A method for preparing photoinitiated phenyl or substituted phenyl γ-ketoamides
By using a photocatalyzed reaction of transition metal salts in an air atmosphere, phenyl or substituted phenyl γ-ketoamides can be directly constructed, solving the problem of complex synthetic routes in existing technologies and realizing an efficient and low-cost preparation method.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHANDONG FIRST MEDICAL UNIV & SHANDONG ACADEMY OF MEDICAL SCI
- Filing Date
- 2026-02-06
- Publication Date
- 2026-05-26
AI Technical Summary
In the existing technology, the synthetic routes of phenyl or substituted phenyl γ-ketoamides are complex, requiring multiple steps and harsh conditions, and there is a lack of simplified and cost-effective preparation methods.
A photocatalytic reaction catalyzed by transition metal salts under air atmosphere was used to directly construct phenyl or substituted phenyl γ-ketoamides via room temperature photocatalytic reaction using 3-phenyl or substituted phenylpiperidin-2,6-dione as raw materials.
The preparation of phenyl or substituted phenyl γ-ketoamides with high yields (over 76%) was achieved. The process is simple, conforms to the principles of green chemistry, and reduces synthesis costs.
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Figure CN121652086B_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical compound synthesis technology, and in particular to a method for preparing photo-initiated phenyl or substituted phenyl γ-ketoamides. Background Technology
[0002] γ-Ketoamides are an important class of organic synthesis intermediates. Their molecular structures contain both amide and carbonyl functional groups, exhibiting good scalability in subsequent functional group transformations, molecular skeleton modifications, and heterocycle construction. Therefore, their construction methods have always attracted attention in the field of organic synthesis. From a pharmaceutical chemical perspective, ketoamide structures, as an important functional group unit, have a clear research foundation in medicinal chemistry. Existing studies have shown that compounds containing ketoamide structures can serve as effective binding units for various biological targets, and some ketoamide derivatives have been successfully applied in drug molecule design, demonstrating the feasibility and application potential of this type of functional group in drug development. Furthermore, γ-ketoamides can be further transformed into γ-lactam structures through reduction and cyclization. γ-lactams, as an important nitrogen-containing heterocyclic skeleton, are widely found in biologically active compounds and drug molecules. Therefore, γ-ketoamides have potential application value as key intermediates in drug molecule synthesis.
[0003] In existing technologies, phenyl or substituted phenyl γ-ketoamides are typically obtained through multi-step reaction routes, such as first constructing the corresponding aryl keto acid or its derivative, and then converting it into the target product via an amidation reaction. These methods often require the prior preparation of key intermediates and rely on condensing agents, activating reagents, or specific reaction conditions. The overall process involves numerous steps and is relatively complex, hindering the simplification of synthetic routes and cost control. On the other hand, piperidine-2,6-diketones and their derivatives, as an important class of nitrogen-containing heterocyclic structures, have been reported in organic synthesis and related molecular design. Their synthetic methods are relatively mature, and the sources of raw materials are well-known, making them suitable starting materials for constructing related amide structures. However, a mature, universal, and mild synthetic route for directly converting 3-phenyl or substituted phenyl piperidine-2,6-diketones into phenyl or substituted phenyl γ-ketoamide structures has not yet been developed.
[0004] In recent years, organic transformations utilizing light and air atmospheres have attracted attention due to their mild reaction conditions and ease of operation. Simultaneously, research on the participation of transition metal salts such as iron salts in organic reactions under light conditions has gradually increased, providing new ideas for developing reaction systems with simplified synthetic steps. However, how to combine the aforementioned photoinitiation conditions with specific substrate structures to construct phenyl or substituted phenyl γ-ketoamides still requires further investigation.
[0005] Therefore, it is necessary to provide a method for the direct conversion of 3-phenyl or substituted phenylpiperidin-2,6-dione to phenyl or substituted phenyl γ-ketoamides under light and air atmosphere conditions, so as to expand the synthetic routes of such compounds and provide new technical options for their subsequent applications. Summary of the Invention
[0006] The purpose of this invention is to provide a mild and simple method for preparing aryl γ-ketoamides. Addressing the problems of existing methods for preparing phenyl or substituted phenyl γ-ketoamides, which typically rely on multi-step reaction routes, require the prior preparation of key intermediates, and involve numerous and complex reaction steps, this invention designs a novel reaction system to directly construct phenyl or substituted phenyl γ-ketoamide structures from specific substrates, thereby simplifying the synthetic route and reducing synthesis costs. These advantages make this method promising for broad applications in the field of pharmaceutical compounds.
[0007] The present invention provides a method for preparing photo-initiated phenyl or substituted phenyl γ-ketoamides, comprising the following steps: under an air atmosphere, dissolving the 3-phenyl or substituted phenylpiperidine-2,6-dione compound of formula (1) in a solvent, adding a catalyst, and reacting under light at room temperature to obtain the aryl γ-ketoamide product of formula (2);
[0008]
[0009] In formulas (1) and (2), R1 is selected from phenyl or substituted phenyl.
[0010] This invention achieves significant technical effects through a transition metal salt catalysis and room temperature light irradiation in an air atmosphere:
[0011] First, the yield is high, with most products yielding over 76% and some over 92%, demonstrating outstanding reaction efficiency.
[0012] Secondly, it is green and environmentally friendly, requiring no precious metal catalysts or toxic oxidants, no condensing agents or activating reagents, and has high atom utilization, which is in line with the concept of green chemistry.
[0013] Third, the conditions are mild; the reaction can be carried out under room temperature and light, without the need for high temperature, high pressure or harsh conditions, and the operation and post-processing are simple.
[0014] Fourth, the cost is controllable. The catalysts, solvents and piperidine-2,6-dione raw materials used in this invention are all of known origin and easy to obtain. The overall raw material system is economical, which helps to reduce costs in experimental and potential industrialization processes and has wide applicability. Attached Figure Description
[0015] Figure 1 This is the reaction formula provided in the embodiments of the present invention;
[0016] Figure 2 It is the product prepared in Example 1 of this invention. 1 H NMR spectrum;
[0017] Figure 3 It is the product prepared in Example 2 of this invention. 1 H NMR spectrum;
[0018] Figure 4 It is the product prepared in Example 3 of this invention. 1 H NMR spectrum;
[0019] Figure 5 It is the product prepared in Example 4 of this invention. 1 H NMR spectrum;
[0020] Figure 6 It is the product prepared in Example 5 of this invention. 1 H NMR spectrum;
[0021] Figure 7 It is the product prepared in Example 6 of this invention. 1 H NMR spectrum. Detailed Implementation
[0022] Example 1
[0023]
[0024] Under air atmosphere and at room temperature, 3-phenylpiperidin-2,6-dione (37.82 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 36 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (31.88 mg, 90% yield). Figure 1 As shown, 1 H NMR (400 MHz, CDCl3) δ 7.98(d, J = 7.2 Hz, 2H), 7.56 (t, J = 7.2 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 5.90(s, 1H), 5.69 (s, 1H), 3.37 (t, J = 6.6 Hz, 2H), 2.67 (t, J = 6.6 Hz, 2H).
[0025] Example 2
[0026]
[0027] Under air atmosphere and at room temperature, 3-(3-bromophenyl)piperidin-2,6-dione (53.62 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 46 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (38.93 mg, yield 76%). Figure 2 As shown, 1 H NMR (400 MHz, CDCl3)δ 7.90 (s, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.48 (m, 1H), 7.35 (t, J = 7.9 Hz,1H), 5.60 (s, 1H), 5.32 (s, 1H), 3.28 (t, J = 6.5 Hz, 2H), 2.61 (t, J = 6.5Hz, 2H).
[0028] Example 3
[0029]
[0030] Under air atmosphere and at room temperature, 3-(3-chlorophenyl)piperidin-2,6-dione (44.73 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 48 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (33.02 mg, yield 78%). Figure 3 As shown, 1 H NMR (400 MHz, CDCl3)δ 7.96 (s, 1H), 7.92 – 7.79 (m, 1H), 7.55 (m, 1H), 7.41 (t, J = 7.9 Hz, 1H),5.68 (s, 1H), 5.39 (s, 1H), 3.34 (t, J= 6.5 Hz, 2H), 2.68 (t, J = 6.5 Hz, 2H).
[0031] Example 4
[0032]
[0033] Under air atmosphere and at room temperature, 3-(4-bromophenyl)piperidin-2,6-dione (53.63 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 18 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (47.13 mg, yield 92%). Figure 4 As shown, 1 H NMR (400 MHz, CDCl3)δ 7.93 (d, J = 8.6 Hz, 2H), 7.44 (d, J = 8.6 Hz, 2H), 5.70 (s, 1H), 5.44 (s,1H), 3.34 (t, J = 6.5 Hz, 2H), 2.67 (t, J = 6.5 Hz, 2H).
[0034] Example 5
[0035]
[0036] Under air atmosphere and at room temperature, 3-(4-fluorophenyl)piperidin-2,6-dione (41.44 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 22 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (34.36 mg, yield 88%). Figure 5 As shown, 1 H NMR (400 MHz, CDCl3)δ 8.02 (dd, J = 8.9, 5.4 Hz, 2H), 7.14 (dd, J= 8.9, 8.3 Hz, 2H), 5.73 (s,1H), 5.47 (s, 1H), 3.34 (t, J = 6.5 Hz, 2H), 2.67 (t, J = 6.5 Hz, 2H).
[0037] Example 6
[0038]
[0039] Under air atmosphere and at room temperature, 3-(4-methoxyphenyl)piperidin-2,6-dione (43.85 mg, 0.2 mmol, 1 eq), acetonitrile:water = 5:1 (6 mL), and ferric chloride (6.49 mg, 0.04 mmol, 0.2 eq) were added to a 25 mL quartz tube and stirred under 395 nm light for 18 hours. After the reaction was complete, the mixture was extracted with dichloromethane and water, the organic layers were combined, dried over anhydrous sodium sulfate, and purified by vacuum distillation to obtain the γ-ketoamide product (27.36 mg, yield 66%). Figure 6 As shown, 1 H NMR (400MHz, CDCl3) δ 7.97 (d, J = 8.9 Hz, 2H), 6.94 (d, J = 9.0 Hz, 2H), 5.78 (s,1H), 5.38 (s, 1H), 3.87 (s, 3H), 3.33 (t, J = 6.5 Hz, 2H), 2.66 (t, J = 6.5Hz, 2H).
[0040] Example 7
[0041] Same as Example 1, except that the catalyst was copper sulfate, and the yield of the γ-ketoamide product was 2%.
[0042] Example 8
[0043] Same as Example 1, except that the catalyst was ferric sulfate, and the yield of the γ-ketoamide product was 27%.
[0044] Example 9
[0045] Same as Example 1, except that the catalyst was ferric nitrate, and the yield of the γ-ketoamide product was 38%.
[0046] Example 10
[0047] Same as Example 1, except that the catalyst was ferric tribromide, and the yield of the γ-ketoamide product was 69%.
[0048] Example 11
[0049] Same as Example 1, except that an acetonitrile aqueous solution with a volume ratio of 1:2 was chosen as the solvent, and the yield of the γ-ketoamide product was 4%.
[0050] Example 12
[0051] Same as Example 1, except that an acetonitrile aqueous solution with a volume ratio of 2:2 was chosen as the solvent, and the yield of the γ-ketoamide product was 12%.
[0052] Example 13
[0053] Same as Example 1, except that an acetonitrile aqueous solution with a volume ratio of 4:2 was chosen as the solvent, and the yield of the γ-ketoamide product was 18%.
[0054] Example 14
[0055] Same as Example 1, except that an acetonitrile aqueous solution with a volume ratio of 6:2 was chosen as the solvent, and the yield of the γ-ketoamide product was 31%.
[0056] Example 15
[0057] Same as Example 1, except that an acetonitrile aqueous solution with a volume ratio of 8:2 was chosen as the solvent, and the yield of the γ-ketoamide product was 67%.
[0058] Example 16
[0059] Same as Example 1, except that the wavelength was 255 nm and the yield of the γ-ketoamide product was 3%.
[0060] Example 17
[0061] Same as Example 1, except that the wavelength was 295 nm and the yield of the γ-ketoamide product was 8%.
[0062] Example 18
[0063] Same as Example 1, except that the wavelength was 365 nm, and the yield of the γ-ketoamide product was 71%.
[0064] Example 19
[0065] Same as Example 1, except that the wavelength was 410 nm, and the yield of the γ-ketoamide product was 73%.
[0066] Example 20
[0067] Same as Example 1, except that the wavelength was 455 nm, and the yield of the γ-ketoamide product was 51%.
[0068] Example 21
[0069] Same as Example 1, except that the wavelength was 480 nm, and the yield of the γ-ketoamide product was 17%.
[0070] Example 22
[0071] Same as Example 1, except that the molar ratio of the compound of formula (1) 3-phenylpiperidine-2,6-dione to the catalyst ferric chloride is 1:2, and the yield of the γ-ketoamide product is 39%.
[0072] Example 23
[0073] Same as Example 1, except that the molar ratio of the 3-phenylpiperidine-2,6-dione compound of formula (1) to the catalyst ferric chloride is 2:2, and the yield of the γ-ketoamide product is 42%.
[0074] Example 24
[0075] Same as Example 1, except that the molar ratio of the 3-phenylpiperidine-2,6-dione compound of formula (1) to the catalyst ferric chloride is 4:2, and the yield of the γ-ketoamide product is 63%.
[0076] Example 25
[0077] Same as Example 1, except that the molar ratio of the 3-phenylpiperidine-2,6-dione compound of formula (1) to the catalyst ferric chloride is 6:2, and the yield of the γ-ketoamide product is 71%.
[0078] Example 26
[0079] Same as Example 1, except that the molar ratio of the compound of formula (1) 3-phenylpiperidine-2,6-dione to the catalyst ferric chloride is 8:2, and the yield of the γ-ketoamide product is 81%.
[0080] As can be seen from the above embodiments, the preparation method provided by the present invention can prepare phenyl or substituted phenyl γ-ketoamide products with high yields simply by using a simple catalyst and light under an air atmosphere.
Claims
1. A method for preparing a photoinitiated phenyl or substituted phenyl γ-ketoamide, characterized in that, The steps include: dissolving the 3-phenyl or substituted phenylpiperidine-2,6-dione compound of formula (1) in a solvent under an air atmosphere, adding a catalyst, and reacting under light at room temperature to obtain the aryl γ-ketoamide product of formula (2); In formulas (1) and (2), R1 is selected from phenyl or substituted phenyl; The catalyst is a transition metal salt, selected from ferric sulfate, ferric nitrate, ferric chloride, or ferric tribromide; The wavelength of the photoreaction is 365-455 nm; The solvent is acetonitrile-water, with a volume ratio of 6-10:
2.
2. The method according to claim 1, characterized in that, The substituted phenyl group is 3-bromophenyl, 3-chlorophenyl, 4-bromophenyl, 4-fluorophenyl, or 4-methoxyphenyl.
3. The method according to any one of claims 1-2, characterized in that, The photoreaction time is 18-48 hours.
4. The method according to any one of claims 1-2, characterized in that, The molar ratio of the 3-phenyl or substituted phenylpiperidine-2,6-dione compound of formula (1) to the catalyst is 1-10:2.