A method for synthesizing a functionalized phthalide lactone compound

Abstract

Phthalide lactones, as an important class of benzopentolactone skeleton, are widely distributed in natural products, medicinal plants and bioactive molecules, and have significant pharmacological activities and synthetic application potential. This kind of structure not only shows various biological activities such as antibacterial, anti-inflammatory, antitumor, antioxidant, but also is an indispensable core structural unit in many drug molecules and lead compounds. At the same time, cyano is a very valuable functional group in the field of organic synthesis and medicinal chemistry, with strong electron-withdrawing properties, strong structural stability and other advantages, which can effectively improve the electronic distribution, lipid solubility and drug performance of the molecule. In view of the important significance of phthalide lactones and cyano in organic synthesis and drug research and development, the present invention develops a synthetic method for efficiently constructing cyano-containing alkyl chain substituted phthalide lactone compounds. It has important value in medicinal chemistry and organic synthesis.

Description

Technical Field

[0001] This invention relates to compound synthesis, specifically to a method for synthesizing functionalized phthalide lactone compounds. Background Technology

[0002] Phenylphthalide lactones are a core class of benzo[a]pentacyclic lactone skeletons, widely found in numerous natural products, medicinal plants, and bioactive molecules, possessing significant biological and synthetic value. These structures not only exhibit a variety of important pharmacological activities, including antitumor, antibacterial, anti-inflammatory, antioxidant, and neuroprotective effects, but also serve as key pharmacodynamic units in many clinical drugs and lead compounds. Among them, 3,3-disubstituted phthalides, due to the presence of a quaternary carbon center, exhibit superior stereoselectivity, metabolic stability, and targeted binding ability, making them crucial structural units in drug molecule design and structure-activity relationship studies. Furthermore, the phthalide lactone ring is readily chemically modified and transformed, serving as a multifunctional synthetic intermediate for constructing complex heterocyclic skeletons, thus holding an irreplaceable and vital position in organic synthesis methodology, medicinal chemistry, and the total synthesis of natural products (Equation 1).

[0003]

[0004] On the other hand, the cyano group is an extremely important functional group in organic synthesis and medicinal chemistry, possessing strong electron-withdrawing effects, structural rigidity, and good metabolic stability. It can not only significantly regulate the polarity, lipophilicity, and electron distribution of molecules, enhancing the biological activity and target binding ability of compounds, but also serve as a key transforming group, conveniently converting them into amines, amides, carboxylic acids, aldehydes, ketones, amidines, and heterocyclic skeletons, making it highly valuable in the synthesis of complex molecules. In drug design, the cyano group is often used to improve pharmacokinetic properties and enhance binding affinity, and is widely present in the structures of various clinical drugs. Furthermore, the cyano group exhibits good functional group compatibility and orthogonality, making it an important directing group in modern synthetic methods such as cross-coupling and CH bond functionalization. Summary of the Invention

[0005] Given the important value of phthalide lactones and cyano compounds in organic chemistry and medicinal chemistry, this invention patent realizes a method for synthesizing phthalide lactones containing cyano chains.

[0006] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: a method for synthesizing functionalized phthalide lactone compounds, characterized in that: using ortho-substituted benzoyl benzoic acid and cyclic ketoxime esters as raw materials, the reaction is carried out in chlorobenzene solvent at 80°C for 12 hours under the promotion of ferrous acetylacetone [Fe(acac)2], to obtain a class of phthalide lactone compounds containing cyano chains with the general formula:

[0007]

[0008] Where R represents hydrogen, methyl, bromine, chlorine, or methoxy.

[0009] Preferably, the amount of ferrous acetylacetone is 20% of the amount of cyclobutanone oxime ester.

[0010] Preferably, the amount of the ortho-substituted benzoic acid is twice the amount of the cyclobutanone oxime ester.

[0011] This method is simple to operate and provides a convenient synthetic route for phthalide lactones containing cyano groups. It has high potential application value in medicinal chemistry and organic chemistry. Detailed Implementation

[0012] The technical solution of the present invention will be further described below through specific embodiments:

[0013] Example 1

[0014] The reaction formula for this embodiment is as follows:

[0015]

[0016] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0017] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography with a separation yield of 70% and a product purity of more than 99%.

[0018] Example 2

[0019] The reaction formula for this embodiment is as follows:

[0020]

[0021] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0022] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 66%, and the product purity was greater than 99%.

[0023] Example 3

[0024] The reaction formula for this embodiment is as follows:

[0025]

[0026] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0027] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 63% and the product purity was greater than 99%.

[0028] Example 4

[0029] The reaction formula for this embodiment is as follows:

[0030]

[0031] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0032] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 61%, and the product purity was greater than 99%.

[0033] Example 5

[0034] The reaction formula for this embodiment is as follows:

[0035]

[0036] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0037] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 71% and the product purity was greater than 99%.

[0038] Example 6

[0039] The reaction formula for this embodiment is as follows:

[0040]

[0041] (1) Ortho-substituted benzene benzoic acid (0.3 mmol, 1.5 equiv), cyclobutanone oxime ester (0.2 mmol, 1.0 equiv), and ferrous acetylacetone (20 mol%) were added to a sealed reaction tube with a side arm and a magnetic inlet under air. The reaction tube was evacuated and then filled with argon gas. 1 mL of chlorobenzene was added to the reaction tube and the reaction was carried out at 80 °C for 12 hours.

[0042] (2) The solvent in the organic phase obtained in step (1) was evaporated to obtain the crude product. The crude product was then purified by silica gel column chromatography. The separation yield was 61%, and the product purity was greater than 99%.

[0043] The amounts of each substance used and the reaction conditions were experimentally extended to the examples to demonstrate that the technical solution of the present invention has good functional group compatibility.

[0044] The present invention has been described in detail above. The above description is only an embodiment of the present invention and should not be construed as limiting the scope of this application. All equivalent changes and modifications made within the scope of this application should still fall within the scope of the present invention.

[0045] Attached Figure Description

[0046] Figure 1 The proton NMR spectrum of compound 1 prepared in this invention;

[0047] Figure 2 The carbon NMR spectrum of compound 1 prepared in this invention;

[0048] Figure 3 The proton NMR spectrum of compound 2 prepared in this invention;

[0049] Figure 4The carbon NMR spectrum of compound 2 prepared in this invention.

[0050] Figure 5 The proton NMR spectrum of compound 3 prepared in this invention;

[0051] Figure 6 The carbon NMR spectrum of compound 3 prepared in this invention.

[0052] Figure 7 The proton NMR spectrum of compound 4 prepared in this invention;

[0053] Figure 8 The carbon NMR spectrum of compound 4 prepared in this invention.

[0054] Figure 9 The proton NMR spectrum of compound 6 prepared in this invention;

[0055] Figure 10 The carbon NMR spectrum of compound 6 prepared in this invention.

Claims

1. A method for synthesizing a functionalized phthalide lactone compound, characterized in that: Using ortho-substituted benzoyl benzoic acid and cyclic ketoxime esters as starting materials, the reaction was carried out in chlorobenzene solvent at 80°C for 12 hours under the promotion of ferrous acetylacetone to obtain a class of phthalide lactone compounds with cyano chains having the general formula: Where R represents hydrogen, methyl, bromine, chlorine, or methoxy.

2. The method for synthesizing a functionalized phthalide lactone compound according to claim 1, wherein the amount of ferrous acetylacetone is 20% of the amount of cyclobutanone oxime ester; and the amount of ortho-substituted benzoyl benzoic acid is twice the amount of cyclobutanone oxime ester.

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