transition metal catalysts, and realizing the preparation of amide compounds under milder conditions. The present invention has the advantages of simplicity, high efficiency, good functional group tolerance, and mild reaction conditions (room temperature and normal pressure), and can be widely applied to the construction of amide drugs and drug derivatives. Detailed implementation mode

[0018] Example 1:

[0019] A method for preparing an amide compound of the present invention comprises the following steps:

[0020] (1) Methyl 4-aminobenzoate (0.2 mmol), iodocyclohexane (0.4 mmol), CsSnBr3 (0.006 mmol), and Cs2CO3 (0.1 mmol) were successively added to a 10 mL reaction tube, and dioxane solution (3 mL) was added. The mixture was evacuated and replaced with a CO balloon three times, then placed in a photoreactor and irradiated with light at 25 °C for 30 h.

[0021] (2) After the reaction was completed, it was filtered through an organic filter membrane (0.22 μm) to obtain a clear solution. The presence of the target product was qualitatively determined using a gas chromatography-mass spectrometer (GC-MS, HP-5 chromatographic column) and a nuclear magnetic resonance spectrometer. Then, the crude product was separated and purified by silica gel column chromatography: a. Column packing: The silica gel (200 - 300 mesh) was packed by the wet method; b. Dry loading: The sample was rotary evaporated and mixed with silica gel (100 - 200 mesh) at a ratio of 1:1. After mixing well, it was evenly spread on top of the silica gel column; c. Elution: The eluent was n-hexane / ethyl acetate = 3 / 1 (v / v); d. Monitoring: The product spots were tracked by thin-layer chromatography (TCL); e. Collection: Fractional collection and rotary evaporation concentration; f. Determination of the product: The purity of the target product was determined using GC-MS and a nuclear magnetic resonance spectrometer, and pure white solid methyl 4-(cyclohexanecarboxamido)benzoate was obtained with a yield of 81%. Its structure is as follows:

[0022]

[0023] The structure characterization data is as follows: 11H NMR (500 MHz, Chloroform-d) δ 7.98 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.53 (s, 1H), 3.89 (s, 3H), 2.25 (tt, J = 11.7, 3.5 Hz, 1H), 1.98 - 1.92 (m, 2H), 1.87 - 1.79 (m, 2H), 1.71 - 1.67 (m, 1H), 1.54 (qd, J = 12.0, 3.3 Hz, 2H), 1.33 - 1.22 (m, 3H).

[0024] Example 2:

[0025] A method for preparing an amide compound of the present invention comprises the following steps:

[0026] (1) Methyl 4-aminobenzoate (0.2 mmol), iodocyclohexane (0.4 mmol), FAPbBr3 (0.0002 mmol), and Na2CO3 (0.6 mmol) were successively added to a 10 mL reaction tube, and dioxane solution (0.25 mL) was added. The mixture was evacuated and replaced with CO balloon three times, then placed in a photoreactor and irradiated under heating at 25 °C for 30 h;

[0027] (2) After the reaction was completed, it was filtered through an organic filter membrane (0.22 μm) to obtain a clear solution. The presence of the target product was qualitatively determined by gas chromatography - mass spectrometry (GC - MS, HP - 5 chromatographic column) and nuclear magnetic resonance spectrometer. Then, the crude product was separated and purified by silica gel column chromatography: a. Column packing: The silica gel (200 - 300 mesh) was packed by wet method; b. Dry sample loading: The sample was rotary evaporated and mixed with silica gel (100 - 200 mesh) in a ratio of 1:1. After mixing well, it was evenly spread on the top of the silica gel column; c. Elution: The eluent was n - hexane / ethyl acetate = 3 / 1 (v / v); d. Monitoring: TLC was used to track the product spots; e. Collection: The product was collected in fractions and rotary evaporated and concentrated; f. Determination of the product: The purity of the target product was determined by GC - MS and nuclear magnetic resonance spectrometer, and the pure white solid methyl 4-(cyclohexanecarboxamido)benzoate was obtained with a yield of 95%. The product structure and structure characterization data were the same as those in Example 1.

[0028] Example 3:

[0029] A method for preparing an amide compound of the present invention comprises the following steps:

[0030] (1) Add methyl 4-aminobenzoate (0.2 mmol), iodocyclohexane (0.4 mmol), and BiFeO3 (0.06 mmol) into a 10 mL reaction tube in sequence. Then add dioxane solution (10 mL), and use a CO balloon to pump and replace the gas three times. Heat under illumination at 50 °C for 30 h.

[0031] (2) After the reaction, filter with an organic filter membrane (0.22 μm) to obtain a clear solution. Then use a gas chromatography - mass spectrometry (GC - MS, HP - 5 chromatographic column) and a nuclear magnetic resonance spectrometer to qualitatively determine whether there is a target product. Finally, separate and purify the crude product by silica gel column chromatography: a. Column packing: Wet - pack the column with silica gel (200 - 300 mesh); b. Dry - loading sample: Evaporate and mix the sample. The ratio of silica gel (100 - 200 mesh) to the sample amount is 1:1. After mixing the sample well, evenly spread it on top of the silica gel column; c. Elution: The eluent is n - hexane / ethyl acetate = 3 / 1 (v / v); d. Monitoring: Track the product spots by TLC; e. Collection: Collect in fractions, evaporate and concentrate; f. Determine the product: Use GC - MS and a nuclear magnetic resonance spectrometer to determine the purity of the target product, and thus obtain pure white solid methyl 4-(cyclohexanecarboxamido)benzoate, with a yield of 60%. The product structure and structure characterization data are the same as those in Example 1.

[0032] Example 4:

[0033] A preparation method of an amide compound of the present invention includes the following steps:

[0034] (1) Add N - methylpiperazine (0.2 mmol), iodocyclohexane (0.1 mmol), MAPbBr3 (0.003 mmol), and DIPEA (0.2 mmol) into a 10 mL reaction tube in sequence. Then add dichloromethane solution (3 mL), use a CO balloon to pump and replace the gas three times, and place it in a photoreactor. Heat under illumination at 25 °C for 6 h.

[0035] (2) After the reaction is completed, filter with an organic filter membrane (0.22 μm) to obtain a clear solution. Use a gas chromatography-mass spectrometry instrument (GC-MS, HP-5 chromatographic column) and a nuclear magnetic resonance instrument to qualitatively determine the presence of the target product. Then, separate and purify the crude product by silica gel column chromatography: a. Column packing: Wet packing of silica gel (200-300 mesh); b. Dry sample loading: Rotary evaporation and mixing of the sample. The ratio of silica gel (100-200 mesh) to the sample dosage is 1:1. After mixing the sample well, evenly spread it on top of the silica gel column; c. Elution: The eluent is dichloromethane / methanol = 9 / 1 (v / v); d. Monitoring: TCL tracking of the product spots; e. Collection: Fractional collection and rotary evaporation concentration; f. Determination of the product: Use GC-MS and a nuclear magnetic resonance instrument to determine the purity of the target product, that is, obtain pure yellow solid pexetol (an antiparasitic drug), with a yield of 89%. Its structure is as follows:

[0036]

[0037] The structure characterization data is as follows: 1 H NMR(500MHz,Chloroform-d)δ3.58(t,J=5.2Hz,2H),3.47(t,J=5.1Hz,2H),2.45-2.29(m,5H),2.26(s,3H),1.80-1.72(m,2H),1.70-1.62(m,3H),1.47(qd,J=12.1,3.7Hz,2H),1.28-1.17(m,3H). 13 C NMR(125MHz,Chloroform-d)δ55.4,54.7,45.9,45.2,41.3,40.3,29.3,25.8,25.8.

[0038] Example 5:

[0039] A preparation method of an amide compound of the present invention includes:

[0040] (1) Sequentially add 4-aminopyridine (0.2 mmol), iodocyclohexane (0.4 mmol), CsPbBr3 (0.0002 mmol), and Et3N (0.2 mmol) to a 10 mL reaction tube. Add ethyl acetate solution (0.25 mL), use a CO balloon to evacuate and replace the gas three times, place it in a photoreactor, and irradiate it for 18 h under heating conditions at 40 °C;

[0041] (2) After the reaction is completed, filter with an organic filter membrane (0.22 μm) to obtain a clear solution. Use a gas chromatography-mass spectrometry (GC-MS, HP-5 chromatographic column) and a nuclear magnetic resonance spectrometer to qualitatively determine the presence of the target product. Then, separate and purify the crude product by silica gel column chromatography: a. Column packing: Wet-pack the silica gel (200-300 mesh); b. Dry loading: Evaporate and mix the sample. The ratio of silica gel (100-200 mesh) to the sample amount is 1:1. After mixing the sample well, evenly spread it on top of the silica gel column; c. Elution: The eluent is dichloromethane / methanol = 20 / 1 (v / v); d. Monitoring: Track the product spots by TLC; e. Collection: Collect in fractions and evaporate to concentrate; f. Determine the product: Use GC-MS and a nuclear magnetic resonance spectrometer to determine the purity of the target product, and obtain the pure white solid N-(pyridin-3-yl)cyclohexanecarboxamide, with a yield of 78%. Its structure is as follows:

[0042]

[0043] The structure characterization data is as follows: 1 H NMR(500MHz,Chloroform-d)δ8.52(s,1H),8.44(d,J=6.3Hz,2H),7.55(d,J=6.6Hz,2H),2.28(tt,J=11.7,3.5Hz,1H),1.96-1.88(m,2H),1.85-1.76(m,2H),1.72-1.62(m,1H),1.53(qd,J=12.0,4.3Hz,2H),1.28-1.19(m,3H). 13 C NMR(126MHz,Chloroform-d)δ175.7,150.1,145.9,113.7,46.4,29.4,25.5,25.5.

[0044] Example 6:

[0045] A preparation method of an amide compound of the present invention includes:

[0046] (1) Sequentially add methyl p-aminobenzoate (0.2 mmol), 1-iodobutane (0.2 mmol), FAPbBr3 (0.0002 mmol), and Cs2CO3 (0.1 mmol) to a 10 mL reaction tube. Add toluene solution (0.25 mL), evacuate and replace with a CO balloon three times, place it in a photoreactor, and irradiate under heating at 40 °C for 18 h;

[0047] (2) After the reaction is completed, filter with an organic filter membrane (0.22 μm) to obtain a clear solution. Use a gas chromatography-mass spectrometry instrument (GC-MS, HP-5 chromatographic column) and a nuclear magnetic resonance instrument to qualitatively determine the presence of the target product. Then, separate and purify the crude product by silica gel column chromatography: a. Column packing: Wet packing of silica gel (200 - 300 mesh); b. Dry sample loading: Rotary evaporation and mixing of the sample. The ratio of silica gel (100 - 200 mesh) to the sample amount is 1:1. After mixing the sample well, evenly spread it on top of the silica gel column; c. Elution: The eluent is toluene / ethyl acetate = 10 / 1 (v / v); d. Monitoring: Tracking the product spots by TLC; e. Collection: Collect in fractions and rotary evaporate and concentrate; f. Determine the product: Use GC-MS and a nuclear magnetic resonance instrument to determine the purity of the target product, and obtain pure white solid methyl 4-[(1-oxopentyl)amino]benzoate, with a yield of 68%. Its structure is as follows:

[0048]

[0049] The structure characterization data is as follows: 1 H NMR(500MHz,Chloroform-d)δ7.98(d,J=8.7Hz,2H),7.67(s,1H),7.61(d,J=8.5Hz,2H),3.89(s,3H),2.38(t,J=7.6Hz,2H),1.70(p,J=7.6Hz,2H),1.39(h,J=7.4Hz,2H),0.93(t,J=7.4Hz,3H).

[0050] Example 7:

[0051] A preparation method of an amide compound of the present invention includes:

[0052] (1) Sequentially add n-butylamine (0.2 mmol), iodocyclohexane (0.4 mmol), CsPbI3 (0.003 mmol), and DMAP (0.2 mmol) to a 10 mL reaction tube, add a tetrahydrofuran solution (3 mL), use a CO balloon to evacuate and replace the gas three times, place it in a photoreactor, and irradiate for 18 h under heating conditions at 20 °C;

[0053] (2) After the reaction was completed, it was filtered through an organic filter membrane (0.22 μm) to obtain a clear solution. A gas chromatography-mass spectrometry (GC-MS, HP-5 chromatographic column) and a nuclear magnetic resonance spectrometer were used to qualitatively determine the presence of the target product. Then, the crude product was separated and purified by silica gel column chromatography: a. Column packing: The silica gel (200 - 300 mesh) was packed by the wet method; b. Dry loading: After rotary evaporation and mixing the sample, the ratio of silica gel (100 - 200 mesh) to the sample amount was 1:1. After mixing well, it was evenly spread on top of the silica gel column; c. Elution: The eluent was n-hexane / ethyl acetate = 3 / 1 (v / v); d. Monitoring: TLC was used to track the product spots; e. Collection: It was collected in fractions and concentrated by rotary evaporation; f. Determination of the product: GC-MS and a nuclear magnetic resonance spectrometer were used to determine the purity of the target product, and then the pure white solid N-butylcyclohexanecarboxamide was obtained with a yield of 85%. Its structure is as follows:

[0054]

[0055] The structure characterization data is as follows: 1 H NMR(500MHz,Chloroform-d)δ5.49(s,1H),3.27-3.18(m,2H),2.04(tt,J=11.8,3.5Hz,1H),1.87-1.81(m,2H),1.80-1.74(m,2H),1.68-1.62(m,1H),1.50-1.14(m,10H),0.90(t,J=7.3Hz,3H).

[0056] Example 8:

[0057] A preparation method of an amide compound of the present invention includes:

[0058] (1) Methyl p-aminobenzoate (0.2 mmol), tert-butyl iodide (0.2 mmol), FAPbBr3 (0.0002 mmol), and Na2CO3 (0.6 mmol) were successively added to a 10 mL reaction tube, and toluene solution (0.25 mL) was added. The air was evacuated and replaced three times using a CO balloon, and then it was placed in a photoreactor and irradiated with light at 40 °C for 4 h;

[0059] (2) After the reaction was completed, it was filtered through an organic filter membrane (0.22 μm) to obtain a clear solution. The gas chromatography-mass spectrometry (GC-MS, HP-5 chromatographic column) and nuclear magnetic resonance spectrometer were used to qualitatively determine the presence of the target product. Then, the crude product was separated and purified by silica gel column chromatography: a. Column packing: The silica gel (200 - 300 mesh) was packed by the wet method; b. Dry loading: The sample was rotary evaporated and mixed with silica gel (100 - 200 mesh) at a ratio of 1:1. After mixing well, it was evenly spread on top of the silica gel column; c. Elution: The eluent was n-hexane / ethyl acetate = 3 / 1 (v / v); d. Monitoring: The product spots were tracked by TLC; e. Collection: Fractional collection and rotary evaporation for concentration; f. Determination of the product: The purity of the target product was determined by GC-MS and nuclear magnetic resonance spectrometer, and the pure white solid methyl 4-pivalamidobenzoate was obtained with a yield of 49%. Its structure is as follows:

[0060]

[0061] The structure characterization data are as follows: 1 H NMR(500MHz,Chloroform-d)δ8.01(d,J=8.7Hz,2H),7.62(d,J=8.8Hz,2H),7.45(s,1H),3.90(s,3H),1.33(s,9H).

[0062] Example 9 - 69:

[0063] For the preparation method of an amide compound of the present invention, the same as in Example 1, the structural formula and yield of the obtained amide compound are as follows:

[0064]

[0065] The above is only a preferred embodiment of the present invention, and it does not impose any form of limitation on the present invention. Any simple modification, equivalent change, and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A method for preparing an amide compound, comprising the following steps: (1) Mixing an amine compound, an organic halide, a photocatalyst, and an additive in a molar ratio of 1.0:0.5 - 2.0:0.001 - 0.3:0 - 3.0 with a solvent to prepare a mixed solution of the amine compound with a molar concentration of 0.02 - 0.8 M, and reacting at 20 - 50 °C for 4 - 30 h under a CO gas atmosphere and visible light irradiation; the photocatalyst is a perovskite material; (2) After the reaction is completed, purifying to obtain the amide compound.

2. The preparation method of an amide compound as claimed in claim 1, wherein: The amine compound is an aromatic amine or a fatty amine.

3. The preparation method of an amide compound as claimed in claim 2, wherein: The aromatic amine and the fatty amine are primary amines and secondary amines.

4. The preparation method of an amide compound as described in claim 1, wherein: The organic halide is a primary alkyl iodide, a secondary alkyl iodide, or a tertiary alkyl iodide.

5. The preparation method of an amide compound as described in claim 1, wherein: The perovskite material is MAPbBr3, FAPbBr3, CsPbBr3, MAPbI3, FAPbI3, CsPbI3, CsSnBr3, BiFeO3, or LaFeO3.

6. The preparation method of an amide compound as claimed in claim 1, wherein: The additive is Et3N, DMAP, DIPEA, Na2CO3, K2CO3, or Cs2CO3.

7. The preparation method of an amide compound as described in claim 1, wherein: The solvent is dichloromethane, toluene, tetrahydrofuran, ethyl acetate, or dioxane.

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