A method for preparing a benzamide compound
Patent Information
- Application Number
- CN202610974581.1
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-07-01
- Publication Date
- 2026-10-27
AI Technical Summary
（1）苄胺路线（J. Org. Chem. 2017, 82, 13632-13642）：以苄胺为底物时需18～36小时的长反应时间，能耗较高且生产效率受限；同时苄胺类原料价格相对较高、部分取代苄胺获取困难
（1）本发明的制备方法采用苄基甲基醚类化合物为原料，其来源广泛、成本低廉。反应前将所有试剂一次性加入，操作简便。反应在70～80℃的温和条件下进行，伯胺或氨可直接参与反应，无需预先保护基团，对含敏感官能团的底物具有良好的兼容性。该反应选择性氧化苄位的C-H键，将其转化为醛/羧酸中间体，随后与胺原位缩合生成酰胺，同时不影响芳环上已有的其他取代基。整个过程省去了中间体的分离与纯化步骤，并能有效控制氧化程度，避免过度氧化，实现了快速高选择性合成苯甲酰胺类化合物。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic compound synthesis technology, and in particular to a method for preparing benzamide compounds. Background Technology
[0002] Amide bonds are among the most important and widespread functional groups in organic chemistry, found extensively in natural products, drug molecules, polymers, and agrochemicals. Statistics show that over 25% of FDA-approved small-molecule drugs contain amide structural units. Therefore, developing efficient, green, and economical methods for amide synthesis has always been a core research topic in organic chemistry and the pharmaceutical industry.
[0003] Traditional amide synthesis mainly relies on the condensation reaction of carboxylic acids and their derivatives (acyl chlorides, anhydrides, reactive esters, etc.) with amines. While these methods are mature and reliable, they suffer from drawbacks such as poor atom economy, generation of stoichiometric waste, and the need for pre-preparation of activated carboxylic acid derivatives. In recent years, oxidative amidation strategies have attracted widespread attention because they can directly utilize the CH bonds of alcohols, aldehydes, alkanes, and even hydrocarbons as carbonyl sources to couple with amines to form amide bonds. These methods offer advantages such as high atom utilization, ease of operation, and avoidance of pre-activation steps.
[0004] Among numerous oxidative amidation systems, the iodine / peroxide catalytic system stands out due to its low cost, availability, low toxicity, environmental friendliness, and high catalytic efficiency. Several publications have reported on the oxidative amidation of benzylamine to prepare benzamide using the I₂ / TBHP system (J. Org. Chem. 2017, 82, 13632-13642), as well as the oxidative coupling of benzyl alcohol and amine (Tetrahedron Lett. 2014). Furthermore, NaI-mediated oxidative amidation of benzyl ethers has also been reported (Tetrahedron Lett. 2021, 62, 153017). However, the aforementioned existing technologies still have the following shortcomings: (1) Benzylamine route (J. Org. Chem. 2017, 82, 13632-13642): When using benzylamine as a substrate, a long reaction time of 18 to 36 hours is required, which results in high energy consumption and limited production efficiency; at the same time, benzylamine raw materials are relatively expensive and it is difficult to obtain partially substituted benzylamine.
[0005] (2) Benzyl alcohol route (Tetrahedron Lett. 2014): The oxidation of benzyl alcohol to aldehyde is slow, and the overall reaction efficiency is limited by the rate of oxidation step. Benzyl alcohol is also prone to oxidation and deterioration during storage, affecting batch stability.
[0006] (3) Benzyl ether-NaI route (Tetrahedron Lett. 2021, 62, 153017): NaI is used as a catalyst, but iodide ions (I - Its oxidative activation ability is weaker than that of elemental iodine (I2), requiring more stringent conditions or a longer reaction time.
[0007] Therefore, this invention proposes a method for preparing benzamide compounds to solve the above-mentioned problems. Summary of the Invention
[0008] The technical problem to be solved by the present invention is to provide a method for preparing benzamide compounds, which uses inexpensive and readily available benzyl methyl ether as a substrate, employs a highly efficient catalytic oxidant, and combines optimized reaction conditions to achieve rapid and highly selective synthesis of benzamide compounds.
[0009] To solve the above-mentioned technical problems, the technical solution of the present invention is: a method for preparing benzamide compounds, the innovation of which is: including the following steps: Benzyl methyl ether compounds are mixed with primary amines or ammonia in a certain proportion and added to a solvent. Catalytic oxidation reaction is carried out under the action of catalyst and oxidant. The reaction is stirred at 70-80℃ for 5 hours. The reaction solution is then post-treated to obtain benzamide compounds. Among them, the structural formula of benzyl methyl ether compounds is Formula I, the structural formula of primary amines is Formula II, and the general structural formula of benzamide compounds is Formula III; Formula I: Formula II: Formula III: Wherein, R is one of hydrogen, meta- or para-substituted -CH3, -OCH3, -X, -NO2, -CF3, and R1 is one of hydrogen, benzyl, cyclopentyl, cyclohexyl, tert-butyl.
[0010] Furthermore, the catalyst is one of elemental I2, tetrabutylammonium iodide (TBAI), CuI, ZnI2, and N-iodosuccinimide (NIS).
[0011] Furthermore, the catalyst is elemental I2.
[0012] Furthermore, the oxidant is tert-butyl hydroperoxide (TBHP).
[0013] Further, the molar ratio of the benzyl methyl ether compound to the primary amine or ammonia, I2, and tert-butyl hydroperoxide (TBHP) is 5:(6~10):(0.5~1.5):(40~60).
[0014] Furthermore, the solvent is acetonitrile.
[0015] Furthermore, the volumetric amount of acetonitrile used, calculated based on the amount of benzyl methyl ether compound, is 2-4 mL / mmol.
[0016] Furthermore, the post-treatment method for the reaction solution includes the following steps: After the catalytic oxidation reaction was completed, the solvent was removed using a rotary evaporator to obtain the reaction mixture. The reaction mixture was then neutralized with a saturated Na₂S₂O₃ solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and eluted using a 200-300 mesh silica gel column. The eluent was collected, distilled under reduced pressure, and the residue was dried and then subjected to… 1 H nuclear magnetic resonance and 13 Identification was performed using nuclear magnetic resonance (NMR).
[0017] Furthermore, the elution uses petroleum ether and ethyl acetate as eluents, with the boiling range of petroleum ether being 60-90℃ and the volume ratio of petroleum ether to ethyl acetate being 10:1.
[0018] Furthermore, the benzamide compounds include Compound III-1a: N-benzylbenzamide, structural formula is
[0019] Compound III-1b: N-(4-methylbenzyl)benzamide, with the following structural formula:
[0020] Compound III-1c: N-(2-methylbenzyl)benzamide, with the following structural formula:
[0021] Compound III-1d: N-(2-chlorobenzyl)benzamide, with the following structural formula:
[0022] Compound III-1e: N-(4-chlorobenzyl)benzamide, with the following structural formula:
[0023] Compound III-1f: N-(4-nitrobenzyl)benzamide, with the following structural formula:
[0024] Compound III-1g: N-cyclopentylbenzamide, structural formula is
[0025] Compound III-1h: N-cyclohexylbenzamide, structural formula is
[0026] Compound III-1i: N-tert-butylbenzamide, structural formula is
[0027] Compound III-1m: N-benzyl-2-methylbenzamide, structural formula is
[0028] Compound III-1n: N-benzyl-3-methylbenzamide, with the following structural formula:
[0029] Compound III-1o: N-benzyl-4-methylbenzamide, with the following structural formula:
[0030] Compound III-1p: N-benzyl-3-bromobenzamide, with the following structural formula:
[0031] Compound III-1q: N-benzyl-4-methoxybenzamide, with the following structural formula:
[0032] Compound III-1r: N-benzyl-3-fluorobenzamide, structural formula is
[0033] Compound III-1s: N-benzyl-4-trifluoromethylbenzamide, structural formula is
[0034] Compound III-1t: N-benzyl-4-nitrobenzamide, with the following structural formula:
[0035] Compound III-1u: N-cyclohexyl-4-trifluoromethylbenzamide, structural formula is
[0036] Compound III-1v: N-cyclopentyl-4-methoxybenzamide, with the following structural formula:
[0037] Compound III-1w: N-tert-butyl-4-methoxybenzamide, with the following structural formula:
[0038] Compound III-1x: N-tert-butyl-4-methylbenzamide, structural formula is
[0039] Compound III-1y: Benzamide, structural formula is
[0040] Compound III-1z: 3-fluoromethylbenzamide, with the following structural formula:
[0041] Compound III-2a: 2-fluorobenzamide, with the following structural formula:
[0042] Compound III-2b: 3-fluorobenzamide, with the following structural formula:
[0043] Compound III-2c: 4-fluorobenzamide, with the following structural formula:
[0044] Compound III-2d: 4-nitrobenzamide, with the following structural formula:
[0045] Compound III-2e: 4-methoxybenzamide, with the following structural formula:
[0046] Compound III-2f: 4-methylbenzamide, with the following structural formula: .
[0047] The advantages of this invention are: (1) The preparation method of this invention uses benzyl methyl ether compounds as raw materials, which are widely available and inexpensive. All reagents are added at once before the reaction, making the operation simple. The reaction is carried out under mild conditions of 70-80℃, and primary amines or ammonia can participate directly in the reaction without the need for pre-protecting groups, showing good compatibility with substrates containing sensitive functional groups. This reaction selectively oxidizes the CH bond at the benzyl position, converting it into an aldehyde / carboxylic acid intermediate, which then condenses with an amine in situ to form an amide, without affecting other substituents already present on the aromatic ring. The entire process eliminates the need for intermediate separation and purification steps, and can effectively control the degree of oxidation, avoiding over-oxidation, thus achieving rapid and highly selective synthesis of benzamide compounds.
[0048] (2) The preparation method of the present invention uses the I2 / TBHP system, which can significantly promote the proton-assisted breaking of the benzylic CO bond, accelerate the formation of key intermediates, greatly shorten the reaction time, and improve product selectivity.
[0049] (3) The preparation method of the present invention is applicable to various types of benzyl methyl ethers and primary amines with different substitutions. It has successfully synthesized benzamide compounds with diverse structures, which have broad industrial application prospects and practical value. Attached Figure Description
[0050] The present invention will now be described in further detail with reference to the accompanying drawings and specific embodiments.
[0051] Figure 1-20 The benzamide compounds III-1a to III-1m of this invention 1 H NMR spectra and 13 C NMR spectrum. Detailed Implementation
[0052] To further illustrate the technical means and effects of the present invention in achieving its intended purpose, the following detailed description of the specific implementation methods, structures, features, and effects of the present invention, in conjunction with the accompanying drawings and preferred embodiments, is provided below.
[0053] Example 1 Preparation of compound III-1a Compound III-1a: N-benzylbenzamide, structural formula is
[0054] The preparation method of compound III-1a includes the following steps: Benzyl methyl ether (610.8 mg, 5 mmol), benzylamine (642.9 mg, 6 mmol), I2 (253.8 mg, 1 mmol), and a 70% TBHP aqueous solution (total aqueous solution mass 6437.1 mg, active ingredient TBHP 50 mmol) were mixed in 10.0 mL of acetonitrile. The mixture was stirred at 70 °C for 5 hours. After the catalytic oxidation reaction was completed, the solvent acetonitrile was removed by rotary evaporation to obtain the reaction mixture. The reaction mixture was then neutralized with saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and then eluted with a 200-300 mesh silica gel column using petroleum ether (boiling range 60-90 °C): ethyl acetate = 10:1 (volume ratio) as the eluent. The eluent was collected, distilled under reduced pressure, and the residue was dried to give the target compound III-1a with a mass of 887.3 mg, yield 84%.
[0055] Compound III-1a via 1H nuclear magnetic resonance and 13 Identification was performed using C-NMR, and the results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 7.80 (m, 2H), 7.78-7.25 (m, 8H), 6.51 (s, 1H), 4.64 (d, J=5.8Hz, 2H).
[0056] 13 C NMR (CDCl3, 100 MHz): δ 167.4, 138.2, 134.4, 131.6, 128.8, 128.6, 127.9, 127.6, 127.0, 44.1.
[0057] Example 2 Preparation of compound III-1a The preparation method of compound III-1a in this embodiment includes the following steps: Benzyl methyl ether (610.8 mg, 5 mmol), benzylamine (642.9 mg, 6 mmol), TBAI (369.4 mg, 1 mmol), and a 70% TBHP aqueous solution (total aqueous solution mass 6437.1 mg, active ingredient TBHP 50 mmol) were mixed in 10.0 mL of acetonitrile. The mixture was stirred at 70 °C for 5 hours. After the catalytic oxidation reaction was completed, the solvent acetonitrile was removed by rotary evaporation to obtain the reaction mixture. The reaction mixture was then neutralized with saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and then eluted with a 200-300 mesh silica gel column using petroleum ether (boiling range 60-90 °C): ethyl acetate = 10:1 (volume ratio) as the eluent. The eluent was collected, distilled under reduced pressure, and the residue was dried to give the target compound III-1a with a mass of 771.1 mg, yield 73%.
[0058] Example 3 Preparation of compound III-1i Compound III-1i: N-tert-butylbenzamide, structural formula is
[0059] The preparation method of compound III-1i in this embodiment includes the following steps: Benzyl methyl ether (610.8 mg, 5 mmol), tert-butylamine (585.1 mg, 8 mmol), I2 (253.8 mg, 1 mmol), and a 70% TBHP aqueous solution (total aqueous solution mass 6437.1 mg, active ingredient TBHP 50 mmol) were mixed in 15.0 mL of acetonitrile. The mixture was stirred at 70 °C for 5 hours. After the catalytic oxidation reaction was completed, the solvent acetonitrile was removed by rotary evaporation to obtain the reaction mixture. The reaction mixture was then neutralized with saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and then eluted with a 200-300 mesh silica gel column using petroleum ether (boiling range 60-90 °C): ethyl acetate = 10:1 (volume ratio) as the eluent. The eluent was collected, distilled under reduced pressure, and the residue was dried to give 771 mg of the target compound III-1i, with a yield of 87%.
[0060] Compound III-1i via 1 H nuclear magnetic resonance and 13 Identification was performed using C-NMR, and the results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 7.73 (m, 2H), 7.47-7.39 (m, 3H), 5.98 (s,1H), 1.48 (s, 9H).
[0061] 13 C NMR (CDCl3, 100 MHz): δ 166.9, 135.9, 131.1, 128.5, 126.7, 51.6, 28.9.
[0062] Example 4 Preparation of Compound III-1t Compound III-1t: N-benzyl-4-nitrobenzamide, with the following structural formula:
[0063] The preparation method of compound III-1t in this embodiment includes the following steps: Methyl 4-nitrobenzyl ether (835.8 mg, 5 mmol), benzylamine (750.1 mg, 7 mmol), I2 (253.8 mg, 1 mmol), and a 70% TBHP aqueous solution (total aqueous solution mass 6437.1 mg, active ingredient TBHP 50 mmol) were mixed in 15.0 mL of acetonitrile. The mixture was stirred at 80 °C for 5 hours. After the catalytic oxidation reaction was completed, the solvent acetonitrile was removed by rotary evaporation to obtain the reaction mixture. The reaction mixture was then neutralized with saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and then eluted with a 200-300 mesh silica gel column using petroleum ether (boiling range 60-90 °C): ethyl acetate = 10:1 (volume ratio) as the eluent. The eluent was collected, distilled under reduced pressure, and the residue was dried to obtain the target compound III-1t with a mass of 1089.1 mg, yield 85%.
[0064] Compound III-1t via 1 H nuclear magnetic resonance and 13 Identification was performed using C-NMR, and the results are as follows: 1 H NMR (CDCl3, 400 MHz): δ 8.28 (d, J=8.8Hz, 2H), 7.96 (d, J=8.8Hz, 2H), 7.38-7.33 (m, 5H), 6.57 (s, 1H), 4.67 (d, J=5.6Hz, 2H).
[0065] 13 C NMR (CDCl3, 100 MHz): δ 165.3, 149.6, 139.9, 137.4, 128.9, 128.2, 128.0, 123.9, 44.5.
[0066] Example 5 Preparation of compound III-1y Compound III-1y: Benzamide, structural formula is
[0067] The preparation method of compound III-1y includes the following steps: Benzyl methyl ether (610.8 mg, 5 mmol), 25% ammonia (680 mg total, 10 mmol active ammonia), I2 (380.7 mg, 1.5 mmol), and 70% TBHP aqueous solution (7724.5 mg total, 60 mmol active TBHP) were mixed in 10.0 mL of acetonitrile. The mixture was stirred at 70 °C for 5 hours. After the catalytic oxidation reaction was completed, the solvent acetonitrile was removed by rotary evaporation to obtain the reaction mixture. The reaction mixture was then neutralized with saturated Na2S2O3 solution and extracted with ethyl acetate. The organic layers were combined, dried with anhydrous sodium sulfate, and then eluted with a 200-300 mesh silica gel column using petroleum ether (boiling range 60-90 °C): ethyl acetate = 10:1 (volume ratio) as the eluent. The eluent was collected, distilled under reduced pressure, and the residue was dried to give 442.2 mg of the target compound III-1y, with a yield of 73%.
[0068] Compound III-1y via 1 H nuclear magnetic resonance and 13 Identification was performed using C-NMR, and the results are as follows: 1 HNMR (400MHz, DMSO-d6) δ: 8.01(s, 1H), 7.91-7.88(m, 2H), 7.54-7.40(m, 4H).
[0069] 13 CNMR (100MHz, DMSO-d6) δ: 168.4, 134.7, 131.7, 128.7, 127.9.
[0070] Validation of preparation method The preparation method of the present invention synthesizes benzamide compounds with diverse structures, and the parameters of each benzamide compound are shown in Table 1. Table 1. Basic information and preparation parameters of benzamide compounds
[0071] Where, n TBHP This refers to the amount of TBHP, the active ingredient, in a 70% TBHP aqueous solution.
[0072] The synthesized benzamide compounds were subjected to separate tests. 1 H nuclear magnetic resonance and 13 The structure was characterized by 1 C nuclear magnetic resonance, and the results are shown in Table 2.
[0073] Table 2. NMR identification results of benzamide compounds
[0074] Through verification, the preparation method of benzamide compounds of the present invention is reasonably designed, with mild reaction conditions, simple process and convenient operation, providing a new method for new drug research and development, and has broad industrial application prospects and practical value.
[0075] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make some modifications or alterations to the above-disclosed technical content to create equivalent embodiments without departing from the scope of the present invention. Any simple modifications, equivalent changes and alterations made to the above embodiments based on the technical essence of the present invention without departing from the scope of the present invention shall still fall within the scope of the present invention.
Claims
1. A method for preparing a benzamide compound, characterized in that: Includes the following steps: Benzyl methyl ether compounds are mixed with primary amines or ammonia in a certain proportion and added to a solvent. Catalytic oxidation reaction is carried out under the action of catalyst and oxidant. The reaction is stirred at 70-80℃ for 5 hours. The reaction solution is then post-treated to obtain benzamide compounds. Among them, the structural formula of benzyl methyl ether compounds is Formula I, the structural formula of primary amines is Formula II, and the general structural formula of benzamide compounds is Formula III; Formula I: Formula II: Formula III: Wherein, R is one of hydrogen, meta- or para-substituted -CH3, -OCH3, -X, -NO2, -CF3, and R1 is one of hydrogen, benzyl, cyclopentyl, cyclohexyl, tert-butyl.
2. The method for preparing benzamide compounds according to claim 1, characterized in that: The catalyst is one of elemental I2, tetra-n-butylammonium iodide (TBAI), CuI, ZnI2, or N-iodosuccinimide (NIS).
3. The method for preparing benzamide compounds according to claim 2, characterized in that: The catalyst is elemental I2.
4. The method for preparing benzamide compounds according to claim 3, characterized in that: The oxidant is tert-butyl hydroperoxide (TBHP).
5. The method for preparing benzamide compounds according to claim 4, characterized in that: The molar ratio of the benzyl methyl ether compound to the primary amine or ammonia, I2, and tert-butyl hydroperoxide (TBHP) is 5:(6~10):(0.5~1.5):(40~60).
6. The method for preparing benzamide compounds according to claim 1, characterized in that: The solvent is acetonitrile.
7. The method for preparing benzamide compounds according to claim 6, characterized in that: The volumetric amount of acetonitrile used, calculated based on the amount of benzyl methyl ether compound, is 2-4 mL / mmol.
8. The method for preparing benzamide compounds according to claim 1, characterized in that: The post-treatment method for the reaction solution includes the following steps: After the catalytic oxidation reaction was completed, the solvent was removed using a rotary evaporator to obtain the reaction mixture. The reaction mixture was then neutralized with a saturated Na₂S₂O₃ solution and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and eluted using a 200-300 mesh silica gel column. The eluent was collected, distilled under reduced pressure, and the residue was dried and then subjected to… 1 H nuclear magnetic resonance and 13 Identification was performed using nuclear magnetic resonance (NMR).
9. The method for preparing benzamide compounds according to claim 1, characterized in that: The elution process uses petroleum ether and ethyl acetate as eluents, with petroleum ether having a boiling range of 60-90℃ and a volume ratio of petroleum ether to ethyl acetate of 10:
1.
10. The method for preparing benzamide compounds according to claim 1, characterized in that: The benzamide compounds include Compound III-1a: N-benzylbenzamide, structural formula is Compound III-1b: N-(4-methylbenzyl)benzamide, with the following structural formula: Compound III-1c: N-(2-methylbenzyl)benzamide, with the following structural formula: Compound III-1d: N-(2-chlorobenzyl)benzamide, with the following structural formula: Compound III-1e: N-(4-chlorobenzyl)benzamide, with the following structural formula: Compound III-1f: N-(4-nitrobenzyl)benzamide, with the following structural formula: Compound III-1g: N-cyclopentylbenzamide, structural formula is Compound III-1h: N-cyclohexylbenzamide, structural formula is Compound III-1i: N-tert-butylbenzamide, structural formula is Compound III-1m: N-benzyl-2-methylbenzamide, structural formula is Compound III-1n: N-benzyl-3-methylbenzamide, with the following structural formula: Compound III-1o: N-benzyl-4-methylbenzamide, with the following structural formula: Compound III-1p: N-benzyl-3-bromobenzamide, with the following structural formula: Compound III-1q: N-benzyl-4-methoxybenzamide, with the following structural formula: Compound III-1r: N-benzyl-3-fluorobenzamide, structural formula is Compound III-1s: N-benzyl-4-trifluoromethylbenzamide, structural formula is Compound III-1t: N-benzyl-4-nitrobenzamide, with the following structural formula: Compound III-1u: N-cyclohexyl-4-trifluoromethylbenzamide, structural formula is Compound III-1v: N-cyclopentyl-4-methoxybenzamide, with the following structural formula: Compound III-1w: N-tert-butyl-4-methoxybenzamide, with the following structural formula: Compound III-1x: N-tert-butyl-4-methylbenzamide, structural formula is Compound III-1y: Benzamide, structural formula is Compound III-1z: 3-fluoromethylbenzamide, with the following structural formula: Compound III-2a: 2-fluorobenzamide, with the following structural formula: Compound III-2b: 3-fluorobenzamide, with the following structural formula: Compound III-2c: 4-fluorobenzamide, with the following structural formula: Compound III-2d: 4-nitrobenzamide, with the following structural formula: Compound III-2e: 4-methoxybenzamide, with the following structural formula: Compound III-2f: 4-methylbenzamide, with the following structural formula: 。